Measurement of peri-prostatic fat thickness using transrectal ultrasonography (TRUS): a new risk factor for prostate cancer

Study Type – Prognosis (cohort) Level of Evidence 2b What's known on the subject? and What does the study add? ADIPOSE tissue secretes various endocrine and paracrine mediators. Some authors have begun to consider whether peri‐prostatic fat (PPF) may interact with the prostate and play a role in carcinogenesis. It has recently been shown that the PPF quantity measured by CT is associated with more aggressive disease in patients undergoing radiation therapy. Our group studied a population not yet diagnosed with prostate cancer. By doing so we were able to identify PPF thickness on transrectal ultrasonography as a risk factor for prostate cancer detection upon biopsy, and as a risk factor for high‐grade disease. Our study also raises interesting questions about the underlying mechanisms of the association between PPF quantity and prostate cancer.

OBJECTIVE

• ? To determine if the amount of peri‐prostatic fat (PPF) on transrectal ultrasonography (TRUS) is a risk factor for incident prostate cancer overall and high‐grade prostate cancer (Gleason ≥4).

PATIENTS AND METHODS

• ? A prospectively maintained database of patients undergoing prostate biopsy at Princess Margaret Hospital for cancer suspicion was used.
• ? All TRUS examinations were retrospectively reviewed upon ‘blinding’ to outcome.
• ? PPF thickness, measured as the distance between the prostate and the pubic bone, was used as an index of the quantity of PPF.
• ? PPF measurements, together with other prostate cancer risk factors, were evaluated against prostate cancer and high‐grade prostate cancer detection upon biopsy with univariable and multivariable logistic regression and area under the receiver operating characteristic curve (AUC) analysis.

RESULTS

• ? Of the 931 patients, 434 (47%) were diagnosed with prostate cancer and 218 (23%) were diagnosed with high‐grade prostate cancer.
• ? The mean (range) PPF thickness was 5.3 (0–15) mm.
• ? Increasing PPF thickness was associated with prostate cancer and high‐grade prostate cancer diagnosis, with graded effect. When adjusting for other variables, the odds of detecting any prostate cancer and high‐grade prostate cancer increased 12% (odds ratio [OR] 1.12, 95% confidence interval [CI] 1.02–1.23) and 20% (OR 1.20, 95% CI 1.07–1.34), respectively, for each millimetre increase in PPF thickness.
• ? The AUCs for the association of PPF with prostate cancer and high‐grade prostate cancer were 0.58 (95% CI 0.54–0.62) and 0.59 (95% CI 0.55–0.64), respectively.

CONCLUSION

• ? The amount of PPF can be estimated with TRUS and is a predictor of prostate cancer and high‐grade prostate cancer at biopsy. To our knowledge, this study is the first to investigate PPF quantity in patients without prior prostate cancer diagnosis.

     

Racial differences in prediction of time to prostate cancer diagnosis in a prospective screening cohort of high‐risk men: effect of TMPRSS2 Met160Val

What’s known on the subject? and What does the study add? The TMPRSS2‐ERG fusion is a common gene fusion event in prostate tumours. Germline genetic variants that predict fusion in the tumour are under study. This study evaluates one germline genetic variant regarding predicting time to prostate cancer diagnosis among high‐risk men undergoing screening for prostate cancer. A specific genotype is associated with earlier time to prostate cancer diagnosis among Caucasian men with a family history of prostate cancer. The results suggest that such variants may be useful after further study in stratifying high‐risk men for individualized early detection approaches.

INTRODUCTION

• ? To evaluate the TMPRSS2‐ERG gene polymorphism with respect to self‐identified race or ethnicity (SIRE), time to prostate cancer (PCA) diagnosis, and screening parameters in the Prostate Cancer Risk Assessment Program, a prospective screening program for high‐risk men.

PATIENTS AND METHODS

• ? A total of 631 men aged between 35 and 69 years were studied. ‘High‐risk’ was defined as ≥ one first degree or two second degree relatives with PCA, any African American (AA) man regardless of familial PCA, and men with BRCA1/2 mutations.
• ? Men with elevated prostate‐specific antigen (PSA) concentrations or other indications for PCA underwent biopsy. Men were followed from time of study entry to PCA diagnosis.
• ? Cox models were used to evaluate time to PCA diagnosis by genotype.

RESULTS

• ? Genotype distribution differed significantly by SIRE (CT/TT vs CC, P < 0.0001). Among 183 Caucasian men with at least one follow‐up visit, PCA was more than doubled in men carrying CT/TT vs CC genotypes (hazard ratio = 2.55, 95% CI = 1.14–5.70) after controlling for age and PSA.
• ? No association was seen among AA men by TMPRSS2 genotype.

CONCLUSIONS

• ? The T‐allele of the Met160Val variant in TMPRSS2, which has been associated with the TMPRSS2–ERG fusion, may be informative of time to PCA diagnosis for a subset of high‐risk Caucasian men who are undergoing regular PCA screening.
• ? This variant, along with other genetic markers, warrant further study for personalizing PCA screening.

     

The role of transperineal template prostate biopsies in restaging men with prostate cancer managed by active surveillance

Study Type – Diagnostic (exploratory cohort) Level of Evidence 3b What's known on the subject? and What does the study add? The optimal method of active surveillance in prostate cancer remains unknown. This study is one of the first to report on the role of transperineal template prostate biopsies in active surveillance. It demonstrates that around one third of men are reclassified with more significant prostate cancer at an early stage in their management. This is a higher proportion than reported in contemporary cancers using standard transrectal biopsies for restaging.

OBJECTIVE

• ? To evaluate the role of transperineal template prostate biopsies in men on active surveillance.

PATIENTS AND METHODS

• ? In all, 101 men on active surveillance for prostate cancer underwent restaging transperineal template prostate biopsies at a single centre.
• ? Criteria for active surveillance were ≤75 years, Gleason ≤3+3, prostate‐specific antigen (PSA) ≤15 ng/mL, clinical stage T1–2a and ≤50% ultrasound‐guided transrectal biopsy cores positive for cancer with ≤10 mm of disease in a single core.
• ? The number of men with an increase in disease volume or Gleason grade on transperineal template biopsy and the number of men who later underwent radical treatment were assessed.
• ? The role of PSA and PSA kinetics were studied.

RESULTS

• ? In all, 34% of men had more significant prostate cancer on restaging transperineal template biopsies compared with their transrectal biopsies.
• ? Of these men, 44% had disease predominantly in the anterior part of the gland, an area often under‐sampled by transrectal biopsies.
• ? In the group of men who had their restaging transperineal template biopsies within 6 months of commencing active surveillance 38% had more significant disease.
• ? There was no correlation with PSA velocity or PSA doubling time.
• ? In total, 33% of men stopped active surveillance and had radical treatment.

CONCLUSIONS

• ? Around one‐third of men had more significant prostate cancer on transperineal template biopsies.
• ? This probably reflects under‐sampling by initial transrectal biopsies rather than disease progression.

     

A biopsy simulation study to assess the accuracy of several transrectal ultrasonography (TRUS)-biopsy strategies compared with template prostate mapping biopsies in patients who have undergone radical prostatectomy

Study Type – Diagnostic (validating cohort) Level of Evidence 1b What's known on the subject? and What does the study add? Transrectal ultrasonography (TRUS)‐guided biopsies can miss prostate cancer and misclassify risk in a diagnostic setting; the exact extent to which it does so in a repeat biopsy strategy in men with low–intermediate risk prostate cancer is unknown. A simulation study of different biopsy strategies showed that repeat 12‐core TRUS biopsy performs poorly. Adding anterior sampling improves on this but the highest accuracy is achieved using transperineal template prostate mapping using a 5 mm sampling frame.

OBJECTIVE

• ? To determine the effectiveness of two sampling strategies; repeat transrectal ultrasonography (TRUS)‐biopsy and transperineal template prostate mapping (TPM) to detect and exclude lesions of ≥0.2 mL or ≥0.5 mL using computer simulation on reconstructed three‐dimensional (3‐D) computer models of radical whole‐mount specimens.

PATIENTS AND METHODS

• ? Computer simulation on reconstructed 3‐D computer models of radical whole‐mount specimens was used to evaluate the performance characteristics of repeat TRUS‐biopsy and TPM to detect and exclude lesions of ≥0.2 mL or ≥0.5 mL.
• ? In all, 107 consecutive cases were analysed (1999–2001) with simulations repeated 500 times for each biopsy strategy.
• ? TPM and five different TRUS‐biopsy strategies were simulated; the latter involved a standard 12‐core sampling and incorporated variable amounts of error, as well as the addition of anterior cores.
• ? Sensitivity, specificity, negative and positive predictive values for detection of lesions with a volume of ≥0.2 mL or ≥0.5 mL were calculated.

RESULTS

• ? The mean (sd ) age and PSA concentration were 61 (6.4) years and 8.5 (5.9) ng/mL, respectively.In all, 53% (57/107) had low–intermediate risk disease.
• ? In all, 665 foci were reconstructed; there were 149 foci ≥0.2 mL and 97 ≥ 0.5 mL in the full cohort and 68 ≥ 0.2 mL and 43 ≥ 0.5 mL in the low–intermediate risk group.
• ? Overall, TPM accuracy (area under the receiver operating curve, AUC) was ≈0.90 compared with AUC 0.70–0.80 for TRUS‐biopsy.
• ? In addition, at best, TRUS‐biopsy missed 30–40% of lesions of ≥0.2 mL and ≥0.5 mL whilst TPM missed 5% of such lesions.

CONCLUSION

• ? TPM under simulation conditions appears the most effective re‐classification strategy, although augmented TRUS‐biopsy techniques are better than standard TRUS‐biopsy.

     

Effect of delaying surgery on radical prostatectomy outcomes: a contemporary analysis

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? For patients electing surgical treatment, the question of the effect of surgical delay on clinical outcomes in prostate cancer is controversial. In this study we examined the effect of delay from diagnosis to surgery on outcomes in men with localized prostate cancer and found no association between time to surgery and risk of biochemical recurrence, even for patients with longer delays and high‐risk disease. Men with localized prostate cancer can be reassured that reasonable delays in treatment will not influence disease outcomes.

OBJECTIVE

• ? To examine the effect of time from last positive biopsy to surgery on clinical outcomes in men with localized prostate cancer undergoing radical prostatectomy (RP).

PATIENTS AND METHODS

• ? We conducted a retrospective review of 2739 men who underwent RP between 1990 and 2009 at our institution.
• ? Clinical and pathological features were compared between men undergoing RP ≤ 60, 61–90 and >90 days from the time of prostate biopsy.
• ? A Cox proportional hazards model was used to analyse the association between clinical features and surgical delay with biochemical progression. Biochemical recurrence (BCR)‐free rates were assessed using the Kaplan–Meier method.

RESULTS

• ? Of the 1568 men meeting the inclusion criteria, 1098 (70%), 303 (19.3%) and 167 (10.7%) had a delay of ≤60, 61–90 and >90 days, respectively, between biopsy and RP. A delay of >60 days was not associated with adverse pathological findings at surgery.
• ? The 5‐year survival rate was similar among the three groups (78–85%, P= 0.11).
• ? In a multivariate Cox model, men with higher PSA levels, clinical stages, Gleason sums, and those of African‐American race were all at higher risk for developing BCR.
• ? A delay to surgery of >60 days was not associated with worse biochemical outcomes in a univariate and multivariate model.

CONCLUSIONS

• ? A delay of >60 days is not associated with adverse pathological outcomes in men with localized prostate cancer, nor does it correlate with worse BCR‐free survival.
• ? Patients can be assured that delaying treatment while considering therapeutic options will not adversely affect their outcomes.

     

Biopsy Gleason score and the duration of testosterone suppression among men treated with external beam radiation and 6 months of combined androgen blockade

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? The return of testosterone to normal levels following short‐course androgen blockade in prostate cancer is variable. Factors associated with a longer time to recovery include older age and lower baseline testosterone level. In this study, we found that among men treated with 6 months of combined androgen blockade and radiation therapy, higher biopsy Gleason grade was associated with a shorter time to testosterone normalization.

OBJECTIVE

• ? To determine whether the biopsy Gleason score is associated with duration of testosterone suppression following 6 months of combined androgen blockade (CAB) and radiation therapy (RT) in men with prostate cancer (PCa).

PATIENTS AND METHODS

• ? The study cohort consisted of 221 men with PCa treated with RT and 6 months of CAB between 1996 and 2005.
• ? We defined the duration of testosterone suppression as the time between the last day of CAB and the date the testosterone returned to ≥252 ng/dL. We used Cox regression multivariable analysis to relate biopsy Gleason score to duration of testosterone suppression following cessation of CAB.

RESULTS

• ? A biopsy Gleason score of 8–10 had an adjusted hazard ratio (AHR) of 1.56 (95% confidence interval [CI] 1.04, 2.34; P= 0.03) for a shorter time to testosterone normalization relative to Gleason 6. Specifically, the 51 men with biopsy Gleason score of 8–10 had a median time to testosterone normalization of 17.0 months compared with 22.1 months and 23.8 months for those with biopsy Gleason ≤6 and 7, respectively.
• ? Increasing age was significantly associated with a longer duration of testosterone suppression (AHR of 0.95 [95% CI 0.92, 0.97; P < 0.001]) as was a higher baseline PSA (AHR 0.82 [95% CI 0.69, 0.97; P= 0.02]).

CONCLUSION

• ? A biopsy Gleason score of 8–10 was associated with a shorter period of testosterone suppression following 6 months of CAB and RT. These data are consistent with the hypothesis that a factor released from high‐grade PCa cells may impact on testosterone production.

     

Does repeat biopsy affect the prognosis of patients with prostate cancer treated with radical prostatectomy? Analysis by the number of cores taken at initial biopsy

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? To date, studies to evaluate clinical significance of prostate cancer detected on repeat biopsy in patients who underwent radical prostatectomy have yielded inconsistent results. The present study confirms that prostate cancer diagnosed after repeat biopsies is related to better pathological outcomes after radical prostatectomy, but not predictive of biochemical recurrence. Additionally, we find that the number of cores taken at initial biopsy do not affect the association between the number of previous biopsies and the prognosis.

OBJECTIVE

• ? To determine whether repeat prostate biopsies are associated with more favourable prognoses compared with diagnosis at initial biopsy in patients who undergo radical prostatectomy for prostate cancer and to determine if this association is affected by the number of cores taken at initial biopsy.

PATIENTS AND METHODS

• ? We reviewed 1147 patients with prostate cancer from 1991 to 2008.
• ? Patients were stratified into two groups by the number of biopsies before diagnosis (initial biopsy vs repeat biopsy: at least two biopsies).
• ? The effects of several variables on pathological outcomes and biochemical recurrence‐free and systemic progression‐free survivals were assessed.

RESULTS

• ? Of the 1147 patients, 1064 (92.8%) were diagnosed with cancer at first biopsy and 83 (7.2%) at repeat biopsy.
• ? Compared with patients diagnosed at initial biopsy, those diagnosed at repeat biopsies were more likely to have a lower clinical stage (cT1c: 79.5% vs 55.5%, P < 0.001) and organ‐confined tumours (78.3% vs 61.3%, P= 0.003), but there was no significant difference in initial biopsy core number (8.3 vs 8.7, P= 0.373).
• ? Five‐year biochemical recurrence‐free and progression‐free survival rates did not show significant differences between the two groups (88.8% vs 82.2%, P= 0.078; 100.0% vs 96.5%, P= 0.105, respectively), and these results were not affected by the number of cores taken at initial biopsy.

CONCLUSIONS

• ? Although prostate cancer diagnosed after repeat biopsies was related to better pathological outcomes after radical prostatectomy, the number of previous biopsies did not predict disease recurrence.
• ? Moreover, the number of cores taken at initial biopsy did not affect these associations.

     

Does the transrectal ultrasound probe influence prostate cancer detection in patients undergoing an extended prostate biopsy scheme? Results of a large retrospective study

Study Type – Diagnostic (exploratory cohort) Level of Evidence 2b What's known on the subject? and What does the study add? The influence of transrectal probe system, end‐fire and side‐fire, has not been studied in detail. Using a sextant biopsy template it has been demonstrated a difference between end‐fire and side‐fire modes in 4–10 ng/mL PSA interval population. No studies evaluated the results in extended biopsy templates before. This study adds the knowledge that end‐fire and side‐fire transrectal probe, which are the two probe systems to perform transrectal prostate biopsy, have similar results in terms of prostate cancer detection rate and can be indifferently employed in extended prostate biopsy templates used in daily practice.

OBJECTIVE

• ? To compare the prostate cancer detection rate and tolerance profile between a transrectal biopsy made with a ‘side fire’ (SF) and an ‘end fire’ (EF) ultrasound probe.

PATIENTS AND METHODS

• ? We selected patients undergoing first biopsy and re‐biopsy of the prostate with a 14‐ and 18‐core template using EF and SF transrectal probes, respectively.
• ? We compared the cancer detection rate between the two probes on first biopsy and re‐biopsy and gauged patient tolerance using a visual analogue scale (VAS).

RESULTS

• ? A total of 1705 patients were included in the first biopsy group, while 487 were in the re‐biopsy group.
• ? The overall detection rate of first biopsy was 37.2%; the overall detection rate of re‐biopsy was 10.1%.
• ? No significant difference was found between the two probes in the first biopsy and re‐biopsy sets (38% vs 36.5%, P= 0.55; 10.8% vs 9.3%, P= 0.7).
• ? The lack of any significant association between the type of probe used and prostate cancer detection was confirmed by univariable and multivariable analyses in both the first biopsy and re‐biopsy sets after accounting for prostate‐specific antigen values, per cent free prostate‐specific antigen, digital rectal examination, and prostate and transition zone volumes.
• ? The patient tolerance profile of the SF group was significantly better than that of the EF group (mean VAS 1.78 ± 2.01 vs 1.45 ± 2.21; P= 0.02).

CONCLUSION

• ? The prostate cancer detection rate does not depend on the type of probe used. However, the SF transrectal probe is associated with a better patient tolerance profile.

     

Advancing age within established Gleason score categories and the risk of prostate cancer-specific mortality (PCSM)

Study Type – Prognosis (case series) Level of Evidence 4 What's known on the subject? and What does the study add? There is limited data that suggests that men aged >70 years have a higher proportion of Gleason 8–10 prostate cancer than men aged <70 years, as well as a higher risk of PSA recurrence, distant metastases, and disease‐specific death on univariate analysis. The present study shows that older as compared with younger men with Gleason score 6 and 7 prostate cancer have an increased risk of prostate cancer‐specific mortality. This may be due to the presence of occult high‐grade disease and suggests further diagnostic studies, e.g. multiparametric MRI, may be indicated in these men to reduce biopsy sampling error.

OBJECTIVE

• ? To determine if advancing age is a risk factor for high‐grade prostate cancer due to occult high‐grade disease in elderly men with Gleason score 6 or 7 prostate cancer. We investigated whether advancing age is associated with the risk of prostate cancer‐specific mortality (PCSM) within established Gleason score categories adjusting for known predictors of PCSM.

PATIENTS AND METHODS

• ? Using data from the Surveillance, Epidemiology and End Results database between 1 January 2004 to 31 December 2007, 166 104 men with non‐metastatic prostate cancer were identified and formed the study cohort.
• ? Within established Gleason score categories, Fine and Gray's multivariable competing risk regressions were used to evaluate whether increasing age at diagnosis was significantly associated with an increased risk of PCSM, adjusting for prostate‐specific antigen level and T‐category at diagnosis and whether treatment was curative or non‐curative.

RESULTS

• ? After adjusting for treatment and prognostic factors, Gleason score 8–10 and 7 as compared with ≤6 was associated with an increased risk of PCSM (P < 0.001).
• ? Increasing age was associated with an increased risk of PCSM only in Gleason score 6 (adjusted hazard ratio [AHR] 1.06, 95% confidence interval [CI] 1.04–1.08, P < 0.001) and 7 (AHR 1.02, 95% CI 1.01–1.03, P < 0.001), but not with Gleason score 8–10 (AHR 0.999, 95% CI 0.995–1.003, P= 0.61).
• ? These risks were highest in men aged >70 years having Gleason score 6 (AHR 1.10, 95% CI 1.07–1.13, P < 0.001) and Gleason score 7 prostate cancer (AHR 1.04, 95% CI 1.02–1.06, P < 0.001).

CONCLUSIONS

• ? PCSM increases with advancing age in men with Gleason score 6 and 7 but not 8–10 prostate cancer.
• ? Techniques to reduce biopsy sampling error in men, particularly those aged >70 years and healthy with Gleason score 6 and 7 disease deserve further study.

     

Positive predictive value of prostate biopsy indicated by prostate‐specific‐antigen‐based prostate cancer screening: trends over time in a European randomized trial*

Study Type – Diagnosis (validating cohort) Level of Evidence 1b What's known on the subject? and What does the study add? The European Randomized study of Screening for Prostate Cancer (ERSPC) showed a reduction in prostate cancer mortality of 21% for PSA‐based screening at a median follow‐up of 11 years. In the ERSPC, men are screened at 4‐year intervals. A prostate biopsy is recommended for men with a PSA level ≥3.0 ng/mL. The study shows that the positive predictive value (PPV) of a prostate biopsy indicated by PSA‐based screening remains equal throughout consecutive screening rounds in men without a previous biopsy. In men who have previously had a benign biopsy, the PPV drops considerably, but 20% of the cancers detected still show aggressive characteristics.

OBJECTIVE

• ? To assess the positive predictive value (PPV) of prostate biopsy, indicated by a prostate‐specific antigen (PSA) threshold of ≥3.0 ng/mL, over time, in the Rotterdam section of the European Randomized study of Screening for Prostate Cancer (ERSPC).

PATIENTS AND METHODS

• ? In the Rotterdam section of the ERSPC, a total of 42 376 participants, aged 55–74 years, identified from population registries were randomly assigned to a screening or control arm.
• ? For the ERSPC men undergo PSA screening at 4‐year intervals. A total of three screening rounds were evaluated; therefore, only men aged 55–69 years at the first screening were eligible for the present study.

RESULTS

• ? PPVs for men without previous biopsy remained equal throughout the three subsequent screenings (25.5, 22.3 and 24.8% respectively).
• ? Conversely, PPVs for men with a previous negative biopsy dropped significantly (12.0 and 15.2% at the second and third screening, respectively).
• ? Additionally, in men with and without previous biopsy, the percentage of aggressive prostate cancers (clinical stage >T2b, Gleason score ≥7) decreased after the first round of screening from 44.4 to 23.8% in the second (P < 0.001) and 18.6% in the third round (P < 0.001).
• ? Repeat biopsies accounted for 24.6% of all biopsies, but yielded only 8.6% of all aggressive cancers.

CONCLUSIONS

• ? In consecutive screening rounds the PPV of PSA‐based screening remains equal in previously unbiopsied men.
• ? In men with a previous negative biopsy the PPV drops considerably, but 20% of cancers detected still show aggressive characteristics.
• ? Individualized screening algorithms should incorporate previous biopsy status in the decision to perform a repeat biopsy with the aim of further reducing unnecessary biopsies.

     

Characteristics and clinical significance of prostate cancers missed by initial transrectal 12-core biopsy

Study Type – Diagnostic (exploratory cohort) Level of Evidence 3a What's known on the subject? and What does the study add? Initial transrectal 12‐core biopsy has a small but definite risk of missing anterior significant prostate cancers irrespective of age, PSA, prostate volume and DRE findings. Our study yields valuable information for diagnosis and treatment decision of prostate cancer based on transrectal 12‐core biopsy.

OBJECTIVE

• ? To characterize prostate cancers missed by initial transrectal 12‐core biopsy.

PATIENTS AND METHODS

• ? Between 2002 and 2008, 715 men with prostate‐specific antigen levels in the range 2.5–20 ng/mL or abnormal digital rectal examination underwent three‐dimensional 26‐core prostate biopsy (i.e. a combination of transrectal 12‐core biopsy and transperineal 14‐core biopsy) on initial examination.
• ? Of the 257 patients diagnosed with cancer, 120 patients subsequently underwent radical prostatectomy.
• ? Cancers were grouped into TR12‐negative cancers (i.e. not detected through transrectal 12‐core biopsy but detected through transperineal 14‐core biopsy) and TR12‐positive (i.e. detected through transrectal 12‐core biopsy) cancers.
• ? Clinicopathological characteristics of the TR12‐negative and TR12‐positive cancers were evaluated.

RESULTS

• ? TR12‐negative cancers comprised 21% of the three‐dimensional 26‐core biopsy‐detected cancers.
• ? The frequency of cancers with a biopsy Gleason score ≤6 and that of cancers with a biopsy primary Gleason grade ≤3 was higher in TR12‐negative cancers, at 58% and 83%, respectively, than in TR12‐positive cancers, at 25% (P < 0.001) and 53% (P < 0.001), respectively.
• ? The median number of positive cores in TR12‐negative cancers was two out of 26.
• ? TR12‐negative cancers were more frequently located anteriorly than posteriorly.
• ? The incidence of the TR12‐negative cancers was not associated significantly with any clinical variable.

CONCLUSION

• ? Many of the cancers missed by initial transrectal 12‐core biopsy are probably low‐grade and low‐volume diseases, although initial transrectal 12‐core biopsy has a small but definite risk of missing anterior significant cancers.

     

The impact of social networks and partnership status on treatment choice in men with localized prostate cancer

Study Type – Decision analysis (cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Very little is known about prostate cancer decision‐making. Hence, marital status is often assumed a proxy for the amount of social support. While marital status is often used as a proxy for social support, we found that the quality of support may impact treatment type more than the extent of the social matrix.

OBJECTIVES

• ? To determine whether martial status and social support impact treatment choice.
• ? The decision to pursue radical prostatectomy for prostate cancer is often influenced by factors outside the realm of tumour risk, such as a man's support system at home.

PATIENTS AND METHODS

• ? We performed a retrospective cohort study of 418 low‐income men who were diagnosed with non‐metastatic prostate cancer and underwent definitive treatment with either radical prostatectomy or radiotherapy.
• ? We performed univariate and multivariate mixed‐effects logistic regression analysis, with the dependent variable being treatment type.
• ? Confidence intervals (CIs) for the predicted probabilities and relative risks were derived using bias‐corrected bootstrapping with 1000 repetitions.

RESULTS

• ? Men with two or more members in their support system were more likely to be older, Hispanic, have less than a high school education, earn more than US $1500 monthly, have high‐risk disease and be in a significant relationship.
• ? In multivariate analysis, partnered men with fewer than two social support members (relative risk, RR, 1.23; 95% CI, 1.02–1.63) were more likely to undergo surgery, whereas men who were morbidly obese (RR, 0.46; 95% CI, 0.09–0.88), high school graduates (RR, 0.80; 95% CI, 0.64–0.99) or had high‐risk disease (RR, 0.58; 95% CI, 0.44–0.85) were less likely to undergo surgery than their respective referent groups.
• ? Partnered men with two or more social support members were no more likely to undergo surgery than unpartnered men who lacked any social support.

CONCLUSIONS

• ? In the present study cohort, married men with fewer than two members in their social network were more likely to have undergone surgery.
• ? Although marital status is often used as a proxy for social support, we find that the quality of support and partner may impact treatment type more than the extent of the social matrix.

     

The absence of voiding symptoms in men with a prostate-specific antigen (PSA) concentration of ≥3.0 ng/mL is an independent risk factor for prostate cancer: results from the Gothenburg Randomized Screening Trial

Study Type – Prognostic (RCT) Level of Evidence 1b What's known on the subject? and What does the study add? There are only a few studies and no consensus concerning the relationship between LUTS and prostate cancer. This paper focuses on 2353 men with an elevated PSA level within the Gothenburg Randomized Screening Trial who underwent biopsy and answered questions regarding LUTS. The main conclusion was that the absence of voiding symptoms is an independent risk factor for prostate cancer detection.

OBJECTIVE

• ? To investigate whether men with obstructive voiding symptoms are at increased risk for being diagnosed with prostate cancer within the Gothenburg randomized population‐based prostate cancer screening trial.

SUBJECTS AND METHODS

• ? In 1995, 20 000 men born between 1930 and 1944 were randomly selected from the population register and randomized to either a screening group (10 000), invited for total prostate‐specific antigen (tPSA) testing every second year until they reached an upper age‐limit pending between 67 and 71 years, or to a control group not invited (10 000).
• ? Men with a PSA concentration of ≥3.0 ng/mL were offered further examination with prostate biopsies. Immediately before the physician's examination a self‐administered, study‐specific questionnaire was completed including one question concerning obstructive voiding symptoms.
• ? Multivariate logistic regression modelling was used to estimate odds ratios (ORs) for associations of age, tPSA, free/total PSA (f/tPSA) ratio, prostate volume and the presence of voiding symptoms in prostate cancer risk. A P < 0.05 was considered statistically significant.

RESULTS

• ? Between 1995 and 2010 there were 2590 men who had an elevated PSA concentration (≥3.0 ng/mL) at least once during the study. Of these, 2353 men (91%) accepted further clinical examination with transrectal ultrasonography (TRUS) and prostate biopsies. In all, 633/2353 men had prostate cancer (27%) on biopsy and 1720/2353 men (73%) had a benign pathology.
• ? Men with prostate cancer reported a lower frequency of voiding symptoms (24% vs 31%, P < 0.001), independent of age and locally advanced tumours (T2b–T4). In the multivariate logistic regression model increasing age and tPSA were positively associated with prostate cancer while prostate volume, f/tPSA ratio and the presence of voiding symptoms were all inversely associated with the risk of detecting prostate cancer in a screening setting. This inverse association of voiding symptoms and prostate cancer detection was restricted to men with large prostates (>37.8 mL); 15% in men with voiding symptoms vs 22% in asymptomatic men (P < 0.001).

CONCLUSION

• ? The presence of voiding symptoms should not be a decision tool for deciding which men with an elevated PSA concentration should be offered biopsies of the prostate.

     

High detection rate of significant prostate tumours in anterior zones using transperineal ultrasound-guided template saturation biopsy

Study Type – Diagnostic (exploratory cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Men with persistent suspicion for prostate cancer after previous negative standard transrectal biopsy series are offered saturation biopsy either transrectally or transperineally to increase cancer detection rate. A high‐risk group of men with at least two previous negative transrectal biopsies underwent transperineal template‐guided saturation biopsy. Prostate cancer was detected in 26%, predominantly in the anterior zones. PSA velocity or doubling time were the most powerful factors to predict cancer.

OBJECTIVE

• ? To evaluate the detection rate and the regional location of prostate cancer in men undergoing transperineal template‐guided saturation biopsy (TTSB).

PATIENTS AND METHODS

• ? In all, 92 consecutive men with at least two previous negative transrectal biopsy series who underwent a multiple‐core prostate TTSB at our centre were included in the study.
• ? Univariable and multivariable logistic regression analyses were used to address the relationship between parameters before TTSB and prostate cancer‐detection rate.
• ? Covariates consisted of age at biopsy, free and total prostate‐specific antigen (PSA), prostate volume, digital rectal examination findings, histological findings on previous biopsy, PSA velocity (PSAV), PSA‐doubling time (PSADT) and the number of previous negative biopsy sets.

RESULTS

• ? Prostate cancer was diagnosed in 26% of the men.
• ? A median of 30 cores was taken by TTSB.
• ? Adenocarcinoma in >2 cores was detected in 58.5% and Gleason score ≥7 was detected in 46% of the diagnosed men.
• ? Most of the tumours (83.3%) were found in the anterior zones of the gland, with a significantly higher number of positive cores vs the posterior zones (mean 4.9 vs 1.5, P= 0.015).
• ? PSADT and PSAV were the only independent predictors of prostate cancer detection at multivariate analyses with odds ratios of 0.71 (P= 0.014) and 1.58 (P= 0.025), respectively.

CONCLUSIONS

• ? TTSB has a high prostate cancer‐detection rate, especially in the anterior zones.
• ? Men after at least two previous negative transrectal biopsy series and persistent suspicion of prostate cancer, as evidenced by rapid PSA dynamics, should be offered TTSB.

     

Validation and comparison of the two Kattan nomograms in patients with prostate cancer treated with (125) iodine brachytherapy

Study Type – Clinical (prospective trial) Level of Evidence 2b What's known on the subject? and What does the study add? In clinical practice, we know that it is necessary to identify new biomarkers that can better detect prostate cancer (PC), at the same time as reducing the number of unnecessary biopsies. Recently, studies have suggested that the most relevant clinical scenario in which the prostate cancer antigen 3 (PCA3) score could be used comprises patients with a previous negative prostate biopsy and persistently elevated PSA levels. At the same time, although multiparametric MRI is not currently used as a first approach for diagnosing PC, it can be useful for directing targeted biopsies, especially in those patients with elevated PSA levels and a previous negative TRUS‐guided biopsy. Considering all of these aspects, the present study aimed to evaluate the role of multiparametric MRI as an additional diagnostic tool for improving the accuracy of the urinary PCA3 test in patients with increased PSA levels and a previous negative prostate biopsy. Our hypothesis is that the potential value of the PCA3 test as a biomarker for PC diagnosis could be improved by the use of multiparametric MRI in directing prostate biopsy. In the present study, we show that, in cases with a previous negative biopsy and persistently elevated PSA levels submitted to multiparametric MRI to direct biopsies, the sensitivity of the PCA3 test significantly improved (79% vs 68%). However, further larger randomized studies on this combination using a new biomarker and a new imaging modality for PC diagnosis are expected.

OBJECTIVE

• ? To evaluate the role of multiparametric magnetic resonance imaging (MRI) as an additional diagnostic tool for improving the accuracy of the urinary prostate cancer antigen 3 (PCA3) test in patients with an increase in prostate‐specific antigen (PSA) levels and a previous negative prostate biopsy.

PATIENTS AND METHODS

• ? The present study comprised a prospective randomized study on patients with a previous negative transrectal ultrasonography (TRUS)‐guided prostate biopsy and elevated PSA levels.
• ? In total, 180 cases were analyzed, and all were submitted to PCA3 assay.
• ? Patients in group A were submitted to a second random TRUS‐guided prostate biopsy, whereas patients in group B were submitted to a multiparametric MRI examination and then to a second TRUS‐guided prostate biopsy.

RESULTS

• ? At the second biopsy, a histological diagnosis of prostate cancer was found in 26 of 84 cases (30.9%) in group A and in 29 of 84 cases (34.5%) in group B.
• ? In group A, the sensitivity and specificity of the PCA3 score were 68.0% and 74.5% respectively (positive predictive value of 53.1%, negative predictive value of 84.6% and accuracy of 72.6%).
• ? In group B, the sensitivity and specificity of the PCA3 score were 79.3% and 72.7%, respectively (positive predictive value of 60.5%, negative predictive value of 86.9% and accuracy of 75.0%).
• ? For the PCA3 score, the area under the receiver‐operator characteristic curve was 0.825 (95% confidence interval, 0.726–0.899) in group A and 0.857 (95% confidence interval, 0.763–0.924) in group B (P < 0.001).

CONCLUSION

• ? In patients with a previous negative biopsy and persistently elevated PSA levels, the use of multiparametric MRI for indicating sites suitable for rebiopsy can significantly improve the sensitivity of the PCA3 test in the diagnosis of prostate cancer.

     

Influence of obesity on tumour volume in patients with prostate cancer

Study Type – Prognosis (individual cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Obesity is associated with more aggressive prostate cancer. Prostate cancer tumour volume is affected by excess weight, after adjustment for all possible clinical and pathological confounders.

OBJECTIVE

• ? To investigate the association between body mass index and tumour volume at radical prostatectomy in a large European population.

PATIENTS AND METHODS

• ? Recent data support the hypothesis that the hormonal environment in overweight and obese men may alter androgen‐dependent prostate growth. Body mass index (BMI) has been implicated in prostate cancer pathophysiology.
• ? We analysed 1275 patients with prostate cancer who underwent radical prostatectomy at a single tertiary care institution. Mean tumour volume (TV) was evaluated according to BMI WHO categories (normal <25 kg/m² vs overweight 25–30 kg/m² vs obese 30–35 kg/m² vs severely obese >35 kg/m²).
• ? Univariable linear regression analyses targeted the association between BMI and TV at radical prostatectomy. Multivariable analyses were adjusted for age, prostate‐specific antigen value, biopsy Gleason sum, clinical stage and prostate volume.

RESULTS

• ? Mean BMI was 26.3 kg/m² (median 26; range 16.7–42.0). Mean TV was 5.6 mL (median 3.3; range 0.1–61.2). The mean prostate‐specific antigen value was 10.3 ng/dL (median 6.6; range 0.3–327).
• ? The mean TV was 5.0, 5.8, 6.3 and 9.2 mL in normal, overweight, obese and severely obese patients, respectively (P= 0.03). TVs in men with a normal BMI were 84% smaller than in severely obese men (5.0 vs 9.2 mL).
• ? On univariable analysis, BMI was correlated with TV at radical prostatectomy (P < 0.001). On multivariable analysis, BMI reached the independent predictor status after adjustment for age, prostate‐specific antigen value, biopsy Gleason score, clinical stage and prostate volume (P= 0.03).

CONCLUSION

• ? We showed that BMI is independently associated with prostate cancer volume at radical prostatectomy. The present results confirm that obesity may play a key role in prostate cancer pathophysiology.

     

Preoperative characteristics of high-Gleason disease predictive of favourable pathological and clinical outcomes at radical prostatectomy

Study Type – Diagnostic (exploratory cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Men with high‐risk prostate cancer experience recurrence, metastases and death at the highest rate in the prostate cancer population. Pathological stage at radical prostatectomy (RP) is the greatest predictor of recurrence and mortality in men with high‐grade disease. Preoperative models predicting outcome after RP are skewed by the large proportion of men with low‐ and intermediate‐risk features; there is a paucity of data about preoperative criteria to identify men with high‐grade cancer who may benefit from RP. The present study adds comprehensive biopsy data from a large cohort of men with high‐grade prostate cancer at biopsy. By adding biopsy parameters, e.g. number of high‐grade cores and >50% involvement of any core, to traditional predictors of outcome (prostate‐specific antigen concentration, clinical stage and Gleason sum), we can better inform men who present with high‐grade prostate cancer as to their risk of favourable or unfavourable disease at RP.

OBJECTIVE

• ? To investigate preoperative characteristics that distinguish favourable and unfavourable pathological and clinical outcomes in men with high biopsy Gleason sum (8–10) prostate cancer to better select men who will most benefit from radical prostatectomy (RP).

PATIENTS AND METHODS

• ? The Institutional Review Board‐approved institutional RP database (1982–2010) was analysed for men with high‐Gleason prostate cancer on biopsy; 842 men were identified.
• ? The 10‐year biochemical‐free (BFS), metastasis‐free (MFS) and prostate cancer‐specific survival (CSS) were calculated using the Kaplan–Meier method to verify favourable pathology as men with Gleason <8 at RP or ≤ pT3a compared with men with unfavourable pathology with Gleason 8–10 and pT3b or N1.
• ? Preoperative characteristics were compared using appropriate comparative tests.
• ? Logistic regression determined preoperative predictors of unfavourable pathology.

RESULTS

• ? There was favourable pathology in 656 (77.9%) men. The 10‐year BFS, MFS and CSS were 31.0%, 60.9% and 74.8%, respectively.
• ? In contrast, men with unfavourable pathological findings had significantly worse 10‐year BFS, MFS and CSS, at 4.3%, 29.1% and 52.3%, respectively (all P < 0.001).
• ? In multivariable logistic regression, a prostate‐specific antigen (PSA) concentration of >10 ng/mL (odds ratio [OR] 2.24, 95% confidence interval [CI] 1.38–3.62, P= 0.001), advanced clinical stage (≥ cT2b; OR 2.55, 95% CI 1.55–4.21, P < 0.001), Gleason pattern 9 or 10 at biopsy (OR 2.55, 95% CI 1.59–4.09, P < 0.001), increasing number of cores positive with high‐grade cancer (OR 1.16, 95% CI 1.01–1.34, P= 0.04) and >50% positive core involvement (OR 2.25, 95% CI 1.17–4.35, P= 0.015) were predictive of unfavourable pathology.

CONCLUSIONS

• ? Men with high‐Gleason sum at biopsy are at high risk for biochemical recurrence, metastasis and death after RP; men with high Gleason sum and advanced pathological stage (pT3b or N1) have the worst prognosis.
• ? Among men with high‐Gleason sum at biopsy, a PSA concentration of >10 ng/mL, clinical stage ≥ T2b, Gleason pattern 9 or 10, increasing number of cores with high‐grade cancer and >50% core involvement are predictive of unfavourable pathology.

     

The relationship between Prostate CAncer gene 3 (PCA3) and prostate cancer significance

Study Type – Diagnostic (exploratory cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Prior studies have shown that the PCA3 Score is indicative of prostate cancer significance and may aid in selecting men with clinically insignificant prostate cancer who could be candidates for active surveillance. This analysis of data from two studies enrolling 1,009 men shows that the PCA3 Score is associated with many biopsy and pathological features of the insignificant prostate cancer. The paper also provides guidance for the use of the PAC3 Assay in clinical practice.

OBJECTIVE

• ? To evaluate the relationship between Prostate CAncer gene 3 (PCA3) and prostate cancer significance.

PATIENTS AND METHODS

• ? Clinical data from two multi‐centre European open‐label, prospective studies evaluating the clinical utility of the PCA3 assay in guiding initial and repeat biopsy decisions were analysed.
• ? First‐catch urine was collected after digital rectal examination (three strokes per lobe) and the PCA3 score was determined using the PROGENSA® PCA3 assay.
• ? Transrectal ultrasound‐guided biopsy (≥8 cores) and radical prostatectomy (RP) specimens were analysed by the local pathologist. The relationship between biopsy and RP outcomes with the PCA3 score was assessed.

RESULTS

• ? Of the 1009 men enrolled, 348 (34%) had a positive biopsy. The median and mean PCA3 scores were statistically significantly lower in men with biopsy Gleason score <7 vs ≥7, with clinical stage T1c vs T2a–T2c, T3a cancers, with ≤33% vs >33% positive biopsy cores and with ‘biopsy indolent’ vs ‘biopsy significant’ prostate cancer (indolent prostate cancer defined by biopsy Epstein criteria).
• ? In all, 175 men with a positive biopsy had a RP: median and mean PCA3 scores were statistically significantly lower in men with pathological Gleason score <7 vs ≥7, and with pathological stage T2a–T2c vs T3a–T3b cancers.

CONCLUSIONS

• ? The PCA3 score may combined with traditional tools aid in identifying men with clinically insignificant prostate cancer, as shown by biopsy and RP pathological features including biopsy Epstein criteria, who could be candidates for active surveillance.
• ? Treatment selection should be based on a combination of clinical and pathological variables. If one wants to use a threshold point to guide treatment decisions in clinical practice, a PCA3 score threshold of 20 may have the highest utility for selecting men with clinically insignificant prostate cancer in whom active surveillance may be appropriate; a PCA3 score threshold of 50 may be used to identify men at high risk of harbouring significant prostate cancer who are candidates for RP.
• ? Although the association between the PCA3 score and prostate cancer aggressiveness needs further evaluation, the inclusion of the PCA3 score into patient management strategies may provide clinicians with another tool to more accurately determine the course of treatment.

     

Evaluation of GSTP1 and APC methylation as indicators for repeat biopsy in a high-risk cohort of men with negative initial prostate biopsies

Study Type – Diagnostic (exploratory cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Hypermethylation of genes such as glutathione‐S‐transferase P1 (GSTP1) and adenomatous polyposis coli (APC) occurs with high frequency in prostate tumour tissue but is much less common in the benign prostate; however, the potential value of gene methylation biomarkers as an adjunct to biopsy histopathology has had little study. When measured in histologically benign prostate biopsy tissue, APC gene hypermethylation was found to have high negative predictive value and high sensitivity. GSTP1 hypermethylation was found to have lower performance than APC.

OBJECTIVE

• ? To evaluate the performance of DNA methylation biomarkers in the setting of repeat biopsy in men with an initially negative prostate biopsy but a high index of suspicion for missed prostate cancer.

PATIENTS AND METHODS

• ? We prospectively evaluated 86 men with an initial histologically negative prostate biopsy and high‐risk features.
• ? All men underwent repeat 12‐core ultrasonography‐guided biopsy.
• ? DNA methylation of glutathione‐S‐transferase P1 (GSTP1) and adenomatous polyposis coli (APC) was determined using tissue from the initially negative biopsy and compared with histology of the repeat biopsy.
• ? The primary outcome was the relative negative predictive value (NPV) of APC compared with GSTP1, and its 95% confidence interval (CI).

RESULTS

• ? On repeat biopsy, 21/86 (24%) men had prostate cancer.
• ? APC and GSTP1 methylation ratios below the threshold (predicting no cancer) produced a NPV of 0.96 and 0.80, respectively. The relative NPV was 1.2 (95% CI: 1.06–1.36), indicating APC has significantly higher NPV.
• ? Methylation ratios above the threshold yielded a sensitivity of 0.95 for APC and 0.43 for GSTP1.
• ? Combining both methylation markers produced a performance similar to that of APC alone.
• ? APC methylation patterns were consistent with a possible field effect or occurrence early in carcinogenesis.

CONCLUSIONS

• ? APC methylation provided a very high NPV with a low percentage of false‐negatives, in the first prospective study to evaluate performance of DNA methylation markers in a clinical cohort of men undergoing repeat biopsy.
• ? The potential of APC methylation to reduce unnecessary repeat biopsies warrants validation in a larger prospective cohort.

     

Contrast-enhanced ultrasonography of the prostate: various imaging findings that indicate prostate cancer

Study Type – Diagnostic (non‐consecutive case series)
Level of Evidence 3b What’s known on the subject? and What does the study add? Contrast‐enhanced ultrasonography (CEUS) can visualize some prostate cancer lesions. Findings suggestive of cancer have been defined as rapid contrast enhancement; increased contrast enhancement. CEUS could be useful for targeted biopsy in patients with a PSA level <10 ng/mL. The CEUS findings suggestive of prostate cancer are more varied than previously reported. Low‐echogenicity areas containing abnormal blood vessels were also found to represent cancer.

OBJECTIVES

• ? To perform transrectal ultrasonography (TRUS) with an ultrasonography (US) contrast agent to visualize prostate cancer.
• ? To explore the possibility of targeted biopsy by studying the findings obtained by different cancerous tissue imaging modalities and evaluating needle biopsies from prostate cancer using contrast‐enhanced ultrasonography (CEUS).

PATIENTS AND METHODS

• ? In all, 41 patients undergoing prostate biopsy and 13 patients undergoing prostatectomy received i.v. injection of the US contrast agent (Sonazoid®).
• ? We evaluated pre‐contrast and contrast‐enhanced US images, and then compared ultrasonographic images and the pathological findings.

RESULTS

• ? Cancer was significantly more frequent at the sites of targeted biopsy where CEUS findings suggested cancer (36.3%) than at sites of systematic biopsy (17.7%, odds ratio = 2.7, P = 0.0026).
• ? In cases with prostate‐specific antigen (PSA) level <10 ng/mL, in particular, prostate cancer was detected at a significantly higher rate by targeted biopsy than by systematic biopsy (27.3 vs 9.5%, odds ratio = 3.4, P = 0.013).
• ? Pathological examination found 26 tumours in prostatectomy specimens. The diameters of the 10 CEUS‐identified tumours were significantly greater than those of the 16 lesions missed by US (mean 18.7 vs 5.9 mm).
• ? CEUS findings suggestive of cancer varied widely: strong contrast enhancement, rapid contrast enhancement, vessels with abnormal perfusion and low contrast enhancement.

CONCLUSIONS

• ? CEUS could be useful for targeted biopsy in patients with a PSA level <10 ng/mL.
• ? The CEUS findings suggestive of prostate cancer are more varied than previously reported.
• ? Detailed examination of CEUS images and application of the data to prostate biopsy could lead to more efficient diagnosis.