Single application of high‐intensity focused ultrasound as a first‐line therapy for clinically localized prostate cancer: 5‐year outcomes

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? High‐intensity focused ultrasound (HIFU) therapy has been proposed for the treatment of localized prostate cancer (PCa) for all risk levels of tumour recurrence. The study adds data on the efficacy of a single HIFU application in the treatment of PCa with different risks of recurrence. Durable cancer control was achieved in 81.7% of patients with low‐risk disease, with rates of efficacy declining in intermediate‐ and high‐risk tumours. The data suggest that the principal domain for minimal invasive HIFU should be low‐risk disease.

OBJECTIVE

• ? To report cancer control results after a single application of high‐intensity focused ultrasonography (HIFU) in patients with localized prostate cancer (PCa), stratified by tumour recurrence risk according to D'Amico risk classification.

PATIENTS AND METHODS

• ? In a retrospective single‐centre study, we analysed the outcomes of patients with localized PCa who were treated with curative intent between December 2002 and October 2006 using an Ablatherm HIFU device (EDAP‐TMS, France).
• ? Transurethral resection of the prostate or adenomectomy were performed before HIFU to downsize large prostate glands.
• ? Oncological failure was determined by the occurrence of biochemical relapse, positive biopsy and/or metastasis. Biochemical relapse was defined as a PSA nadir +1.2 ng/mL (Stuttgart definition), or as a rise in PSA level to ≥0.5 ng/mL if PSA doubling time was ≤6 months. Kaplan–Meier analysis was performed for survival estimates.

RESULTS

• ? A total of 191 consecutive patients were included in the study. The median (range) patient age was 69.7 (51–82) years, and 38, 34 and 28% of these patients were in the low‐, intermediate‐ and high‐risk groups, respectively.
• ? The median (range) follow‐up was 52.8 (0.2–79.8) months.
• ? At 5 years, overall and cancer‐specific survival rates were 86.3% and 98.4%, respectively.
• ? Stratified by risk group, negative biopsy rates were 84.2%, 63.6%, and 67.5% (P = 0.032), 5‐year biochemical‐free survival rates were 84.8%, 64.9% and 54.9% (P < 0.01), and 5‐year disease‐free survival rates were 81.7%, 53.2% and 51.2% (P < 0.01), respectively.

CONCLUSION

• ? Single‐session HIFU is recommended as a curative approach in elderly patients with low‐risk PCa. Patients at higher risk of tumour progression should be counselled regarding the likely need for salvage therapy, including repeat HIFU.

     

Six years' experience with high-intensity focused ultrasonography for prostate cancer: oncological outcomes using the new 'Stuttgart' definition for biochemical failure

Study Type – Therapy (outcomes research) Level of Evidence 2b

OBJECTIVE

? To determine oncological outcomes after high‐intensity focused ultrasonography (HIFU) treatment in patients with localized prostate cancer using a new, more accurate, definition (‘Stuttgart’ definition) of biochemical failure.

PATIENTS AND METHODS

? We performed a retrospective review of all patients in our centre who received first‐line treatment with a second‐generation Ablatherm^TM device (EDAP‐TMS, Lyon, France). ? Oncological failure was given either by biochemical failure (prostate‐specific antigen, PSA, nadir plus 1.2 g/mL) (Stuttgart definition) or the start of salvage therapy because of a persistently positive biopsy after the HIFU procedure. ? The 5‐year biochemical‐free survival rate and 5‐year disease‐free survival rate were calculated.

RESULTS

? In total, 53 patients were included (mean age, 72.5 ± 4.5 years, range 60–79 years; 28 low risk and 25 intermediate risk). None had undergone previous hormonal therapy. Mean ±sd follow‐up was 45.4 ± 15.5 months (range 16–71 years). Mean (range) pre‐treatment PSA was 8.5 ± 4 (0.29–18) ng/mL. The median (range) PSA nadir value was 1 (0.01–14) ng/mL and occurred after a mean (range) of 5.09 (3–24) months. ? Overall, 36 patients (67.9%) experienced oncological failure. ? These included 33 cases (62.2%) of biochemical failure. A PSA nadir of ≤0.2, 0.21–1.0 and >1 ng/mL was reached in 20.8%, 30.2% and 49% of patients, respectively, and was associated with biochemical failure in 9.1%, 30.3% and 60.6%, respectively. ? The 5‐year biochemical‐free survival rate and disease‐free survival rate were 21.7% and 13.5%, respectively. In multivariate analysis, a PSA nadir of >1 ng/mL was significantly associated with a risk of biochemical and oncological failure (P= 0.002 and P < 0.001). ? Oncological failure was not associated with any risk group. ? No patient died from prostate cancer.

CONCLUSIONS

? In our experience, Ablatherm^TM treatment for clinically localized prostate cancer was associated with a high rate of biochemical failure as determined by the ‘Stuttgart’ definition, and did not achieve effective cancer control. ? The PSA nadir value after HIFU treatment was a significant predictor of treatment failure.     

Outcomes in patients with Gleason score 8-10 prostate cancer: relation to preoperative PSA level

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? High‐grade prostate cancers are associated with poor disease‐specific outcomes. A proportion of these tumours produce little PSA. This study demonstrates that among Gleason 8–10 prostate cancers, some of the worst survival outcomes are associated with the lowest PSA levels.

OBJECTIVE

• ? To assess outcomes of patients with Gleason score 8–10 prostate cancer (CaP) with a low (≤2.5 ng/mL) vs higher preoperative serum PSA levels.

PATIENTS AND METHODS

• ? From 1983 to 2003, 5544 patients underwent open radical prostatectomy, of whom 354 had a Gleason 8–10 tumour in the prostatectomy specimen.
• ? Patients were stratified according to preoperative PSA level into four strata: ≤2.5 ng/mL (n= 31), 2.6–4 ng/mL (n= 31), 4.1–10 ng/mL (n= 174), and >10 ng/mL (n= 118).
• ? We compared biochemical progression‐free survival (PFS), metastasis‐free survival (MFS), and cancer‐specific survival (CSS) as a function of preoperative PSA level.

RESULTS

• ? Patients with PSA level ≤2.5 ng/mL were more likely to have seminal vesicle invasion (P= 0.003).
• ? On Kaplan–Meier survival analysis, patients with a PSA level ≤2.5 ng/mL had proportionately worse outcomes than their counterparts with higher PSA levels.
• ? The 7‐year PFS in the PSA ≤2.5 ng/mL stratum was lower than those of the PSA 2.6–4 ng/mL and 4–10 ng/mL strata (36% vs 50 and 42%, respectively); however, the lowest 7‐year PFS was found in those with a PSA level >10 ng/mL (32%, P= 0.02).
• ? Gleason score 8–10 tumours with a PSA level ≤2.5 ng/mL also tended to have the lowest 7‐year MFS (75, 93, 89 and 92% for PSA level ≤2.5, 2.6–4, 4.1–10 and >10 ng/mL, respectively, P= 0.2) and CSS (81, 100, 94 and 90% for PSA level ≤2.5, 2.6–4, 4.1–10 and >10 ng/mL, respectively, P= 0.3), although these differences were not statistically significant.
• ? In the subset with palpable disease, Gleason grade 8–10 disease with PSA level ≤2.5 ng/mL also was associated with a worse prognosis.

CONCLUSIONS

• ? In patients with Gleason grade 8–10 disease, a proportion of these tumours are so poorly differentiated that they produce relatively little PSA.
• ? Patients with high‐grade, low‐PSA tumours had less favourable outcomes than many of those with higher PSA levels.

     

Cost-effectiveness of Prostate Health Index for prostate cancer detection

Study Type – Diagnostic (cost effectiveness) Level of Evidence 2b What's known on the subject? and What does the study add? The Beckman Coulter prostate health index (phi) was developed as a combination of serum prostate specific antigen (PSA), free PSA and a PSA precursor form [?2]proPSA to calculate the probability of prostate cancer and was used as an aid in distinguishing prostate cancer from benign prostatic conditions for men with PSA test 2–10 ng/mL and non‐suspicious digital rectal examination. Phi has been shown to improve diagnostic accuracy in prostate cancer detection compared with total and free PSA. An earlier 1‐year budget impact analysis revealed it to be a complementary approach to current prostate cancer screening strategies. The current study evaluated the cost‐effectiveness of early prostate cancer detection with phi in combination with a PSA test compared with a PSA test alone from the US societal perspective. The model with over 25 annual screening cycles for men aged 50–75 years indicated that PSA plus phi dominated the PSA test alone in prostate cancer detection and consequent treatment. PSA plus phi may be an important strategy for prostate cancer detection.

OBJECTIVE

• ? To evaluate the cost‐effectiveness of early prostate cancer detection with the Beckman Coulter Prostate Health Index (phi) (not currently available in the USA) adding to the serum prostate‐specific antigen (PSA) test compared with the PSA test alone from the US societal perspective.

PATIENTS AND METHODS

• ? Phi was developed as a combination of PSA, free PSA, and a PSA precursor form [?2]proPSA to calculate the probability of prostate cancer and was used as an aid in distinguishing prostate cancer from benign prostatic conditions for men with a borderline PSA test (e.g. PSA 2–10 ng/mL or 4–10 ng/mL) and non‐suspicious digital rectal examination.
• ? We constructed a Markov model with probabilistic sensitivity analysis to estimate expected costs and utilities of prostate cancer detection and consequent treatment for the annual prostate cancer screening in the male population aged 50–75 years old.
• ? The transition probabilities, health state utilities and prostate cancer treatment costs were derived from the published literature. The diagnostic performance of phi was obtained from a multi‐centre study. Diagnostic related costs were obtained from the 2009 Medicare Fee Schedule.
• ? Cost‐effectiveness was compared between the strategies of PSA test alone and PSA plus phi under two PSA thresholds (≥2 ng/mL and ≥4 ng/mL) to recommend a prostate biopsy.

RESULTS

• ? Over 25 annual screening cycles, the strategy of PSA plus phi dominated the PSA‐only strategy using both thresholds of PSA ≥2 ng/mL and PSA ≥4 ng/mL, and was estimated to save $1199 or $443, with an expected gain of 0.08 or 0.03 quality adjusted life years, respectively.
• ? The probabilities of PSA plus phi being cost effective were approximately 77–70% or 78–71% at a range of $0–$200 000 willingness to pay using PSA thresholds ≥2 ng/mL and ≥4 ng/mL, respectively.

CONCLUSION

• ? The strategy PSA plus phi may be an important strategy for prostate cancer detection at both thresholds of PSA ≥2 ng/mL and PSA ≥4 ng/mL to recommend a prostate biopsy compared with using PSA alone.

     

Prostate-specific antigen velocity (PSAV) risk count improves the specificity of screening for clinically significant prostate cancer

Study Type – Prognosis (retrospective cohort analysis) Level of Evidence 2b What's known on the subject? and What does the study add? PSA screening reduces prostate cancer mortality but also may lead to unnecessary biopsies and overdiagnosis of insignificant tumours. PSA velocity (PSAV) risk count (number of serial PSAV exceeding 0.4 ng/ml/year) significantly improves the performance characteristics of screening for overall prostate cancer and high‐grade disease on biopsy. Risk count may be useful to reduce unnecessary biopsies and prostate cancer overdiagnosis compared to PSA alone.

OBJECTIVE

• ? To determine whether the prostate‐specific antigen velocity (PSAV) risk count (i.e. the number of times PSAV exceeds a specific threshold) could increase the specificity of screening for prostate cancer and potentially life‐threatening tumours.

PATIENTS AND METHODS

• ? From 1989 to 2001, we calculated two serial PSAV measurements in 18 214 prostate cancer screening‐study participants, of whom 1125 (6.2%) were diagnosed with prostate cancer.
• ? The PSAV risk count was determined as the number of PSAV measurements of >0.4 ng/mL/year (0, 1, or 2).
• ? We used receiver operating characteristic (ROC) and reclassification analyses to examine the ability of PSAV risk count to predict screen‐detected and high‐grade prostate cancer.

RESULTS

• ? The PSAV was >0.4 ng/mL/year twice (risk count 2) in 40% of prostate cancer cases compared with only 4% of those with no cancer (P < 0.001).
• ? After adjusting for age and PSA level, a PSAV risk count of 2 was associated with an 8.2‐fold increased risk of prostate cancer (95% confidence interval 7.0–9.6, P < 0.001) and 5.4‐fold increased risk of Gleason score 8–10 prostate cancer on biopsy.
• ? Compared with a model with age and PSA level, the addition of the PSAV risk count significantly improved discrimination (area under the ROC curve 0.625 vs 0.725, P= 0.031) and reclassified individuals for the risk of high‐grade prostate cancer (net reclassification, P < 0.001).

CONCLUSIONS

• ? Sustained rises in PSA indicate a significantly greater risk of prostate cancer, particularly high‐grade disease.
• ? Compared with men with a risk count of ≤1, those with two PSAV measurements of >0.4 ng/mL/year (risk count 2) had an 8‐fold increased risk of prostate cancer and 5.4‐fold increased risk of Gleason 8–10 disease on biopsy, adjusting for age and PSA level.
• ? Compared to PSA alone, PSAV risk count may be useful in reducing unnecessary biopsies and the diagnosis of low‐risk prostate cancer.

     

A comparative performance analysis of total prostate-specific antigen, percentage free prostate-specific antigen, prostate-specific antigen velocity and urinary prostate cancer gene 3 in the first, second and third repeat prostate biopsy

Study Type – Diagnostic (cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Although non‐recommended PSA testing has been reported in men younger than 40 years of age, there are few recognized data on PSA in younger American men, particularly younger African‐American men, to provide age‐ and race‐specific references. Using data from an existing large study of young, male members of the US military, aged 28–36 years, the present study provides PSA reference distributions for young Caucasian‐American men (median = 0.56, 95th percentile = 1.42, range: <0.01–3.34 ng/mL) and African‐American men (median = 0.64, 95th percentile = 1.89, range: 0.12–6.45 ng/mL). Previous estimates from the literature are also summarized.

OBJECTIVE

• ? To provide race‐specific prostate‐specific antigen (PSA) reference distributions for young men less than 40 years of age who might have undergone non‐recommended PSA testing because of their family history of prostate cancer or inadvertently as part of a standard panel of tests.

MATERIALS AND METHODS

• ? We used data from a large existing study of young, male Caucasian‐ and African‐American members of the US military with stored serum in the Department of Defense serum repository.
• ? As part of this previous study, we selected a random sample of 373 Caucasian‐ and 366 African‐American men aged 28–36 years with an archived serum specimen collected for standard military purposes from 2004 to 2006.
• ? We measured serum total PSA concentration in this specimen using the Beckman Coulter Access Hybritech PSA assay.

RESULTS

• ? The PSA level ranged from <0.01 to 3.34 ng/mL among Caucasian‐American men, with a median of 0.56 ng/mL and a 95th percentile of 1.42 ng/mL.
• ? The PSA level ranged from 0.12 to 6.45 ng/mL among African‐American men, with a median of 0.64 ng/mL and 95th percentile of 1.89 ng/mL.
• ? The PSA level was significantly higher in African‐ than in Caucasian‐American men (P= 0.001).

CONCLUSION

• ? The PSA estimates, together with those summarized from the literature, provide age‐ and race‐specific PSA reference distributions for young men who might have undergone non‐recommended PSA testing.
• ? Comparisons by race could also begin to inform the timing of divergence of prostate cancer risk by race.

     

A prospective, randomized trial comparing the Vienna nomogram to an eight-core prostate biopsy protocol

Study Type – Diagnostic (RCT) Level of Evidence 1b What’s known on the subject? and What does the study add? Several studies have shown that increasing the number of prostate biopsy cores will increase the detection rate of prostate cancer, but also risks overdiagnosing insignificant cancer, particularly in the elderly. Our study suggests that there is no significant advantage in using the Vienna nomogram to determine the number of prostate biopsies to be taken, compared to an eight‐core biopsy protocol.

OBJECTIVE

• ? To compare prostate cancer detection rates using the Vienna nomogram versus an 8‐core prostate biopsy protocol. To compare the complication rates of transrectal prostate biopsy in the two groups.

PATIENTS AND METHODS

• ? In a prospective randomized trial, men with a serum PSA ≥ 2.5 ng/ml were stratified according to serum PSA (I = PSA 2.5–10; II = PSA 10.1–30; III = PSA 30.1–50 ng/mL) and were then randomized to group A (number of cores determined according to the Vienna nomogram) or group B (8‐core prostate biopsy).
• ? Statistical analysis was performed using Student’s t‐test for parametric data, Mann‐Whitney test for nonparametric data and Fisher’s exact test for contingency tables. A two‐tailed p‐value <0.05 was accepted as statistically significant.

RESULTS

• ? In the period July 2006 to July 2009, 303 patients were randomized to group A (n = 152) or group B (n = 151). There were no significant differences in serum PSA, prostate volume, PSA density or post‐biopsy complications between the groups.
• ? The cancer detection rate was lower in group A than in group B for the whole study cohort (35.5% vs 38.4%), for those with PSA < 10 ng/ml (28.1% vs 33%) and for those with prostate volume >50 ml (22% vs 25.8%). These differences were not statistically significant (NSS).

CONCLUSION

• ? These findings suggest that there is no significant advantage in using the Vienna nomogram to determine the number of prostate biopsy cores to be taken, compared to an 8‐core biopsy protocol.

     

Achieving the 'bifecta' using salvage cryotherapy for locally recurrent prostate cancer: analysis of the Cryo On-Line Data (COLD) registry data

Study Type – Outcomes (cohort) Level of Evidence 2b What's known on the subject? and What does the study add? The cancer‐specific outcomes of salvage cryotherapy for locally recurrent prostate cancer have been well established within contemporary scientific literature. However, very little is known about the outcomes of salvage cryotherapy encompassing health‐related quality of life considerations such as continence after treatment. We think the present study is quite novel, as it proposes a new therapeutic endpoint to evaluate the efficacy and outcomes of salvage therapies for locally recurrent prostate cancer, which we have termed the ‘bifecta’. In addition, we report that in a large multicentre data registry, such as the COLD Registry, the therapeutic ‘bifecta’ can be achieved in most patients.

OBJECTIVES

• ? To evaluate the contemporary outcomes of salvage cryotherapy for locally recurrent prostate cancer using the Cryo On‐Line Data (COLD) Registry.
• ? We also evaluate the outcomes of salvage cryotherapy in achieving the therapeutic ‘bifecta’ consisting of: (i) achieving a post‐cryotherapy nadir serum PSA level of <0.6 ng/mL and (ii) no urinary incontinence.

PATIENTS AND METHODS

• ? A prospectively, centrally collected secure online database has been developed of patients undergoing salvage cryoablation for locally recurrent prostate cancer. Of the patients undergoing salvage cryotherapy (in the absence of neoadjuvant hormonal ablative therapy) included within the COLD Registry, complete medical records pertaining to continence status and serial PSA measurements after treatment were available in 183 patients.

RESULTS

• ? The therapeutic ‘bifecta’ was achieved in 133 of these patients (72.7%).
• ? Of the patients achieving the ‘bifecta’, the mean (sd ) age at presentation was 71.5 (6.6) years.
• ? Most patients (91%) had a baseline pre‐salvage total serum PSA level of <10 ng/mL and a pre‐treatment biopsy Gleason score of <8 (85%).
• ? The mean duration of follow‐up of patients achieving the ‘bifecta’ was 36.5 months.

CONCLUSIONS

• ? The therapeutic ‘bifecta’, a new surrogate benchmark for salvage therapies, can be achieved in most patients undergoing salvage cryotherapy.
• ? Therefore, salvage cryotherapy is a reasonable treatment choice for locally recurrent prostate cancer in appropriately selected patients.

     

The relationship between prostate volume and prostate-specific antigen variability: data from the Baltimore Longitudinal Study of Aging and the Johns Hopkins Active Surveillance Program

Study Type – Prognostic (cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Previous studies have attempted to characterize the normal biological variability in PSA among men without prostate cancer. These reports suggest that PSA variability is unrelated to age, but there are conflicting data on its association with the baseline PSA level. There are limited published data regarding the effects of prostate volume on PSA variability. A prior study assessing whether prostate volume changes would confound the use of PSA velocity in clinical practice reported that prostate volume changes were not significantly related to PSA changes. This study did not directly address the effect of baseline prostate volume on serial PSA variability. The objective of the current study was to further examine the relationship between prostate volume and PSA variability. Our hypothesis was that larger baseline prostate volume would be associated with increased PSA variability in men without known prostate cancer and in those with suspected small‐volume disease. The results of the study suggest that baseline PSA, not prostate volume, is the primary driver of PSA variability in these populations.

OBJECTIVE

• ? To clarify the relationship between serial prostate‐specific antigen (PSA) variability and prostate volume in both cancer‐free participants from the Baltimore Longitudinal Study of Aging (BLSA) and patients with low‐risk prostate cancer from the Johns Hopkins Active Surveillance Program (AS).

MATERIALS AND METHODS

• ? In all, 287 men from the BLSA and 131 patients from the AS were included in the analysis, all with at least two PSA measurements and concurrent prostate volume measurements.
• ? PSA variability was calculated in ng/mL per year, and a linear mixed‐effects model was used to determine the relative effects of prostate volume, baseline PSA and age on PSA change over time.

RESULTS

• ? In a model with prostate volume, age and baseline PSA, there was no significant relationship between prostate volume and PSA variability (BLSA, P= 0.57; AS, P= 0.49).
• ? Only baseline PSA showed a significant relationship to PSA yearly variability (PSAYV) (P < 0.001). Specifically, a one unit higher baseline PSA (ng/mL) corresponded on average to 0.09 and 0.06 ng/mL per year higher PSAYV in the BLSA and AS populations, respectively.

CONCLUSIONS

• ? The results of the present study suggest that the primary driver of PSA variability is the baseline PSA level, rather than prostate volume.
• ? Clinicians might consider the baseline PSA level to help predict the expected variability in serial PSA measurements.

     

Transatlantic Consensus Group on active surveillance and focal therapy for prostate cancer

Study Type – Prognosis (inception cohort) Level of Evidence 2a What's known on the subject? and What does the study add? There is little data on the utility of digital rectal examination (DRE) as a diagnostic tool in the era of prostate‐specific antigen (PSA) testing. Using a population‐based database, we found that detection of prostate cancer while still localized among men with high‐grade PSA‐occult disease may result in survival benefit.

OBJECTIVE

• ? To determine whether detection of high‐grade prostate cancer while still clinically localised on digital rectal examination (DRE) can improve survival in men with a normal prostate‐specific antigen (PSA) level.

PATIENTS AND METHODS

• ? From the Surveillance, Epidemiology and End Results database, 166 104 men with prostate cancer diagnosed between 2004 and 2007 were identified.
• ? Logistic regression was used to identify factors associated with the occurrence of palpable, PSA‐occult (PSA level of <2.5 ng/mL), Gleason score 8–10 prostate cancer.
• ? Fine and Gray's and Cox multivariable regressions were used to analyse whether demographic, treatment, and clinicopathological factors were associated with the risk of prostate cancer‐specific mortality (PCSM) and all‐cause mortality (ACM), respectively.

RESULTS

• ? Both increasing age (adjusted odds ratio [aOR] 1.02, 95% confidence interval (CI) 1.01–1.03; P < 0.001) and White race (aOR 1.26, 95% CI 1.03–1.54; P= 0.027) were associated with palpable, Gleason 8–10 prostate cancer. Of 166 104 men, 685 (0.4%) had this subset of prostate cancer.
• ? Significant factors associated with risk of PCSM included PSA level (adjusted hazard ratio [aHR] 0.71, 95% CI 0.51–0.99; P= 0.04), higher Gleason score (aHR 2.20, 95% CI 1.25–3.87; P= 0.006), and T3–T4 vs T2 disease (aHR 3.11, 95% CI 1.79–5.41; P < 0.001).
• ? Significant factors associated with risk of ACM included age (aHR 1.03, 95% CI 1.01–1.06; P= 0.006), higher Gleason score (aHR 2.05, 95% CI 1.36–3.09; P < 0.001), and T3–T4 vs T2 disease (aHR 2.11, 95% CI 1.38–3.25, P < 0.001)

CONCLUSIONS

• ? Clinically localised disease on DRE among men with PSA‐occult high‐grade prostate cancer was associated with improved PCSM and ACM, suggesting that DRE in this cohort (older age and White race) may have the potential to improve survival.

     

A post‐radical‐prostatectomy nomogram incorporating new pathological variables and interaction terms for improved prognosis

Study Type – Prognosis (systematic review)
Level of Evidence 2a What’s known on the subject? and What does the study add? Nomograms are commonly used by urologists to assess a patient’s risk of developing biochemical failure (PSA recurrence) after radical prostatectomy. The nomograms currently available on websites and in the published literature do not take into account recent developments in pathological reporting which may improve our ability to more accurately predict patient prognosis. Furthermore, currently available nomograms treat all clinical predictors as independent variables without considering the possibility that these factors may be interlinked, which may alter their predictive value. Our study assesses the predictive value of several new pathological variables and demonstrates that the per cent of Gleason patterns 4 and/or 5 (% 4/5), intraductal prostatic carcinoma and prostate weight significantly improve the predictive value of a model based on established pathological variables. We also show that consideration of interactions between % 4/5, surgical margin status and extracapsular extension further improves our accuracy in predicting patient PSA recurrence. Finally, we find that published nomograms based on PSA recurrence defined as ≥0.4 ng/mL provide over‐optimistic predictions for prostate cancer patients where PSA recurrence was defined as ≥0.2 ng/mL.

OBJECTIVE

• ? To evaluate new variables in prostate pathology reporting including, the per cent of Gleason patterns 4 and/or 5 (% 4/5), presence or absence of intraductal carcinoma of the prostate (IDCP), tumour volume and the prostatic zone of tumour origin as predictors of post‐radical‐prostatectomy (RP) biochemical recurrence (BCR).
• ? To develop an optimal postoperative nomogram for patients with prostate cancer.

PATIENTS AND METHODS

• ? Our study cohort was 1939 eligible patients from the Abbott West Australian Prostatectomy Database.
• ? Multivariate Cox proportional hazard regression models were developed to predict BCR which was defined as prostate‐specific antigen (PSA) ≥0.2 ng/mL.
• ? Our models and the 2009 Kattan postoperative nomogram were compared in terms of discrimination and calibration, with internal validation of our final model performed using bootstrapping methods. Our final model is presented as a nomogram.

RESULTS

• ? The Kattan nomogram was accurate in discriminating our patients according to risk (concordance index: 0.791) but calibration analysis indicated underestimation of patient risk, particularly for high‐risk disease.
• ? Our nomogram incorporates % 4/5, IDCP and prostate weight plus interaction terms between % 4/5, positive surgical margins and extracapsular extension, giving improved predictive accuracy (concordance index: 0.828) and calibration.

CONCLUSIONS

• ? Nomograms that predict risk of BCR defined as PSA ≥0.4 ng/mL may not be optimal for patient cohorts where BCR is defined as PSA ≥0.2 ng/mL.
• ? If our findings are validated in other populations, current post‐RP nomograms may be improved to a modest degree by incorporating the new variables prostate weight, IDCP and % 4/5, and by considering interactions between predictive variables.

     

Primary full-gland prostate cryoablation in older men (> age of 75 years): results from 860 patients tracked with the COLD Registry

Study Type – Therapy (outcomes research) Level of Evidence 2c What's known on the subject? and What does the study add? Most elderly patient with prostate cancer undergo radiation therapy, but cryoablation has gained popularity. This study demonstrates the safety and efficiency of this new approach.

OBJECTIVE

• ? To report on the largest data set regarding outcomes for whole gland prostate cryoablation as a primary treatment of prostate cancer in older men, which we empirically defined as age >75 years.

MATERIALS AND METHODS

• ? The COLD (Cryo On‐Line Data) Registry consists of case report forms with pre‐ and post‐treatment information obtained from patients undergoing prostate cryoablation.
• ? A total of 860 patients were stratified into low‐, intermediate‐ and high‐risk groups (D'Amico 2003 risk definitions).
• ? Biochemical disease‐free survival (bDFS) was defined according to the traditional American Society for Therapeutic Radiology and Oncology definition (3 increases) and the newer (Phoenix) definition (nadir +2).
• ? Biopsy was performed at physician discretion but most commonly for cause if a patient had an increasing or suspicious prostate‐specific antigen level (PSA).

RESULTS

• ? The median age was 79 years (76–91) and the median follow‐up was 16 months (4–60).
• ? The 5‐year [95% confidence interval (CI)] bDFS for the entire population using ASTRO and Phoenix definitions was 79% (4%) and 62.6% (8.3%), respectively.
• ? Stratified by risk group, 5‐year bDFS (ASTRO) was 82.4% (7.9%), 78.3% (5.8%) and 77.6% (7.7%) for low, moderate and high risk, respectively.
• ? Using the Phoenix definition, 5‐year bDFS was 74.9%± 15.3%, 61.4%± 13.2% and 58.0%± 11.9% for low‐, moderate‐ and high‐risk groups, respectively.
• ? Incontinence was reported in eight patients (0.9%).

CONCLUSION

• ? Whole gland cryoablation in older men maintains oncological efficacy similar to that of younger men without increased morbidity.

     

Clinical evaluation of a novel method for the measurement of prostate-specific antigen, AccuPSA(TM) , as a predictor of 5-year biochemical recurrence-free survival after radical prostatectomy: results of a pilot study

Study Type – Diagnostic (validating cohort) Level of Evidence 1b What's known on the subject? and What does the study add? Nadir Ultrasensitive PSA levels has some value for predicting BCR following RD. AccuPSA assays lower limit of PSA quantification of <0.01 pg/ml greatly enhances sensitivity and specificity of nadir PSA to predict BCR following RP. Our pilot study shows an AccuPSA of 3 pg/ml has a sensitory and specificity of 100% and 75% respectively for predicting 5 year BCR following RP. OBJECTIVES

• ? To conduct a proof of concept study to evaluate a novel digital single molecule immunoassay (AccuPSA^TM) that detects prostate‐specific antigen (PSA) a thousandfold more sensitively than current PSA detection methods.
• ? To determine the ability of the AccuPSA^TM assay to predict 5‐year biochemical recurrence (BCR)‐free survival after radical prostatectomy (RP).

PATIENTS AND METHODS

• ? A total of 31 frozen serum specimens were obtained from specimen logs maintained at New York University Langone Medical Center and the Johns Hopkins University School of Medicine on men who had undergone RP. Those men without evidence of BCR had a minimum of 5 years' PSA follow‐up.
• ? In all cases, preoperative and pathological information were available, as was a serum specimen 3–6 months after RP, with a PSA level of <0.1 ng/mL measured by conventional PSA methods at the time of serum collection.
• ? Specimens were tested using the AccuPSA^TM method.
• ? A Cox proportional hazard model and Kaplan–Meier analysis were used to determine whether AccuPSA^TM predicted the risk of BCR.

RESULTS

• ? Overall, 11/31 (35.5%) men developed BCR.
• ? Mean AccuPSA^TM nadir levels were significantly different (P < 0.001) between the non‐BCR group (2.27 pg/mL) and the BCR group (46.99 pg/mL).
• ? Using a multivariate Cox proportional hazard model, AccuPSA^TM nadir level was a significant predictor of BCR‐free survival (P < 0.01).
• ? Kaplan–Meier analysis of up to 5 years follow‐up showed that 100% of men with AccuPSA^TM nadir values <3 pg/mL did not develop BCR, whereas 62.5% of men with values >3 pg/mL developed BCR (P= 0.00024).
• ? The sensitivity, specificity, positive predictive value and negative predictive value of the AccuPSA^TM method was 100%, 75%, 69% and 100%, respectively.

CONCLUSIONS

• ? AccuPSA^TM assay predicts 5‐year BCR‐ free survival after RP.
• ? Identifying a reliable predictor of BCR soon after RP has important implications for frequency of PSA testing, selection of candidates for adjuvant therapy, and reassuring a large subset of men that they are not at risk of recurrence.
• ? Larger studies are needed to validate these findings.

     

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.

     

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.

     

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.

     

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.

     

Antibiotics and observation have a similar impact on asymptomatic patients with a raised PSA

Study Type – Therapy (case series)
Level of Evidence 4 What's known on the subject? and What does the study add? As PSA exhibits suboptimal specificity, different strategies have been proposed in order to decrease the number of negative biopsies. An empirical course of antibiotics has been proposed as a cost‐saving strategy to differentiate patients with benign cancer as it could potentially avoid unnecessary biopsies. Despite being limited by its non‐randomized open‐label design, our data suggest that no specific PSA reduction threshold can accurately discriminate prostate cancer. The empirical use of antibiotics for asymptomatic patients with elevated PSA levels should be discouraged.

OBJECTIVES

• ? To compare the influence of a 4‐week course of empirical antimicrobial therapy or observation on the prostate‐specific antigen (PSA) levels of asymptomatic patients with a raised baseline PSA.
• ? To identify whether a decrease in PSA can predict the risk of prostate cancer (PCa) detection on prostate biopsy.

PATIENTS AND METHODS

• ? Patients were referred to our ambulatory centre because of a raised PSA level (>2.5 ng/mL) with a normal digital rectal examination. A 12‐core prostate biopsy was indicated in these patients and they were offered antibiotic treatment with levofloxacin 500 mg daily for 30 days.
• ? Patients who did not agree to use antibiotics but who still showed interest in participating underwent simple observation, serving as controls.
• ? Total and free PSA levels at baseline and after 45 days were measured. Variation in PSA level was calculated.
• ? All patients underwent a 12‐core prostate biopsy 6 weeks after the initial visit.

RESULTS

• ? In all, 245 men were enrolled, but 43 were lost due to follow‐up. A total of 145 patients who used antibiotics and 57 controls were included in the analysis.
• ? The median baseline PSA levels were 7.6 and 7.7 ng/mL in the antibiotic and control groups, respectively, with median follow‐up levels of 6.8 and 7.0 ng/mL. The follow‐up PSA level was significantly lower than the initial PSA level (P = 0.009).
• ? Mean absolute and percentage variation in PSA level were similar in both groups (P = 0.828 and 0.128, respectively).
• ? The overall PCa detection rate was 15.8%, and did not differ among the groups (P = 0.203). Regarding the percentage variation in PSA level, patients diagnosed with PCa tended to have their PSA level increased (22.4 vs –5.3%; P = 0.001). Indeed, a decrease of 20% in PSA was not predictive of a negative prostate biopsy (P = 0.41).
• ? The area under the receiver operating characteristic curve for percentage PSA variation as a predictor of PCa was 0.660.

CONCLUSIONS

• ? PSA levels tend to fall when repeated after 45 days, regardless of antibiotic use.
• ? Despite being associated with the chance of PCa, no percentage PSA variation threshold value exhibits satisfactory discriminatory properties.

     

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.