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.     

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-specific antigen and long-term prediction of prostate cancer incidence and mortality in the general population

Background

It is largely unknown whether prostate-specific antigen (PSA) level at first date of testing predicts long-term risk of prostate cancer (PCa) incidence and mortality in the general population.

Objective

Determine whether baseline PSA levels predict long-term risk of PCa incidence and mortality.

Design, setting, and participants

We examined 4383 men aged 20–94 yr from the Danish general population in the prospective Copenhagen City Heart Study. PSA was measured in plasma samples obtained in 1981–1983.

Measurements

PCa incidence and mortality as a function of baseline PSA was assessed using Kaplan-Meier plots of cumulative incidence and competing risk subhazard ratios.

Results and limitations

During 28 yr of follow-up, 170 men developed PCa, and 94 men died from PCa. Median follow-up was 18 yr (range: 0.5–28 yr). For PCa incidence, the subhazard ratio was 3.0 (95% confidence interval [CI], 1.9–4.6) for a PSA level of 1.01–2.00 ng/ml, 6.8 (95% CI, 4.2–11) for PSA 2.01–3.00 ng/ml, 6.6 (95% CI, 3.4–13) for PSA 3.01–4.00 ng/ml, 16 (95% CI, 10.4–25) for PSA 4.01–10.00 ng/ml, and 57 (95% CI, 32–104) for PSA >10.00 ng/ml versus 0.01–1.00 ng/ml. For PCa mortality, corresponding subhazard ratios were 2.2 (95% CI, 1.3–3.9), 5.1 (95% CI, 2.8–9.0), 4.2 (95% CI, 1.8–10), 7.0 (95% CI, 3.8–14), and 14 (95% CI, 6.0–32). For men with PSA levels of 0.01–1.00 ng/ml, the absolute 10-yr risk of PCa was 0.6% for ages <45 yr, 0.7% for ages 45–49 yr, 1.1% for ages 50–54 yr, 1.2% for ages 55–59 yr, 1.3% for ages 60–64 yr, 1.1% for ages 65–69 yr, 1.3% for ages 70–74 yr, and 1.5% for ages ≥75 yr; corresponding values for PSA levels >10.00 ng/ml were 35%, 41%, 63%, 71%, 77%, 69%, 75%, and 88%, respectively.

Conclusions

Stepwise increases in PSA at first date of testing predicted a 3–57-fold increased risk of PCa, a 2–16-fold increased risk of PCa mortality, and a 35–88% absolute 10-yr risk of PCa in men with PSA levels >10.00 ng/ml. Equally important, the absolute 10-yr risk of PCa in men with PSA levels 0.01–1.00 ng/ml was only 0.6–1.5%.     

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).     

Long-term risk of clinical progression after biochemical recurrence following radical prostatectomy: the impact of time from surgery to recurrence

Background

The natural history of biochemical recurrence (BCR) after radical retropubic prostatectomy (RRP) is variable and does not always translate into systemic progression or prostate cancer (PCa) death.

Objective

To evaluate long-term clinical outcomes of patients with BCR and to determine predictors of disease progression and mortality in these men.

Design, setting, and participants

We reviewed our institutional registry of 14 632 patients who underwent RRP between 1990 and 2006 to identify 2426 men with BCR (prostate-specific antigen [PSA] levels ≥0.4 ng/ml) who did not receive neoadjuvant or adjuvant therapy. Median follow-up was 11.5 yr after RRP and 6.6 yr after BCR.

Intervention

RRP.

Measurements

Patients were grouped into quartiles according to time from RRP to BCR. Survival after BCR was estimated using the Kaplan-Meier method and compared using the log-rank test. Cox proportional hazard regression models were used to analyze clinicopathologic variables associated with systemic progression and death from PCa.

Results and limitations

Median systemic progression-free survival (PFS) and cancer-specific survival (CSS) had not been reached after 15 yr of follow-up after BCR. Cancer-specific mortality 10 yr after BCR was 9.9%, 9.3%, 7.8%, and 4.7% for patients who experienced BCR <1.2 yr, 1.2–3.1 yr, 3.1–5.9 yr, and >5.9 yr after RRP, respectively (p = 0.10). On multivariate analysis, time from RRP to BCR was not significantly associated with the risk of systemic progression (p = 0.50) or cancer-specific mortality (p = 0.81). Older patient age, increased pathologic Gleason score, advanced tumor stage, and rapid PSA doubling time (DT) predicted systemic progression and death from PCa. Limitations included retrospective design, varied utilization of salvage therapies, and the inclusion of few patients with positive lymph nodes.

Conclusions

Only a minority of men experience systemic progression and death from PCa following BCR. The decision to institute secondary therapies must balance the risk of disease progression with the cost and morbidity of treatment, independent of time from RRP to BCR.     

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.     

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.     

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.     

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.     

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.     

Long-term Prostate-specific Antigen Velocity in Improved Classification of Prostate Cancer Risk and Mortality

Background

It remains unclear whether adding long-term prostate-specific antigen velocity (PSAV) to baseline PSA values improves classification of prostate cancer (PCa) risk and mortality in the general population.

Objective

To determine whether long-term PSAV improves classification of PCa risk and mortality in the general population.

Design, setting, and participants

We studied 503 men aged 30–80 yr, with and without PCa, who had repeated PSA measurements over 20 yr and up to 28 yr before PCa diagnosis. These were selected from among 7455 men in the Copenhagen City Heart Study, a prospective, general population study with follow-up from 1981 through 2010. Results were subsequently applied to all 1 351 441 men aged 40–80 yr living in Denmark from 1997 through 2006.

Outcome measurements and statistical analysis

PCa risk and mortality were assessed using Cox regression. Improvement in risk classification was assessed using the net reclassification index (NRI).

Results

Age-adjusted hazard ratios for PCa risk and mortality were 2.7–5.3 and 2.3–3.4, respectively, for long-term PSAV when added to models already including baseline PSA values. For PCa risk and mortality, adding long-term PSAV to models already including baseline PSA values and age yielded continuous NRIs of 98–99% and 56–106%, respectively. Used on a nationwide scale (eg, for men aged 60–64 yr), long-term PSAV >0.35 versus ≤0.35 ng/ml per year appropriately reclassified 128 of 10 000 men with PCa and 8095 of 10 000 men with no PCa. Correspondingly, inappropriately reclassified were 49 of 10 000 men with PCa and 1658 of 10 000 men with no PCa.

Conclusions

Long-term PSAV in addition to baseline PSA value improves classification of PCa risk and mortality. Applying long-term PSAV nationwide, the ratio of appropriately to inappropriately classified men would typically be 5:1.     

Long-term Outcomes Among Noncuratively Treated Men According to Prostate Cancer Risk Category in a Nationwide,Population-based Study

Background

Limited data exist on long-term outcomes among men with prostate cancer (PCa) from population-based cohorts incorporating information on clinical risk category.

Objective

To assess 15-yr mortality for men with PCa treated with noncurative intent according to clinical stage, Gleason score (GS), serum levels of prostate specific antigen (PSA), comorbidity, and age.

Design, setting, and participants

Register-based cohort study of 76 437 cases in the National Prostate Cancer Register (NPCR) of Sweden diagnosed from 1991 through 2009 and treated with noncurative intent. Each case was placed in one of five risk categories: (1) low risk: T1–T2 tumor, PSA level <10 ng/ml, and GS ≤6; (2) intermediate risk: T1–T2 tumor and PSA level 10–<20 ng/ml or GS 7; (3) high risk: T3 tumor or PSA level 20–<50 ng/ml or GS ≥8; (4) regional metastases: N1 or T4 tumor or PSA level 50–100 ng/ml; and (5) distant metastases: M1 tumor or PSA ≥100 ng/ml.

Outcome measurements and statistical analysis

Ten- and 15-yr cumulative risk of death after diagnosis from PCa, cardiovascular disease, and other causes.

Results and limitations

Among men with a Charlson Comorbidity Index (CCI) score of 0, no differences were found in observed versus expected all-cause mortality in the low-risk group. Observed mortality was only slightly greater in the intermediate-risk group, but men with high-risk localized PCa or more advanced disease had substantially higher mortality than expected. CCI was strongly associated with cumulative 10-yr mortality from causes other than PCa, especially for men <65 yr. Limitations include potential misclassification in risk category due to GS assignment.

Conclusions

PCa mortality rates vary 10-fold according to risk category. The risk of death from causes other than PCa is most strongly related to comorbidity status in younger men.     

Development of a New Method for Monitoring Prostate-Specific Antigen Changes in Men with Localised Prostate Cancer: A Comparison of Observational Cohorts

Background

Prostate-specific antigen (PSA) measurements are increasingly used to monitor men with localised prostate cancer (PCa), but there is little consensus about the method to use.

Objective

To apply age-specific predictions of PSA level (developed in men without cancer) to one cohort of men with clinically identified PCa and one cohort of men with PSA-detected PCa. We hypothesise that among men with clinically identified cancer, the annual increase in PSA level would be steeper than in men with PSA-detected cancer.

Design, setting, and participants

The Scandinavian Prostate Cancer Group 4 (SPCG-4) cohort consisted of 321 men assigned to the watchful waiting arm of the SPCG-4 trial. The UK cohort consisted of 320 men with PSA-detected PCa in the Prostate testing for cancer and Treatment (ProtecT) study who opted for monitoring. Multilevel models describing changes in PSA level were fitted to the two cohorts, and average PSA level at age 50, change in PSA level with age, and predicted PSA values were derived.

Measurements

PSA level.

Results and limitations

In the SPCG-4 cohort, mean PSA at age 50 was similar to the cancer-free cohort but with a steeper yearly increase in PSA level (16.4% vs 4.0%). In the UK cohort, mean PSA level was higher than that in the cancer-free cohort (due to a PSA biopsy threshold of 3.0 ng/ml) but with a similar yearly increase in PSA level (4.1%). Predictions were less accurate for the SPCG-4 cohort (median difference between observed and predicted PSA level: −2.0 ng/ml; interquartile range [IQR]: −7.6–0.7 ng/ml) than for the UK cohort (median difference between observed and predicted PSA level: −0.8 ng/ml; IQR: −2.1–0.1 ng/ml).

Conclusions

In PSA-detected men, yearly change in PSA was similar to that in cancer-free men, whereas in men with symptomatic PCa, the yearly change in PSA level was considerably higher. Our method needs further evaluation but has promise for refining active monitoring protocols.     

The relationship between prostate inflammation and lower urinary tract symptoms: examination of baseline data from the REDUCE trial

Objective

The ongoing REDUCE trial is a 4-yr, phase 3, placebo-controlled study to determine if daily dutasteride 0.5 mg reduces the risk of biopsy detectable prostate cancer. Prostate biopsies performed in all men prior to entry were centrally reviewed, thus allowing an examination of the relationship between inflammatory changes and lower urinary tract symptoms (LUTS).

Methods

Eligible men were aged 50–75 yr, with serum prostate-specific antigen ≥2.5 ng/ml and ≤10 ng/ml (50–60 yr), or ≥3.0 ng/ml and ≤10 ng/ml (>60 yr) and an International Prostate Symptom Score (IPSS) < 25 (or <20 if already on alpha-blocker therapy). Acute prostatitis was an exclusion criterion. For a given individual, inflammation was assessed across all cores and the amount of inflammation scored as none (0), mild (1), moderate (2), or marked (3). LUTS was assessed with the use of the IPSS. The relationship between inflammation scores (averaged over all cores) and total IPSS; grouped IPSS (0–3, 4–7, 8–11, 12–15, 16–19, ≥20); and irritative, obstructive, and nocturia subscores was determined by Spearman rank correlations. The relative contribution of inflammation, age, and body mass index was then examined with the use of linear regression analyses.

Results

Data were available for 8224 men. Statistically significant but relatively weak correlations were found between average and maximum chronic inflammation and IPSS variables (correlation coefficients, 0.057 and 0.036, respectively; p < 0.001 for total IPSS). Both age and average chronic inflammation were significant in the linear regression after adjustment for other covariates; for both variables, more severe inflammation was associated with higher IPSS scores.

Conclusions

In the REDUCE population, there is evidence of a relationship between the degree of LUTS and the degree of chronic inflammation. Study entry criteria that selected older men and decreased enrolment of men with a greater degree of inflammation and LUTS may have limited the strength of this relationship. The impact of baseline prostate inflammation on progression of LUTS and/or associated complications will be determined during 4-yr longitudinal follow-up.     

A Genetic Score Can Identify Men at High Risk for Prostate Cancer Among Men With Prostate-Specific Antigen of 1–3 ng/ml

Background

The diagnostic performance of a genetic score based on single nucleotide polymorphisms (SNPs) is unknown in the prostate-specific antigen (PSA) range of 1–3 ng/ml. A substantial proportion of men in this PSA span have prostate cancer (PCa), but biomarkers to determine who should undergo a prostate biopsy are lacking.

Objective

To evaluate whether a genetic risk score identifies men in the PSA range of 1–3 ng/ml who are at higher risk for PCa.

Design, setting, and participants

Men aged 50–69 yr with PSA 1–3 ng/ml and without a previous prostate biopsy were selected from the STHLM2 cohort. Of 2696 men, 49 SNPs were genotyped, and a polygenic risk score was calculated. Of these men, 860 were invited according to risk score, and 172 underwent biopsy.

Outcome measurements and statistical analysis

The risk of PCa was assessed using univariate and multivariate logistic regression analysis.

Results and limitations

PCa was diagnosed in 47 of 172 participants (27%), with Gleason sum 6 in 36 of 47 men (77%) and Gleason sum ≥7 in 10 of 47 men (21%); one man had intraductal cancer. The genetic score was a significant predictor of a positive biopsy (p = 0.028), even after adjusting for PSA, ratio of free to total PSA, prostate volume, age, and family history. There was an increase in the odds ratio of 1.60 (95% confidence interval, 1.05–2.45) with increasing genetic risk score. The absolute risk difference of positive biopsy was 19 percentage points, comparing the high and low genetic risk group (37% vs 18%).

Conclusions

A risk score based on SNPs predicts biopsy outcome in previously unbiopsied men with PSA 1–3 ng/ml. Introducing a genetic-based risk stratification tool can increase the proportion of men being classified in line with their true risk of PCa.     

Performance of the Prostate Cancer Antigen 3 (PCA3) Gene and Prostate-Specific Antigen in Prescreened Men: Exploring the Value of PCA3 for a First-line Diagnostic Test

Background

The performance characteristics of serum prostate-specific antigen (PSA) as a diagnostic test for prostate cancer (PCa) are poor. The performance of the PCa antigen 3 (PCA3) gene as a primary diagnostic is unknown.

Objective

Assess the value of PCA3 as a first-line diagnostic test.

Design, setting and participants

Participants included men aged 63–75 who were invited for rescreening in the period from September 2007 to February 2009 within the European Randomised Study of Screening for Prostate Cancer, Rotterdam section.

Interventions

Lateral sextant biopsies were performed if the serum PSA value was ≥3.0 ng/ml and/or the PCA3 score was ≥10.

Measurements

Measurements included distribution and correlation of PSA value and PCA3 score and their relation to the number of cases and the characteristics of PCa detected. Additional value of PCA3 was included in men with previous negative biopsy and/or PSA <3.0 ng/ml.

Results and limitations

In 721 men, all biopsied, 122 PCa cases (16.9%) were detected. Correlation between PSA and PCA3 is poor (Spearman rank correlation: ρ = 0.14; p < 0.0001). A PSA ≥3.0 ng/ml misses 64.7% of the total PCa that can be detected with the sextant biopsy technique and 57.9% of serious PCa (T2a or higher and/or Gleason grade ≥4, n = 19), and 68.2% of biopsies could have been avoided; the respective data for PCA3 ≥35 are 32%, 26.3%, and 51.7%. Performance of PCA3 in men with low PSA (area under the curve [AUC]: 0.63) and/or previous negative biopsy (AUC: 0.68) is unclear but has limited reliability due to small numbers.

Conclusions

PCA3 as a first-line screening test shows improvement of the performance characteristics and identification of serious disease compared with PSA in this prescreened population.     

A Calculator for Prostate Cancer Risk 4 Years After an Initially Negative Screen: Findings from ERSPC Rotterdam

Background

Inconclusive test results often occur after prostate-specific antigen (PSA)–based screening for prostate cancer (PCa), leading to uncertainty on whether, how, and when to repeat testing.

Objective

To develop and validate a prediction tool for the risk of PCa 4 yr after an initially negative screen.

Design, setting, and participants

We analyzed data from 15 791 screen-negative men aged 55–70 yr at the initial screening round of the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer.

Outcome measurements and statistical analysis

Follow-up and repeat screening at 4 yr showed either no PCa, low-risk PCa, or potentially high-risk PCa (defined as clinical stage >T2b and/or biopsy Gleason score ≥7 and/or PSA ≥10.0 ng/ml). A multinomial logistic regression analysis included initial screening data on age, PSA, digital rectal examination (DRE), family history, prostate volume, and having had a previous negative biopsy. The 4-yr risk predictions were validated with additional follow-up data up to 8 yr after initial screening.

Results and limitations

Positive family history and, especially, PSA level predicted PCa, whereas a previous negative biopsy or a large prostate volume reduced the likelihood of future PCa. The risk of having PCa 4 yr after an initially negative screen was 3.6% (interquartile range: 1.0–4.7%). Additional 8-yr follow-up data confirmed these predictions. Although data were based on sextant biopsies and a strict protocol-based biopsy indication, we suggest that men with a low predicted 4-yr risk (eg, ≤1.0%) could be rescreened at longer intervals or not at all, depending on competing risks, while men with an elevated 4-yr risk (eg, ≥5%) might benefit from immediate retesting. These findings need to be validated externally.

Conclusions

This 4-yr future risk calculator, based on age, PSA, DRE, family history, prostate volume, and previous biopsy status, may be a promising tool for reducing uncertainty, unnecessary testing, and overdiagnosis of PCa.     

Detectable Prostate-Specific Antigen Nadir During Androgen-Deprivation Therapy Predicts Adverse Prostate Cancer–Specific Outcomes: Results from the SEARCH Database

Background

A prostate-specific antigen (PSA) level <0.2 ng/ml 8 mo after starting on androgen-deprivation therapy (ADT) is correlated with better outcomes. However, not all men reach a nadir PSA level within 8 mo. Whether the lowest PSA on ADT—specifically, <0.2 ng/ml—can be used for risk stratification is untested.

Objective

We examined the predictive value of small but detectable PSA nadir values on prostate cancer (PCa)–specific outcomes in men treated with early ADT after radical prostatectomy (RP).

Design, setting, and participants

We performed a retrospective review of men treated with ADT after RP before metastases from the SEARCH database. We identified 402 men treated with ADT for elevated PSA following RP, of whom 294 men had complete data. Median follow-up after PSA nadir was 49 mo. All men had a PSA nadir <4 ng/ml; 223 men (76%) had an undetectable nadir.

Intervention

ADT for an elevated PSA following RP with no radiographic evidence of metastatic disease.

Outcome measurements and statistical analysis

PSA nadir on ADT was defined as the lowest PSA value during ADT. Proportional hazards models and the C index were used to test the association and predictive accuracy, respectively, between PSA nadir and PCa-specific outcomes.

Results and limitations

Men with a PSA nadir between 0.01 and 0.2 ng/ml had a greater risk of progression to castration-resistant PCa (CRPC) (hazard ratio [HR]: 5.14; p < 0.001), metastases (HR: 3.98; p = 0.006), and PCa-specific mortality (PCSM) (HR: 5.33; p = 0.003) than men with an undetectable nadir. When data were restricted to men followed with ultrasensitive PSA values (sensitivity of 0.01 ng/ml), the C index of PSA nadir alone for predicting CRPC, metastases, and PCSM was 0.88, 0.91, and 0.96, respectively.

Conclusions

A PSA nadir on ADT, even at a very low level, strongly predicts progression to CRPC, metastases, and PCSM. Men with a detectable PSA nadir during ADT should be considered for clinical trials.     

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.