Contrast-enhanced ultrasonography with contrast-tuned imaging technology for the detection of prostate cancer: comparison with conventional ultrasonography

Study Type – Diagnostic (exploratory cohort) Level of Evidence 2b What's known on the subject? and What does the study add? The present study was to perform contrast‐tuned imaging (CnTI) technology to detect prostate cancer and compare the use of CnTI technology for the detection of prostate cancer with conventional ultrasonography. The preliminary data from our study suggested that targeted biopsy of the prostate with CnTI technology could improve the cancer detection and detect higher grade prostate cancers.

OBJECTIVES

• ? To perform contrast‐enhanced ultrasonography (CEUS) using contrast‐tuned imaging (CnTI) technology to detect prostate cancer.
• ? To evaluate the detection of prostate cancer with CnTI compared with conventional grey‐scale and power Doppler ultrasonography.

PAIENTS AND METHODS

• ? In all, 150 patients referred for prostate biopsy were evaluated using transrectal grey‐scale, power Doppler and CnTI ultrasonography.
• ? Biopsy was performed at 10 sites in each patient. If an abnormality was found at any of these three ultrasonography examinations, a biopsy specimen was targeted towards from the corresponding site.
• ? The performances of the three ultrasonography techniques for prostate cancer detection were compared.

RESULTS

• ? Prostate cancer was detected at 383 sites from 73 patients. The combination of these three examinations detected more patients with prostate cancer than grey‐scale (P= 0.002), power Doppler (P= 0.001) or baseline imaging (the combination of grey‐scale and power Doppler; P= 0.031) alone.
• ? By biopsy site, CnTI had higher sensitivity and accuracy (73.1% and 83.7%) than grey‐scale (50.9%; P < 0.001 and 78.8%; P < 0.001) or power Doppler (48.3%; P < 0.001 and 77.7%; P < 0.001), while the specificity was similar for grey‐scale (88.4%), power Doppler (87.8%) and CnTI (87.3%; P > 0.05 in each case). CnTI had higher sensitivity (73.1% vs 62.9%; P < 0.001), specificity (87.3% vs 82.1%; P < 0.001) and accuracy (83.7% vs 77.2%; P < 0.001) than baseline imaging.
• ? The mean Gleason score of CnTI‐positive cases was significantly higher than CnTI‐negative cases (7.1 vs 6.3; P= 0.002).

CONCLUSIONS

• ? CEUS using CnTI technology enables a visualization of the microvasculature associated with prostate cancer.
• ? CnTI technology could be used to guide biopsy and improve the detection rate of prostate cancer.
• ? CnTI technology was able to detect higher grade prostate cancers.

     

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.

     

Contrast-enhanced ultrasound using a time-intensity curve for the diagnosis of renal cell carcinoma

Study Type – Diagnosis (non‐consecutive series) Level of Evidence 3b What’s known on the subject? and What does the study add? In terms of imaging differentiation, distinguishing complex cystic renal masses that require surgery from those that do not remains a common and difficult diagnostic problem. Magnetic resonance imaging (MRI) is useful for characterizing complex cystic renal masses. But there are some cases that are difficult to diagnose differentially on computed tomography (CT) or MRI. We evaluated the usefulness of contrast‐enhanced ultrasound (CEUS) for the diagnosis of cystic renal cell carcinoma by using a time‐intensity curve (TIC). Assessments of blood flow in the solid component of a cystic tumour by CEUS using a second‐generation US contrast agent and TIC analysis have made it easier to objectively diagnose cystic renal cancer.

OBJECTIVE

• ? To evaluate the usefulness of contrast‐enhanced ultrasound (CEUS) for the diagnosis of renal cell carcinoma by employing a time‐intensity curve (TIC).

PATIENTS AND METHODS

• ? From May 2008 to October 2009, CEUS was performed prior to surgery in 30 patients with renal masses.
• ? In all, 10 of the 30 patients had cystic renal masses. The final diagnoses of all patients were pathologically confirmed. Contrast enhancement as a function of time was measured in two (tumour or solid component of cystic lesions and normal parenchyma) regions of interest (ROI) and TICs were obtained.
• ? The time to the contrast enhancement peak (TTP), intensity change from the baseline to peak (ΔI) and ΔI/TTP of the tumour and the normal parenchyma were measured from the TIC.

RESULTS

• ? Pathological diagnoses were renal cell carcinoma in 30 patients.
• ? The TTP of the cancer was shorter than that of the normal parenchyma in all cases (6.0 ± 2.0 vs 10.4 ± 3.0 s; P < 0.0001).
• ? The ΔI did not differ between the cancer and normal parenchyma [21.3 ± 5.9 vs 20.9 ± 7.0 decibels (db); P= 0.68]; the ΔI/TTP of the cancer was significantly higher than that of the normal parenchyma (3.9 ± 1.4 vs 2.2 ± 0.94 db/s; P < 0.0001).
• ? TIC patterns of solid cancer and cystic cancer were very similar.

CONCLUSIONS

• ? An objective and quantitative diagnosis of renal cell carcinoma by CEUS using a second‐generation ultrasound contrast agent can be made by employing a TIC.
• ? The TIC patterns of solid and cystic cancers were very similar, despite their morphological and vascular differences.
• ? CEUS using TIC is a promising tool in the diagnosis of cystic renal cancer.

     

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.

     

Transrectal ultrasonography-guided biopsy does not reliably identify dominant cancer location in men with low-risk prostate cancer

Study Type – Diagnostic (exploratory cohort) Level of Evidence 2b What's known on the subject? and What does the study add? The widespread use of serum PSA testing followed by TRUS‐guided biopsy have resulted in profound prostate cancer stage migration with many patients presenting with focal rather than multifocal disease. There is increasing interest in the use of focal rather than whole‐gland treatment. However, current biopsy schemes may still miss cancer or, even when cancer is identified, its extent or grade might not be accurately characterized. In order for focal therapy to be effective, the area of highest tumour volume and/or grade needs to localized accurately. The aim of this study was to assess how well biopsy, as currently performed, locates the focus of highest prostate cancer volume and/or grade.

OBJECTIVE

• ? To evaluate the ability of transrectal ultrasonography (TRUS)‐guided extended core biopsy to identify the dominant tumour accurately in men with early stage prostate cancer.

PATIENTS AND METHODS

• ? Patients with early stage, low‐risk prostate cancer who subsequently underwent radical prostatectomy (RP) and had complete surgical specimens were identified.
• ? Re‐review was performed by a single uropathologist using ImageJ software to identify tumour location, dominant grade (DG) and dominant volume (DV).
• ? Pathology findings were then compared with biopsy results.

RESULTS

• ? A total of 51 men with early stage, low‐risk prostate cancer, who had undergone RP, had complete specimens for review and a median of 15 biopsy cores taken for diagnosis and grading.
• ? Sixteen men had a single diagnostic biopsy, 21 had one repeat biopsy, and 14 had two or more repeat biopsies.
• ? Compared with surgical findings, biopsy correctly identified the sextant with the largest tumour volume in 55% (95% CI 0.5–0.6) of specimens and the highest grade in 37% (95 CI 0.3–0.5).
• ? No demographic or clinical factors were significantly associated with identification of DG. Interval between last biopsy and RP, total tissue length taken and total length of tumour identified were significantly associated with correct identification of DV.

CONCLUSIONS

• ? Our findings show that TRUS‐guided biopsy detects and localizes DV better than it does DG.
• ? Even with an extended scheme, TRUS‐guided biopsy does not reliably identify dominant cancer location in this low‐risk cohort of men with early stage prostate cancer.
• ? TRUS‐guided biopsy may perform better in similar men with low stage, but higher volume disease.

     

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.

     

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.

     

New drugs for prostate cancer

What's known on the subject? and What does the study add? Recent studies have demonstrated the efficacy of various new treatments. These have been in diverse areas of therapeutics research, including immunology and targeted biological therapy, as well as in new ways of approaching hormone refractory disease. The present paper seeks to review all of the key advances that have been reported in late‐stage clinical studies and place them into the context of managing patients with advanced prostate cancer.

OBJECTIVE

• ? To describe some of the most exciting late stage clinical developments in the field of new therapies for advanced prostate cancer.

METHODS

• ? Pubmed was searched for articles pertaining to prostate cancer therapeutics clinical trials in the last 3 years.

RESULTS

• ? Key positive trials in the areas of androgen resistance, tumour immunology, molecularly targeted agents and cytotoxics were reviewed and discussed in the context of metastatic prostate cancer.

CONCLUSION

• ? Treatments emerging from these areas of scientific endeavour are progressing into clinical trials and are both good cause for hope in patients, and excellent examples of mechanism based drug discovery.

     

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.

     

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.

     

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.

     

The use of estramustine phosphate in the modern management of advanced prostate cancer

What’s known on the subject? and What does the study add? Estramustine phosphate has anti‐tumour properties and it improves patient outcomes if combined with other chemotherapy agents such as doeetaxel. The efficacy of estramustine phosphate in selected patients and its safety profile, provided used with any low‐molecular‐weight heparin support its use as a second‐line treatment in hormone‐resistant prostate cancer.

OBJECTIVES

• ? Estramustine phosphate is a nitrogen mustard derivative of estradiol‐17β‐phosphate and has anti‐tumour properties.
• ? Interest in estramustine has been renewed because of the results of clinical studies showing improved patient outcomes if estramustine is combined with other chemotherapy agents such as docetaxel.

PATIENTS AND METHODS

• ? Relevant clinical studies using chemotherapy combinations including estramustine are discussed.
• ? Efficacy and safety outcomes are summarized.

RESULTS

• ? Combination therapy with estramustine and docetaxel can increase PSA response rates, improve quality of life and increase median patient survival compared with chemotherapy regimens that do not include estramustine.
• ? Although the overall tolerability of estramustine is favourable, its use can be associated with an increased risk of thromboembolic events.

CONCLUSIONS

• ? The identification of suitable patient groups and the effective management of the risk of thromboembolism with the adjunct of low‐molecular‐weight heparins support the use of estramustine as an effective second‐line treatment strategy in hormone‐resistant prostate cancer.
• ? These promising findings warrant further investigation in a randomized clinical trial.

     

Patients aged more than 70 had higher risk of locally advanced prostate cancers and biochemical recurrence in Korea

Study Type – Prognosis (cohort series) Level of Evidence 2b What's known on the subject? and What does the study add? This study reports that patients aged 70 years or older have a higher possibility of locally advanced cancer than younger patients. Instead of conservative management, radical eradication of clinically localized prostate cancer should be actively considered in well‐selected healthy patients older than 70 years.

OBJECTIVE

• ? To analyse the differences in the clinicopathological results between two groups of Korean patients aged younger or older than 70 years with clinically localized prostate cancer.

METHODS

• ? A cohort of consecutive male patients who underwent radical prostatectomy was retrospectively analysed. In total, 995 patients (74.6%) were younger than 70 years, and 338 patients (25.4%) were 70 years or older.
• ? Biochemical recurrence (BCR) ‐free survival was evaluated in the patients, who were followed up for more than 24 months.
• ? The Kaplan–Meier method was used to calculate survival estimates for BCR‐free survival. Multivariate Cox proportional hazard regression analysis was performed to predict non‐organ‐confined status and BCR.

RESULTS

• ? Mean preoperative prostate‐specific antigen (PSA) levels and biopsy or pathological Gleason scores showed no differences between the two age groups.
• ? Older patients, aged more than 70 years, displayed significantly higher risk of locally advanced prostate cancer and BCR than younger patients.
• ? Subgroup analysis showed that the risk of the presence of locally advanced disease was significantly increased in patients of 70 years or older when we compared the proportion of locally advanced disease only in patients with PSA <4 ng/mL.
• ? Multivariate analysis showed that old age, high PSA and high Gleason score were significantly associated with non‐organ confined status and BCR.

CONCLUSIONS

• ? Patients aged 70 years or older had a higher possibility of locally advanced cancer than younger patients.
• ? Radical eradication of clinically localized prostate cancer should be actively considered in well‐selected healthy patients older than 70 years.

     

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.

     

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.

     

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.

     

Evolution of the clinical presentation of men undergoing radical prostatectomy for high-risk prostate cancer

Study Type – Prognosis cohort series (multi‐centre) Level of Evidence 4 What's known on the subject? and What does the study add? Men with high‐risk prostate cancer experience recurrence, metastases and death at a higher rate in the prostate cancer population. This study adds greater than 20‐year data regarding the continued evolution of high‐risk prostate cancer toward high‐Gleason disease as the sole determinant of high‐risk status prior to radical prostatectomy. It validates the accumulation of multiple‐risk factors as a poor prognostic indicator in a radical prostatectomy population and demonstrates long‐term cancer specific outcomes, extending the findings demonstrated by previous publications.

OBJECTIVE

• ? To investigate the outcomes and potential effect of improved longitudinal screening in men presenting with high‐risk (advanced clinical stage [>T2b], Gleason score 8–10 or prostate‐specific antigen [PSA] level >20 ng/mL) prostate cancer (PC).

PATIENTS AND METHODS

• ? The Institutional Review Board approved, Institutional Radical Prostatectomy Database (1992–2010) was queried for men with high‐risk PC based on D'Amico criteria.
• ? Year of surgery was divided into two cohorts: the Early PSA Era (EPE, 1992–2000) and the Contemporary PSA Era (CPE, 2001–2010).
• ? PC features and outcomes were evaluated using appropriate comparative tests.

RESULTS

• ? In total, 667 men had high‐risk PC in the EPE and 764 in the CPE.
• ? In the EPE, 598 (89.7%) men presented with one high‐risk feature; 173 (29.0%) men had a Gleason score of 8–10 on biopsy. In the CPE, 717 (93.9%) men presented with one high‐risk feature (P= 0.004) and 494 (68.9%) men had a Gleason score of 8–10.
• ? At 10 years, biochemical‐free survival (BFS) was 44.1% and 36.4% in the EPE and CPE, respectively (P= 0.04); metastases‐free survival (MFS) was 77.1% and 85.1% (P= 0.6); and PC‐specific survival (CSS) was 83.3% and 96.2% (P= 0.5).
• ? BFS, MFS and CSS were worse for men with more than one high‐risk feature in both eras.

CONCLUSIONS

• ? Over the PSA era, an increasing percentage of men with high‐risk PC were categorized by a biopsy Gleason score of 8–10.
• ? The accumulation of multiple high‐risk features increases the risk of biochemical recurrence, the development of metastases and death from PC.
• ? BFS, MFS and CSS are stable over the PSA era for these men. The balance between a greater proportion of men having high Gleason disease and a greater proportion with small, less advanced tumours may explain the stability in MFS and CSS over time.

     

Compliance with biopsy recommendations of a prostate cancer risk calculator

Study Type – Diagnostic (cohort) Level of Evidence 2b What's known on the subject? and What does the study add? So far, few publications have shown that a prediction model influences the behaviour of both physicians and patients. To our knowledge, it was unknown whether urologists and patients are compliant with the recommendations of a prostate cancer risk calculator and their reasons for non‐compliance. Recommendations of the European Randomized study of Screening for Prostate Cancer risk calculator (ERSPC RC) about the need of a prostate biopsy were followed in most patients. In most cases of non‐compliance with ‘no biopsy’ recommendations, a PSA level ≥3 ng/mL was decisive to opt for biopsy. Before implementation of the ERSPC RC in urological practices at a large scale, it is important to obtain insight into the use of guidelines that might counteract the adoption of the use of the RC as a result of opposing recommendations.

OBJECTIVES

• ? To assess both urologist and patient compliance with a ‘no biopsy’ or ‘biopsy’ recommendation of the European Randomized study of Screening for Prostate Cancer (ERSPC) Risk Calculator (RC), as well as their reasons for non‐compliance.
• ? To assess determinants of patient compliance.

PATIENTS AND METHODS

• ? The ERSPC RC calculates the probability on a positive sextant prostate biopsy (P_posb) using serum prostate‐specific antigen (PSA) level, outcomes of digital rectal examination and transrectal ultrasonography, and ultrasonographically assessed prostate volume. A biopsy was recommended if P_posb≥20%.
• ? Between 2008 and 2011, eight urologists from five Dutch hospitals included 443 patients (aged 55–75 years) after a PSA test with no previous biopsy.
• ? Urologists calculated the P_posb using the RC in the presence of patients and completed a questionnaire about compliance.
• ? Patients completed a questionnaire about prostate cancer knowledge, attitude towards prostate biopsy, self‐rated health (12‐Item Short Form Health Survey), anxiety (State Trait Anxiety Inventory‐6, Memorial Anxiety Scale for Prostate Cancer) and decision‐making measures (Decisional Conflict Scale).

RESULTS

• ? Both urologists and patients complied with the RC recommendation in 368 of 443 (83%) cases.
• ? If a biopsy was recommended, almost all patients (96%; 257/269) complied, although 63 of the 174 (36%) patients were biopsied against the recommendation of the RC.
• ? Compliers with a ‘no biopsy’ recommendation had a lower mean P_posb than non‐compliers (9% vs 14%; P < 0.001).
• ? Urologists opted for biopsies against the recommendations of the RC because of an elevated PSA level (≥3 ng/mL) (78%; 49/63) and patients because they wanted certainty (60%; 38/63).

CONCLUSIONS

• ? Recommendations of the ERSPC RC on prostate biopsy were followed in most patients.
• ? The RC hence may be a promising tool for supporting clinical decision‐making.

     

Quantitative tissue analyses of prostate cancer foci in an unselected cystoprostatectomy series

What's known on the subject? and What does the study add? Much of our understanding of the pathological basis of prostate cancer comes from our analysis of radical prostatectomy specimens. Prostate cancer diagnosed by transrectal ultrasonography‐guided biopsy is more likely to be posterior and basal in orientation rather than anterior or apical. Quantitative tissue analyses have not been undertaken both with details and in an unselected population, e.g. prostate specimens from autopsy cystoprostatectomy series from bladder cancer. Quantitative tissue analysis of incidentally detected prostate cancer such as largest cancer surface area, volume, site of origin, multifocality and laterality could be of paramount importance when trying to understand the findings of screen‐detected programmes and focal therapy. Cancers were found in 30% of prostates. In the 96 prostates, 215 cancer foci were identified (mean 2.24). Prostate cancer was multifocal in 60% and bilateral in 80% of cases. The site of origin was in the peripheral and transition zone (TZ) in 75% and 25%, respectively. Overall, 90% of cancer foci were clinically insignificant with volume of <0.5 mL and no grades 4–5. In all, 75% of the cancer foci were in the peripheral zone, the remainder were within the TZ. One third of cancer foci were anteriorly located beyond the area sampled by posterior biopsies. One fifth of cancer foci were ≤6 mm of the apex.

OBJECTIVE

• ? To describe multifocality, volume and location of prostate cancers incidentally found in cystoprostatectomy specimens. Quantitative tissue analysis of prostate cancer in a population free of the evaluation bias associated with prostate‐specific antigen level and biopsy is important as some men are likely to be offered tissue‐preserving therapeutic strategies in the future.

PATIENTS AND METHODS

• ? Cystoprostatectomy specimens for bladder cancer from 345 consecutive patients without clinically manifest prostate cancer were included.
• ? Cancers were found in 104/345 (30%) of prostates. Cases with largest cancer >2 mL (eight patients) were excluded from morphometric study. Quantitative tissue analysis of 3‐mm step‐sectioned glands included largest cancer surface area, volume, site of origin, multifocality and laterality.

RESULTS

• ? In the 96 prostates, 215 cancer foci were identified (mean 2.24). Prostate cancer was multifocal in 58% and bilateral in 79% of cases.
• ? Of the 215 cancers, 90% were <0.5 mL and 79% <0.2 mL. Overall, 88% of cancer foci were clinically insignificant with a volume of <0.5 mL and no grades 4–5.
• ? In all, 75% of the cancer foci were in the peripheral zone, the remainder were within the transition zone.
• ? One third of cancer foci were anteriorly located beyond the area sampled by posterior biopsies. One fifth of cancer foci were ≤6 mm of the apex.
• ? Limitations include the fact that cystoprostatectomy cancer foci are at an earlier stage than screened‐detected cancers.

CONCLUSION

• ? This detailed morphometric analysis of prostate cancer foci in a population that is free from the selection bias associated with screening can help inform our diagnostic and treatment strategies.

     

Erectile dysfunction is predictive of all-cause mortality in patients with prostate cancer treated with permanent interstitial brachytherapy

Study Type – Prognosis (individual cohort) Level of Evidence 2b What’s known on the subject? and What does the study add? Cardiovascular disease is a leading cause of death in prostate cancer patients. Pretreatment ED is a surrogate for vascular pathology. Aggressive treatment of medical co‐morbidity in prostate cancer patients may positively impact overall survival.

OBJECTIVE

• ? To evaluate the relationship between pre‐treatment erectile function and all‐cause mortality in patients with prostate cancer treated with brachytherapy.

PATIENTS AND METHODS

• ? In all, 1279 consecutive patients with clinically localized prostate cancer and pre‐implant erectile function assessed by the International Index of Erectile Function‐6 (IIEF‐6) underwent brachytherapy.
• ? Potency was defined as an IIEF‐6 score of ≥13 without pharmacological or mechanical support.
• ? Patients were stratified into IIEF‐6‐score cohorts (≤12, 13–23 and 24–30).
• ? The median follow‐up was 5.0 years.

RESULTS

• ? The 8‐year overall survival (OS) of the study population was 85.1%.
• ? The 8‐year OS for IIEF‐6scores ≤12, 13–23 and 24–30 were 78.0%, 92.8% and 91.4%, respectively (P < 0.001).
• ? Cardiovascular events accounted for a significant portion of deaths in each IIEF‐6 group.
• ? When combined with other risk factors for cardiovascular disease, an IIEF‐6 score of ≤12 had an additive effect on all‐cause mortality (IIEF‐6 score of ≤12 and less than two comorbidities vs two or more comorbidities were 18.2% and 32.1%).

CONCLUSIONS

• ? A pre‐implant IIEF‐6score of ≤12 was associated with a higher incidence of all‐cause mortality.
• ? Pre‐treatment erectile dysfunction is a surrogate for underlying vascular pathology, probably explaining the lower OS in this subset of patients.
• ? Aggressive treatment of medical co‐morbidity is warranted to impactOS.