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.     

Should Pathologists Routinely Report Prostate Tumour Volume? The Prognostic Value of Tumour Volume in Prostate Cancer

Background

The independent prognostic value of tumour volume in radical prostatectomy (RP) specimens is controversial, and it remains a matter of debate whether pathologists should report a measure of tumour volume. In addition, tumour volume might be of value in substaging of pathologic tumour stage (pT2) prostate cancer (PCa).

Objective

To assess the prognostic value of PCa tumour volume.

Design, setting, and participants

The cohort consisted of 344 participants in the European Randomised Study of Screening for Prostate Cancer (ERSPC), Rotterdam section, whose PCa was treated with RP. Mean time of follow-up was 96.2 mo.

Measurements

Tumour volume was measured in totally embedded RP specimens with a morphometric, computer-assisted method and assessed as a continuous variable, as relative tumour volume (tumour volume divided by prostate volume), and in a binary fashion (≥0.5 ml or <0.5 ml). These variables were related to prostate-specific antigen (PSA) progression, local recurrence, or distant metastasis and PCa-related mortality using univariate and multivariable Cox proportional hazards analyses. The analyses were repeated in the subgroup with pT2 tumours.

Results and limitations

Tumour volume was related to tumour stage, Gleason score, seminal vesicle invasion (SVI), and surgical margin status. In univariate analyses, tumour volume and relative tumour volume were predictive for all outcome variables. In multivariable analyses, including age, tumour stage, Gleason score, SVI, and surgical margin status, neither tumour volume nor relative volume were independent predictors of progression or mortality. Tumour volume ≥0.5 ml was predictive for PSA recurrence and local and/or distant progression in univariate analyses but not in multivariable analyses. Tumour volume was not predictive for recurrence or mortality in univariate or multivariable analyses in the pT2 subgroup.

Conclusions

Tumour volume did not add prognostic value to routinely assessed pathologic parameters. Therefore, there seems to be little reason to routinely measure tumour volume in RP specimens.     

Preoperative prostate-specific antigen isoform p2PSA and its derivatives, %p2PSA and prostate health index, predict pathologic outcomes in patients undergoing radical prostatectomy for prostate cancer

Background

Currently available predictive models fail to assist clinical decision making in prostate cancer (PCa) patients who are possible candidates for radical prostatectomy (RP). New biomarkers would be welcome.

Objective

Test the hypothesis that prostate-specific antigen (PSA) isoform p2PSA and its derivates, percentage of p2PSA to free PSA (%p2PSA) and the Prostate Health Index (PHI), predict PCa characteristics at final pathology after RP.

Design, setting, and participants

An observational prospective study was performed in 350 consecutive men diagnosed with clinically localised PCa who underwent RP.

Measurements

We determined the predictive accuracy of serum total PSA (tPSA), free PSA (fPSA), fPSA-to-tPSA ratio (%fPSA), p2PSA, %p2PSA, and PHI. The primary end point was to determine the accuracy of these biomarkers in predicting the presence of pT3 disease, pathologic Gleason sum ≥7, Gleason sum upgrading, and tumour volume <0.5 ml.

Intervention

Open retropubic and robot-assisted laparoscopic RP was performed. Pelvic lymphadenectomy was performed according to baseline oncologic parameters and the surgeon's judgement.

Results and limitations

The %p2PSA and PHI levels were significantly higher in patients with pT3 disease, pathologic Gleason sum ≥7, and Gleason sum upgrading (all p values <0.001). Conversely, %p2PSA and PHI levels were significantly lower in patients with tumour volume <0.5 ml (p < 0.001). By univariate analysis, both %p2PSA and PHI were accurate predictors of pT3 disease, pathologic Gleason sum ≥7, Gleason sum upgrading, and tumour volume <0.5 ml. By multivariate analyses, the inclusion of both %p2PSA and PHI significantly increased the predictive accuracy of a base multivariate model (excluding the tumour volume prediction for both variables, and Gleason sum upgrading for the model including %p2PSA) that included patient age, tPSA, fPSA, f/tPSA, clinical stage, and biopsy Gleason sum.

Conclusions

We found that p2PSA and its derivatives are predictors of PCa characteristics at final pathology after RP and are more accurate than currently available markers.     

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.     

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%).     

Efforts to resolve the contradictions in early diagnosis of prostate cancer: a comparison of different algorithms of sarcosine in urine

Controversial data on sarcosine as a promising biomarker for prostate cancer (PCa) detection are present. The objective was to clarify these discrepancies and reevaluate the potential value of sarcosine in PCa. Sarcosine algorithms (supernatant and sediment sarcosine/creatinine, supernatant and sediment log2 (sarcosine/alanine)) in urine samples from 71 untreated patients with PCa, 39 patients with no evidence of malignancy (NEM) and 20 healthy women and men were quantified by liquid chromatography/tandem mass spectrometry. Although any sarcosine algorithms were significantly higher in PCa patients than in NEM patients (all P<0.05), comparable sarcosine values were measured in healthy women and men. Additionally, neither biopsy Gleason score nor clinical T-stage were correlated with sarcosine algorithms (all P>0.05), and receiver operating characteristic curve analysis indicated that the diagnostic power of any of sarcosine algorithms was nonsignificantly higher than that of serum and urine PSA, but nonsignificantly lower than prostate cancer antigen 3 (PCA3) and the percent-free PSA (%fPSA). Improved diagnostic performances were observed when any of sarcosine algorithms was combined with PCA3 or %fPSA. In conclusion, the predictive power of sarcosine in PCa is modest compared with PCA3 and %fPSA. Sarcosine, which awaits more validation before it reaches the clinic, could be included into the list of candidate PCa biomarkers.     

Radical Prostatectomy for Incidental (Stage T1a–T1b) Prostate Cancer: Analysis of Predictors for Residual Disease and Biochemical Recurrence

Background

Controversies exist about the most appropriate management for patients with incidental prostate cancer after surgery for benign prostatic hyperplasia (BPH).

Objectives

To test the accuracy of preoperative clinical variables in predicting the presence of residual disease and biochemical recurrence in patients with incidental prostate cancer treated with radical retropubic prostatectomy.

Design, Setting, and Participants

We analyzed 126 T1a–T1b prostate cancers diagnosed at surgery for BPH between 1995 and 2007.

Intervention

All patients underwent radical retropubic prostatectomy within 6 mo of surgery for BPH.

Measurements

Univariate and multivariate logistic regression models addressed the association between the predictors (age, prostate-specific antigen [PSA] before and after surgery for BPH, T1a–T1b stage, prostate volume, and Gleason score at surgery for BPH) and the presence of residual cancer at radical retropubic prostatectomy. Cox proportional hazards regression analyses tested the relationship between the same predictors and the rate of biochemical recurrence after radical retropubic prostatectomy.

Results and Limitations

Seventy-five (59.5%) patients were stage T1a and 51 (40.5%) were stage T1b. At radical retropubic prostatectomy, 21 (16.7%) patients were pT0 and seven (5.6%) patients had extraprostatic disease (pT3). PSA before and after surgery for BPH and Gleason score at surgery for BPH were the only independent predictors of residual cancer at radical retropubic prostatectomy (all p < 0.04). Stage (T1a vs T1b) did not predict residual cancer or the rate of biochemical recurrence. With a mean follow-up of 57 mo, the 5- and 10-yr biochemical recurrence-free survival rates were 92% and 87%, respectively. PSA after surgery for BPH and Gleason score at surgery for BPH were the only significant multivariate predictors of biochemical recurrence (all p < 0.04). The main limitation of this study is the requirement of an external validation before implementation of the clinical recommendations.

Conclusion

PSA measured before and after surgery for BPH and Gleason score at surgery for BPH were the only significant predictors of the presence of residual cancer at radical retropubic prostatectomy. PSA measured after surgery for BPH and Gleason score at surgery for BPH were the only independent predictors of biochemical recurrence after radical retropubic prostatectomy.     

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).     

Multicenter European External Validation of a Prostate Health Index–based Nomogram for Predicting Prostate Cancer at Extended Biopsy

Background

External validation of a prediction tool is mandatory to assess the tool's accuracy and generalizability within different patient cohorts.

Objective

To externally validate a previously developed Prostate Health Index (PHI)–based nomogram for predicting the presence of prostate cancer (PCa) at biopsy.

Design, setting, and participants

The study population consisted of 883 patients who were scheduled for a prostate biopsy at one of five European tertiary care centers. Total prostate-specific antigen (tPSA), free prostate-specific antigen (fPSA), and [−2]pro–prostate-specific antigen (p2PSA) levels were determined. The fPSA-to-tPSA ratio (%fPSA), p2PSA, and PHI ([p2PSA / fPSA] × √tPSA) were calculated.

Intervention

Extended initial and repeat prostate biopsy.

Outcome measurements and statistical analysis

Logistic regression models were fitted to test the predictors of PCa and to determine their predictive accuracy. A calibration plot was used to evaluate the extent of overestimation or underestimation between nomogram predictions and observed PCa rate. Decision curve analysis (DCA) provided an estimate of the net benefit obtained by using the PHI-based nomogram.

Results and limitations

Of 833 patients, 365 (41.3%) were diagnosed with PCa at extended prostate biopsy. In accuracy analyses, PHI was the most informative predictor of PCa (0.68), outperforming tPSA (0.51) and %fPSA (0.64). The predictive accuracy of the previously developed nomogram was 75.2% (95% confidence interval, 71.4–78.1). Calibration of the nomogram was good in patients at a low to intermediate predicted probability of PCa, while calibration was suboptimal, with a tendency to overestimate the presence of PCa, in high-risk patients. Finally, DCA demonstrated that the use of the PHI-based nomogram resulted in the highest net benefit. The main limitation of the study is the fact that only Caucasian patients were included.

Conclusions

At external validation, the previously developed PHI-based nomogram confirmed its ability to determine the presence of PCa at biopsy. These findings provide further evidence supporting the potential role of the nomogram in the biopsy decision pathway for European men with suspected PCa.

Patient summary

In the current study, we externally validated a Prostate Health Index–based nomogram to predict the presence of prostate cancer (PCa) at biopsy. This tool may help clinicians determine the need for a prostate biopsy in European patients with suspected PCa.     

High incidence of clinically significant concomitant prostate cancer in patients undergoing radical cystectomy for bladder cancer: A 10-year single-center experience

Aim

To analyze prostate cancer (PCa) incidence, clinical significance, and recurrence in 213 patients who underwent radical cystectomy (RC) for advanced bladder cancer (BC).

When to Perform Bone Scan in Patients with Newly Diagnosed Prostate Cancer: External Validation of the Currently Available Guidelines and Proposal of a Novel Risk Stratification Tool

Background

Several guidelines have indicated that in patients with well-differentiated or moderately well-differentiated prostate cancer (PCa), a staging bone scan may be omitted. However, the guidelines recommendations have not yet been externally validated.

Objective

The aim of the study was to externally validate the available guidelines regarding the need for a staging bone scan in patients with newly diagnosed PCa. Moreover, we developed a novel risk stratification tool aimed at improving the accuracy of these guidelines.

Design, setting, and participants

The study included 853 consecutive patients diagnosed with PCa between January 2003 and June 2008 at a single centre. All patients underwent bone scan using technetium Tc 99m methylene diphosphonate at diagnosis.

Measurements

The area under the curve (AUC) of the criteria suggested by the guidelines (European Association of Urology, American Urological Association, National Comprehensive Cancer Network, and American Joint Committee on Cancer) to perform a baseline bone scan was assessed and compared with the accuracy of a classification and regression tree (CART) including prostate-specific antigen (PSA), clinical stage, and biopsy Gleason sum as covariates.

Results and limitations

The AUC of the guidelines ranged between 79.7% and 82.6%. However, the novel CART model, which stratified patients into low risk (biopsy Gleason ≤7, cT1–T3, and PSA <10 ng/ml), intermediate risk (biopsy Gleason ≤7, cT2/T3, and PSA >10 ng/ml), and high risk (biopsy Gleason >7) was significantly more accurate (AUC: 88.0%) than all the guidelines (all p ≤ 0.002). The limitation of this study resides in its retrospective design. Moreover, the proposed risk stratification tool can be considered only for patients who are candidates for radical prostatectomy until validated in other clinical settings.

Conclusions

This is the first study aimed at externally validating the available guidelines addressing the need for staging baseline bone scans in PCa patients. All guidelines showed high accuracy. However, their accuracy was significantly lower compared with the accuracy of the novel risk stratification tool. According to this tool, staging bone scans might be considered only for patients with a biopsy Gleason score >7 or with a PSA >10 ng/ml and palpable disease (cT2/T3) prior to treatment. However, before recommending its use in clinical practice, our model needs to be externally validated.     

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.     

Risk-Adjusted Hazard Rates of Biochemical Recurrence for Prostate Cancer Patients after Radical Prostatectomy

Background

Current prostate cancer (PCa) follow-up guidelines do not account for the risk of disease relapse.

Objective

To examine the annual hazard rate (anHR) of biochemical recurrence (BCR) according to risk strata in patients treated with radical prostatectomy (RP) for localised PCa. These rates might be used to devise a risk-adjusted follow-up.

Design, setting, and participants

From January 1992 to December 2005, 2911 patients underwent RP for localised PCa in one institution. This cohort was used to identify three distinct risk groups for BCR. A cohort of 2875 patients operated on in a second institution was used for validation purpose.

Intervention

RP, prostate-specific antigen (PSA) tests.

Measurements

Cox regression models addressing BCR were used to identify significant predictors and cut-offs for risk group stratification. The anHR for BCR was calculated (number of events divided by number of patients at risk) for each risk group.

Results and limitations

Three risk groups could be identified: (1) low risk (23.7%), defined as PSA <11 ng/ml plus clinical stage T1c plus pathological Gleason <6 plus negative surgical margins plus organ confined tumour; (2) high risk (18.9%), defined as PSA >22 ng/ml or seminal vesicle invasion or pathological Gleason sum >8 or lymph node invasion or clinical stage T3; and (3) intermediate risk (57.4%), defined as all other patients. The anHR for the low-risk groups remained very low throughout follow-up (0–2.6). The anHR in the intermediate-risk group was initially low but remained elevated (1.3–7.2). The anHR for the high-risk group was initially markedly high (up to 32) and remained elevated during follow-up.

Conclusions

Annual hazard rates of BCR differ according to risk strata. These data might be used to devise a risk-adjusted follow-up protocol. Low-risk patients appear to need less frequent follow-up, whereas high-risk patients might need to be followed more frequently, relative to the current recommendations.     

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.     

Overexpression of ELAV-like protein HuR is associated with increased COX-2 expression in atrophy, high-grade prostatic intraepithelial neoplasia, and incidental prostate cancer in cystoprostatectomies

Background

The human ELAV-like protein HuR regulates the stability of several mRNA targets, including that of cyclooygenase-2 (COX-2). Their expression in prostatic carcinogenesis is uncertain.

Objective

To analyze HuR and COX-2 expression in cystoprostatectomies (CyPs) with incidental prostate cancer and compare their expression with those in radical prostatectomies (RPs) with clinically detected cancer.

Design, setting, and participants

HuR and COX-2 were immunohistochemically evaluated in normal-looking epithelium (NEp), atrophy, high-grade prostatic intraepithelial neoplasia (HGPIN), and prostate carcinoma (PCa) in 20 CyPs and 20 RPs, both types of specimens with pT2a Gleason score 6 PCa.

Measurements

At least 1000 cells were counted in contiguous 400X microscopic fields in each case, separately for NEp, atrophy, HGPIN, and PCa.

Results and limitations

There was an increase in the percentage of secretory cells with cytoplasmic HuR staining from NEp to atrophy, HGPIN, and PCa. The mean percentages in NEp, atrophy, and HGPIN adjacent to PCa were greater than away from cancer, both in the CyP and RPs. There was a trend towards a reduced nuclear HuR expression in atrophy, HGPIN, and PCa, compared to NEp. COX-2 staining was seen in the cytoplasm of the basal and secretory cells. There was a reduction in the mean proportion of positive basal cells and progressive increase in the percentage of positive secretory cells from atrophy to HGPIN and PCa, compared to NEp. Cytoplasmic HuR overexpression was correlated with COX-2 expression. There was no difference in HuR and COX-2 expression between cancers with tumour volume <0.5 ccm or >0.5 ccm.The limitations of this study were the small number of cases investigated and lack of a control group without cancer.

Conclusions

The secretory cells showed shift in HuR staining from nuclear in NEp to cytoplasmic in PCa. This is associated with a parallel shift in COX-2 expression from basal to secretory cells.     

Prostate-Specific Antigen (PSA) Isoform p2PSA in Combination with Total PSA and Free PSA Improves Diagnostic Accuracy in Prostate Cancer Detection

Background

Novel markers for prostate cancer (PCa) detection are needed. Total prostate-specific antigen (tPSA) and percent free prostate-specific antigen (%fPSA = tPSA/fPSA) lack diagnostic specificity.

Objective

To evaluate the use of prostate-specific antigen (PSA) isoforms p2PSA and benign prostatic hyperplasia–associated PSA (BPHA).

Design, setting, and participants

Our study included 405 serum samples from the Rotterdam arm of the European Randomised Study of Screening for Prostate Cancer and 351 samples from the Urology Department of Innsbruck Medical University.

Measurements

BPHA, tPSA, fPSA, and p2PSA levels were measured by Beckman-Coulter Access Immunoassay. In addition, the Beckman Coulter Prostate Health Index was calculated: phi = (p2PSA/fPSA) × √(tPSA).

Results and limitations

The p2PSA and phi levels differed significantly between men with and without PCa. No difference in BPHA levels was observed. The highest PCa predictive value in both cohorts was achieved by phi with areas under the curve (AUCs) of 0.750 and 0.709, a significant increase compared to tPSA (AUC: 0.585 and 0.534) and %fPSA (AUC: 0.675 and 0.576). Also, %p2PSA (p2PSA/fPSA) showed significantly higher AUCs compared to tPSA and %fPSA (AUC: 0.716 and 0.695, respectively). At 95% and 90% sensitivity, the specificities of phi were 23% and 31% compared to 10% and 8% for tPSA, respectively. In both cohorts, multivariate analysis showed a significant increase in PCa predictive value after addition of p2PSA to a model consisting of tPSA and fPSA (increase in AUC from 0.675 to 0.755 and from 0.581 to 0.697, respectively). Additionally, the specificity at 95% sensitivity increased from 8% to 24% and 7% to 23%, respectively. Furthermore, %p2PSA, phi, and the model consisting of tPSA and fPSA with or without the addition of p2PSA missed the least of the tumours with a biopsy or pathologic Gleason score ≥7 at 95% and 90% sensitivity.

Conclusions

This study shows significant increases in PCa predictive value and specificity of phi and %p2PSA compared to tPSA and %fPSA. p2PSA has limited additional value in identifying aggressive PCa (Gleason score ≥7).     

The Role of Choline Positron Emission Tomography/Computed Tomography in the Management of Patients with Prostate-Specific Antigen Progression After Radical Treatment of Prostate Cancer

Context

Choline positron emission tomography (PET)/computed tomography (CT) is a currently used diagnostic tool in restaging prostate cancer (PCa) patients with increasing prostate-specific antigen (PSA) after either radical prostatectomy (RP) or external-beam radiation therapy (EBRT). However, no final recommendations have been made on the use of this modality for patient management.

Objective

To critically analyse the current evidence for the use of choline PET/CT scanning in the management of patients with a progressive increase in PSA after radical treatment for PCa, evaluating its diagnostic accuracy in the detection of recurrences, the clinical predictors of positive PET/CT examinations, and the modalities’ role as a guide for tailored therapeutic strategies.

Evidence acquisition

Data on recently published (2003–2010) original articles, review articles, and editorials concerning the role of choline PET/CT in this scenario were analysed.

Evidence synthesis

The diagnostic accuracy of choline PET in detecting sites of PCa relapse has been investigated by several authors, and the overall reported sensitivity ranges between 38% and 98%. It has been demonstrated that choline PET technology's positive detection rate improves with increasing PSA values. The routine use of choline PET/CT cannot be recommended for PSA values <1 ng/ml. However, in addition to PSA serum value, PSA doubling time (PSA DT), and other clinical and pathologic features—including locally advanced tumour (pT3b–T4) or lymph node involvement at initial staging—should be considered to refer patients to choline PET/CT study. Choline PET/CT may be also proposed as a image guide either for experimental surgical or radiation therapy treatments.

Conclusions

According to the current available data, choline PET/CT plays a role in the management of biochemical relapse. Its accuracy is correlated to PSA value, PSA DT, and other pathologic features. Choline PET/CT may be proposed as a guide for individualised treatment of recurrence.     

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.     

Olfactory detection of prostate cancer by dogs sniffing urine: a step forward in early diagnosis

Background

Volatiles organic compounds (VOCs) in urine have been proposed as cancer biomarkers.

Objective

To evaluate the efficacy of prostate cancer (PCa) detection by trained dogs on human urine samples.

Design, setting, and participants

A Belgian Malinois shepherd was trained by the clicker training method (operant conditioning) to scent and recognize urine of people having PCa. All urine samples were frozen for preservation and heated to the same temperature for all tests. After a learning phase and a training period of 24 mo, the dog's ability to discriminate PCa and control urine was tested in a double-blind procedure. Urine was obtained from 66 patients referred to a urologist for elevated prostate-specific antigen or abnormal digital rectal examination. All patients underwent prostate biopsy and two groups were considered: 33 patients with cancer and 33 controls presenting negative biopsies.

Measurements

During each “run,” the dog was asked to signal a cancer urine among six samples containing only one cancer urine and five randomly selected controls. Sensitivity and specificity of the test were assessed.

Results and limitations

The dog completed all the runs and correctly designated the cancer samples in 30 of 33 cases. Of the three cases wrongly classified as cancer, one patient was rebiopsied and a PCa was diagnosed. The sensitivity and specificity were both 91%.

Conclusions

This study shows that dogs can be trained to detect PCa by smelling urine with a significant success rate. It suggests that PCa gives an odor signature to urine. Identification of the VOCs involved could lead to a potentially useful screening tool for PCa.     

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.