Prostate cancer detection and dutasteride: utility and limitations of prostate-specific antigen in men with previous negative biopsies

Context

We addressed the question whether the change of serum prostate-specific antigen (PSA) in men who use 5α-reductase inhibitor (5-ARI) dutasteride is sensitive for the detection of aggressive prostate cancer (PCa).

Objective

The case of a man using dutasteride diagnosed with Gleason 7 transition zone cancer at biopsy indicated by a rising PSA is described. The following issues are discussed: (1) Is a rise of PSA in patients using dutasteride predictive of aggressive PCa in men with prior negative biopsies? (2) Is it safe not to biopsy men using dutasteride who do not show a rising PSA? (3) How can we avoid potentially unnecessary biopsies in men using dutasteride without a rising PSA?

Evidence acquisition

We reviewed the recent literature addressing our objective that relates to two studies: the Prostate Cancer Prevention Trial and the Reduction by Dutasteride of Prostate Cancer Events trial.

Evidence synthesis

In men using dutasteride, the positive predictive value/detection rate of Gleason 7–10 PCa is 13.2% and 4.0% for men with and without a rising PSA, respectively. However, a substantial proportion of Gleason 7–10 cases (42.9%) would be missed if a rising PSA was used as the only biopsy indication. Currently available data do not provide selective mechanisms to diagnose these cancers.

Conclusions

A rising PSA for a patient using dutasteride should be an indication for prostate biopsies. Currently, in the case of stable PSA a biopsy may still be considered. Options for a selective approach are therefore suggested in this review to avoid unnecessary biopsies and to achieve a more selective PCa detection in men on 5-ARI treatment.     

High incidence of prostate cancer detected by saturation biopsy after previous negative biopsy series

Objectives

We explored the yield of saturation biopsy and developed a nomogram predicting the probability of prostate cancer (PCa) on the basis of saturation biopsy.

Materials and methods

Between 2001 and 2004, saturation biopsies (average of 24 cores) were performed in 161 men with persistently elevated prostate specific antigen (PSA) level (median, 9 ng/ml). All had at least two previously negative, eight-core biopsy sessions. PCa predictors on saturation biopsy were integrated within multivariate nomograms.

Results

PCa detection was 41% (n = 66 of 161). PSA density and transition zone volume were the most significant predictors of PCa on saturation biopsy. The accuracy of the nomogram with the best performance characteristics was 72%.

Conclusions

Saturation biopsy may be indicated in men with a persistent suspicion of PCa. High-risk individuals can be identified accurately with our nomogram.     

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.     

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.     

Performance of prostate cancer antigen 3 (PCA3) and prostate-specific antigen in Prescreened men: reproducibility and detection characteristics for prostate cancer patients with high PCA3 scores (≥ 100)

Background

Prostate cancer antigen 3 (PCA3) is considered to be prostate cancer (PCa) specific and highly overexpressed in cancer. Therefore a high PCA3 score should result in a high positive predictive value (PPV) and specificity for a positive biopsy.

Objective

Our aim was to reevaluate, retest PCA3, and rebiopsy men with an initial PCA3 ≥100 and no PCa detected and compare the results with a random cohort of men with an initial PCA3 < 100.

Design, setting, and participants

We invited men 63–75 yr of age with a PCA3 ≥100 for retesting and a control group with an initial PCA3 < 100 to participate in the European Randomized Study of Screening for Prostate Cancer, section Rotterdam.

Interventions

Blood and urine sampling were used to determine prostate-specific antigen (PSA) and PCA3. Prostate biopsies were performed if the PSA was ≥2.5 ng/ml and/or the PCA3 score was ≥35.

Measurements

We correlated the initial and reevaluated PCA3 scores. Our assessment of the PPV after rebiopsy was based on the newly determined PCA3 score.

Results and limitations

After a mean study period of 19 mo, more cases of PCa were detected in rebiopsied men with initial PCA3 scores ≥100 than in the controls with PCA3 scores <100 (30.0% vs 18.8%). Combining initial and rebiopsy data resulted in a PPV of 52.2% in men with PCA3 ≥100. Over time, changes in PSA and PCA3 levels were quite different.

Conclusions

In spite of our rescreened population, PPV and specificity were comparable with all reported studies of men with PCA3 scores ≥100. These findings do not explain why these PCA3 scores were excessively high in spite of the absence of biopsy-detectable PCa.     

Predictors of attendance for prostate-specific antigen screening tests and prostate biopsy

Background

Little is known about factors influencing men's decisions to undergo screening and diagnostic tests for prostate cancer (PCa).

Objective

Identify predictors of attendance for prostate-specific antigen (PSA) testing and prostate biopsy.

Design, setting, and participants

Literature searches and interviews with men undergoing PSA testing and prostate biopsy formed the basis of a self-report questionnaire designed to identify predictors of health behaviour, which was completed by men eligible for PSA invitation and prostate biopsy. Multitrait scaling analyses established the final questionnaire content. This revised instrument was distributed to a new cohort of men before PSA testing and biopsy invitations were received. Ethical committee approval was obtained from Trent Multicentre Research Ethics Committee (MREC/01/4/025 – 21/06/2001).

Measurements

Predictors of health behaviour and attendance rates for PSA test or prostate biopsy were measured. Associations between questionnaire scores and health behaviour (PSA and prostate biopsy attendance) were examined using logistic regression.

Results and limitations

The provisional 49-item health behaviour questionnaire was completed by 468 of 810 men (57.8%). Multitrait scaling refined the questionnaire to 26 items in six scales (A: health benefits, B: threats to health, C: barriers to testing, D: health intentions, E: external influences, F: current general health). A total of 1455 of 2657 men (54.8%) completed the revised instrument before invitations for PSA test or biopsy were received; 395 (43.4%) and 434 (91.6%) attended. Strong associations between men's health intentions (scale D) and PSA and biopsy attendance (odds ratio: 1.56 or 3.67, respectively; p < 0.001) were observed with modest associations between the other five scales and attendance for PSA testing. Average questionnaire response rates represent the major limitation of this study.

Conclusions

Knowledge and beliefs about PCa and testing predict men's intentions and attendance for PSA testing and prostate biopsy. Understanding men's health behaviour is important for the management of patients seeking PSA testing in general practice.     

Dutasteride Treatment Over 2 Years Delays Prostate-specific Antigen Progression in Patients with Biochemical Failure After Radical Therapy for Prostate Cancer: Results from the Randomised,Placebo-controlled Avodart After Radical Therapy for Prostate Cancer Study (ARTS)

Background

Rising prostate-specific antigen (PSA) levels after radical therapy are indicative of recurrent or residual prostate cancer (PCa). This biochemical recurrence typically predates clinically detectable metastatic disease by several years. Management of patients with biochemical recurrence is controversial.

Objective

To assess the effect of dutasteride on progression of PCa in patients with biochemical failure after radical therapy.

Design, setting, and participants

Randomised, double-blind, placebo-controlled trial in 294 men from 64 centres across 9 European countries.

Intervention

The 5α-reductase inhibitor, dutasteride.

Outcome measurements and statistical analysis

The primary end point was time to PSA doubling from start of randomised treatment, analysed by log-rank test stratified by previous therapy and investigative-site cluster. Secondary end points included time to disease progression and the proportion of subjects with disease progression.

Results and limitations

Of the 294 subjects randomised (147 in each treatment group), 187 (64%) completed 24 mo of treatment and 107 discontinued treatment prematurely (71 [48%] of the placebo group, 36 [24%] of the dutasteride group). Dutasteride significantly delayed the time to PSA doubling compared with placebo after 24 mo of treatment (p < 0.001); the relative risk (RR) reduction was 66.1% (95% confidence interval [CI], 50.35–76.90) for the overall study period. Dutasteride also significantly delayed disease progression (which included PSA- and non-PSA-related outcomes) compared with placebo (p < 0.001); the overall RR reduction in favour of dutasteride was 59% (95% CI, 32.53–75.09). The incidence of adverse events (AEs), serious AEs, and AEs leading to study withdrawal were similar between the treatment groups. A limitation was that investigators were not blinded to PSA levels during the study.

Conclusions

Dutasteride delayed the biochemical progression of PCa in patients with biochemical failure after radical therapy for clinically localised disease. The safety and tolerability of dutasteride were generally consistent with previous experience.

Clinical trial registry

ClinicalTrials.gov, NCT00558363.     

Alcohol Intake Increases High-grade Prostate Cancer Risk Among Men Taking Dutasteride in the REDUCE Trial

Background

Although most studies found no association between alcohol intake and prostate cancer (PCa) risk, an analysis of the Prostate Cancer Prevention Trial found that high alcohol intake significantly increased PCa risk among men randomized to the 5α-reductase inhibitor (5-ARI) finasteride.

Objective

Determine whether alcohol affects PCa risk among men taking the 5-ARI dutasteride.

Design, settings, and participants

Reduction by Dutasteride of Prostate Cancer Events was a 4-yr, multicenter, randomized, double-blind, placebo-controlled trial to compare PCa after dutasteride administration (0.5 mg/d) with placebo. Participants had a baseline prostate-specific antigen between 2.5 and 10.0 ng/ml and a recent negative prostate biopsy. Alcohol intake was determined by baseline questionnaire, and participants underwent a prostate biopsy to determine PCa status at 2 yr and 4 yr of follow-up.

Outcome measurements and statistical analysis

Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between alcohol intake and low-grade (Gleason <7) and high-grade (Gleason >7) PCa.

Results and limitations

Of 6374 participants in our analysis, approximately 25% reported no alcohol consumption, 49% were moderate drinkers (one to seven drinks per week), and 26% were heavy drinkers (more than seven drinks per week). Alcohol intake was not associated with low- or high-grade PCa in the placebo arm and was not associated with low-grade PCa among men taking dutasteride. In contrast, men randomized to dutasteride and reporting more than seven drinks per week were 86% more likely to be diagnosed with high-grade PCa (p = 0.01). Among alcohol abstainers, dutasteride was associated with significantly reduced risk of high-grade PCa (OR: 0.59; 95% CI, 0.38–0.90), but dutasteride was no longer associated with reduced high-grade PCa among men reporting high alcohol intake (OR: 0.99; 95% CI, 0.67–1.45).

Conclusions

Alcohol consumption negated a protective association between dutasteride and high-grade PCa.

Patient summary

We confirmed a prior study that alcohol affects PCa prevention in patients taking 5-ARIs. Patients taking 5-ARIs may wish to eliminate alcohol intake if they are concerned about PCa.     

Digital rectal examination and the diagnosis of prostate cancer--a study based on 8 years and three screenings within the European Randomized Study of Screening for Prostate Cancer (ERSPC), Rotterdam

Background

Evidence indicates that an abnormal digital rectal examination (DRE) is a risk factor for high-grade prostate cancer (PC).

Objective

To determine whether men with an initially suspicious DRE, a prostate-specific antigen (PSA) level ≥3.0 ng/ml, and a benign prostate biopsy are at higher risk for significant PC at rescreening than men with an initially normal DRE, and whether an adaptation of the rescreening interval is warranted for this group.

Design, Setting, and Participants

Within the European Randomized Study of Screening for Prostate Cancer (ERSPC), Rotterdam, 2218 men underwent biopsy of the prostate (from 1993 to 2000) with a benign result at initial screening. The serum PSA was determined every 4 yr. A PSA level of ≥3.0 ng/ml prompted a DRE and a lateralised sextant biopsy.

Measurements

Number and characteristics of PCs found at repeat screenings and as interval cancers (ICs) were compared between men with or without a suspicious DRE result at initial screening. Multivariate logistic regression analyses were performed to evaluate if an initially suspicious DRE was a significant predictor for detecting cancer at consecutive screenings.

Results and Limitations

After 4 yr, the total number of PCs detected in men with and without an initially suspicious DRE was, respectively, 27 (6%) versus 103 (6%) (p = 0.99). After 8 yr these numbers increased, respectively, to,45 (10%) versus 167 (10%) (p = 0.88). The proportion of clinically significant PCs was 2% and 3%, respectively, for the group with initially normal and abnormal DRE after 8 yr. Having a suspicious DRE result at initial screening was not a significant predictor for detecting PC after 4 yr [odds ratio (OR) = 1.15, p = 0.59) or 8 yr (OR = 1.41, p = 0.43)]. A limitation of this study is the relatively short follow-up of 8 yr.

Conclusions

During a follow-up of 8 yr after initial cancer-negative biopsy, an initially suspicious DRE did not influence the chance for detection of cancer or significant cancer at later screens. An adaptation of the rescreening interval on the basis of the initial DRE-outcome is not warranted in future population-based screening for prostate cancer.     

Prostate cancer detection in the "grey area" of prostate-specific antigen below 10 ng/ml: head-to-head comparison of the updated PCPT calculator and Chun's nomogram, two risk estimators incorporating prostate cancer antigen 3

Background

Prostate cancer antigen 3 (PCA3) holds promise in diagnosing prostate cancer (PCa), but no consensus has been reached on its clinical use. Multivariable predictive models have shown increased accuracy over individual risk factors.

Objective

To compare the performance of the two available risk estimators incorporating PCA3 in the detection of PCa in the “grey area” of prostate-specific antigen (PSA) <10 ng/ml: the updated Prostate Cancer Prevention Trial (PCPT) calculator and Chun's nomogram.

Design, setting, and participants

Two hundred eighteen patients presenting with an abnormal PSA (excluding those with PSA >10 ng/ml) and/or abnormal digital rectal examination were prospectively enrolled in a multicentre Italian study between October 2008 and October 2009. All patients underwent ≥12-core prostate biopsy.

Measurements

PCA3 scores were assessed using the Progensa assay (Gen-Probe, San Diego, CA, USA). Comparisons between the two models were performed using tests of accuracy (area under the receiver operating characteristic curve [AUC-ROC]), calibration plots, and decision curve analysis. Biopsy predictors were identified by univariable and multivariable logistic regression. In addition, performance of PCA3 was analysed through AUC-ROC and predictive values.

Results and limitations

PCa was detected in 73 patients (33.5%). Among predictors included in the models, only PCA3, PSA, and prostate volume retained significant predictive value. AUC-ROC was higher for the updated PCPT calculator compared to Chun's nomogram (79.6% vs 71.5%; p = 0.043); however, Chun's nomogram displayed better overall calibration and a higher net benefit on decision curve analysis. Using a probability threshold of 25%, no high-grade cancers would be missed; the PCPT calculator would save 11% of biopsies, missing no cancer, whereas Chun's nomogram would save 22% of avoidable biopsies, although missing 4.1% non–high-grade cancers. The small number of patients may account for the lack of statistical significance in the predictive value of individual variables or model comparison.

Conclusions

Both Chun's nomogram and the PCPT calculator, by incorporating PCA3, can assist in the decision to biopsy by assignment of an individual risk of PCa, specifically in the PSA levels <10 ng/ml.     

Phase 1 and 2 studies demonstrate the safety and efficacy of intraprostatic injection of PRX302 for the targeted treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia

Background

PRX302 is a prostate specific antigen (PSA)–activated pore-forming protein toxin under development as a targeted approach for improving lower urinary tract symptoms (LUTS) caused by benign prostatic hyperplasia (BPH) without affecting sexual function.

Objective

To evaluate the safety and efficacy of PRX302 in men with moderate to severe BPH.

Design, setting, and participants

Eligible subjects were refractory, intolerant, or unwilling to undergo medical therapies for BPH and had International Prostate Symptom Score (IPSS) ≥12, a quality of life (QoL) score ≥3, and prostate volumes between 30 and 80 g. Fifteen patients were enrolled in phase 1 studies, and 18 patients entered phase 2 studies.

Interventions

Subjects received intraprostatic injection of PRX302 into the right and left transition zone via a transperineal approach in an office-based setting. Phase 1 subjects received increasing concentrations of PRX302 at a fixed volume; phase 2 subjects received increasing volumes per deposit at a fixed concentration.

Measurements

IPSS, QoL, prostate volume, maximum flow rate (Q_max), International Index of Erectile Function, serum PSA levels, pharmacokinetics, and adverse events were recorded at 30, 60, 90, 180, 270, and 360 d after treatment with PRX302.

Results and limitations

Sixty percent of men in the phase 1 study and 64% of men in the phase 2 study treated with PRX302 had ≥30% improvement compared to baseline in IPSS out to day 360. Patients also experienced improvement in QoL and reduction in prostate volume out to day 360. Patients receiving ≥1 ml of PRX302 per deposit had the best response overall. PRX302 had no deleterious effect on erectile function. Adverse events were mild to moderate and transient in nature. The major study limitation was the small sample size.

Conclusions

The promising safety profile and evidence of efficacy in the majority of treated subjects in these phase 1 and 2 studies supports further development of PRX302 as a minimally invasive, targeted treatment for BPH.     

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.     

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.     

Effect of dutasteride,tamsulosin and the combination on patient‐reported quality of life and treatment satisfaction in men with moderate‐to‐severe benign prostatic hyperplasia: 2‐year data from the CombAT trial

OBJECTIVE

To investigate the effect of dutasteride and tamsulosin as combined therapy compared with each monotherapy for improving patient‐reported health outcomes in men with moderate‐to‐severe urinary symptoms and prostate enlargement, reporting the pre‐planned 2‐year analyses from the CombAT trial.

PATIENTS AND METHODS

The CombAT study is an ongoing, international, double‐blind, randomized, parallel‐group trial. Men aged ≥50 years with a clinical diagnosis of benign prostatic hyperplasia (BPH), an International Prostate Symptom Score (IPSS) of ≥12 units, a prostate volume of ≥30 mL, a total serum prostate‐specific antigen level of 1.5–10 ng/mL and a peak urinary flow of >5 and ≤15 mL/s, with a minimum voided volume of ≥125 mL, were randomized to receive 0.5 mg dutasteride, 0.4 mg tamsulosin or the combination once daily for 4 years. Symptoms were assessed every 3 months. The primary endpoint at 2 years was the change in IPSS from baseline. Secondary endpoints included various measures of health outcomes, which included the BPH Impact Index (BII), IPSS Question 8 (Q8), and the Patient Perception of Study Medication (PPSM) questionnaire.

RESULTS

Combined therapy resulted in significantly greater improvements in BII and IPSS Q8 from baseline than did dutasteride from 3 months and compared with tamsulosin from 9 months (BII) or 12 months (IPSS Q8). Assessments using the PPSM questionnaire showed that a significantly higher proportion of patients were satisfied with and would request dutasteride and tamsulosin combined therapy than with each monotherapy at 24 months.

CONCLUSIONS

Dutasteride and tamsulosin combined therapy provides significantly greater improvements in patient‐reported quality of life and treatment satisfaction than both monotherapies at 2 years, following the trends for clinical improvements in symptom scores and peak urinary flow rates, in men with moderate‐to‐severe BPH symptoms.     

Three-tesla magnetic resonance-guided prostate biopsy in men with increased prostate-specific antigen and repeated, negative, random, systematic, transrectal ultrasound biopsies: detection of clinically significant prostate cancers

Background

Patients with elevated prostate-specific antigen (PSA) and one or more previous negative transrectal ultrasound (TRUS) biopsy sessions are subject to diagnostic uncertainty due to TRUS-biopsy undersampling. Magnetic resonance (MR)–guided biopsy (MRGB) has shown high prostate cancer (PCa)–detection rates in studies with limited patient numbers.

Objective

Determine the detection rate of (clinically significant) PCa for MRGB of cancer-suspicious regions (CSRs) on 3-T multiparametric MR imaging (MP-MRI) in patients with elevated PSA and one or more negative TRUS-biopsy sessions.

Design, setting, and participants

Of 844 patients who underwent 3-T MP-MRI in our referral centre between March 2008 and February 2011, 438 consecutive patients with a PSA >4.0 ng/ml and one negative TRUS-biopsy session or more were included. MRGB was performed in 265 patients. Exclusion criteria were existent PCa, endorectal coil use, and MP-MRI for indications other than cancer detection.

Intervention

Patients underwent MRGB of MP-MRI CSRs.

Measurements

(Clinically significant) MRGB cancer-detection rates were determined. Clinically significant cancer was defined by accepted (i.a. Epstein and d’Amico) criteria based on PSA, Gleason score, stage, and tumour volume. Follow-up PSA and histopathology were collected. Sensitivity analysis was performed for patients with MP-MRI CSRs without MRGB.

Results and limitations

In a total of 117 patients, cancer was detected with MRGB (n = 108) or after negative MRGB (n = 9). PCa was detected in 108 of 438 patients (25%) and in 41% (108 of 265) of MRGB patients. The majority of detected cancers (87%) were clinically significant. Clinically significant cancers were detected in seven of nine (78%) negative MRGB patients in whom PCa was detected during follow-up. Sensitivity analysis resulted in increased cancer detection (47–56%). Complications occurred in 0.2% of patients (5 of 265).

Conclusions

In patients with elevated PSA and one or more negative TRUS-biopsy sessions, MRGB of MP-MRI CSRs had a PCa-detection rate of 41%. The majority of detected cancers were clinically significant (87%).     

Monotherapy with tadalafil or tamsulosin similarly improved lower urinary tract symptoms suggestive of benign prostatic hyperplasia in an international, randomised, parallel, placebo-controlled clinical trial

Background

Tadalafil improved lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH; LUTS/BPH) in clinical studies but has not been evaluated together with an active control in an international clinical study.

Objective

Assess tadalafil or tamsulosin versus placebo for LUTS/BPH.

Design, setting, and participants

A randomised, double-blind, international, placebo-controlled, parallel-group study assessed men ≥45 yr of age with LUTS/BPH, International Prostate Symptom Score (IPSS) ≥13, and maximum urinary flow rate (Q_max) ≥4 to ≤15 ml/s. Following screening and washout, if needed, subjects completed a 4-wk placebo run-in before randomisation to placebo (n = 172), tadalafil 5 mg (n = 171), or tamsulosin 0.4 mg (n = 168) once daily for 12 wk.

Measurements

Outcomes were assessed using analysis of covariance (ANCOVA) or ranked analysis of variance (ANOVA) (continuous variables) and Cochran-Mantel-Haenszel test or Fisher exact test (categorical variables).

Results and limitations

IPSS significantly improved versus placebo through 12 wk with tadalafil (−2.1; p = 0.001; primary efficacy outcome) and tamsulosin (−1.5; p = 0.023) and as early as 1 wk (tadalafil and tamsulosin both −1.5; p < 0.01). BPH Impact Index significantly improved versus placebo at first assessment (week 4) with tadalafil (−0.8; p < 0.001) and tamsulosin (−0.9; p < 0.001) and through 12 wk (tadalafil −0.8, p = 0.003; tamsulosin −0.6, p = 0.026). The IPSS Quality-of-Life Index and the Treatment Satisfaction Scale–BPH improved significantly versus placebo with tadalafil (both p < 0.05) but not with tamsulosin (both p > 0.1). The International Index of Erectile Function–Erectile Function domain improved versus placebo with tadalafil (4.0; p < 0.001) but not tamsulosin (−0.4; p = 0.699). Q_max increased significantly versus placebo with both tadalafil (2.4 ml/s; p = 0.009) and tamsulosin (2.2 ml/s; p = 0.014). Adverse event profiles were consistent with previous reports. This study was limited in not being powered to directly compare tadalafil versus tamsulosin.

Conclusions

Monotherapy with tadalafil or tamsulosin resulted in significant and numerically similar improvements versus placebo in LUTS/BPH and Q_max. However, only tadalafil improved erectile dysfunction.

Trial registration

Clinicaltrials.gov ID NCT00970632     

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.     

Clinical outcomes after combined therapy with dutasteride plus tamsulosin or either monotherapy in men with benign prostatic hyperplasia (BPH) by baseline characteristics: 4-year results from the randomized, double-blind Combination of Avodart and Tamsulosin (CombAT) trial

What’s known on the subject? and What does the study add? Treatment of benign prostatic hyperplasia (BPH) centres on two drug classes, 5α‐reductase inhibitors and α‐blockers. The 4‐year Combination of Avodart® and Tamsulosin (CombAT) study investigated whether the combination of dutasteride and tamsulosin was more effective than either monotherapy in reducing the relative risk of AUR, BPH‐related surgery, and BPH clinical progression in men with moderate‐to‐severe LUTS who were at increased risk of disease progression. Data from the 2‐ and 4‐year, pre‐planned primary and secondary endpoint analyses for the CombAT study have been reported previously. This study reports the outcomes of post hoc analyses of the influence of baseline parameters on the incidence of AUR, BPH‐related surgery, and overall clinical progression in patients treated with tamsulosin, dutasteride, or combination therapy with both agents.

OBJECTIVE

? To investigate the influence of baseline variables on the 4‐year incidence of acute urinary retention (AUR), benign prostatic hyperplasia (BPH)‐related surgery and overall clinical progression in men treated with tamsulosin, dutasteride, or a combination of both.

PATIENTS AND METHODS

? The 4‐year Combination of Avodart® and Tamsulosin (CombAT) study was a multicenter, randomized, double‐blind, parallel‐group study of clinical outcomes in men aged ≥50 years with symptomatic (International Prostate Symptom Score [IPSS]≥12) BPH, with prostate‐specific antigen (PSA) levels of ≥1.5 ng/mL and ≤10 ng/mL, and a prostate volume (PV) of ≥30 mL. ? Eligible patients received tamsulosin 0.4 mg, dutasteride 0.5 mg, or a combination of both. ? The primary endpoint was time to first AUR or BPH‐related surgery. Secondary endpoints included clinical progression of BPH and symptoms. Posthoc analyses of the influence of baseline variables (including age, IPSS health‐related quality of life [HRQL], PV, PSA, IPSS, peak urinary flow rate [Q_max] and body‐mass index [BMI]) on the incidence of AUR or BPH‐related surgery, clinical progression of BPH, and symptoms were performed.

RESULTS

? There were 4844 men in the intent‐to‐treat population. Overall baseline characteristics were similar across all patient groups. ? Regardless of baseline subgroup, the incidence of AUR or BPH‐related surgery was higher in men treated with tamsulosin than in those treated with dutasteride or combined therapy. ? Combined therapy was statistically better than tamsulosin in reducing the risk of AUR or BPH‐related surgery in subgroups of baseline PV > 42.0 mL, in all subgroups of baseline PSA level, and all other baseline subgroups (P≤ 0.001). ? Across treatment groups, the incidence of clinical progression was highest in men with a baseline IPSS of <20 or IPSS HRQL score of <4. The incidence of clinical progression was also higher in men receiving tamsulosin than dutasteride or combined therapy in all baseline subgroups, except for men with a baseline PV of <40 mL. Combined therapy reduced the relative risk (RR) of clinical progression compared with tamsulosin across all baseline subgroups and compared with dutasteride across most baseline subgroups. ? Symptom deterioration was the most common progression event in each treatment group regardless of baseline subgroup, except in those men with an IPSS of ≥20 at baseline. Combined therapy reduced the RR of symptom deterioration compared with tamsulosin across all but one baseline subgroup (the reduction was not significant for men with a baseline PV of <40 mL) and compared with dutasteride in most subgroups.

CONCLUSIONS

? Men with a baseline PV of ≥40 mL and any baseline PSA level of ≥1.5 ng/mL had greater reductions in the RR of AUR or BPH‐related surgery and greater reductions in the RR of clinical progression and symptom deterioration on combined therapy or dutasteride monotherapy than on tamsulosin monotherapy. ? These analyses support the long‐term use of combined therapy with dutasteride plus tamsulosin in men with moderate‐to‐severe BPH symptoms and a slightly enlarged prostate.     

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.