Prediction of pathological stage based on clinical stage, serum prostate-specific antigen, and biopsy Gleason score: Partin Tables in the contemporary era.

OBJECTIVE: To update the Partin Tables for prediction of pathological stage in the contemporary setting and examine trends in patients treated with radical prostatectomy (RP) over the past three decades. PATIENTS AND METHODS: From January 2010 to October 2015, 4459 men meeting inclusion criteria underwent RP and pelvic lymphadenectomy for histologically confirmed prostate cancer at the Johns Hopkins Hospital. Preoperative clinical stage, serum prostate-specific antigen (PSA) level, and biopsy Gleason score (i.e. prognostic Grade Group) were used in a polychotomous logistic regression model to predict the probability of pathological outcomes categorised as: organ-confined (OC), extraprostatic extension (EPE), seminal vesicle involvement (SV+), or lymph node involvement (LN+). Preoperative characteristics and pathological findings in men treated with RP since 1983 were collected and clinical-pathological trends were described. RESULTS: The median (range) age at surgery was 60 (34-77) years and the median (range) PSA level was 4.9 (0.1-125.0) ng/mL. The observed probabilities of pathological outcomes were: OC disease in 74%, EPE in 20%, SV+ in 4%, and LN+ in 2%. The probability of EPE increased substantially when biopsy Gleason score increased from 6 (Grade Group 1, GG1) to 3 + 4 (GG2), with smaller increases for higher grades. The probability of LN+ was substantially higher for biopsy Gleason score 9-10 (GG5) as compared to lower Gleason scores. Area under the receiver operating characteristic curves for binary logistic models predicting EPE, SV+, and LN+ vs OC were 0.724, 0.856, and 0.918, respectively. The proportion of men treated with biopsy Gleason score ≤6 cancer (GG1) was 47%, representing a substantial decrease from 63% in the previous cohort and 77% in 2000-2005. The proportion of men with OC cancer has remained similar during that time, equalling 73-74% overall. The proportions of men with SV+ (4.1% from 3.4%) and LN+ (2.3% from 1.4%) increased relative to the preceding era for the first time since the Partin Tables were introduced in 1993. CONCLUSIONS: The Partin Tables remain a straightforward and accurate approach for projecting pathological outcomes based on readily available clinical data. Acknowledging these data are derived from a tertiary care referral centre, the proportion of men with OC disease has remained stable since 2000, despite a substantial decline in the proportion of men with biopsy Gleason score 6 (GG1). This is consistent with the notion that many men with Gleason score 6 (GG1) disease were over treated in previous eras.

Prevalence of the HOXB13 G84E prostate cancer risk allele in men treated with radical prostatectomy.

OBJECTIVE: To determine the prevalence and clinical correlates of the G84E mutation in the homeobox transcription factor, or HOXB13, gene using DNA samples from 9559 men with prostate cancer undergoing radical prostatectomy. PATIENTS AND METHODS: DNA samples from men treated with radical prostatectomy at the University of Michigan and John Hopkins University were genotyped for G84E and this was confirmed by Sanger sequencing. The frequency and distribution of this allele was determined according to specific patient characteristics (family history, age at diagnosis, pathological Gleason grade and stage). RESULTS: Of 9559 patients, 128 (1.3%) were heterozygous carriers of G84E. Patients who possessed the variant were more likely to have a family history of prostate cancer than those who did not (46.0 vs 35.4%; P = 0.006). G84E carriers were also more likely to be diagnosed at a younger age than non-carriers (55.2 years vs 58.1 years; P < 0.001). No difference in the proportion of patients diagnosed with high grade or advanced stage tumours according to carrier status was observed. CONCLUSIONS: In the present study, carriers of the rare G84E variant in HOXB13 were both younger at the time of diagnosis and more likely to have a family history of prostate cancer compared with homozygotes for the wild-type allele. No significant differences in allele frequency were detected according to selected clinical characteristics of prostate cancer. Further investigation is required to evaluate the role of HOXB13 in prostate carcinogenesis.

Outcomes of men with an elevated prostate-specific antigen (PSA) level as their sole preoperative intermediate- or high-risk feature.

OBJECTIVE: To investigate the post-prostatectomy and long-term outcomes of men presenting with an elevated pretreatment prostate-specific antigen (PSA) level (>10 ng/mL), but otherwise low-risk features (biopsy Gleason score ≤6 and clinical stage ≤T2a). PATIENTS AND METHODS: PSA-incongruent intermediate-risk (PII) cases were defined as those patients with preoperative PSA >10 and ≤20 ng/mL but otherwise low-risk features, and PSA-incongruent high-risk (PIH) cases were defined as men with PSA >20 ng/mL but otherwise low-risk features. Our institutional radical prostatectomy database (1992-2012) was queried and the results were stratified into D'Amico low-, intermediate- and high risk, PSA-incongruent intermediate-risk and PSA-incongruent high-risk cases. Prostate cancer (PCa) features and outcomes were evaluated using appropriate comparative tests. Multivariable analyses were adjusted for age, race and year of surgery. RESULTS: Of the total cohort of 17 608 men, 1132 (6.4%) had PII-risk disease and 183 (1.0%) had PIH-risk disease. Compared with the low-risk group, the odds of upgrading at radical prostatectomy (RP) were 2.20 (95% CI 1.93-2.52; P < 0.001) for the PII group and 3.58 (95% CI 2.64-4.85; P < 0.001) for the PIH group, the odds of extraprostatic disease at RP were 2.35 (95% CI 2.05-2.68; P < 0.001) for the PII group and 6.68 (95% CI 4.89-9.15; P < 0.001) for the PIH group, and the odds of positive surgical margins were 1.97 (95% CI 1.67-2.33; P < 0.001) for the PII group and 3.54 (95% CI 2.50-4.95, P < 0.001) for the PIH group. Compared with low-risk disease, PII-risk disease was associated with a 2.85-, 2.99- and 3.32-fold greater risk of biochemical recurrence (BCR), metastasis and PCa-specific mortality, respectively, and PIH-risk disease was associated with a 5.32-, 6.14- and 7.07-fold greater risk of BCR, metastasis and PCa-specific mortality, respectively (P ≤ 0.001 for all comparisons). For the PII group, the higher risks of positive surgical margins, upgrading, upstaging and BCR were dependent on PSA density (PSAD): men in the PII group who had a PSAD <0.15 ng/mL/g were not at higher risk compared with those in the low-risk group. Men in the PII group with a PSAD ≥0.15 ng/mL/g and men in the PIH group were more likely to have an anterior component of the dominant tumour (59 and 64%, respectively) compared with those in the low- (35%) and intermediate-risk group (39%) and those in the PII-risk group with PSAD <0.15 ng/mL/g (29%). CONCLUSIONS: Men with PSA >20 ng/mL or men with PSA >10 and ≤20 ng/mL with a PSAD ≥0.15 ng/mL/g, but otherwise low-risk PCa, are at greater risk of adverse pathological and oncological outcomes and may be inappropriate candidates for active surveillance. These men are at greater risk of having anterior tumours that are undersampled at biopsy, so if treatment is deferred, ancillary testing such as anterior zone sampling or magnetic resonance imaging should be strongly encouraged. Men with elevated PSA levels >10 and ≤20 ng/mL but low PSAD have outcomes similar to those in the low-risk group, and consideration of surveillance is appropriate in these cases.

An updated prostate cancer staging nomogram (Partin tables) based on cases from 2006 to 2011.

OBJECTIVE: To update the 2007 Partin tables in a contemporary patient population. PATIENTS AND METHODS: The study population consisted of 5,629 consecutive men who underwent RP and staging lymphadenectomy at the Johns Hopkins Hospital between January 1, 2006 and July 30, 2011 and met inclusion criteria. Polychotomous logistic regression analysis was used to predict the probability of each pathologic stage category: organ-confined disease (OC), extraprostatic extension (EPE), seminal vesicle involvement (SV+), or lymph node involvement (LN+) based on preoperative criteria. Preoperative variables included biopsy Gleason score (6, 3+4, 4+3, 8, and 9-10), serum PSA (0-2.5, 2.6-4.0, 4.1-6.0, 6.1-10.0, greater than 10.0 ng/mL), and clinical stage (T1c, T2c, and T2b/T2c). Bootstrap re-sampling with 1000 replications was performed to estimate 95% confidence intervals for predicted probabilities of each pathologic state. RESULTS: The median PSA was 4.9 ng/mL, 63% had Gleason 6 disease, and 78% of men had T1c disease. 73% of patients had OC disease, 23% had EPE, 3% had SV+ but not LN+, and 1% had LN+ disease. Compared to the previous Partin nomogram, there was no change in the distribution of pathologic state. The risk of LN+ disease was significantly higher for tumours with biopsy Gleason 9-10 than Gleason 8 (O.R. 3.2, 95% CI 1.3-7.6). The c-indexes for EPE vs. OC, SV+ vs. OC, and LN+ vs. OC were 0.702, 0.853, and 0.917, respectively. Men with biopsy Gleason 4+3 and Gleason 8 had similar predicted probabilities for all pathologic stages. Most men presenting with Gleason 6 disease or Gleason 3+4 disease have <2% risk of harboring LN+ disease and may have lymphadenectomy omitted at RP. CONCLUSIONS: The distribution of pathologic stages did not change at our institution between 2000-2005 and 2006-2011. The updated Partin nomogram takes into account the updated Gleason scoring system and may be more accurate for contemporary patients diagnosed with prostate cancer.

Causes of death after radical prostatectomy at a large tertiary center.

PURPOSE: Most men treated with radical prostatectomy do not die of prostate cancer. We evaluated the cause of death in a large series of patients who underwent radical prostatectomy and compared the rate of death to that of the general American population. MATERIALS AND METHODS: The study population consisted of 18,209 men who underwent radical prostatectomy at our institution between 1975 and 2009. Close patient followup and a national database were used to identify which patients died and classify the cause of death. These data were compared with general American population data from the National Vital Statistics System. RESULTS: Median age at radical prostatectomy was 59 years (IQR 54.0-63.0). At a median followup of 7.4 years (IQR 3.7-11.9) 1,419 patients had died (7.8%), including 379 of prostate cancer. Actuarial 10 and 20-year overall survival rates after radical prostatectomy were 92.6% and 69.2%, respectively. The overall death rate was lower in men treated with radical prostatectomy than in the general American population (standardized mortality ratio 0.47, 95% CI 0.44-0.49). Differences were particularly pronounced for heart disease, chronic respiratory conditions, diabetes and infection. Of men who died of a nonprostate cancer cause 44.0% died of a secondary malignancy. CONCLUSIONS: Overall survival after radical prostatectomy is excellent. Men who undergo radical prostatectomy usually die of a nonprostate cancer cause. Almost half of patients who survive prostate cancer die of a secondary malignancy, likely due to the selection of surgical candidates at low cardiopulmonary risk.

The natural history of metastatic progression in men with prostate-specific antigen recurrence after radical prostatectomy: long-term follow-up.

OBJECTIVE: To describe metastasis-free survival (MFS) in men with prostate-specific antigen (PSA) recurrence following radical prostatectomy, and to define clinical prognostic factors modifying metastatic risk. PATIENTS AND METHODS: We conducted a retrospective analysis of 450 men treated with prostatectomy at a tertiary hospital between July 1981 and July 2010 who developed PSA recurrence (≥0.2 ng/mL) and never received adjuvant or salvage therapy before the development of metastatic disease. We estimated MFS using the Kaplan-Meier method, and investigated factors influencing the risk of metastasis using Cox proportional hazards regression. RESULTS: Median follow-up after prostatectomy was 8.0 years, and after biochemical recurrence was 4.0 years. At last follow-up, 134 of 450 patients (29.8%) had developed metastases, while median MFS was 10.0 years. Using multivariable regressions, two variables emerged as independently predictive of MFS: PSA doubling time (<3.0 vs 3.0-8.9 vs 9.0-14.9 vs ≥15.0 months) and Gleason score (≤6 vs 7 vs 8-10). Using these stratifications of Gleason score and PSA doubling time, tables were constructed to predict median, 5- and 10-year MFS after PSA recurrence. In different patient subsets, median MFS ranged from 1 to 15 years. CONCLUSIONS: In men undergoing prostatectomy, MFS after PSA recurrence is variable and is most strongly influenced by PSA doubling time and Gleason score. These parameters serve to stratify men into different risk groups with respect to metastatic progression. Our findings may provide the background for appropriate selection of patients, treatments and endpoints for clinical trials.

Can we stop prostate specific antigen testing 10 years after radical prostatectomy?

PURPOSE: The risk of biochemical recurrence is inversely related to the relapse-free interval after radical prostatectomy. We examined predictors of late biochemical recurrence, and the relationship between timing of biochemical recurrence and long-term survival outcomes. MATERIALS AND METHODS: Of 10,609 men treated with radical prostatectomy 1,684 had biochemical recurrence. We examined predictors of late biochemical recurrence (more than 10 years after radical prostatectomy), and calculated metastasis-free and cancer specific survival rates from the time of biochemical recurrence. In the subset of 1,583 men with an undetectable prostate specific antigen at 10 years we calculated actuarial metastasis-free and cancer specific survival estimates at 20 years after radical prostatectomy. RESULTS: Of the biochemical recurrence studied 77.0%, 16.6%, 4.9% and 1.5% occurred at 5 or less, greater than 5 to 10, greater than 10 to 15 and more than 15 years postoperatively. Late recurrence was associated with more favorable pathological features, as well as higher metastasis-free and cancer specific survival rates. For men with an undetectable prostate specific antigen at 10 years the actuarial probability of biochemical recurrence and metastasis at 20 years varied by stage and grade, with no metastases in patients with a prostatectomy Gleason score 6 or less. A single patient with an undetectable prostate specific antigen at 10 years died of prostate cancer within 20 years after radical prostatectomy. CONCLUSIONS: Men with an undetectable prostate specific antigen for more than 10 years have a low risk of subsequent biochemical recurrence, with correspondingly lower rates of metastasis and death. These patients should be counseled that their risk of subsequent cancer related morbidity and mortality is low. Furthermore, these results suggest that annual prostate specific antigen testing may be safely discontinued after 10 years for men with a prostatectomy Gleason score 6 or less and/or limited life expectancy.

Association of statin use with pathological tumor characteristics and prostate cancer recurrence after surgery.

PURPOSE: Prospective studies suggest that statins protect against advanced stage and possibly high grade prostate cancer. However, few studies have investigated the influence of stains on outcomes in men with prostate cancer. Thus, we evaluated the association of statin use with pathological tumor characteristics and prostate cancer recurrence after prostatectomy in a retrospective cohort. MATERIALS AND METHODS: A total of 2,399 patients of 1 surgeon at Johns Hopkins Hospital who underwent radical prostatectomy in 1993 to 2006 and had not previously received hormone or radiation therapy were followed for recurrence. The surgeon routinely asked during the preoperative consultation what medications the men were using. Additional information on statin use was obtained from a mailed survey. We estimated the association of statin use with nonorgan confined disease (pT3a/b or N1) and high grade disease (Gleason sum [4 + 3] or greater) using logistic regression (OR), and recurrence using Cox proportional hazards regression (HR). RESULTS: The 16.1% of men who used a statin at prostatectomy were statistically significantly less likely to have nonorgan confined disease than nonusers (OR 0.66, 95% CI 0.50-0.85). Statin use was inversely associated with high grade disease only in men with preoperative PSA 10 ng/ml or greater (OR 0.35, 95% CI 0.13-0.93, p-interaction = 0.02). The HR of recurrence among men who used a statin for 1 year or greater compared to nonusers was 0.77 (95% CI 0.41-1.42). CONCLUSIONS: Our findings support the hypothesis that statin use may protect against prostate cancer with poorer pathological characteristics. We could not rule in or out that longer term statin use may protect against recurrence after prostatectomy.

Impact of surgical technique (open vs laparoscopic vs robotic-assisted) on pathological and biochemical outcomes following radical prostatectomy: an analysis using propensity score matching.

OBJECTIVE: • To investigate a single institution experience with radical retropubic prostatectomy (RRP), laparoscopic radical prostatectomy (LRP) and robot-assisted radical prostatectomy (RARP) with respect to pathological and biochemical outcomes. PATIENTS AND METHODS: • A group of 522 consecutive patients who underwent RARP between 2003 and 2008 were matched by propensity scoring on the basis of patient age, race, preoperative prostate-specific antigen (PSA), biopsy Gleason score and clinical stage with an equal number of patients who underwent LRP and RRP at our institution. • Pathological and biochemical outcomes of the three cohorts were examined. RESULTS: • Overall positive surgical margin rates were lower among patients who underwent RRP (14.4%) and LRP (13.0%) compared to patients who underwent RARP (19.5%) (P= 0.010). There were no statistically significant differences in positive margin rates between the three surgical techniques for pT2 disease (P= 0.264). • In multivariate logistic regression analysis, surgical technique (P= 0.016), biopsy Gleason score (P < 0.001) and preoperative PSA (P < 0.001) were predictors of positive surgical margins. • Kaplan-Meier analysis did not show any statistically significant differences with respect to biochemical recurrence for the three surgical groups. CONCLUSIONS: • RRP, LRP and RARP represent effective surgical approaches for the treatment for clinically localized prostate cancer. A higher overall positive SM rate was observed for the RARP group compared to RRP and LRP; however, there was no difference with respect to biochemical recurrence-free survival between groups. • Further prospective studies are warranted to determine whether any particular technique is superior with regard to long-term clinical outcomes.

Prostate specific antigen at the initial diagnosis of metastasis to bone in patients after radical prostatectomy.

PURPOSE: Among men with biochemical progression after radical prostatectomy little is known about prostate specific antigen at the time of metastasis to bone in hormone naïve patients. This information would be useful in determining when to initiate androgen deprivation therapy. MATERIALS AND METHODS: From a large radical prostatectomy series we identified 193 hormone naïve men in whom bone metastases developed at a mean of 6 years postoperatively. We examined the prostate specific antigen distribution at bone scan conversion by time from radical prostatectomy to metastasis. ANOVA and linear regression were also used to examine the association of clinicopathological tumor features with prostate specific antigen at bone metastasis. RESULTS: Median prostate specific antigen was 31.9 ng/ml at the initial diagnosis of metastatic disease. Bone scan conversion occurred at a prostate specific antigen of less than 10, 10 to 100 and greater than 100 ng/ml in 50 (25.9%), 98 (50.8%) and 45 (23.3%) men, respectively. Lower prostate specific antigen at diagnosis, higher prostatectomy Gleason scores and shorter time to metastasis were associated with lower prostate specific antigen at bone metastasis, whereas prostate specific antigen at metastasis was not significantly associated with other clinicopathological features. CONCLUSIONS: Prostate specific antigen at the time of bone scan detected metastasis is highly variable. Unlike the pretreatment setting when metastases are rare at a prostate specific antigen of less than 10 ng/ml, 25.9% of bone metastases after radical prostatectomy occurred at a prostate specific antigen of less than 10 ng/ml. Because metastasis may occur at a low prostate specific antigen, patients with biochemical progression managed expectantly need regular bone scans even if prostate specific antigen is low to detect metastasis before symptoms.

Does perineural invasion on prostate biopsy predict adverse prostatectomy outcomes?

OBJECTIVE: To determine the relationship between perineural invasion (PNI) on prostate biopsy and radical prostatectomy (RP) outcomes in a contemporary RP series, as there is conflicting evidence on the prognostic significance of PNI in prostate needle biopsy specimens. PATIENTS AND METHODS: From 2002 to 2007, 1256 men had RP by one surgeon. Multivariable logistic regression and Cox proportional hazards models were used to examine the relationship of PNI with pathological tumour features and biochemical progression, respectively, after adjusting for prostate-specific antigen level, clinical stage and biopsy Gleason score. Additional Cox models were used to examine the relationship between nerve-sparing and biochemical progression among men with PNI. RESULTS: PNI was found in 188 (15%) patients, and was significantly associated with aggressive pathology and biochemical progression. On multivariate analysis, PNI was significantly associated with extraprostatic extension and seminal vesicle invasion (P < 0.001). Biochemical progression occurred in 10.5% of patients with PNI, vs 3.5% of those without PNI (unadjusted hazard ratio 3.12, 95% confidence interval 1.77-5.52, P < 0.001). However, PNI was not a significant independent predictor of biochemical progression on multivariate analysis. Finally, nerve-sparing did not adversely affect biochemical progression even among men with PNI. CONCLUSION: PNI is an independent risk factor for aggressive pathology features and a non-independent risk factor for biochemical progression after RP. However, bilateral nerve-sparing surgery did not compromise the oncological outcomes for patients with PNI on biopsy.

The impact of preoperative erectile dysfunction on survival after radical prostatectomy.

PURPOSE: Erectile dysfunction (ED) and cardiovascular disease (CVD) share etiology and pathophysiology. The underlying pathology for preoperative ED may adversely affect survival following radical prostatectomy (RP). We examined the association between preoperative ED and survival following RP. MATERIALS AND METHODS: Between 1983 and 2000, a single surgeon performed RP on 2511 men, with preoperative ED (ED group, n= 231, 9.2%) or without ED (No ED group, n= 2280, 90.8%). We retrospectively analysed their CVD-specific survival (CVDSS), prostate cancer-specific survival (PCSS), non-PCSS (NPCSS) and overall survival (OS) from time of surgery. RESULTS: With median follow-up of 13 years after RP, 449 men (18%) died (140 from prostate cancer, 309 from other causes). Kaplan-Meier analyses demonstrated significant differences in CVDSS (P < 0.001), NPCSS (P < 0.001) and OS (P < 0.001), but not in PCSS (P= 0.12), between the ED group vs No ED group. In univariate proportional hazards analyses, preoperative ED was associated with a significant decrease in OS, hazard ratio (HR), 1.71 (95% CI, 1.34-2.23), P < 0.001. However, in multivariable analyses, the association of ED with survival became non-significant (HR, 1.25 (95% CI, 0.97-1.66), P= 0.111) after adjusting for other prognostic factors, such as age, preoperative prostate-specific antigen (PSA) level, Gleason score, pathologic stage, body mass index and Charlson Comorbidity Index. CONCLUSIONS: Preoperative ED is associated with decreased overall survival and survival from causes other than prostate cancer following RP. However, preoperative ED was not an independent predictor of overall survival after adjusting for other predictors of survival. Urologists should carefully assess pretreatment ED status to enhance appropriate treatment recommendation for men with prostate cancer.

Benign prostate glands at the bladder neck margin in robotic vs open radical prostatectomy.

OBJECTIVE: To compare the prevalence and extent of benign glands at the bladder neck (BN) margin in a large population undergoing open retropubic radical prostatectomy (RRP) and robotic-assisted laparoscopic RP (RALP), as RALP was previously suggested to be associated with a higher rate of benign glands at the surgical margin than RRP. PATIENTS AND METHODS: From 2005 to 2008, 137 RRP and 152 RALP were performed by one surgeon. Pathology slides were re-reviewed while unaware of origin to examine the extent of benign glands at the BN margin (minimal, moderate, or extensive). Statistical analysis was used to assess the prevalence and extent of benign glands in the two procedures. RESULTS: Benign prostatic glands were present at the margins in 89 (58.2%) RALP and 57 (41.6%) RRP specimens (P= 0.005). There were also a significantly greater extent of benign glands in RALP vs RRP (P= 0.031). After multivariate adjustment for prostate-specific antigen (PSA) level, clinical stage, and biopsy Gleason score, RALP maintained a significant association with both the presence (P= 0.019) and extent (P= 0.018) of benign glands at the BN. Two patients with organ-confined disease (no cancerous margins) with benign glands at the BN margin had an initially high postoperative PSA level. CONCLUSIONS: Benign prostate glands were present at the BN margin in a greater proportion of RALP than RRP specimens, possibly due to differences in the surgical approach to BN dissection. Additional study is necessary to determine the long-term biological significance, if any, of these histological differences.

Predicting the outcome of prostate biopsy: comparison of a novel logistic regression-based model, the prostate cancer risk calculator, and prostate-specific antigen level alone.

OBJECTIVES: To develop a logistic regression-based model to predict prostate cancer biopsy at, and compare its performance to the risk calculator developed by the Prostate Cancer Prevention Trial (PCPT), which was based on age, race, prostate-specific antigen (PSA) level, a digital rectal examination (DRE), family history, and history of a previous negative biopsy, and to PSA level alone. PATIENTS AND METHODS: We retrospectively analysed the data of 1280 men who had a biopsy while enrolled in a prospective, multicentre clinical trial. Of these, 1108 had all relevant clinical and pathological data available, and no previous diagnosis of prostate cancer. Using the PCPT risk calculator, we calculated the risks of prostate cancer and of high-grade disease (Gleason score > or =7) for each man. Receiver operating characteristic (ROC) curves for the risk calculator, PSA level and the novel regression-based model were compared. RESULTS: Prostate cancer was detected in 394 (35.6%) men, and 155 (14.0%) had Gleason > or =7 disease. For cancer prediction, the area under the ROC curve (AUC) for the risk calculator was 66.7%, statistically greater than the AUC for PSA level of 61.9% (P < 0.001). For predicting high-grade disease, the AUCs were 74.1% and 70.7% for the risk calculator and PSA level, respectively (P = 0.024). The AUCs increased to 71.2% (P < 0.001) and 78.7% (P = 0.001) for detection and high-grade disease, respectively, with our novel regression-based models. CONCLUSIONS: ROC analyses show that the PCPT risk calculator modestly improves the performance of PSA level alone in predicting an individual's risk of prostate cancer or high-grade disease on biopsy. This predictive tool might be enhanced by including percentage free PSA and the number of biopsy cores.

Prostate specific antigen versus prostate specific antigen density as a prognosticator of pathological characteristics and biochemical recurrence following radical prostatectomy.

PURPOSE: The usefulness of prostate specific antigen density for predicting pathological stage and biochemical recurrence after radical prostatectomy has not been well defined. We investigated whether prostate specific antigen density yielded an advantage over total prostate specific antigen for predicting adverse pathological characteristics and disease recurrence following radical prostatectomy. MATERIALS AND METHODS: A total of 13,434 men who underwent radical prostatectomy for clinically localized prostate cancer between 1984 and 2006 were included in this study. The study population was stratified by Gleason score (6 or less, 7, and 8 or greater), and the clinical and pathological characteristics of each group were compared. We constructed ROC curves and determined the ROC AUC and concordance index to specifically investigate the accuracy of prostate specific antigen and prostate specific antigen density for predicting pathological stage and biochemical recurrence. RESULTS: Prostate specific antigen density was better than prostate specific antigen for predicting extraprostatic extension and biochemical-free recurrence in patients with a biopsy Gleason score of 6 or less (each p <0.001). In patients with a biopsy Gleason score of 7 prostate specific antigen was more predictive than prostate specific antigen density for seminal vesicle involvement (p <0.001), lymph node involvement (p = 0.017) and biochemical-free recurrence (p <0.001). In men with a biopsy Gleason score of 8 or greater there was no statistical difference between prostate specific antigen and prostate specific antigen density in terms of prognostic value for pathological or clinical outcomes. CONCLUSIONS: Prostate specific antigen density is highly associated with pathological stage and biochemical-free survival following radical prostatectomy. In lower grade prostate cancers prostate specific antigen density is significantly more accurate for predicting extraprostatic extension and biochemical-free recurrence compared to total prostate specific antigen. It should be considered when counseling patients on outcomes following radical prostatectomy.

The natural history of men treated with deferred androgen deprivation therapy in whom metastatic prostate cancer developed following radical prostatectomy.

PURPOSE: We report on the natural history and factors influencing the prognosis of a cohort of hormone naïve, prostate specific antigen era patients in whom metastatic prostate cancer developed after radical prostatectomy who were followed closely and treated with deferred androgen deprivation therapy at the time of metastasis. MATERIALS AND METHODS: A total of 3,096 men underwent radical prostatectomy performed by a single surgeon at Johns Hopkins Hospital between 1987 and 2005. Of these men 422 had prostate specific antigen failure. Distant metastasis developed in 123 patients, of whom 91 with complete data formed the study cohort initially treated during the prostate specific antigen era (1987 to 2005) and receiving androgen deprivation therapy after documented metastasis. A total of 41 men died of prostate cancer. Median survival times were estimated by Kaplan-Meier analysis. Prognostic impact was estimated as the hazard ratio derived from the Cox proportional hazards model. RESULTS: Median followup from radical prostatectomy was 120 months (range 24 to 216). Kaplan-Meier median (range) times to failure were 24 months (12 to 144) from radical prostatectomy to prostate specific antigen failure, 36 months (0 to 132) from prostate specific antigen failure to metastasis, 84 months (12 to 180) from metastasis to death and 168 months (24 to 216) from radical prostatectomy to death. Statistically significant univariate risk factors for prostate cancer specific mortality at the time of metastasis were pain at diagnosis of metastases (p = 0.002), time from radical prostatectomy to metastasis (p = 0.024) and prostate specific antigen doubling time less than 3 months during the 24 months before metastasis (p = 0.016). Multivariable analysis demonstrated independent predictors of prostate cancer specific mortality at the time of metastasis, namely pain (HR 3.5, p = 0.003) and prostate specific antigen doubling time less than 3 months (HR 3.4, p = 0.017). CONCLUSIONS: Men treated with deferred androgen deprivation therapy for the development of metastasis after radical prostatectomy may have a long life span, 169 months after radical prostatectomy (range 24 to 216). The presence of pain and short prostate specific antigen doubling time predicted an unfavorable outcome.

Progression after radical prostatectomy for men in their thirties compared to older men.

OBJECTIVE: To assess the biochemical outcome after radical prostatectomy (RP) specifically for men aged 30-39 years, as previous studies suggest that prostate cancer in young men might be more aggressive. PATIENTS AND METHODS: From a large (15 899) database of RPs (1975-2007) we identified 42 men aged 30-39, 893 aged 40-49, 4085 aged 50-59, 3766 aged 60-69, and 182 men aged > or =70 years old. The clinical characteristics and treatment outcomes were compared between men aged 30-39 years and older men. RESULTS: Among the men in their thirties, 81% had organ-confined disease in the RP specimen, vs 62% of men aged > or =40 years. At a mean follow-up of 5 years, there was biochemical progression in 4.8% of men in their thirties and 16.1% of men age > or =40 years (P = 0.055). The corresponding 5-year biochemical progression-free survival estimates were 95% for men in their thirties and 83% for men aged > or =40 years (P = 0.045). On multivariate analysis, increasing age was a significant independent predictor of biochemical progression. CONCLUSION: Contrary to earlier reports, in the present study men in their thirties did not have more aggressive disease. Instead, they had more favourable pathological features and progression-free survival rates than their older counterparts. After controlling for other prognostic variables on multivariate analysis, being in the fourth decade was independently associated with a lower risk of biochemical progression. These results suggest that early aggressive treatment for these patients with a long life-expectancy is associated with favourable long-term biochemical outcomes.

Prostate cancer-specific survival following salvage radiotherapy vs observation in men with biochemical recurrence after radical prostatectomy.

CONTEXT: Biochemical disease recurrence after radical prostatectomy often prompts salvage radiotherapy, but no studies to date have had sufficient numbers of patients or follow-up to determine whether radiotherapy improves survival, and if so, the subgroup of men most likely to benefit. OBJECTIVES: To quantify the relative improvement in prostate cancer-specific survival of salvage radiotherapy vs no therapy after biochemical recurrence following prostatectomy, and to identify subgroups for whom salvage treatment is most beneficial. DESIGN, SETTING, AND PATIENTS: Retrospective analysis of a cohort of 635 US men undergoing prostatectomy from 1982-2004, followed up through December 28, 2007, who experienced biochemical and/or local recurrence and received no salvage treatment (n = 397), salvage radiotherapy alone (n = 160), or salvage radiotherapy combined with hormonal therapy (n = 78). MAIN OUTCOME MEASURE: Prostate cancer-specific survival defined from time of recurrence until death from disease. RESULTS: With a median follow-up of 6 years after recurrence and 9 years after prostatectomy, 116 men (18%) died from prostate cancer, including 89 (22%) who received no salvage treatment, 18 (11%) who received salvage radiotherapy alone, and 9 (12%) who received salvage radiotherapy and hormonal therapy. Salvage radiotherapy alone was associated with a significant 3-fold increase in prostate cancer-specific survival relative to those who received no salvage treatment (hazard ratio [HR], 0.32 [95% confidence interval {CI}, 0.19-0.54]; P<.001). Addition of hormonal therapy to salvage radiotherapy was not associated with any additional increase in prostate cancer-specific survival (HR, 0.34 [95% CI, 0.17-0.69]; P = .003). The increase in prostate cancer-specific survival associated with salvage radiotherapy was limited to men with a prostate-specific antigen doubling time of less than 6 months and remained after adjustment for pathological stage and other established prognostic factors. Salvage radiotherapy initiated more than 2 years after recurrence provided no significant increase in prostate cancer-specific survival. Men whose prostate-specific antigen level never became undetectable after salvage radiotherapy did not experience a significant increase in prostate cancer-specific survival. Salvage radiotherapy also was associated with a significant increase in overall survival. CONCLUSIONS: Salvage radiotherapy administered within 2 years of biochemical recurrence was associated with a significant increase in prostate cancer-specific survival among men with a prostate-specific antigen doubling time of less than 6 months, independent of other prognostic features such as pathological stage or Gleason score. These preliminary findings should be validated in other settings, and ultimately, in a randomized controlled trial.

Utility of Risk Models in Decision Making After Radical Prostatectomy: Lessons from a Natural History Cohort of Intermediate- and High-Risk Men.

BACKGROUND: Current guidelines suggest adjuvant radiation therapy for men with adverse pathologic features (APFs) at radical prostatectomy (RP). We examine at-risk men treated only with RP until the time of metastasis. OBJECTIVE: To evaluate whether clinicopathologic risk models can help guide postoperative therapeutic decision making. DESIGN, SETTING, AND PARTICIPANTS: Men with National Comprehensive Cancer Network intermediate- or high-risk localized prostate cancer undergoing RP in the prostate-specific antigen (PSA) era were identified (n=3089). Only men with initial undetectable PSA after surgery and who received no therapy prior to metastasis were included. APFs were defined as pT3 disease or positive surgical margins. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Area under the receiver operating characteristic curve (AUC) for time to event data was used to measure the discrimination performance of the risk factors. Cumulative incidence curves were constructed using Fine and Gray competing risks analysis to estimate the risk of biochemical recurrence (BCR) or metastasis, taking censoring and death due to other causes into consideration. RESULTS AND LIMITATIONS: Overall, 43% of the cohort (n=1327) had APFs at RP. Median follow-up for censored patients was 5 yr. Cumulative incidence of metastasis was 6% at 10 yr after RP for all patients. Cumulative incidence of metastasis among men with APFs was 7.5% at 10 yr after RP. Among men with BCR, the incidence of metastasis was 38% 5 yr after BCR. At 10 yr after RP, time-dependent AUC for predicting metastasis by Cancer of the Prostate Risk Assessment Postsurgical or Eggener risk models was 0.81 (95% confidence interval [CI], 0.72-0.97) and 0.78 (95% CI, 0.67-0.97) in the APF population, respectively. At 5 yr after BCR, these values were lower (0.58 [95% CI, 0.50-0.66] and 0.70 [95% CI, 0.63-0.76]) among those who developed BCR. Use of risk model cut points could substantially reduce overtreatment while minimally increasing undertreatment (ie, use of an Eggener cut point of 2.5% for treatment of men with APFs would spare 46% from treatment while only allowing for metastatic events in 1% at 10 yr after RP). CONCLUSIONS: Use of risk models reduces overtreatment and should be a routine part of patient counseling when considering adjuvant therapy. Risk model performance is significantly reduced among men with BCR. PATIENT SUMMARY: Use of current risk models can help guide decision making regarding therapy after surgery and reduce overtreatment.

Tissue-based Genomics Augments Post-prostatectomy Risk Stratification in a Natural History Cohort of Intermediate- and High-Risk Men.

BACKGROUND: Radical prostatectomy (RP) is a primary treatment option for men with intermediate- and high-risk prostate cancer. Although many are effectively cured with local therapy alone, these men are by definition at higher risk of adverse pathologic features and clinical disease recurrence. It has been shown that the Decipher test predicts metastatic progression in cohorts that received adjuvant and salvage therapy following RP. OBJECTIVE: To evaluate the Decipher genomic classifier in a natural history cohort of men at risk who received no additional treatment until the time of metastatic progression. DESIGN, SETTING, AND PARTICIPANTS: Retrospective case-cohort design for 356 men who underwent RP between 1992 and 2010 at intermediate or high risk and received no additional treatment until the time of metastasis. Participants met the following criteria: (1) Cancer of the Prostate Risk Assessment postsurgical (CAPRA-S) score ≥3; (2) pathologic Gleason score ≥7; and (3) post-RP prostate-specific antigen nadir <0.2 ng/ml. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was defined as regional or distant metastases. Time-dependent receiver operating characteristic (ROC) curves, extension of decision curve analysis to survival data, and univariable and multivariable Cox proportional-hazards models were used to measure the discrimination, net benefit, and prognostic potential of genomic and pathologic risk factors. Cumulative incidence curves were constructed using Fine-Gray competing-risks analysis with appropriate weighting of the controls to account for the case-cohort study design. RESULTS AND LIMITATIONS: Ninety six patients had unavailable tumor blocks or failed microarray quality control. Decipher scores were then obtained for 260 patients, of whom 99 experienced metastasis. Decipher correlated with increased cumulative incidence of biochemical recurrence, metastasis, and prostate cancer-specific mortality (p<0.01). The cumulative incidence of metastasis was 12% and 47% for patients with low and high Decipher scores, respectively, at 10 yr after RP. Decipher was independently prognostic of metastasis in multivariable analysis (hazard ratio 1.26 per 10% increase; p<0.01). Decipher had a c-index of 0.76 and increased the c-index of Eggener and CAPRA-S risk models from 0.76 and 0.77 to 0.86 and 0.87, respectively, at 10 yr after RP. Although the cohort was large, the single-center retrospective design is an important limitation. CONCLUSIONS: In a patient population that received no adjuvant or salvage therapy after prostatectomy until metastatic progression, higher Decipher scores correlated with clinical events, and inclusion of Decipher scores improved the prognostic performance of validated clinicopathologic risk models. These results confirm the utility already reported for Decipher. PATIENT SUMMARY: The Decipher test improves identification of patients most at risk of metastatic progression and death from prostate cancer after radical prostatectomy.