The relationship between total and free serum testosterone and the risk of prostate cancer and tumour aggressiveness

OBJECTIVE

To analyse the relationship between the levels of total and free serum testosterone and the risk of prostate cancer and tumour aggressiveness.

PATIENTS AND METHODS

Total and free serum testosterone were determined in 478 patients consecutively assessed by transrectal ultrasonography‐guided prostate biopsy because of an abnormal digital rectal examination and/or serum prostate‐specific antigen (PSA) level of >4.0 ng/mL. Tumour aggressiveness was assessed according to serum PSA level, biopsy Gleason score and clinical stage in the subset of 216 patients with cancer (45.2%). We also compared prostate cancer risk and tumour aggressiveness in 80 hypogonadal patients (16.7%) and 398 eugonadal patients (83.3%).

RESULTS

The median total serum testosterone level in patients without and with prostate cancer was 466.0 and 466.5 ng/dL, respectively (P > 0.05); the median levels of free serum testosterone were 9.9 and 10.0 pg/mL, respectively (P > 0.05). The cancer detection rate in hypogonadal patients was 41.3% (33/80) and 46.0% in eugonadal patients (183/398) (P > 0.05). The median level of total testosterone was 433 ng/dL in patients with low‐risk prostate cancer, 467 ng/dL in those with intermediate‐risk tumours and 468 ng/dL in those with high‐risk tumours (P > 0.05); the median levels of free testosterone were 9.4, 9.8 and 10.3 pg/mL, respectively (P > 0.05).

CONCLUSIONS

Prostate cancer risk and tumour aggressiveness are not related to serum levels of total and free testosterone, but hypogonadal patients do not have a greater risk of prostate cancer and tumour aggressiveness.     

Prostate‐specific antigen changes and prostate cancer in hypogonadal men treated with testosterone replacement therapy

OBJECTIVES

To retrospectively review hypogonadal men receiving testosterone replacement therapy (TRT), and evaluate the changes in prostate‐specific antigen (PSA) levels over an extended period, and thus evaluate the occurrence of prostate cancer, as a primary concern in treating late‐onset hypogonadism (LOH) is the potential increased risk of prostate cancer; we also recorded the cardiovascular effects of TRT.

PATIENTS AND METHODS

In all, 81 hypogonadal men (mean age 56.8 years) were followed for a mean (range) of 33.8 (6–144) months after starting TRT. All men had a normal baseline PSA level before TRT and had routine laboratory investigations, including measurements of body mass index (BMI), haematocrit, lipid profile, and liver function tests (LFTs). Testosterone and PSA levels were assessed every 6–12 months. Patients with a biopsy‐confirmed or recent history of prostatitis before treatment were excluded. TRT was discontinued in men who developed prostate cancer.

RESULTS

Before and 36 months after treatment the total testosterone levels were 241.1 and 379.8 ng/dL (P < 0.05), respectively. Four men (4.9%) developed prostate cancer at a mean (range) of 32.5 (22–41) months after starting TRT. In men without prostate cancer (95.1%), PSA levels did not increase significantly at 1‐year intervals for 5 years. There was no statistical difference in PSA level change from baseline to 36 months when patients without prostate cancer were stratified into groups according to age (≤50, 55–65 and ≥70 years). In men with prostate cancer there was an increase in mean PSA level from baseline to 18 months of 1.8 ng/mL, and to 36 months of 3.2 ng/mL (P < 0.05). Total cholesterol improved from 203.8 to 166.6 mg/dL (P < 0.05) after 36 months of TRT; the BMI, haematocrit and LFTs did not change significantly.

CONCLUSIONS

LOH is an increasingly prevalent disease characterized by a symptomatically low testosterone level, and TRT is effective in normalizing serum testosterone levels, providing a beneficial cardiovascular effect, and improving sexual function and overall quality of life. PSA levels remain stable after normalization of testosterone for ≥5 years, prostate cancer can be effectively diagnosed and treated in men taking TRT, and the incidence of prostate cancer among men with LOH on TRT is no greater than that in the general population.     

Derivatives of prostate‐specific antigen as predictors of incidental prostate cancer

OBJECTIVE

To search for an optimal derivative of prostate‐specific antigen (PSA) identifying patients at risk of incidental prostate cancer.

PATIENTS AND METHODS

In all, 693 patients who underwent transurethral resection of the prostate (TURP) with a normal digital rectal examination, no history of prostate cancer and a PSA level of 2.5–10 ng/mL were studied. The total PSA (tPSA), percentage of free/total PSA (%fPSA), complexed PSA (cPSA), PSA density, cPSA density and the ratio of fPSA to cPSA were measured. Specificity, sensitivity, positive and negative predictive values were determined for all possible threshold values indicating the risk of incidental prostate cancer (T1a or T1b). Furthermore, the patients were subdivided according to age and the presence of an indwelling transurethral catheter. The areas under the receiver operating characteristic curves (AUC) were compared.

RESULTS

In the whole sample, the %fPSA was the best test predicting all incidental prostate cancers (AUC 0.618, reference: tPSA 0.494), whereas cPSA density was the best predictor of T1b disease (AUC 0.720, reference: tPSA 0.548). Stratification by age did not meaningfully alter the results, the presence of a transurethral catheter, however, was associated with a superiority of tests based on fPSA (AUC 0.620–0.670) compared with tests based on tPSA or cPSA (AUC 0.421–0.581).

CONCLUSION

Replacing tPSA by PSA derivatives (%fPSA or cPSA density) and stratifying by the presence of an indwelling transurethral catheter may improve the prediction of the risk of incidental prostate cancer and spare unnecessary biopsies before TURP in the tPSA range 2.5–10 ng/mL.     

Is the utility of prostate‐specific antigen velocity for prostate cancer detection affected by age?

OBJECTIVE

To determine whether prostate‐specific antigen velocity (PSAV) is useful for prostate cancer detection in men from different age groups, and whether the same PSAV thresholds can reasonably be applied to all men aged ≥40 years.

PATIENTS AND METHODS

From a large prostate cancer screening study, 13 615 men had data on age and a calculable PSAV. We used statistical analysis to examine the ability of PSAV to predict prostate cancer risk in each age decade.

RESULTS

For men of all ages, the median PSAV was 0.6–0.7 ng/mL/year in men with prostate cancer, and 0–0.1 ng/mL/year in men with no prostate cancer (P < 0.005 for all). On receiver operating characteristic (ROC) analysis, the area under the curve was 0.800, 0.697, 0.693, and 0.668 for predicting prostate cancer risk using PSAV for men aged 40–49, 50–59, 60–69 and ≥70 years, respectively. In the multivariate model controlling for race, family history, and the total PSA level, both PSA and PSAV were significant independent predictors of prostate cancer risk in men of all ages.

CONCLUSIONS

The PSAV is significantly higher in men of all ages with prostate cancer compared with men with no prostate cancer; although on ROC analysis it performed the best in young men. Interestingly, the median PSAV in men with prostate cancer was <0.75 ng/mL/year regardless of age, suggesting that this threshold may be too high. Overall, this data confirms that PSAV is a useful tool for prostate cancer detection for men aged ≥40 years.     

Evaluation of the Prostate Cancer Prevention Trial Risk calculator in a high‐risk screening population

Study Type – Diagnostic (exploratory cohort)
Level of Evidence 2b

OBJECTIVE

To evaluate the Prostate Cancer Prevention Trial (PCPT) risk calculator in a screening cohort of young, racially diverse, high‐risk men with a low baseline prostate‐specific antigen (PSA) level and enrolled in the Prostate Cancer Risk Assessment Program (PRAP). The PCPT calculator provides an assessment of prostate cancer risk based on age, PSA level, race, previous biopsy, and family history.

PATIENTS AND METHODS

Eligibility for PRAP includes men aged 35–69 years who are African‐American, have a family history of prostate cancer, or have a known BRCA1/2 mutation. PCPT risk scores were determined for PRAP participants, and were compared to observed prostate cancer rates.

RESULTS

In all, 624 participants were evaluated, including 382 (61.2%) African‐American men and 242 (38.7%) men with a family history of prostate cancer; the median (range) age was 49.0 (34.0–69.0) years and the median PSA level 0.9 (0.1–27.2) ng/mL. The PCPT risk score correlated with prostate cancer diagnosis, as the median baseline risk score in patients diagnosed with prostate cancer was 31.3%, vs 14.2% in patients not diagnosed with prostate cancer (P < 0.001). The PCPT calculator similarly stratified the risk of diagnosis of Gleason score ≥7 disease, as the median risk score was 36.2% in patients diagnosed with Gleason ≥7 prostate cancer vs 15.2% in all other participants (P < 0.001).

CONCLUSION

The PCPT risk calculator score was found to stratify prostate cancer risk in a cohort of young, primarily African‐American men with a low baseline PSA level. These results support further evaluation of this predictive tool for assessing the risk of prostate cancer in high‐risk men.     

The role of the percentage free PSA in the diagnosis of prostate cancer in Blacks: Findings in indigenous West African men using TRUS guided biopsy

Introduction

In Western and Asian literature, the measurement of percentage free prostate specific antigen (%fPSA) has been known to enhance the predictive role of total prostate specific antigen (tPSA) in early prostate cancer (Ca-P) detection. Relationship between the tPSA and Ca-P are known to be influenced by race. To the best of our knowledge, the relationship between %fPSA and Ca-P has not been studied in sub-Saharan Africa using current established biopsy protocol.

Second to fourth digit ratio: a predictor of prostate‐specific antigen level and the presence of prostate cancer

Study Type – Diagnostic (exploratory cohort) Level of Evidence 2b What’s known on the subject? and What does the study add? The Homeobox genes, Hox a and d, control urinogenital system differentiation and digit development. The patterns of digit formation may be related to gonad function and may be reflected in 2nd to 4th digit ratio (digit ratio). Digit ratio is negatively correlated with prenatal testosterone levels and androgen receptor activity which is related to the increased prostate cancer risk. Patients with a lower digit ratio have a higher risk of prostate biopsy due to high PSA level, and of prostate cancer. Digit ratio could be a predictor of high PSA level and the presence of prostate cancer.

OBJECTIVE

To investigate the relationships between the 2nd to 4th digit ratio (digit ratio) and prostate volume, prostate‐specific antigen (PSA) level, and the presence of prostate cancer.

PATIENTS AND METHODS

Of the men that presented with lower urinary tract symptoms (LUTS) at a single tertiary academic center, 366 men aged 40 or older with a PSA level ≤40 ng/mL were prospectively enrolled. Right‐hand 2nd and 4th digit lengths were measured prior to the PSA determinations and transrectal ultrasonography (TRUS). Prostate volumes were measured by TRUS without information about digit length. Patients with a PSA level ≥3 ng/mL underwent prostate biopsy.

RESULTS

No relationship was found between prostate volume and digit ratio [correlation coefficient (r) =?0.038, P= 0.466]. But, significant negative correlations were found between digit ratio and PSA (r=?0.140, P= 0.007). When the patients were divided into two groups (Group A: digit ratio <0.95, n= 184; Group B: digit ratio ≥0.95, n= 182), Group A had a higher mean PSA level than Group B (3.26 ± 5.54 ng/mL vs 1.89 ± 2.24 ng/mL, P= 0.002) and had significantly higher risks of prostate biopsy [odds ratio (OR) = 1.75, 95% CI = 1.07–2.84] and prostate cancer (OR = 3.22, 95% CI = 1.33–7.78).

CONCLUSIONS

Patients with a lower digit ratio have higher risks of prostate biopsy and prostate cancer.     

The utility of prostate-specific antigen velocity thresholds in clinical practice: a population-based analysis

OBJECTIVE

To investigate the ability of prostate‐specific antigen velocity (PSAV) to predict prostate cancer, and assess the test characteristics of several PSAV thresholds for identifying prostate cancer and high‐grade cancers.

PATIENTS AND METHODS

From a population‐based database of PSA results, men with an initial PSA level of <10.0 ng/mL, taken between I January 1994 and 31 December 2003, were identified. Those with three or more PSA tests before diagnosis, taken over ≥18 months, were included. Men were followed for a diagnosis of prostate cancer or histologically confirmed benign disease until 31 December 2003.

RESULTS

In all, 24 709 men were included, with 716 (2.9%) diagnosed with prostate cancer and 1488 (6.0%) with benign histology. The mean (10.38 vs 0.43 ng/mL/year) and median (1.47 vs 0.03 ng/mL/year) PSAV were considerably higher in men with prostate cancer than in those with no cancer (P < 0.001). There was no PSAV threshold that could reliably identify prostate cancer or high‐grade cancers without requiring many men to proceed to prostate biopsy.

CONCLUSION

In this population, PSAV had additional value over one PSA value in identifying men with prostate cancer. Many men with prostate cancer might have a ‘normal’ (<0.75 ng/mL/year) PSAV. As with total PSA level, there was no PSAV threshold that could reliably predict prostate cancer, but rather a continuum of risk of cancer associated with PSAV level.     

The effect of obesity and lower serum prostate‐specific antigen levels on prostate‐cancer screening results in American men

OBJECTIVE

To determine if lower serum total prostate specific antigen (PSA) levels in obese American men affect prostate‐cancer screening results, as an increased body mass index (BMI) is inversely associated with PSA level, but the effect of this association on PSA screening results for prostate cancer is unknown.

SUBJECTS AND METHODS

We analysed the most recent National Health and Nutrition Examination Surveys (NHANES 2001–2002, 2003–2004, and 2005–2006), a nationally representative cross‐sectional sample of non‐institutionalized adults aged ≥20 years. Logistic regression was used to estimate the odds of an ‘abnormal’ PSA level (4.0 or 2.5 ng/mL) based on BMI categories of normal (18.5–24.9 kg/m²), overweight (25–29.9) and obese (30–39.9) in men who were eligible for prostate‐cancer screening with serum total PSA tests (age 40–75 years, BMI 18.5–39.9 kg/m², PSA <20 ng/mL).

RESULTS

In all, 3152 participants with no known prostate cancer, representing 46 million American men, were eligible for prostate‐cancer screening. After controlling for age and race, there was a statistically significant trend of a lower likelihood of having a serum total PSA level of ≥4.0 ng/mL with increased BMI. When men were stratified by race, this effect was apparent only in white non‐Hispanic men, with obese men in this group having a 46% lower likelihood of having an ‘abnormal’ PSA level (odds ratio 0.54, 95% confidence interval 0.31–0.91; P = 0.024) than those with a normal BMI. There was no observable trend in either African‐American or Hispanic men. In addition, there was no observable trend with a serum total PSA threshold of 2.5 ng/mL, regardless of race.

CONCLUSIONS

Obese white non‐Hispanic men are about half as likely as those with a normal BMI to have a PSA level of ≥4.0 ng/mL. These results might affect prostate‐cancer screening with serum total PSA. Further studies are needed to better define the association of BMI and PSA in racial minority subgroups.     

Associations of lower urinary tract symptoms with prostate-specific antigen levels, and screen-detected localized and advanced prostate cancer: a case-control study nested within the UK population-based ProtecT (Prostate testing for cancer and Treatment) study

OBJECTIVE

To determine associations of lower urinary tract symptoms (LUTS) with prostate‐specific antigen (PSA) levels and screen‐detected localized and advanced prostate cancer.

SUBJECTS AND METHODS

A case‐control study nested within the UK population‐based ProtecT (Prostate testing for cancer and Treatment) study. Men aged 50–69 years were invited for PSA testing and those with a PSA level of ≥3.0 ng/mL were invited for biopsy. We determined whether LUTS were associated with a PSA level of ≥3.0 ng/mL and prostate cancer using logistic regression models adjusted for age, family history of prostate cancer and PSA level as appropriate. Areas under receiver operating characteristic curves (AUC) were compared between models with and without symptoms.

RESULTS

In all, 65 871 men had a PSA test: 7251 had a PSA level of ≥3.0 ng/mL including 2467 subsequently diagnosed with prostate cancer (2119 localized, 348 advanced). LUTS were positively associated with a PSA level of ≥3.0 ng/mL: odds ratios (ORs) were 1.18 (95% confidence interval, CI 1.01–1.38), 1.69 (95% CI 1.32–2.16), and 1.60 (95% CI 1.33–1.93) for daytime urination frequency (hourly vs less frequent), urgency and hesitancy (most/all the time vs never), respectively. LUTS among men with a PSA level of ≥3 ng/mL were negatively associated with prostate cancer: ORs were 0.44 (95% CI 0.22–0.83), 0.74 (95% CI 0.63–0.87), and 0.83 (95% CI 0.73–0.94) for nocturia (4+ vs 0), leakage and hesitancy (occasionally/sometimes vs never), respectively. LUTS improved the prediction of a PSA level of ≥3.0 ng/mL (AUC 0.635 vs 0.606, P < 0.001) and prostate cancer (AUC 0.661 vs 0.638; P < 0.001).

CONCLUSIONS

A history of LUTS before PSA testing marginally improves the prediction of an individual’s risk for prostate cancer; men with a PSA level of ≥3 ng/mL and LUTS were more likely to be diagnosed with benign disease than prostate cancer.     

Diagnostic value of free prostate-specific antigen among men with a prostate-specific antigen level of <3.0 microg per liter

Objectives

The percentage of free prostate-specific antigen (%fPSA) improves the diagnostic accuracy for prostate cancer when the serum level of total PSA (tPSA) is elevated. Approximately 14% of men with a tPSA below 3 μg/l have prostate cancer on biopsy, but the diagnostic value of %fPSA in such men is rather unknown. The purpose was to estimate the impact of %fPSA on future prostate cancer risk among men with a normal tPSA in prostate cancer screening.

Subjects and methods

The first round of the Finnish arm of the European Randomized Trial for Screening of Prostate Cancer in 1996 to 1999 comprised 20,793 men aged 55–67 yr. Screen-negative men (tPSA level below 3.0 μg/l, n = 17,680) were followed up until the end of 2003. Cumulative risk of prostate cancer was calculated as a function of %fPSA.

Results

During the median follow-up of 5.8 yr (range, 0–7.7 yr), 327 men were diagnosed with prostate cancer and 25% of them had a Gleason score of 7 or higher. Five years after the first screening, cumulative risk of prostate cancer was 1.7% (95%CI, 1.5–1.9%). Men with a %fPSA in the lowest quartile (<14.2%) showed a 6.9-fold risk compared with those with a level in the highest quartile (>23.7%).

Conclusions

In men with a low serum tPSA, a low %fPSA is a strong predictor of later diagnosis of prostate cancer.     

Is the body mass index a predictor of adverse outcome in prostate cancer after radical prostatectomy in a mid‐European study population?

OBJECTIVES

To evaluate the effect of body mass index (BMI) on the histopathological and clinical outcome in prostate cancer.

PATIENTS AND METHODS

In a prospective urological cancer database, 620 patients with prostate cancer had a radical prostatectomy (RP) as a curative treatment. The patients were categorized into three groups of BMI (kg/m²); ≤25.0 (190, ‘normal weight’), >25.0–30.0 (343, ‘overweight’) and >30.0 (87, ‘obese’). We evaluated the histopathological features and the clinical follow‐up after RP. The median (range) age of the men was 64.4 (41.1–80.1) years and the median follow‐up 5.5 (0.1–15.1) years. The preoperative median prostate‐specific antigen (PSA) levels for normal, overweight and obese patients were 9.0 (0.3–133.0), 8.9 (0.4–230.0) and 9.2 (0.5–194.0) ng/mL, respectively.

RESULTS

Serum PSA levels were no different among the three groups (P = 0.92). The normal, overweight and obese patients had organ‐confined prostate cancer in 53.7%, 57.1% and 58.6%, respectively (P = 0.34) and had lymph node metastases in 7.9%, 7.6% and 4.6% (P = 0.58). Tumour grading was no different for the three groups (P = 0.25). The PSA recurrence‐free, prostate cancer‐specific and overall survival for the three BMI groups did not differ significantly (each P > 0.05).

CONCLUSION

The BMI cannot be shown to be a predictor of adverse prognosis either for histopathological features or for the clinical outcome, e.g. PSA‐free, prostate cancer‐specific and overall survival, in a mid‐European study population after RP.     

Prostate-specific antigen velocity in untreated, localized prostate cancer

OBJECTIVE

To report the results of a prospective study of active surveillance of untreated prostate cancer, with a focus on baseline predictors of prostate‐specific antigen (PSA) velocity, as PSA velocity before treatment is an important predictor of prostate cancer mortality, and patients on active surveillance are monitored for several years to estimate the PSA velocity and thus select patients for radical treatment.

PATIENTS AND METHODS

A prospective study of active surveillance for localized prostate cancer opened at the Royal Marsden Hospital in 2002. Eligible patients had clinical stage T1/T2a, N0/Nx, M0/Mx adenocarcinoma of the prostate with a serum PSA level of <15 ng/mL, a Gleason score of ≤7 with primary grade ≤3, and less than half the biopsy cores positive. The PSA velocity before treatment was analysed in relation to baseline clinical characteristics.

RESULTS

In all, 237 patients on surveillance were followed for a median of 24 months (median age 67 years; median initial PSA level 6.5 ng/mL; median pretreatment PSA velocity 0.44 ng/mL per year). On multivariate analysis, PSA density (i.e. serum PSA level/prostate volume) was the only significant determinant of PSA velocity (P < 0.001). Patients with a PSA density above or below the median (0.185 ng/mL/mL) had a median (interquartile range) PSA velocity of 0.92 (0.34–1.77) ng/mL per year and 0.35 (? 0.06, 0.80) ng/mL per year, respectively.

CONCLUSIONS

PSA density, which is readily available at the time of diagnosis, is an independent determinant of PSA velocity in untreated, localized prostate cancer. If this is confirmed, PSA density could be used to inform the often difficult choice between active surveillance and immediate radical treatment.     

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.

     

The presence of prostate cancer on saturation biopsy can be accurately predicted

Study Type – Diagnostic (non‐consecutive)
Level of Evidence 3b

OBJECTIVE

To improve the ability of our previously reported saturation biopsy nomogram quantifying the risk of prostate cancer, as the use of office‐based saturation biopsy has increased.

PATIENTS AND METHODS

Saturation biopsies of 540 men with one or more previously negative 6–12 core biopsies were used to develop a multivariable logistic regression model‐based nomogram, predicting the probability of prostate cancer. Candidate predictors were used in their original or stratified format, and consisted of age, total prostate‐specific antigen (PSA) level, percentage free PSA (%fPSA), gland volume, findings on a digital rectal examination, cumulative number of previous biopsy sessions, presence of high‐grade prostatic intraepithelial neoplasia on any previous biopsy, and presence of atypical small acinar proliferation (ASAP) on any previous biopsy. Two hundred bootstraps re‐samples were used to adjust for overfit bias.

RESULTS

Prostate cancer was diagnosed in 39.4% of saturation biopsies. Age, total PSA, %fPSA, gland volume, number of previous biopsies, and presence of ASAP at any previous biopsy were independent predictors for prostate cancer (all P < 0.05). The nomogram was 77.2% accurate and had a virtually perfect correlation between predicted and observed rates of prostate cancer.

CONCLUSIONS

We improved the accuracy of the saturation biopsy nomogram from 72% to 77%; it relies on three previously included variables, i.e. age, %fPSA and prostate volume, and on three previously excluded variables, i.e. PSA, the number of previous biopsy sessions, and evidence of ASAP on previous biopsy. Our study represents the largest series of saturation biopsies to date.     

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.

     

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.

     

Is there a prostate‐specific antigen upper limit for radical prostatectomy?

Study Type – Prognosis (retrospective cohort) Level of Evidence 2b

OBJECTIVE

? To assess the feasibility of radical prostatectomy (RP) in a series of patients with prostate cancer with very high prostate‐specific antigen (PSA) levels by comparing the clinical outcomes of different PSA thresholds (20.1–50 ng/mL, 50.1–100 ng/mL and >100 ng/mL, respectively).

PATIENTS AND METHODS

? Within a multicentre European retrospective database of 712 RP in patients with a baseline PSA level >20 ng/mL, we identified 48 patients with prostate cancer with a preoperative PSA level >100 ng/mL, 137 with a PSA level between 50.1 and 100 ng/mL and 527 with PSA values between 20.1 and 50 ng/mL. ? Comparisons between groups were performed using chi‐square test, analysis of variance and Kaplan–Meier analysis with log‐rank test.

RESULTS

? Ten‐year projected cancer‐specific survival (79.8% in the PSA >100 ng/mL group vs 85.4% in the PSA 50.1–99 ng/mL group vs 90.9% in the PSA 20.1–50 ng/mL interval; P= 0.037) but not overall survival (59.6% in the PSA >100 ng/mL group vs 71.8% in the PSA 50.1–99 ng/mL group vs 75.3% in the PSA 20.1–50 ng/mL interval; P= 0.087) appeared significantly affected by the different PSA thresholds. ? At a median follow‐up of 78.7 months, 25.8%, 6.6% and 8.3% of patients in the PSA level groups for 20.1–50 ng/mL, 50.1–100 ng/mL and >100 ng/mL respectively, were cured by surgery alone.

CONCLUSIONS

? Ten‐year cancer‐specific survival, while showing significant reduction with increasing PSA values intervals, remain relatively high even for PSA levels >100 ng/mL. ? As part of a multimodal treatment strategy, RP may therefore be an option, even in selected patients with prostate cancer whose PSA level is >100 ng/mL.     

An artificial neural network for five different assay systems of prostate-specific antigen in prostate cancer diagnostics

OBJECTIVE

To compare separate prostate‐specific antigen (PSA) assay‐specific artificial neural networks (ANN) for discrimination between patients with prostate cancer (PCa) and no evidence of malignancy (NEM).

PATIENTS AND METHODS

In 780 patients (455 with PCa, 325 with NEM) we measured total PSA (tPSA) and free PSA (fPSA) with five different assays: from Abbott (AxSYM), Beckman Coulter (Access), DPC (Immulite 2000), and Roche (Elecsys 2010) and with tPSA and complexed PSA (cPSA) assays from Bayer (ADVIA Centaur). ANN models were developed with five input factors: tPSA, percentage free/total PSA (%fPSA), age, prostate volume and digital rectal examination status for each assay separately to examine two tPSA ranges of 0–10 and 10–27 ng/mL.

RESULTS

Compared with the median tPSA concentrations (range from 4.9 [Bayer] to 6.11 ng/mL [DPC]) and especially the median %fPSA values (range from 11.2 [DPC] to 17.4%[Abbott], for tPSA 0–10 ng/mL), the areas under the receiver operating characteristic curves (AUC) for all calculated ANN models did not significantly differ from each other. The AUC were: 0.894 (Abbott), 0.89 (Bayer), 0.895 (Beckman), 0.882 (DPC) and 0.892 (Roche). At 95% sensitivity the specificities were without significant differences, whereas the individual absolute ANN outputs differed markedly.

CONCLUSIONS

Despite only slight differences, PSA assay‐specific ANN models should be used to optimize the ANN outcome to reduce the number of unnecessary prostate biopsies. We further developed the ANN named ‘ProstataClass’ to provide clinicians with an easy to use tool in making their decision about follow‐up testing.     

Prostate-specific antigen (PSA) kinetics in untreated, localized prostate cancer: PSA velocity vs PSA doubling time

OBJECTIVE

To compare the accuracy of prostate‐specific antigen (PSA) velocity (PSAV) vs PSA doubling time (DT) for predicting the repeat biopsy results in men with localized prostate cancer on active surveillance (AS), as the utility of PSAV vs PSADT in untreated prostate cancer has not been well studied.

PATIENTS AND METHODS

Eligible patients had favourable‐risk localized prostate cancer (T1/2a, PSA level ≤15 ng/mL, Gleason score ≤3 + 4, and percentage positive biopsy cores ≤50%), and consented to AS between 2002 and 2005. Repeat biopsies were taken after 18–24 months, with adverse histology defined as any of: primary Gleason grade ≥4, >50% cores positive, or initial Gleason score 3 + 3 upgraded to ≥3 + 4. Using all PSA values for the 2 years preceding repeat biopsy, the PSAV and PSADT were calculated using linear regression and the log‐slope method (DT = ln2/slope), respectively.

RESULTS

In all, 199 patients were assessable; the median PSAV and PSADT were 0.71 ng/mL/year and 5.29 years, respectively. Fifty‐three patients (27%) had adverse histology on repeat biopsy. On univariate analyses, PSAV (P < 0.001) and PSADT (P = 0.019) were associated with adverse histology. The area under the receiver operating characteristic curve for predicting adverse histology was 0.70 and 0.63 for PSAV and PSADT, respectively. The mean difference was 0.07 (95% confidence interval 0.03–0.12; P < 0.001).

CONCLUSIONS

PSAV is more accurate than PSADT for predicting adverse histology on repeat biopsies. These data suggest that PSAV should be used in preference to PSADT to describe PSA kinetics in untreated, localized prostate cancer.