Analysis of T1c prostate cancers treated at very low prostate-specific antigen levels

Background

The Prostate Cancer Prevention Trial (PCPT) has challenged the validity of recommended prostate-specific antigen (PSA) thresholds for prostate biopsy (>2.5 ng/ml) given the 17% prostate cancer (pCA) detection rate at PSA of 1.1–2.0. The outcome of patients treated at PSA ≤2.5 is poorly defined, and advantages associated with such an early diagnosis are uncertain.

Objective

Compare the outcome of patients with T1c pCA with pretreatment PSA ≤2.5 and 2.6–4.0.

Design, setting, and participants

Since 1998, 351 patients with clinical stage T1c and PSA ≤4.0 have been treated at our institution; 84 (24%) of those patients had PSA ≤2.5. Clinical information was obtained from a prospective database. Treatment was radical prostatectomy (RP), brachytherapy, and external-beam radiotherapy (EBRT) in 261 (74%), 67 (19%), and 23 (7%) patients, respectively.

Intervention

Definitive therapy for clinically localized pCA.

Measurements

Progression-free probability and pathologic end points.

Results and limitations

No significant differences between the groups were observed in terms of biopsy (18% vs 22%) or specimen Gleason score 7–8 (44% vs 56%), non–organ-confined cancer (11% vs 13%), indolent cancer (34% vs 24%), or 5-yr progression-free probability (89% vs 93%; p > 0.1 for all). More biologically unimportant cancers (defined as pathologically organ-confined and Gleason ≤6) were identified among patients with PSA ≤2.5 (55% vs 41%, p = 0.050), and indolent cancers were three times more frequent than non–organ-confined cancers among these patients (p = 0.003).

Conclusions

The pathologic features and outcome of patients treated at low PSA levels are favorable and similar for patients with PSA ≤2.5 versus 2.6–4.0. However, >50% of the former have potentially biologically unimportant cancer. We failed to identify a therapeutic benefit to the diagnosis of cancers below accepted PSA thresholds for biopsy.     

Outcomes of men with screen-detected prostate cancer eligible for active surveillance who were managed expectantly

Background

The incidence of small, localised, well-differentiated prostate cancer (PCa) is increasing, mainly as a result of screening. Many of these cancers will not progress, and radical therapy may lead to substantial overtreatment. Active surveillance (AS) has emerged as an alternative.

Objective

To retrospectively validate the currently used criteria for eligibility for AS.

Design, setting, and participants

For this cohort study, data from 616 men who were diagnosed with PCa between 1994 and 2007 at a mean age of 66.3 yr in four centres of the European Randomized Study of Screening for Prostate Cancer (ERSPC) were combined. All patients fit the criteria for AS (prostate-specific antigen [PSA] ≤10.0 ng/ml, PSA-density <0.2 ng/ml per ml, stage T1C/T2, Gleason score ≤3 + 3 = 6, and ≤2 positive biopsy cores), and initially they were managed expectantly. Median follow-up was 3.91 yr.

Measurements

Disease specific-, overall-, and treatment-free survival were studied. Present PSA characteristics were assessed and also compared between men who were switching to deferred active therapy during follow-up and men remaining untreated.

Results and limitations

The calculated (Kaplan-Meier) 10-yr PCa-specific survival (21 patients at risk) was 100%, which sharply contrasted with 77% overall survival. Men still alive showed favourable PSA characteristics. Although the calculated 10-yr treatment-free survival was only 43%, objective signs of progression often did not indicate the shift to radical treatment. The cohort consisted of men on AS and those on watchful waiting (WW); information on comorbidity or psychological distress was not available.

Conclusions

AS seems justified in selected men with screen-detected PCa. Prospective protocol-based AS programs are necessary to optimise selection criteria and to find the appropriate trigger points for switching to active therapy. Possible negative psychological reactions with AS against improved quality of life by withholding side-effects from radical treatment should be considered.     

Prostate cancer antigen 3 score accurately predicts tumour volume and might help in selecting prostate cancer patients for active surveillance

Background

The optimal selection of prostate cancer (PCa) patients for active surveillance (AS) is currently being debated.

Objective

To assess the impact of urinary prostate cancer antigen 3 (PCA3) score as an AS criterion instead of and in addition to the current criteria.

Design, setting, and participants

We prospectively studied 106 consecutive low-risk PCa patients (prostate-specific antigen [PSA] ≤10 ng/ml, clinical stage T1c–T2a, and biopsy Gleason score 6) who underwent a PCA3 urine test before radical prostatectomy (RP).

Measurements

Performance of AS criteria (biopsy criteria, PCA3 score, PSA density, and magnetic resonance imaging [MRI] findings) was tested in predicting four prognostic pathologic findings in RP specimens: (1) pT3–4 disease; (2) overall unfavourable disease (OUD) defined by pT3–4 disease and/or pathologic primary Gleason pattern 4; (3) tumour volume <0.5 cm³; and (4) insignificant PCa.

Results and limitations

The PCA3 score was strongly correlated with the tumour volume in a linear regression analysis (p < 0.001, r = 0.409). The risk of having a cancer ≥0.5 cm³ and a significant PCa was increased three-fold in men with a PCA3 score of ≥25 compared with men with a PCA3 score of <25 with most AS biopsy criteria used. There was a trend towards higher PCA3 scores in patients with unfavourable and non–organ-confined disease and Gleason >6 cancers. In a multivariate analysis taking into account each AS criterion, a high PCA3 score (≥25) was an important predictive factor for tumour volume ≥0.5 cm³ (odds ratio [OR]: 5.4; p = 0.010) and significant PCa (OR: 12.7; p = 0.003). Biopsy criteria and MRI findings were significantly associated with OUD (OR: 3.9 and 5.0, respectively; p = 0.030 and p = 0.025, respectively).

Conclusions

PCA3 score may be a useful marker to improve the selection for AS in addition to the current AS criteria. With a predictive cut-off of 25, PCA3 score is strongly indicative for tumour volume and insignificant PCa.     

Predicting the probability of deferred radical treatment for localised prostate cancer managed by active surveillance

Objectives

Outcome data from a prospective study of active surveillance of localised prostate cancer were analysed to identify factors, present at the time of diagnosis, that predict subsequent radical treatment.

Methods

Eligible patients had clinical stage T1–T2a, N0–Nx, M0–Mx adenocarcinoma of the prostate with serum PSA < 15 ng/ml, Gleason score ≤ 7, primary Gleason grade ≤ 3, and % positive biopsy cores (pbc) ≤ 50%. Monitoring included serial PSA measurement and repeat prostate biopsies. Radical treatment was initiated in the event of biochemical progression (PSA velocity > 1 ng/ml/yr) or histological progression (primary Gleason grade ≥ 4, or %pbc > 50%). Multivariate Cox regression analysis of baseline variables was performed with respect to time to radical treatment.

Results

The 326 men recruited from 2002 to 2006 have been followed for a median of 22 mo. Median age was 67 yr, and median initial PSA (iPSA) 6.4 ng/ml. Sixty-five patients (20%) had deferred radical treatment, 16 (5%) changed to watchful waiting because of increasing comorbidity, 7 (2%) died of other causes, and 238 (73%) remain on surveillance. On multivariate Cox regression analysis, the free/total PSA ratio (p < 0.001) and clinical T stage (p = 0.006) were independent determinants of time to radical treatment.

Conclusions

In addition to established prognostic factors, the free/total PSA ratio may predict time to radical treatment in patients with untreated, localised prostate cancer managed by active surveillance. This possibility warrants further study.     

A Study of Diffusion-Weighted Magnetic Resonance Imaging in Men with Untreated Localised Prostate Cancer on Active Surveillance

Background

Markers that predict the behaviour of localised prostate cancer are needed to identify patients that require treatment.

Objective

We have analysed the apparent diffusion coefficient (ADC) generated from diffusion-weighted magnetic resonance imaging (DW-MRI) with respect to repeat biopsy findings and time to radical treatment in patients in a prospective study of active surveillance.

Design, setting, and participants

Some 86 men recruited between 2002 and 2006 were followed for a median of 29 mo. Patients had clinical stage T1/T2a N0/Nx M0/Mx adenocarcinoma of the prostate, prostate-specific antigen (PSA) level <15 ng/ml, Gleason score ≤7, primary Gleason grade ≤3, and positive biopsy cores (pbc) ≤50%.

Measurements

All patients had DW-MRI in addition to standard MRI sequences. Tumour regions of interest (ROIs) were identified using T2-weighted fast-spin echo images as focal areas of restricted diffusion. Univariate analyses including all clinical variables and tumour ADC data were performed with respect to repeat biopsy findings and time to radical treatment. Receiver operating curves (ROC) compared predictive variables.

Results and limitations

Patients in the study had a median age of 66 yr and a median initial PSA level of 6.7 ng/ml. Some 39 patients (45%) received deferred radical treatment, and 34 patients (40%) had adverse histology on repeat biopsy. According to univariate analysis, tumour ADC was a significant predictor of both adverse repeat biopsy findings (p < 0.0001; hazard ratio [HR]: 1.3; 95% confidence interval [CI]: 1.1–1.6), and time to radical treatment (p < 0.0001; HR: 1.5; 95% CI: 1.2–1.8). ROC curves for ADC showed an area under the curve (AUC) of 0.7 for prediction of adverse repeat biopsy findings and an AUC of 0.83 for prediction of radical treatment.

Conclusions

In patients with low-risk, localised disease, tumour ADC on DW-MRI may be a useful marker of prostate cancer progression and may help to identify patients who stand to benefit from radical treatment. This possibility warrants further study.     

Upgrading and downgrading of prostate cancer from biopsy to radical prostatectomy: incidence and predictive factors using the modified Gleason grading system and factoring in tertiary grades

Background

Prior studies assessing the correlation of Gleason score (GS) at needle biopsy and corresponding radical prostatectomy (RP) predated the use of the modified Gleason scoring system and did not factor in tertiary grade patterns.

Objective

To assess the relation of biopsy and RP grade in the largest study to date.

Design, setting, and participants

A total of 7643 totally embedded RP and corresponding needle biopsies (2004–2010) were analyzed according to the updated Gleason system.

Interventions

All patients underwent prostate biopsy prior to RP.

Measurements

The relation of upgrading or downgrading to patient and cancer characteristics was compared using the chi-square test, Student t test, and multivariable logistic regression.

Results and limitations

A total of 36.3% of cases were upgraded from a needle biopsy GS 5–6 to a higher grade at RP (11.2% with GS 6 plus tertiary). Half of the cases had matching GS 3 + 4 = 7 at biopsy and RP with an approximately equal number of cases downgraded and upgraded at RP. With biopsy GS 4 + 3 = 7, RP GS was almost equally 3 + 4 = 7 and 4 + 3 = 7. Biopsy GS 8 led to an almost equal distribution between RP GS 4 + 3 = 7, 8, and 9–10. A total of 58% of the cases had matching GS 9–10 at biopsy and RP. In multivariable analysis, increasing age (p < 0.0001), increasing serum prostate-specific antigen level (p < 0.0001), decreasing RP weight (p < 0.0001), and increasing maximum percentage cancer/core (p < 0.0001) predicted the upgrade from biopsy GS 5–6 to higher at RP. Despite factoring in multiple variables including the number of positive cores and the maximum percentage of cancer per core, the concordance indexes were not sufficiently high to justify the use of nomograms for predicting upgrading and downgrading for the individual patient.

Conclusions

Almost 20% of RP cases have tertiary patterns. A needle biopsy can sample a tertiary higher Gleason pattern in the RP, which is then not recorded in the standard GS reporting, resulting in an apparent overgrading on the needle biopsy.     

Critical assessment of preoperative urinary prostate cancer antigen 3 on the accuracy of prostate cancer staging

Background

Knowledge about the staging significance of the prostate cancer antigen 3 (PCA3) score to better identify pathologic features after radical prostatectomy (RP) is limited and controversial.

Objective

Our aim was to study the clinical staging significance of PCA3 to identify pathologic favorable and/or unfavorable features in the RP specimen.

Design, setting, and participants

Complete retrospective clinical and pathologic data of consecutive men who had undergone RP from three tertiary referral centers including preoperative PCA3 scores (n = 305) and computer-assisted planimetrically measured tumor volume data (n = 160) were available.

Intervention

All patients were treated with RP.

Measurements

PCA3 scores were assessed using the PROGENSA assay (Gen-Probe, San Diego, CA, USA). Beyond standard risk factors (age, digital rectal examination, prostate-specific antigen, prostate volume, biopsy Gleason score, percentage of positive cores), five different PCA3 codings were used in logistic regression models to identify five distinct pathologic end points: (1) low-volume disease (<0.5 ml), (2) insignificant prostate cancer (PCa) according to the Epstein criteria, (3) extracapsular extension (ECE), (4) seminal vesicle invasion (SVI), and (5) aggressive disease defined as Gleason sum ≥7. Accuracy estimates of each end point were quantified using the area under the curve (AUC) of the receiver operator characteristic analysis in models with and without PCA3.

Results and limitations

PCA3 scores were significantly lower in low-volume disease and insignificant PCa (p ≤ 0.001). AUC of multivariable low-volume disease (+2.4 to +5.5%) and insignificant PCa models (+3 to +3.9%) increased when PCA3 was added to standard clinical risk factors. In contradistinction, regardless of its coding, PCA3 scores were not significantly elevated in pathologically confirmed ECE (p = 0.4) or SVI (p = 0.5), respectively. Higher PCA3 scores were associated with aggressive disease (p < 0.001). Importantly, the addition of PCA3 to multivariable intermediate- and high-grade models did not improve prediction. Despite reporting the largest pathologic PCA3 study, the main limitation resides in its small sample size.

Conclusions

PCA3 was confirmed as a valuable predictor of pathologically confirmed low-volume disease and insignificant PCa. Further exploration of its role as an additional marker to select patients for active surveillance may be warranted. In contradistinction, assessment of pathologically advanced or aggressive PCa is not improved using PCA3.     

The Epstein Criteria Predict for Organ-Confined But Not Insignificant Disease and a High Likelihood of Cure at Radical Prostatectomy

Background

Few reports attempt to validate the role of Epstein criteria in selecting patients for an active surveillance protocol.

Objective

To determine the performance of the Epstein biopsy criteria for predicting pathologic end points and biochemical relapse-free survival (bRFS) in men with early stage prostate cancer (PCa) treated by radical prostatectomy (RP).

Design, setting, and participants

Between October 1999 and January 2007, 746 consecutive patients were biopsied, and then underwent RP at our tertiary care institution. Two hundred sixty-eight patients met the entry criteria of Gleason 6 disease only on initial biopsy with complete pathologic information.

Measurements

Primary end point was insignificant disease. Insignificant disease was defined using a classical (organ-confined, Gleason score <6, and tumor volume <0.5 cm³) and more liberal (organ-confined, Gleason <6 tumor of any volume) formulation. Secondary end points included organ-confined disease and bRFS.

Results and limitations

One hundred thirty-six men (51%) met the Epstein biopsy criteria, and 167 (62%) had organ-confined cancer. Insignificant disease by the classical and liberal definitions was present in 68 (25%) and 92 (34%) patients, respectively. Cases meeting Epstein biopsy criteria were more likely to have insignificant disease by either definition (p < 0.001) and more likely to have organ-confined tumors (p < 0.001). Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) varied widely among the end points, with sensitivity (74%) and NPV (86%) best for the classical definition of insignificant disease and specificity (74%) and PPV (92%) best for organ-confined disease. The estimated 5-yr bRFS was 100% for those meeting Epstein biopsy criteria compared to 83% for those not meeting these criteria.

Conclusions

The Epstein biopsy criteria predict for a high likelihood of organ-confined disease and the absence of biochemical failure up to 5 yr after RP. These criteria are insufficiently robust to predict the presence of biologically insignificant disease.     

Prostate cancer incidence and disease-specific survival of men with initial prostate-specific antigen less than 3.0 ng/ml who are participating in ERSPC Rotterdam

Background

The European Randomised Study of Screening for Prostate Cancer (ERSPC) applies a prostate-specific antigen (PSA) cut-off value ≥3.0 ng/ml as an indication for lateralised sextant biopsy.

Objective

To analyse the incidence and disease-specific mortality for prostate cancer (PCa) in men with an initial PSA <3.0 ng/ml.

Design, setting and participants

From November 1993 to December 1999, a total of 42 376 men identified from population registries in the Rotterdam region (55–74 yr of age) were randomised to an intervention or control arm. A total of 19 950 men were screened during the first screening round.

Intervention

A PSA <3.0 ng/ml was below the biopsy threshold. PCa cases were identified at rescreens every 4 yr or as interval cancers.

Measurements

Distribution of incidence, aggressiveness, and disease-specific mortality of PCa per PSA range was measured. Causes of death were evaluated by an independent committee, and follow-up was complete until 31 December 2008.

Results and limitations

From 1993 to 2008, 915 PCa cases were diagnosed in 15 758 men (5.8%) with an initial PSA <3.0 ng/ml and a median age of 62.3 yr. Median overall follow-up was 11 yr. PCa incidence increased significantly with higher initial PSA levels. Aggressive PCa (clinical stage ≥T2c, Gleason score ≥8, PSA >20 ng/ml, positive lymph nodes, or metastases at diagnosis) was detected in 66 of 733 screen-detected PCa cases (9.0%) and 72 of 182 interval-detected PCa cases (39.6%). Twenty-three PCa deaths occurred in the total population (0.15%), with an increasing risk of PCa mortality in men with higher initial PSA values.

Conclusions

The risk of PCa, aggressive PCa and PCa mortality in a screening population with initial PSA <3.0 ng/ml increases significantly with higher initial PSA levels. These results contribute to the risk stratification and individual management of men in PSA-based screening programmes.     

Prognostic Parameters,Complications, and Oncologic and Functional Outcome of Salvage Radical Prostatectomy for Locally Recurrent Prostate Cancer after 21st-Century Radiotherapy

Background

Salvage radical prostatectomy (SRP) for radiorecurrent prostate cancer (PCa) is a second local treatment with curative intent in patients with true organ-confined recurrent PCa.

Objective

We evaluated preoperative prognostic risk factors to predict organ-confined, locally recurrent PCa after primary radiotherapy (RT).

Design, setting, and participants

Fifty-five men with biopsy-proven, locally recurrent PCa underwent SRP and extended pelvic lymph node dissection (ePLND) after external-beam radiotherapy (EBRT) or low- or high-dose brachytherapy.

Measurements

Prostate-specific antigen (PSA), clinical stage, biopsy Gleason score prior to RT and SRP, PSA nadir, time to recurrence, PSA doubling time (PSA DT), PSA prior to surgery, and pathohistology of the SRP specimen were analysed to predict organ-confined recurrent disease. Uni- and multivariate statistical analysis was performed.

Results and limitations

Forty (72.7%) and 15 (27.3%) patients demonstrated organ-confined and locally advanced PCa, respectively. Eleven patients (20%) and seven patients (12.7%) had lymph node metastases and positive surgical margins (PSM), respectively. On multivariate analysis, biopsy Gleason score prior to SRP (p = 0.02), <50% positive biopsy cores (p = 0.001), PSA DT >12 mo (p = 0.001), and low-dose brachytherapy (p = 0.001) were significant predictors of organ-confined PCa with negative surgical margins (NSM). Limitations of the study are its retrospective nature and the relatively low number of patients.

Conclusions

SRP is a surgically challenging but effective secondary local treatment of radiorecurrent PCa with curative intent. The identified predictive parameters will help to select patients most suitable for SRP with long-term cure and good functional outcome.     

Focal cryotherapy for clinically unilateral, low-intermediate risk prostate cancer in 73 men with a median follow-up of 3.7 years

Background

Evolution of cryotherapy for prostate cancer is likely to result in parenchyma-sparing modifications adjacent to the urethra and neurovascular bundle. Results of initial series of focal therapy to minimize cryosurgery-related morbidity without compromising oncologic control have been encouraging, but limited in short-term outcomes.

Objective

To retrospectively report (1) median 3.7-yr follow-up experience of primary focal cryotherapy for clinically unilateral prostate cancer with oncologic and functional outcomes, and (2) matched-pair analysis with contemporaneous patients undergoing radical prostatectomy (RP).

Design, setting, and participants

Over 8.5 yr (September 2002 to March 2011), focal cryoablation (defined as ablation of one lobe) was performed in 73 carefully selected patients with biopsy-proven, clinically unilateral, low-intermediate risk prostate cancer. All patients underwent transrectal ultrasound (TRUS) and Doppler-guided sextant and targeted biopsies at entry.

Outcome measurements and statistical analysis

Post-therapy follow-up included measuring prostate-specific antigen (PSA) level every 3–6 mo; TRUS biopsies at 6–12 mo and yearly, as indicated; and validated symptom questionnaires. Matched-pair analysis compared oncologic outcomes of focal cryotherapy and RP (matched for age, PSA, clinical stage, and biopsy Gleason score).

Results and limitations

Complete follow-up was available in 70 patients (median follow-up: 3.7 yr; range: 1–8.5 yr). No patient died or developed metastases. Precryotherapy mean PSA was 5.9 ng/ml and Gleason score was 6 (n = 30) or 7 (n = 43). Postcryotherapy mean PSA was 1.6 ng/ml (70% reduction compared to precryotherapy; p < 0.001). Of 48 patients undergoing postcryotherapy biopsy, 36 (75%) had negative biopsies; positive biopsy for cancer (n = 12) occurred in the untreated contralateral (n = 11) or treated ipsilateral lobe (n = 1). Complete continence (no pads) and potency sufficient for intercourse were documented in 100% and 86% of patients, respectively. Matched-pair comparison of focal cryotherapy and RP revealed similar oncologic outcome, defined as needing salvage treatment.

Conclusions

Primary focal cryoablation for low-intermediate risk unilateral cancer affords encouraging oncologic and functional outcomes over a median 3.7-yr follow-up. Close surveillance with follow-up whole-gland biopsies is mandatory.     

Early salvage radiation therapy does not compromise cancer control in patients with pT3N0 prostate cancer after radical prostatectomy: results of a match-controlled multi-institutional analysis

Background

Previous randomised trials demonstrated that adjuvant radiation therapy (aRT) improves cancer control in patients with pT3 prostate cancer (PCa). However, there is currently no evidence supporting early salvage radiation therapy (eSRT) as equivalent to aRT in improving freedom from biochemical recurrence (BCR) after radical prostatectomy (RP).

Objective

To evaluate BCR-free survival for aRT versus observation followed by eSRT in cases of relapse in patients undergoing RP for pT3pN0, R0–R1 PCa.

Design, setting, and participants

Using a European multi-institutional cohort, 890 men with pT3pN0, R0–R1 PCa were identified.

Intervention

All patients underwent RP. Subsequently, patients were stratified into two groups: aRT versus initial observation followed by eSRT in cases of relapse.

Outcome measurements and statistical analyses

Propensity-matched analysis was employed, and patients were stratified into two groups: aRT versus observation and eventual eSRT, defined as RT given at a postoperative serum prostate-specific antigen (PSA) ≤0.5 ng/ml at least 6 mo after RP. BCR, defined as PSA >0.20 ng/ml and rising after administration of RT, was compared between aRT and initial observation followed by eSRT in cases of relapse using Kaplan-Meier and Cox regression methods.

Results and limitations

Overall, 390 (43.8%) and 500 (56.2%) patients were treated with aRT and initial observation, respectively. Within the latter group, 225 (45.0%) patients experienced BCR and underwent eSRT. In the postpropensity-matched cohort, the 2- and 5-yr BCR-free survival rates were 91.4% and 78.4% in aRT versus 92.8% and 81.8% in patients who underwent initial observation and eSRT in cases of relapse, respectively (p = 0.9). No differences in the 2- and 5-yr BCR-free survival rates were found, even when patients were stratified according to pT3 substage and surgical margin status (all p ≥ 0.4). These findings were also confirmed in multivariable analyses (p = 0.6). Similar results were achieved when the cut-off to define eSRT was set at 0.3 ng/ml (all p ≥ 0.5).

Conclusions

The current study suggests that timely administration of eSRT is comparable to aRT in improving BCR-free survival in the majority of pT3pN0 PCa patients. Therefore, eSRT may not compromise cancer control but significantly reduces overtreatment associated with aRT.     

Effect of dutasteride on prostate biopsy rates and the diagnosis of prostate cancer in men with lower urinary tract symptoms and enlarged prostates in the Combination of Avodart and Tamsulosin trial

Background

A 23% relative risk reduction (RRR) in prostate cancer (PCa) was shown in men receiving dutasteride in the 4-yr Reduction by Dutasteride of Prostate Cancer Events study, in whom biopsies were protocol dependent.

Objective

Our aim was to explore PCa risk reduction in men with benign prostatic hyperplasia (BPH) from the Combination of Avodart and Tamsulosin (CombAT) study, in which biopsies were undertaken for cause.

Design, setting, and participants

CombAT was a 4-yr randomized double-blind parallel group study in 4844 men ≥50 yr of age with clinically diagnosed moderate to severe BPH, International Prostate Symptom Score ≥12, prostate volume ≥30 ml, and serum prostate-specific antigen (PSA) 1.5–10 ng/ml. Men underwent annual PSA measurement and digital rectal examination (DRE), and prostate biopsies were performed for cause.

Intervention

All patients took tamsulosin 0.4 mg/d, dutasteride 0.5 mg/d, or a combination of both.

Measurements

The primary end point was incidence of PCa. Secondary end points included postbaseline prostate biopsy rates and Gleason score of cancers.

Results and limitations

Dutasteride (alone or in combination with tamsulosin) was associated with a 40% RRR of PCa diagnosis compared with tamsulosin monotherapy (95% confidence interval, 16–57%; p = 0.002) and a 40% reduction in the likelihood of biopsy. There were similar reductions in low- and high-grade Gleason score cancers. The biopsy rate in the groups receiving dutasteride trended toward a higher diagnostic yield (combination: 29%, dutasteride: 28%, tamsulosin: 24%). One limitation was the lack of a standardized approach to PCa diagnosis and grading.

Conclusions

Dutasteride, alone or in combination with tamsulosin, significantly reduced the relative risk of PCa diagnosis in men with BPH undergoing annual DRE and PSA screening. Consistent with the increased usefulness of PSA for PCa detection, men receiving dutasteride had a numerically lower biopsy rate and higher yield of PCa on biopsy.

Trial registration

Clinicaltrials.gov identifier: NCT00090103 (http://www.clinicaltrials.gov/ct2/show/NCT00090103).     

The Role of Biopsy Core Number in Selecting Prostate Cancer Patients for Active Surveillance

Background

Studies offer wide variations in inclusion criteria for active surveillance (AS) in prostate cancer (PCa), but the role of the biopsy core number has not been thoroughly assessed.

Objective

To evaluate the impact of the biopsy core number on the risk of misclassification for AS eligibility.

Design, setting, and participants

: This prospective study included 411 men eligible for AS who fulfilled at least one of four of the criteria reported in the literature groupings among a screening cohort of 2917 patients.

Intervention

All patients underwent a 21-core biopsy with cores mapped by location and acted as controls of themselves for the analysis of biopsy core number (6-, 12- and 21-core schemes). Radical prostatectomy (RP) was performed in 297 men (72%).

Measurements

The number of included patients, PCa extent on biopsy, rate of unfavorable disease in RP specimens, and biochemical recurrence-free survival were compared as a function of (1) the different criteria groupings for AS and (2) the biopsy core number (6, 12, or 21).

Results and limitations

Of the 1104 patients with PCa, the proportion eligible for AS ranged from 22.5% to 35.4% based on AS criteria. In men who fulfilled AS criteria only in a 12-core strategy, tumor length and percentage of cancer involvement on biopsy were significantly greater than in those who fulfilled AS criteria in a 21-core scheme. The rate of unfavorable disease on RP specimens was also higher in the former group, from 28.6% to 35.9% relative to AS criteria (p = 0.014, 0.044, and 0.113 in groups 2, 3, and 4, respectively).

Conclusions

Men eligible for AS based on a 21-core strategy have cancers with a lower extent of disease on biopsies and a lower risk of unfavorable disease on RP specimens regardless of how AS criteria are defined, compared with men eligible in a 12-core scheme.     

A competing-risks analysis of survival after alternative treatment modalities for prostate cancer patients: 1988-2006

Background

The efficacy of prostate cancer (PCa) treatment modalities is a subject of continuous debate.

Objective

We tested the hypothesis that significant differences in survival rates may exist among PCa patients treated with radical prostatectomy (RP), radiation therapy (RT), and observation.

Design, setting, and participants

We focused on 404 604 patients with clinically localized PCa within 17 Surveillance, Epidemiology and End Results registries.

Measurements

Competing-risks survival analyses were used to estimate cancer-specific mortality (CSM) and other-cause mortality (OCM) rates. Patients were stratified according to treatment type, age group, and PCa risk group (high risk: T2c and/or Gleason score 8–10; low to intermediate risk: all others).

Results and limitations

The 10-yr CSM and OCM rates were 6.1% and 29.2%, respectively. In RP, RT, and observation patients, CSM rates were 3.6%, 6.5%, and 10.8% (p < 0.001), respectively; OCM rates were 17.1%, 32.4%, and 48.9% (p < 0.001), respectively. In low- to intermediate-risk patients, the lowest CSM (1.3–3.7%) and OCM (6.9–31.6%) rates within all age categories except octogenarians (8.9% and 62.8%, respectively) were recorded in RP. In high-risk patients, the lowest CSM (5.8–7.2%) and OCM (8.7–16.1%) rates in patients aged ≤69 yr were also recorded in RP. RT was equally favorable to RP in the 70–79 age category and appeared ideal in all octogenarian patients.

Conclusions

Our results showed that RP provides the most favorable survival rates in most patients. The exception is octogenarian men, in whom RT provides the best results. Finally, the least-favorable outcomes were recorded after observation. However, these findings must be interpreted within the context of the limitations of observational data.     

The prognostic significance of capsular incision into tumor during radical prostatectomy

Background

The prognostic significance of capsular incision (CapI) into tumor during radical prostatectomy (RP) with otherwise organ-confined disease remains uncertain.

Objective

To evaluate the impact of CapI into tumor on oncologic outcome.

Design, setting, and participants

A retrospective review of 8110 consecutive patients with prostate cancer treated at Ottawa Hospital and at Memorial Sloan–Kettering Cancer Center, both tertiary academic centers, between 1985 and 2008.

Intervention

All patients underwent an open, laparoscopic or robotic RP.

Measurements

Patients were divided into four pathologic categories: group 1 (CapI group), positive surgical margins (PSMs) without extraprostatic extension (EPE); group 2, negative surgical margins (NSMs) without EPE; group 3, NSM with EPE; group 4, PSMs with EPE. Estimates of recurrence-free survival were generated with the Kaplan-Meier method. Recurrence was defined as a prostate-specific antigen (PSA) >0.2 ng/ml and rising. Cox proportional hazards regression was used to estimate the hazard ratio (HR) for recurrence controlling for pretreatment PSA, RP date, RP Gleason sum, seminal vesicle invasion, and lymph node involvement. Pathologic categories were defined in the model by including the variables EPE and surgical margins (SMs) as well as their interaction.

Results and limitations

Median follow-up was 37.3 mo. The 5-yr recurrence-free probability after RP for the CapI group was 77% (95% confidence interval [CI], 72–83). This was not only inferior to patients with NSMs and no EPE (log rank p < 0.0001) but also to those with NSMs and EPE (log rank p = 0.0002). In multivariate analysis the interaction between EPE and SM was not significant (p = 0.26). In the adjusted model excluding the interaction term, patients with EPE had an increased risk for recurrence (HR: 1.80; 95% CI, 1.49–2.17; p < 0.0001) as did those with positive margins (HR: 1.81; 95% CI, 1.51–2.15; p < 0.0001). This was a retrospective study.

Conclusions

CapI into tumor has a significant impact on patient outcome following RP. Patients, who otherwise would have organ-confined disease, will now have a higher probability of recurrence than those with completely resected extraprostatic disease.     

The risk of upstaged disease increases with body mass index in low-risk prostate cancer patients eligible for active surveillance

Background

Obese patients have a greater risk of adverse pathologic features and biochemical recurrence after radical prostatectomy (RP). The impact of body mass index (BMI) on the risk of reclassification and deferred treatment in active surveillance (AS) programs has not been thoroughly assessed.

Objective

To evaluate the impact of BMI on the risk of reclassification for AS eligibility.

Design, setting, and participants

We assessed 230 men who underwent an immediate RP and were eligible for AS according to the following criteria: prostate-specific antigen (PSA) ≤10 ng/ml, clinical stage T1c, Gleason score ≤6, fewer than three positive cores, extent of cancer in any core <50%, and life expectancy >10 yr.

Intervention

All patients underwent a standardised 21-core biopsy and RP at our department between January 2001 and December 2010.

Measurements

Reclassification was defined as upstaged disease (pathologic stage >pT2) and/or upgraded disease (Gleason score ≥7; primary Gleason pattern 4) in RP specimens. PSA outcomes were also recorded.

Results and limitations

Mean BMI was 26.4 kg/m², and 13% of patients were obese (BMI >30). Mean BMI was the only preoperative factor significantly associated with the risk of upstaged disease. In multivariate analysis, BMI >30 remained an independent predictive factor for upstaged disease (p = 0.003; odds ratio: 4.2). The risk of upgraded disease (primary Gleason pattern 4) was significantly decreased 4.5-fold in large prostate glands (>50 ml; p = 0.008). The biochemical recurrence-free survival curves were not significantly different between men who were or were not overweight (p = 0.950).

Conclusions

Obese men are at higher risk of upstaged disease, with a proportion of 30% of pT3 disease in RP specimens. BMI should be taken into account for inclusion of low-risk prostate cancer patients in AS programs, and our results may help urologists better inform their obese patients eligible for AS about this risk of reclassification and improve treatment decision making.     

Medium-term Outcomes of Active Surveillance for Localised Prostate Cancer

Background

Active surveillance (AS) aims to allow men with favourable-risk, localised prostate cancer to avoid unnecessary treatment.

Objective

To describe the clinical outcomes of a prospective study of AS.

Design, setting, and participants

A single-centre, prospective cohort study. Eligibility criteria included histologically proven prostate adenocarcinoma, age 50–80 yr, stage T1/T2, prostate-specific antigen level (PSA) <15 ng/ml, Gleason score (GS) ≤3 + 3 (GS ≤3 + 4 if aged >65 yr), and percent positive biopsy cores (PPC) ≤50%.

Intervention

Patients were assessed by serum PSA level, and digital rectal examination at 3-mo intervals in year 1, 4-mo intervals in year 2, and at 6-mo intervals thereafter. Transrectal ultrasound-guided prostate biopsy was performed after 18–24 mo and every 2 yr thereafter. Treatment was recommended for PSA velocity (PSAV) >1 ng/ml per year or adverse histology, defined as GS ≥4 + 3 or PPC >50%.

Outcome measurements and statistical analysis

Outcomes described, using Kaplan-Meier methods, were rate of adverse histology on repeat biopsy, freedom from treatment, biochemical control after deferred treatment, and overall survival. Analyses using Cox regression were performed to determine predictors of deferred treatment and adverse histology.

Results and limitations

The study enrolled 471 eligible patients from 2002 to 2011. Median age was 66 yr and median initial PSA value was 6.4 ng/ml. Eighty-eight percent of patients had T1 disease and 93% had GS ≤3 + 3. At median follow-up of 5.7 yr, the 5-yr rate of adverse histology and treatment-free probability was 22% (95% confidence interval [CI], 16–29%) and 70% (95% CI, 65–75%), respectively. There were two deaths from prostate cancer. Predictors of time to adverse histology were GS 7, PSAV >1 ng/ml per year, low ratio of free PSA to total PSA, and PPC >25%. Longer follow-up is needed to confirm the safety of this strategy.

Conclusions

This study demonstrates satisfactory medium-term outcomes for AS in selected men with localised prostate cancer.     

Active Surveillance for Low-Risk Prostate Cancer Worldwide: The PRIAS Study

Background

Overdiagnosis and subsequent overtreatment are important side effects of screening for, and early detection of, prostate cancer (PCa). Active surveillance (AS) is of growing interest as an alternative to radical treatment of low-risk PCa.

Objective

To update our experience in the largest worldwide prospective AS cohort.

Design, setting, and participants

Eligible patients had clinical stage T1/T2 PCa, prostate-specific antigen (PSA) ≤10 ng/ml, PSA density <0.2 ng/ml per milliliter, one or two positive biopsy cores, and Gleason score ≤6. PSA was measured every 3–6 mo, and volume-based repeat biopsies were scheduled after 1, 4, and 7 yr. Reclassification was defined as more than two positive cores or Gleason >6 at repeat biopsy. Recommendation for treatment was triggered in case of PSA doubling time <3 yr or reclassification.

Outcome measurements and statistical analysis

Multivariate regression analysis was used to evaluate predictors for reclassification at repeat biopsy. Active therapy–free survival (ATFS) was assessed with a Kaplan-Meier analysis, and Cox regression was used to evaluate the association of clinical characteristics with active therapy over time.

Results and limitations

In total, 2494 patients were included and followed for a median of 1.6 yr. One or more repeat biopsies were performed in 1480 men, of whom 415 men (28%) showed reclassification. Compliance with the first repeat biopsy was estimated to be 81%. During follow-up, 527 patients (21.1%) underwent active therapy. ATFS at 2 yr was 77.3%. The strongest predictors for reclassification and switching to deferred treatment were the number of positive cores (two cores compared with one core) and PSA density. The disease-specific survival rate was 100%. Follow-up was too short to draw definitive conclusions about the safety of AS.

Conclusions

Our short-term data support AS as a feasible strategy to reduce overtreatment. Clinical characteristics and PSA kinetics during follow-up can be used for risk stratification. Strict monitoring is even more essential in men with high-risk features to enable timely recognition of potentially aggressive disease and offer curative intervention. Limitations of using surrogate end points and markers in AS should be recognized.

Trial registration

The current program is registered at the Dutch Trial Register with ID NTR1718 (http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1718).