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1.  Results From the Scandinavian Prostate Cancer Group Trial Number 4: A Randomized Controlled Trial of Radical Prostatectomy Versus Watchful Waiting 
In the Scandinavian Prostate Cancer Group Trial Number 4 (SPCG-4), 347 men were randomly assigned to radical prostatectomy and 348 to watchful waiting. In the most recent analysis (median follow-up time = 12.8 years), the cumulative mortality curves had been stable over the follow-up. At 15 years, the absolute risk reduction of dying from prostate cancer was 6.1% following randomization to radical prostatectomy, compared with watchful waiting. Hence, 17 need to be randomized to operation to avert one death. Data on self-reported symptoms, stress from symptoms, and quality of life were collected at 4 and 12.2 years of median follow-up. These questionnaire studies show an intricate pattern of symptoms evolving after surgery, hormonal treatments, signs of tumor progression, and also from natural aging. This article discusses some of the main findings of the SPCG-4 study.
doi:10.1093/jncimonographs/lgs025
PMCID: PMC3540876  PMID: 23271778
2.  Individualized Estimation of the Benefit of Radical Prostatectomy from the Scandinavian Prostate Cancer Group Randomized Trial 
European Urology  2012;62(2):204-209.
Background
Although there is randomized evidence that radical prostatectomy improves survival, there are few data on how benefit varies by baseline risk.
Objective
We aimed to create a statistical model to calculate the decrease in risk of death associated with surgery for an individual patient, using stage, grade, prostate-specific antigen, and age as predictors.
Design, setting, and participants
A total of 695 men with T1 or T2 prostate cancer participated in the Scandinavian Prostate Cancer Group 4 trial (SPCG-4).
Intervention
Patients in SPCG-4 were randomized to radical prostatectomy or conservative management.
Outcome measurements and statistical analysis
Competing risk models were created separately for the radical prostatectomy and the watchful waiting group, with the difference between model predictions constituting the estimated benefit for an individual patient.
Results and limitations
Individualized predictions of surgery benefit varied widely depending on age and tumor characteristics. At 65 yr of age, the absolute 10-yr risk reduction in prostate cancer mortality attributable to radical prostatectomy ranged from 4.5% to 17.2% for low- versus high-risk patients. Little expected benefit was associated with surgery much beyond age 70. Only about a quarter of men had an individualized benefit within even 50% of the mean. A limitation is that estimates from SPCG-4 have to be applied cautiously to contemporary patients.
Conclusions
Our model suggests that it is hard to justify surgery in patients with Gleason 6, T1 disease or in those patients much above 70 yr of age. Conversely, surgery seems unequivocally of benefit for patients who have Gleason 8, or Gleason 7, stage T2. For patients with Gleason 6 T2 and Gleason 7 T1, treatment is more of a judgment call, depending on patient preference and other clinical findings, such as the number of positive biopsy cores and comorbidities.
doi:10.1016/j.eururo.2012.04.024
PMCID: PMC3389180  PMID: 22541389
Prostatic neoplasms; Statistics and research design; Randomized controlled trial; Prostatectomy
3.  The Prostate Cancer Intervention Versus Observation Trial:VA/NCI/AHRQ Cooperative Studies Program #407 (PIVOT): Design and Baseline Results of a Randomized Controlled Trial Comparing Radical Prostatectomy With Watchful Waiting for Men With Clinically Localized Prostate Cancer 
Prostate cancer is the most common noncutaneous malignancy and the second leading cause of cancer death in men. In the United States, 90% of men with prostate cancer are more than age 60 years, diagnosed by early detection with the prostate-specific antigen (PSA) blood test, and have disease believed confined to the prostate gland (clinically localized). Common treatments for clinically localized prostate cancer include watchful waiting (WW), surgery to remove the prostate gland (radical prostatectomy), external-beam radiation therapy and interstitial radiation therapy (brachytherapy), and androgen deprivation. Little is known about the relative effectiveness and harms of treatments because of the paucity of randomized controlled trials. The Department of Veterans Affairs/National Cancer Institute/Agency for Healthcare Research and Quality Cooperative Studies Program Study #407:Prostate Cancer Intervention Versus Observation Trial (PIVOT), initiated in 1994, is a multicenter randomized controlled trial comparing radical prostatectomy with WW in men with clinically localized prostate cancer. We describe the study rationale, design, recruitment methods, and baseline characteristics of PIVOT enrollees. We provide comparisons with eligible men declining enrollment and men participating in another recently reported randomized trial of radical prostatectomy vs WW conducted in Scandinavia. We screened 13 022 men with prostate cancer at 52 US medical centers for potential enrollment. From these, 5023 met initial age, comorbidity, and disease eligibility criteria, and a total of 731 men agreed to participate and were randomized. The mean age of enrollees was 67 years. Nearly one-third were African American. Approximately 85% reported that they were fully active. The median PSA was 7.8ng/mL (mean 10.2ng/mL). In three-fourths of men, the primary reason for biopsy leading to a diagnosis of prostate cancer was a PSA elevation or rise. Using previously developed tumor risk categorizations incorporating PSA levels, Gleason histologic grade, and tumor stage, it was found that approximately 40% had low-risk, 34% had medium-risk, and 21% had high-risk prostate cancer based on local histopathology. Comparison to our national sample of eligible men declining PIVOT participation as well as to men enrolled in the Scandinavian trial indicated that PIVOT enrollees are representative of men being diagnosed and treated in the United States and quite different from men in the Scandinavian trial. PIVOT enrolled an ethnically diverse population representative of men diagnosed with prostate cancer in the United States. Results will yield important information regarding the relative effectiveness and harms of surgery compared with WW for men with predominately PSA-detected clinically localized prostate cancer.
doi:10.1093/jncimonographs/lgs041
PMCID: PMC3540866  PMID: 23271771
4.  Risk Assessment for Prostate Cancer Metastasis and Mortality at the Time of Diagnosis 
Background
Although many tools for the assessment of prostate cancer risk have been published, most are designed to predict only biochemical recurrence, usually after a single specified treatment. We assessed the accuracy of the Cancer of the Prostate Risk Assessment (CAPRA) score, which was validated previously to predict pathological and biochemical outcomes after radical prostatectomy, to predict metastases, prostate cancer–specific mortality, and all-cause mortality.
Methods
We studied 10 627 men with clinically localized prostate cancer in the Cancer of the Prostate Strategic Urologic Research Endeavor registry, who underwent primary radical prostatectomy, radiation therapy (external beam or interstitial), androgen deprivation monotherapy, or watchful waiting/active surveillance, and had at least 6 months of follow-up after treatment. CAPRA scores were calculated at diagnosis from the prostate-specific antigen level, Gleason score, percentage of biopsy cores that were positive for cancer, clinical tumor stage, and age at diagnosis. Survival was studied with Kaplan–Meier analyses. Associations between increasing CAPRA scores and bone metastasis, cancer-specific mortality, and all-cause mortality were examined by use of proportional hazards regression, with adjustment for primary treatment; for all-cause mortality, the analysis also included adjustment for age and comorbidity. Accuracy of the CAPRA score was assessed with the concordance (c)-index.
Results
Among the 10 627 patients, 311 (2.9%) men developed bone metastases, 251 (2.4%) died of prostate cancer, and 1582 (14.9%) died of other causes. Each single-point increase in the CAPRA score was associated with increased bone metastases (hazard ratio [HR] for bone metastases = 1.47, 95% confidence interval [CI] = 1.39 to 1.56), cancer-specific mortality (HR for prostate cancer death = 1.39, 95% CI = 1.31 to 1.48), and all-cause mortality (HR for death = 1.13, 95% CI = 1.10 to 1.16). The CAPRA score was accurate for predicting metastases (c-index = 0.78), cancer-specific mortality (c-index = 0.80), and all-cause mortality (c-index = 0.71).
Conclusions
In a large cohort of patients with clinically localized prostate cancer who were managed with one of five primary modalities, the CAPRA score predicted clinical prostate cancer endpoints with good accuracy. These results support the value of the CAPRA score as a risk assessment and stratification tool for both research studies and clinical practice.
doi:10.1093/jnci/djp122
PMCID: PMC2697208  PMID: 19509351
5.  Outcomes in Localized Prostate Cancer: National Prostate Cancer Register of Sweden Follow-up Study 
Background
Treatment for localized prostate cancer remains controversial. To our knowledge, there are no outcome studies from contemporary population-based cohorts that include data on stage, Gleason score, and serum levels of prostate-specific antigen (PSA).
Methods
In the National Prostate Cancer Register of Sweden Follow-up Study, a nationwide cohort, we identified 6849 patients aged 70 years or younger. Inclusion criteria were diagnosis with local clinical stage T1–2 prostate cancer from January 1, 1997, through December 31, 2002, a Gleason score of 7 or less, a serum PSA level of less than 20 ng/mL, and treatment with surveillance (including active surveillance and watchful waiting, n = 2021) or curative intent (including radical prostatectomy, n = 3399, and radiation therapy, n = 1429). Among the 6849 patients, 2686 had low-risk prostate cancer (ie, clinical stage T1, Gleason score 2-6, and serum PSA level of <10 ng/mL). The study cohort was linked to the Cause of Death Register, and cumulative incidence of death from prostate cancer and competing causes was calculated.
Results
For the combination of low- and intermediate-risk prostate cancers, calculated cumulative 10-year prostate cancer–specific mortality was 3.6% (95% confidence interval [CI] = 2.7% to 4.8%) in the surveillance group and 2.7% (95% CI = 2.1% to 3.45) in the curative intent group. For those with low-risk disease, the corresponding values were 2.4% (95% CI = 1.2% to 4.1%) among the 1085 patients in the surveillance group and 0.7% (95% CI = 0.3% to 1.4%) among the 1601 patients in the curative intent group. The 10-year risk of dying from competing causes was 19.2% (95% CI = 17.2% to 21.3%) in the surveillance group and 10.2% (95% CI = 9.0% to 11.4%) in the curative intent group.
Conclusion
A 10-year prostate cancer–specific mortality of 2.4% among patients with low-risk prostate cancer in the surveillance group indicates that surveillance may be a suitable treatment option for many patients with low-risk disease.
doi:10.1093/jnci/djq154
PMCID: PMC2897875  PMID: 20562373
6.  Long-Term Followup of 3-Month Neoadjuvant Hormone Therapy Before Radical Prostatectomy in a Randomized Trial 
BJU international  2009;105(2):185-190.
Objective
Neoadjuvant hormone therapy (NHT) prior to radical prostatectomy results in pathologic downstaging, but generally no reduction in biochemical recurrence (BCR) on early followup. In an institutional randomized prospective trial of radical prostatectomy with or without a 3-month course of NHT, we observed no reduction in BCR at 3 years. We report our long-term followup of this cohort.
Patients and Methods
From December 1992 to June 1996, 148 patients with clinically localized prostate cancer were randomized to radical prostatectomy only or 3 months of goserelin acetate and flutamide before radical prostatectomy. BCR was defined as a detectable serum prostate specific antigen (greater than 0.1 ng/mL) at least 6 weeks after surgery with a confirmatory rise.
Results
The median followup for recurrence-free patients was 8 years. There was no significant difference in recurrence-free probabilities between groups (p = 0.7). The BCR-free probability at 7 years was 78% for patients undergoing RP only and 80% for patients undergoing NHT and RP (difference of 2%; 95% CI, 12%–16%). A Cox regression showed no significant relationship between NHT and BCR (HR 1.16; 95% CI, 0.56 – 2.39, p = 0.7). Overall, 2 patients had local recurrence and 6 patients developed metastases, and were evenly split among the RP only and NHT groups.
Conclusion
Although our study was not originally powered to detect differences in BCR, we did not demonstrate an overall benefit in BCR-free probability, local recurrence or metastasis with 3 months of NHT at 8 years of followup. Pending evidence of improvement in patient outcomes, NHT before radical prostatectomy appears unjustified outside of clinical trials.
doi:10.1111/j.1464-410X.2009.08698.x
PMCID: PMC2807908  PMID: 19594741
prostate; prostatic neoplasms; prostatectomy; neoadjuvant therapy; hormones
7.  A Decision Analysis for Treatment of Clinically Localized Prostate Cancer 
OBJECTIVE
To determine the preferred treatment of clinically localized prostate cancer.
DESIGN
Cancer grade, patient age, and comorbidities are considered in a Markov model with Monte Carlo sensitivity analyses. Large and recent pooled analyses and patient-derived utilities are included.
RESULTS
Principal findings suggest benefit for radical prostatectomy relative to watchful waiting for men under 70 years of age with low to moderate comorbidity. Men older than 70 with high comorbidity and disease of low to moderate grade do better with watchful waiting.
CONCLUSIONS
Cohort-level sensitivity analyses suggest a quality-adjusted treatment benefit for radical prostatectomy for younger men and treatment harm for older men. Tailored patient and clinician decisions remain necessary, especially for men older than 70 in good health but with aggressive cancers.
doi:10.1046/j.1525-1497.1997.012005299.x
PMCID: PMC1497110  PMID: 9159699
decision analysis; prostate cancer; watchful waiting; patient-derived utilities; radical prostatectomy
8.  Outcomes After Radical Prostatectomy in Men Receiving Prior Pelvic Radiation for Non-Prostate Malignancies 
BJU international  2009;104(4):482-485.
Purpose
Morbidity associated with salvage radical prostatectomy for locally recurrent prostate cancer after primary radiotherapy is well documented, but little is known about the impact on surgical difficulty and outcomes for radical prostatectomy in men who have had prior pelvic radiotherapy for non-prostate malignancies. We report functional outcomes of 9 patients treated at our institution.
Materials and Methods
From 1993 to 2007, 9 patients underwent radical prostatectomy following external beam radiotherapy for testicular seminoma (6), anorectal cancer (2), and colon cancer (1). Clinical information was obtained from a prospective prostate cancer database.
Results
Radical prostatectomy was completed without identifiable injury to adjacent structures in all 9 patients. Four patients had significant pelvic fibrosis, 3 required bilateral neurovascular bundle resection. Neurovascular bundle preservation was performed in the remaining 6 patients, 4 with good preoperative erectile function. However, no patient recovered erectile function postoperatively at a median follow-up time of 75 months (range 12 to 172). Of preoperatively continent men, 57% required ≤1 pad daily and 43% were completely dry, achieving complete urinary control at a median follow-up time of 7.5 months (range 2 to 20). Two patients developed anastomotic stricture, one being associated with concomitant ureteral stricture.
Conclusions
Radical prostatectomy after pelvic radiotherapy for non-prostate malignancies was not associated with increased intraoperative morbidity. However, rates of anastomotic stricture, erectile dysfunction, and urinary incontinence appear to be higher than those observed after radical prostatectomy in men with no prior radiotherapy and comparable to those seen in the salvage radical prostatectomy setting.
doi:10.1111/j.1464-410X.2009.08428.x
PMCID: PMC2865893  PMID: 19239447
Perioperative complications; Prostate; Prostate cancer; Radical prostatectomy; Radiotherapy
9.  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
10.  Increasing use of radical prostatectomy for non-lethal prostate cancer in Sweden 
Purpose
The number of patients in Sweden treated with radical prostatectomy for localized prostate cancer has increased exponentially. The extent to which this increase reflects treatment of non-lethal disease detected through PSA screening is unknown.
Experimental design
We undertook a nationwide study of all 18,837 prostate cancer patients treated with radical prostatectomy in Sweden from 1988 to 2008 with complete follow-up through 2009. We compared cumulative incidence curves, fit Cox regression and cure models and performed a simulation study to determine changes in treatment of non-lethal cancer, in cancer-specific survival over time, and effect of lead-time due to PSA screening.
Results
The annual number of radical prostatectomies increased 25-fold during the study period. The five-year cancer-specific mortality decreased from 3.9% (95% CI 2.5 to 5.3) among patients diagnosed between 1988 and 1992 to 0.7% (95% CI 0.4–1.1) among those diagnosed between 1998 and 2002 (p for trend < 0.001). According to the cure model, the risk of not being cured declined by 13% (95% CI 12–14%) with each calendar year. The simulation study indicated that only about half of the improvement in disease-specific survival could be accounted for by lead-time.
Conclusion
Patients overdiagnosed with non-lethal prostate cancer appear to account for a substantial and growing part of the dramatic increase in radical prostatectomies in Sweden but increasing survival rates are likely also due to true reductions in the risk of disease-specific death over time. Because the magnitude of harm and costs due to overtreatment can be considerable, identification of men who likely benefit from radical prostatectomy is urgently needed.
doi:10.1158/1078-0432.CCR-12-1537
PMCID: PMC3711175  PMID: 22927485
Overdiagnosis; prostate cancer; PSA screening; radical prostatectomy
11.  Long-term results of radical prostatectomy with immediate adjuvant androgen deprivation therapy for pT3N0 prostate cancer 
BMC Urology  2014;14:13.
Background
Radical prostatectomy is used to treat patients with clinically localized prostate cancer, but there have been few reports of its use in locally advanced disease. We evaluated the long-term results of radical prostatectomy and immediate adjuvant androgen deprivation therapy in Japanese patients with pT3N0M0 prostate cancer.
Methods
We retrospectively reviewed 128 patients with pT3N0M0 prostate cancer who underwent radical prostatectomy at our institute from 2000 to 2006. All pT3N0 patients were treated with adjuvant androgen deprivation therapy shortly after radical prostatectomy. Immediate adjuvant androgen deprivation therapy was continued for at least 5 years. Twenty-three were excluded because of preoperative hormonal therapy, missing data, or others. Death from any cause, death from prostate cancer, clinical recurrence and hormone-refractory biochemical progression were analyzed by Kaplan-Meier graphs. Relative risks of progression were estimated using Cox proportional hazards models with 95% confidence intervals.
Results
The 10-year hormone-refractory biochemical progression-free survival rate was 88.3% and the cancer-specific survival rate was 96.3% after a median follow-up period of 8.2 years (range 25.6-155.6 months). Higher clinical stage (p = 0.013), higher Gleason score at biopsy (p = 0.001), seminal vesicle invasion (p = 0.003) and microlymphatic invasion (p = 0.006) were predictive factors for hormone-refractory biochemical progression by univariate analyses. Multivariate analyses identified Gleason score at biopsy (p = 0.027) and seminal vesicle invasion (p = 0.030) as independent prognostic factors for hormone-refractory biochemical progression. None of the patients with clinical T1 cancers (n = 20), negative surgical margin (n = 12), or negative perineural invasion (n = 11) experienced hormone-refractory biochemical progression.
Conclusions
Radical prostatectomy with immediate adjuvant androgen deprivation therapy may be a valid treatment option for patients with pT3N0M0 prostate cancer.
doi:10.1186/1471-2490-14-13
PMCID: PMC3912934  PMID: 24476554
Adjuvant androgen deprivation therapy; Pathological T3; Prognosis; Prognostic factor; Prostate cancer; Radical prostatectomy
12.  Adverse Effects of Robotic-Assisted Laparoscopic Versus Open Retropubic Radical Prostatectomy Among a Nationwide Random Sample of Medicare-Age Men 
Journal of Clinical Oncology  2012;30(5):513-518.
Purpose
Robotic-assisted laparoscopic radical prostatectomy is eclipsing open radical prostatectomy among men with clinically localized prostate cancer. The objective of this study was to compare the risks of problems with continence and sexual function following these procedures among Medicare-age men.
Patients and Methods
A population-based random sample was drawn from the 20% Medicare claims files for August 1, 2008, through December 31, 2008. Participants had hospital and physician claims for radical prostatectomy and diagnostic codes for prostate cancer and reported undergoing either a robotic or open surgery. They received a mail survey that included self-ratings of problems with continence and sexual function a median of 14 months postoperatively.
Results
Completed surveys were obtained from 685 (86%) of 797 eligible participants, and 406 and 220 patients reported having had robotic or open surgery, respectively. Overall, 189 (31.1%; 95% CI, 27.5% to 34.8%) of 607 men reported having a moderate or big problem with continence, and 522 (88.0%; 95% CI, 85.4% to 90.6%) of 593 men reported having a moderate or big problem with sexual function. In logistic regression models predicting the log odds of a moderate or big problem with postoperative continence and adjusting for age and educational level, robotic prostatectomy was associated with a nonsignificant trend toward greater problems with continence (odds ratio [OR] 1.41; 95% CI, 0.97 to 2.05). Robotic prostatectomy was not associated with greater problems with sexual function (OR, 0.87; 95% CI, 0.51 to 1.49).
Conclusion
Risks of problems with continence and sexual function are high after both procedures. Medicare-age men should not expect fewer adverse effects following robotic prostatectomy.
doi:10.1200/JCO.2011.36.8621
PMCID: PMC3295553  PMID: 22215756
13.  Radical Prostatectomy versus Observation for Localized Prostate Cancer 
The New England journal of medicine  2012;367(3):203-213.
BACKGROUND
The effectiveness of surgery versus observation for men with localized prostate cancer detected by means of prostate-specific antigen (PSA) testing is not known.
METHODS
From November 1994 through January 2002, we randomly assigned 731 men with localized prostate cancer (mean age, 67 years; median PSA value, 7.8 ng per milliliter) to radical prostatectomy or observation and followed them through January 2010. The primary outcome was all-cause mortality; the secondary outcome was prostate-cancer mortality.
RESULTS
During the median follow-up of 10.0 years, 171 of 364 men (47.0%) assigned to radical prostatectomy died, as compared with 183 of 367 (49.9%) assigned to observation (hazard ratio, 0.88; 95% confidence interval [CI], 0.71 to 1.08; P = 0.22; absolute risk reduction, 2.9 percentage points). Among men assigned to radical prostatectomy, 21 (5.8%) died from prostate cancer or treatment, as compared with 31 men (8.4%) assigned to observation (hazard ratio, 0.63; 95% CI, 0.36 to 1.09; P = 0.09; absolute risk reduction, 2.6 percentage points). The effect of treatment on all-cause and prostate-cancer mortality did not differ according to age, race, coexisting conditions, self-reported performance status, or histologic features of the tumor. Radical prostatectomy was associated with reduced all-cause mortality among men with a PSA value greater than 10 ng per milliliter (P = 0.04 for interaction) and possibly among those with intermediate-risk or high-risk tumors (P = 0.07 for interaction). Adverse events within 30 days after surgery occurred in 21.4% of men, including one death.
CONCLUSIONS
Among men with localized prostate cancer detected during the early era of PSA testing, radical prostatectomy did not significantly reduce all-cause or prostate-cancer mortality, as compared with observation, through at least 12 years of follow-up. Absolute differences were less than 3 percentage points. (Funded by the Department of Veterans Affairs Cooperative Studies Program and others; PIVOT ClinicalTrials.gov number, NCT00007644.)
doi:10.1056/NEJMoa1113162
PMCID: PMC3429335  PMID: 22808955
14.  Is it necessary to cure prostate cancer when it is possible? (Understanding the role of prostate inflammation resolution to prostate cancer evolution) 
Clinical Interventions in Aging  2007;2(1):153-161.
Objective:
Definitive therapy with radical prostatectomy, cryotherapy, or radiation therapy generally follows the initial diagnosis of prostate cancer, particularly when men have at least 10 additional years of life expectancy. There is growing concern regarding the optimal conservative treatment for patients who decline or do not otherwise qualify for such definitive curative treatment. For those patients who choose a watchful waiting approach, it would be beneficial to know what specific dietary and nutritional methods could potentially slow the progression of their disease. In this prospective study, it was our goal to analyze the efficacy and safety of treating prostate cancer conservatively using the principles of a Mediterranean diet in association with a specific prostate nutritional supplement.
Method:
Twenty-three men aged 43–74 (median age: 64) with biopsy proven, organ-confined prostate cancer who had already declined immediate hormonal therapy and attempts at a curative cancer treatment agreed to participate in a Chronic Disease Management (CDM) protocol highlighted by diet with a specific prostate nutritional supplement. The diet recommended was a modified Mediterranean diet while a patented nutritional prostatitis formula (Peenuts®) was the supplement common to all patients. Prostate specific antigen (PSA), a recognized marker of prostate disease and prostate cancer activity, was the primary indicator to validate exacerbation or suppression of disease. All men were followed with serial PSA testing, a digital rectal exam, an International Prostate Symptom Score index (IPSS-Index) and an expressed prostatic secretion (EPS) examination. The primary Gleason sum/score represented in this study was 6 (n = 11), while Gleason sum patterns 5, 5/6, 6/7, and 7 were also evaluated. Referencing the Partin Tables, organ confinement was predicted to be 66%.
Results:
Eighty-seven percent of men (n = 20) noted a 58% reduction (range of improvement: 13%–90%) in PSA over an average of 38.5 months (range: 13–84 months). The remaining 13% of men included three men who experienced a mild elevation in PSA of 0.3 ng/ml, 0.7 ng/ml, and 0.9 ng/ml over 14 months, 42 months, and 34 months, respectively. Fifteen men had completed an initial and secondary IPSS-Index while 14 men had undergone an initial and secondary EPS. The mean percentage reduction in IPSS-Index was 61% (range: 20%–100% with a median of 55%), while men evaluated with EPS examinations noted a mean percentage reduction in white blood cells of 77.5% (range: 33%–99% with a median of 82%). These results were evaluated using the t-test, Wilcoxon Analysis and the Null Hypothesis and found to be statistically significant.
Conclusion:
Clearly there is a need to develop effective alternative conservative therapies for the increasing numbers of prostate cancer patients who will not tolerate definitive curative measures or simply choose a conservative approach. Although this prospective study had no control arm, was of limited duration and included only 23 participants, it did appear to show significant benefit to the majority of prostate cancer patients treated with selective nutritional and dietary therapy alone. Such treatments may provide a safe and effective long-term treatment alternative for some patients. Further study is encouraged.
PMCID: PMC2684075  PMID: 18044088
Prostate cancer; prostatitis; prostate cancer nutrition; PSA; EPS; Gleason score; voiding symptoms; Mediterranean diet
15.  Factors associated with initial treatment and survival for clinically localized prostate cancer: results from the CDC-NPCR Patterns of Care Study (PoC1) 
BMC Cancer  2010;10:152.
Background
Despite the large number of men diagnosed with localized prostate cancer, there is as yet no consensus concerning appropriate treatment. The purpose of this study was to describe the initial treatment patterns for localized prostate cancer in a population-based sample and to determine the clinical and patient characteristics associated with initial treatment and overall survival.
Methods
The analysis included 3,300 patients from seven states, diagnosed with clinically localized prostate cancer in 1997. We examined the association of sociodemographic and clinical characteristics with four treatment options: radical prostatectomy, radiation therapy, hormone therapy, and watchful waiting. Diagnostic and treatment information was abstracted from medical records. Socioeconomic measures were derived from the 2000 Census based on the patient's residence at time of diagnosis. Vital status through December 31, 2002, was obtained from medical records and linkages to state vital statistics files and the National Death Index. Multiple logistic regression analysis and Cox proportional hazards models identified factors associated with initial treatment and overall survival, respectively.
Results
Patients with clinically localized prostate cancer received the following treatments: radical prostatectomy (39.7%), radiation therapy (31.4%), hormone therapy (10.3%), or watchful waiting (18.6%). After multivariable adjustment, the following variables were associated with conservative treatment (hormone therapy or watchful waiting): older age, black race, being unmarried, having public insurance, having non-screen detected cancer, having normal digital rectal exam results, PSA values above 20, low Gleason score (2-4), comorbidity, and state of residence. Among patients receiving definitive treatment (radical prostatectomy or radiation therapy), older age, being unmarried, PSA values above 10, unknown Gleason score, state of residence, as well as black race in patients under 60 years of age, were associated with receipt of radiation therapy. Overall survival was related to younger age, being married, Gleason score under 8, radical prostatectomy, and state of residence. Comorbidity was only associated with risk of death within the first three years of diagnosis.
Conclusions
In the absence of clear-cut evidence favoring one treatment modality over another, it is important to understand the factors that inform treatment selection. Since state of residence was a significant predictor of both treatment as well as overall survival, true regional differences probably exist in how physicians and patients select treatment options. Factors affecting treatment choice and treatment effectiveness need to be further explored in future population-based studies.
doi:10.1186/1471-2407-10-152
PMCID: PMC2876077  PMID: 20403178
16.  The Relationship of the Intensity of Posttreatment Prostate-Specific Antigen Surveillance and Prostate Cancer Outcomes: Results From a Population-Based Cohort 
Mayo Clinic Proceedings  2012;87(6):540-547.
Objective
To determine whether higher intensity of prostate-specific antigen (PSA) surveillance was associated with earlier detection of biochemical recurrence (BCR) or survival.
Patients and Methods
We identified a population-based cohort of 832 men diagnosed with nonmetastatic prostate cancer between January 1, 1995, and July 31, 2006. These men were treated with radical prostatectomy (RP), brachytherapy or external beam radiation therapy (RT), or primary androgen deprivation therapy or chose watchful waiting. To test the associations of intensity in PSA surveillance with study outcomes, we used a 2-year landmark analysis to assess whether the number of PSA tests during the first 2 years after treatment was associated with earlier detection of BCR, prostate cancer–related mortality, and all-cause mortality. We used landmark analysis to assess the association of PSA intensity, adjusting for clinicopathologic covariate, with outcome.
Results
Median follow-up time for the entire cohort was 6.7 years. Higher Gleason score was the only clinicopathologic variable associated with higher PSA frequency in multivariable analysis for both the RP and RT groups (P value of .001 and .05, respectively). After adjustment for other covariates, the frequency of PSA tests during the first 2 years after RP did not increase the ability to detect BCR (hazard ratio, 1.00; 95% confidence interval, 0.84-1.19) or all-cause mortality (hazard ratio, 0.95; 95% confidence interval, 0.70-1.30) in the landmark analysis.
Conclusion
Higher intensity of PSA surveillance during the 2 years after RP or RT did not improve earlier detection of BCR or survival. Evidence-based guidelines for PSA surveillance after primary treatment are needed.
doi:10.1016/j.mayocp.2012.01.017
PMCID: PMC3498058  PMID: 22677074
ACM, all-cause mortality; ADT, androgen deprivation therapy; BCR, biochemical recurrence; HR, hazard ratio; PCSM, prostate cancer–specific mortality; PSA, prostatic-specific antigen; RP, radical prostatectomy; RT, radiation therapy; WW, watchful waiting
17.  TEN-YEAR FOLLOW-UP OF NEOADJUVANT THERAPY WITH GOSERELIN ACETATE AND FLUTAMIDE PRIOR TO RADICAL PROSTATECTOMY FOR CLINICAL T3 AND T4 PROSTATE CANCER: UPDATE ON SOUTHWEST ONCOLOGY GROUP STUDY 9109 
Urology  2012;79(3):10.1016/j.urology.2011.11.019.
Purpose
The optimal management for clinical stage T3 and T4 (N0, M0) prostate cancer is uncertain. Herein we update the results with ten-year data of a phase II prospective trial of neoadjuvant hormonal therapy with goserelin acetate and flutamide followed by radical prostatectomy for locally-advanced prostate cancer (SWOG 9109).
Materials and Methods
62 patients with clinical stage T3 and T4 (N0, M0) prostate cancer were enrolled. Cases were classified by stage T3 versus T4 and by volume of disease (bulky > 4 cm and non-bulky ≤ 4 cm).
Results
A total of 55 of 61 eligible patients completed the trial with radical prostatectomy after neoadjuvant androgen deprivation therapy (ADT). The median pre-operative PSA value was 19.8 ng/ml, and 67% of patients had a Gleason score of 7 or higher. Among 41 patients last known to be alive, median follow-up is 10.6 years (range 5.1–12.6 years). In all, 38 patients have had disease progression (30/55, 55%) or died without progression (8/55, 15%) for a ten-year PFS estimate of 40% (95% CI, 27–53%). Median progression-free survival (PFS) was 7.5 years, and median survival has not been reached. The ten-year overall survival (OS) estimate is 68% (95% CI, 56–80%).
Conclusions
In this small, prospective phase II study, neoadjuvant hormonal therapy with goserelin acetate and flutamide followed by radical prostatectomy achieves long-term PFS and OS comparable to alternative treatments. This approach is feasible and may be an alternative to a strategy of combined radiation and ADT.
doi:10.1016/j.urology.2011.11.019
PMCID: PMC3839235  PMID: 22386416
prostate cancer; PSA; radical prostatectomy; survival; locally-advanced
18.  Comparative risk-adjusted mortality outcomes following primary surgery, radiation therapy, or androgen deprivation therapy for localized prostate cancer 
Cancer  2010;116(22):5226-5234.
Purpose
No adequate randomized trials comparing active treatment modalities for localized prostate cancer have been reported. We analyzed risk-adjusted cancer-specific mortality outcomes among men undergoing radical prostatectomy, external-beam radiation therapy, or primary androgen deprivation therapy.
Methods
The CaPSURE registry comprises men from 40 urologic practice sites followed prospectively under uniform protocols, regardless of treatment. 7538 men with localized disease were analyzed. Prostate cancer risk was assessed using the Kattan preoperative nomogram and the Cancer of the Prostate Risk Assessment (CAPRA) score, both well-validated instruments calculated from clinical data at the time of diagnosis. A parametric survival model was constructed to compare outcomes across treatments, adjusting for risk and age.
Results
226 men died of prostate cancer during followup. Adjusting for age and risk, the hazard ratio for cancer-specific mortality relative to prostatectomy was 2.21 (1.50–3.24) for radiation, and 3.22 (2.16–4.81) for androgen deprivation. Absolute differences between prostatectomy and radiation therapy were small for men at low risk, but increased substantially for men at intermediate and high risk. These results were robust to a variety of different analytic techniques including competing risks regression analysis, adjustment by CAPRA rather than Kattan score, and examination of overall survival as the endpoint.
Conclusions
Prostatectomy for localized prostate cancer was associated with a significant and substantial reduction in mortality relative to radiation or androgen deprivation monotherapy. Although not a randomized study, given the multiple adjustments and sensitivity analyses it is unlikely that unmeasured confounding would account for the large observed differences in survival.
doi:10.1002/cncr.25456
PMCID: PMC2975879  PMID: 20690197
prostate neoplasms; comparative effectiveness; surgery; radiation; hormonal therapy; CaPSURE
19.  Poorly Differentiated Prostate Cancer Treated With Radical Prostatectomy: Long-Term Outcome and Incidence of Pathological Downgrading 
The Journal of urology  2006;176(3):991-995.
Purpose:
Patients with high grade (Gleason score 8 to 10) prostate cancer on biopsy are at high risk for cancer recurrence after local treatment, such as radiation therapy and radical prostatectomy. We examined long-term outcomes in patients with high grade prostate cancer on biopsy who were treated with radical prostatectomy alone. We also investigated the impact on outcomes of changes in the radical prostatectomy Gleason score.
Materials and Methods:
Of 5,662 patients who underwent radical prostatectomy during 20 years 238 had a biopsy Gleason score of 8 to 10. We analyzed the rate of biochemical recurrence in this subgroup according to the Gleason grade of cancer in the radical prostatectomy specimen.
Results:
Ten-year biochemical recurrence-free probability in the cohort was 39%. However, 45% of patients (95% CI 38 to 51%) with Gleason score 8 to 10 cancer on biopsy had a Gleason score of 7 or less in the radical prostatectomy specimen. These patients had a 10-year biochemical recurrence-free probability of 56% compared to 27% in those with a final Gleason score that remained 8 to 10 (p = 0.0004). On multivariate analysis neither prostate specific antigen nor biopsy features, including total number of cores, number of cores with cancer and percent of cancer in the cores, was a significant predictor of downgrading. However, clinical stage and biopsy Gleason score were significant with 58% of cT1c and 51% of biopsy Gleason score 8 cancers downgraded. Almost 65% of cT1c Gleason score 8 cancers were downgraded compared to 11% of cT3 Gleason score 9 cancers.
Conclusions:
Patients diagnosed with poorly differentiated prostate cancer (Gleason score 8 to 10) on biopsy do not uniformly have a poor prognosis. Of the patients 39% remain free of cancer recurrence 10 years after radical prostatectomy. Of these cancers 45% have a lower Gleason score in the radical prostatectomy specimen and a correspondingly more favorable long-term outcome. Predictors of downgrading are lower clinical stage (cT1c) and Gleason score 8 in the biopsy specimen.
doi:10.1016/j.juro.2006.04.048
PMCID: PMC2239297  PMID: 16890678
prostate; prostatic neoplasms; prostatectomy; mortality; biopsy
20.  Changes in radical prostatectomy and radiation therapy rates for African Americans and whites. 
There are racial differences in prostate cancer outcomes. One variable influencing end results is treatment for cure: either radical prostatectomy (RP) or radiation therapy (RT). The purpose of this report is to determine changes in diagnosis rates of localized prostate cancer between the years before prostate-specific antigen (PSA) use (1973-1988) and the years after PSA use (1989-1996), to evaluate differences in RP and RT rates between the pre-PSA and post-PSA eras, to assess differences in RP and RT rates between African Americans and whites between these intervals. The Surveillance, Epidemiology, and End Results (SEER) data were used and evaluated. Both African Americans and whites had statistically increased rates of localized prostate cancer diagnosed (70.4 and 49.0 in 1973 through 1988 and 123.1 and 84.9 in 1989 through 1996, respectively [p < 0.05]). The differences between the pre-PSA and post-PSA eras for African Americans and whites for RP (3.6 vs. 44.3 and 5.0 vs. 44.9, respectively) and RT (23.6 vs. 61.6 and 17.0 vs. 38.1, respectively) were all significant (p < 0.05). Both African Americans and whites had increased rates of RP from 3.6 and 5.0 to 44.3 and 44.9, respectively, and RT from 23.6 and 17.0 to 61.6 and 38.1 during the pre- and post-PSA years.
PMCID: PMC2640525  PMID: 10918763
21.  Telomere DNA Content in Prostate Biopsies Predicts Early Rise in Prostate Specific Antigen Following Radical Prostatectomy for Prostate Cancer 
Urology  2009;75(3):724-729.
Objective
To determine whether measurement of telomere DNA content (TC) in prostate biopsy tissue predicts PSA recurrence in men after undergoing radical prostatectomy for prostate cancer.
Methods
Slot blot titration assay was used to quantitate TC in archived diagnostic prostate needle biopsy specimens for subjects (n=103) diagnosed with prostate cancer and who subsequently underwent radical prostatectomy between 1993 and 1997. TC was compared to the clinical outcome measure, PSA recurrence, defined as an increase in PSA ≥0.2ng/mL on two or more consecutive measurements post-prostatectomy, observed retrospectively, for a mean follow-up period of 114 months (range 1–165).
Results
In the cohort, 46 subjects had a PSA recurrence. In a univariate Cox proportional hazards model, low TC (<0.3 of standard) demonstrated a significant risk for PSA recurrence (HR=1.94; 95% CI:1.02–3.69, p=0.04). In a subset analysis of men with biopsy Gleason sum ≤6 (n=63; 25 recurrences), a univariate Cox proportional hazards model demonstrated low TC had a greater risk of PSA recurrence (HR=4.53; 95% CI:2.00–10.2, p<0.01). In a multivariate Cox proportional hazards model, low TC was also significantly associated with PSA recurrence in this subset after controlling for pre-operative PSA levels (HR=6.62; 95% CI:2.69–16.3, p<0.01).
Conclusions
Low TC measured in prostate biopsy tissue predicts early likelihood of post-prostatectomy PSA recurrence in a retrospective analysis and in men with biopsy Gleason sum ≤6 disease is also independent of pre-operative PSA level.
doi:10.1016/j.urology.2009.04.032
PMCID: PMC2835834  PMID: 19615720
prostate adenocarcinoma; genomic instability; prognosis; telomere; PSA recurrence
22.  Implementation and scientific evaluation of rehabilitative sports groups for prostate cancer patients: study protocol of the ProRehab Study 
BMC Cancer  2012;12:312.
Background
Although treatment regimen have improved in the last few years, prostate cancer patients following a radical prostatectomy still experience severe disease- and treatment-related side effects, including urinary incontinence, erectile dysfunction and psychological issues. Despite high incidence rates and the common adverse effects there is a lack of supportive measures for male patients and specific physical exercise recommendations for prostate cancer patients during rehabilitation or in the aftercare are still missing.
Methods/Design
The ProRehab Project aims to establish rehabilitative sports groups particularly for prostate cancer patients and to evaluate the effects of the offered exercise program. Starting 8–12 weeks after prostatectomy or combination therapy, prostate cancer patients will exercise for 15 months within a patient preference randomized controlled trial. One exercise session will be conducted within a pre-established rehabilitative sports group, while the other will be completed independently. Patients in the control group will not participate in the intervention. The main outcomes of the study include aerobic fitness, quality of life, incontinence and erectile dysfunction.
Discussion
By combining science, practice, and public relations the first rehabilitative sports groups for prostate cancer patients in Germany have been set up and thus contribute to the care structure for prostate cancer patients. By offering a 15-month physical exercise intervention that is conducted in supervised group sessions, long-term lifestyle changes and therefore improvements in quality of life in prostate cancer patients can be expected.
Trial registration
German Clinical Trials Register DRKS00004184
doi:10.1186/1471-2407-12-312
PMCID: PMC3414755  PMID: 22827935
Prostate cancer; Rehabilitative sports groups; Physical activity; Exercise
23.  Effect of Soy Protein Isolate Supplementation on Biochemical Recurrence of Prostate Cancer After Radical Prostatectomy 
IMPORTANCE
Soy consumption has been suggested to reduce risk or recurrence of prostate cancer, but this has not been tested in a randomized trial with prostate cancer as the end point.
OBJECTIVE
To determine whether daily consumption of a soy protein isolate supplement for 2 years reduces the rate of biochemical recurrence of prostate cancer after radical prostatectomy or delays such recurrence.
DESIGN, SETTING, AND PARTICIPANTS
Randomized, double-blind trial conducted from July 1997 to May 2010 at 7 US centers comparing daily consumption of a soy protein supplement vs placebo in 177 men at high risk of recurrence after radical prostatectomy for prostate cancer. Supplement intervention was started within 4 months after surgery and continued for up to 2 years, with prostate-specific antigen (PSA) measurements made at 2-month intervals in the first year and every 3 months thereafter.
INTERVENTION
Participants were randomized to receive a daily serving of a beverage powder containing 20 g of protein in the form of either soy protein isolate (n=87)or, as placebo, calcium caseinate (n=90).
MAIN OUTCOMES AND MEASURES
Biochemical recurrence rate of prostate cancer (defined as development of a PSA level of ≥0.07 ng/mL) over the first 2 years following randomization and time to recurrence.
RESULTS
The trial was stopped early for lack of treatment effects at a planned interim analysis with 81 evaluable participants in the intervention group and 78 in the placebo group. Overall, 28.3% of participants developed biochemical recurrence within 2 years of entering the trial (close to the a priori predicted recurrence rate of 30%). Among these, 22 (27.2%) occurred in the intervention group and 23 (29.5%) in the placebo group. The resulting hazard ratio for active treatment was 0.96 (95% CI, 0.53–1.72; log-rank P = .89). Adherence was greater than 90% and there were no apparent adverse events related to supplementation.
CONCLUSION AND RELEVANCE
Daily consumption of a beverage powder supplement containing soy protein isolate for 2 years following radical prostatectomy did not reduce biochemical recurrence of prostate cancer in men at high risk of PSA failure.
doi:10.1001/jama.2013.7842
PMCID: PMC3921119  PMID: 23839751
24.  The deep vein thrombosis caused by lymphocele after endoscopic extraperitoneal radical prostatectomy and pelvic lymph node dissection 
Pelvic lymphocele is a postoperative complications than can result after endoscopic extraperitoneal radical prostatectomy and pelvic lymph node dissection. Radical prostatectomy have many risk factors of deep vein thrombosis including location of target organ, malignancy, old age, Trendelenburg position, pelvic lymph node dissection, and long procedure time. A 57-year-old man with a localized prostate cancer was treated with endoscopic extraperitoneal radical prostatectomy and pelvic lymph node dissection. Deep vein thrombosis was detected as a first sign of pelvic lymphocele. Lymphocele was managed with a percutaneous drainage without sclerosant. We report a case of deep vein thrombosis due to pelvic lymphocele after endoscopic extraperitoneal radical prostatectomy.
doi:10.5489/cuaj.10093
PMCID: PMC3125587  PMID: 21672491
25.  Current Laser Treatments for Benign Prostatic Hyperplasia 
Korean Journal of Urology  2010;51(11):737-744.
The latest technical improvements in the surgical armamentarium are remarkable. In particular, advancements in the urologic field are so exceptional that we could observe the flare-up of robot-assisted laparoscopic radical prostatectomy for prostate cancer and laser prostatectomy for benign prostatic hyperplasia (BPH). Photoselective vaporization of the prostate (PVP) and holmium laser prostatectomy are the most generalized options for laser surgery of BPH, and both modalities have shown good postoperative results. In comparison to transurethral prostatectomy (TURP), they showed similar efficacy and a much lower complication rate in randomized prospective clinical trials. Even in cases of large prostates, laser prostatectomy showed comparable efficacy and safety profiles compared to open prostatectomy. From a technical point of view, PVP is considered to be an easier technique for the urologist to master. Furthermore, patients can be safely followed up in an outpatient clinic. Holmium laser enucleation of the prostate (HoLEP) mimics open prostatectomy because the adenomatous tissue is peeled off the surgical capsule in both procedures. Therefore, HoLEP shows notable volume reduction of the prostate similar to open prostatectomy with fewer blood transfusions, shorter hospital stay, and cost reduction regardless of prostate size. Outcomes of laser prostatectomy for BPH are encouraging but sometimes are unbalanced because safety and feasibility studies were reported mainly for PVP, whereas long-term data are mostly available for HoLEP. We need longer-term randomized clinical data to identify the reoperation rate of PVP and to determine which procedure is the ideal alternative to TURP and open prostatectomy for each patient.
doi:10.4111/kju.2010.51.11.737
PMCID: PMC2991569  PMID: 21165192
Laser therapy; Prostatic hyperplasia; Solid-state lasers

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