Prostate cancer screening in the Prostate,Lung, Colorectal and Ovarian cancer screening trial: update on findings from the initial four rounds of screening in a randomized trial

OBJECTIVE

To describe the results of the first four rounds (T0‐T3) of prostate cancer screening in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial (designed to determine the value of screening in the four cancers), that for prostate cancer is evaluating whether annual screening with prostate‐specific antigen (PSA) and a digital rectal examination (DRE) reduces prostate cancer‐specific mortality.

SUBJECTS AND METHODS

In all, 38 349 men aged 55–74 years were randomized to undergo annual screening with PSA (abnormal >4.0 ng/mL) and a DRE. The follow‐up of abnormal screening results was at the discretion of subjects’ physicians. PLCO staff obtained records related to diagnostic follow‐up of positive screen results.

RESULTS

Compliance with screening decreased slightly from 89% at baseline to 85% at T3. Both PSA positivity rates (range 7.7–8.8% at T0‐T3) and DRE positivity rates (range 6.8–7.6% at T0‐T3) were relatively constant over time. The positive predictive value (PPV) of a PSA level of >4.0 ng/mL decreased from 17.9% at T0 to 10.4–12.3% at T1‐T3; the PPV for DRE (in the absence of a positive PSA test) was constant over time (2.9–3.6%). Cancer was diagnosed in 1902 men (4.9%). Screen‐detected cancers at T0 (549) were more likely to be clinical stage III/IV (5.8%) and to have a Gleason score of 7–10 (34%) than screen‐detected cancers at T1‐T3 (1.5–4.2% stage III/IV and 24–27% Gleason score 7–10 among 1054 cases).

CONCLUSION

The present findings on serial prostate screening are similar to those reported from other multi‐round screening studies. Determining the effect of PSA screening on prostate cancer mortality awaits further follow‐up.     

Screening for prostate cancer: Updated experience from the Tyrol study

The aim of the Tyrol study was to monitor the impact of screening in a natural experiment by comparing prostate cancer mortality in Tyrol, where prostate-specific antigen (PSA) testing was introduced at no charge, with the rest of Austria, where it was not strictly organized and not free of charge. In 1993, PSA testing was made freely available to men between the ages of 45 and 75 years in the Federal State of Tyrol, Austria. At least 70% of all of the men in this age range have been tested at least once during the first 10 years of the study. Initially, only total PSA was measured, but free PSA measurement was added in 1995. Since 2001, complexed PSA also has been measured. Digital rectal examination was not part of the screening examination. Significant migration to lower clinical and pathological stages has been observed since the introduction of this screening program. These findings are consistent with the hypothesis that the policy of making PSA testing freely available, and the wide acceptance by men in the population, is associated with a reduction in prostate cancer mortality in an area in which urology services and radiotherapy are available freely to all patients. It is our opinion that most of this decline is likely a result of aggressive downstaging and successful treatment and that any contribution from detecting and treating early cancers will become apparent in the years to come.     

Over-diagnosis and under-diagnosis of screen- vs non-screen-detected prostate cancers with in men with prostate-specific antigen levels of 2.0-10.0 ng/mL

OBJECTIVES

To evaluate possible over‐ and under‐diagnosis of prostate cancer in a screened vs a referral population in the same range of prostate‐specific antigen (PSA).

PATIENTS AND METHODS

In all, 1445 patients undergoing radical prostatectomy and with a PSA level of <10 ng/mL were evaluated; 237 were from outside Tyrol (Austria) and represented the unscreened group, and 1208 were Tyrolean screening volunteers. Over‐diagnosis was defined as a pathological stage of pT2a and a Gleason score of <7 with no positive surgical margins. Under‐diagnosis was defined as a pathological stage of ≥pT3a or positive surgical margins. The chi‐square test was used to assess the differences, with P < 0.05 considered to indicate statistical significance.

RESULTS

There were no significant differences in patient age or PSA levels between the study groups. There was over‐diagnosis in the screening and referral groups in 17.4% and 8.9%, respectively, and under‐diagnosis in 18.6% and 42.2%, respectively.

CONCLUSION

This study suggests that patients with prostate cancer participating in a screening programme are less likely to be under‐diagnosed or have extracapsular disease than their counterparts in a referral population, even in the same PSA range, after radical prostatectomy. Furthermore, there was more under‐diagnosis in the referral group than over‐diagnosis in the screened group.     

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.

     

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.

     

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.

     

Focal cryotherapy for localized prostate cancer: a report from the national Cryo On-Line Database (COLD) Registry

Study Type – Therapy (data synthesis) Level of Evidence 2b What's known on the subject? and What does the study add? The efficacy of prostate cancer screening using PSA testing is still being debated, with conflicting results in randomized trials. The study shows that, even using the hypothesis most favourable to prostate cancer screening with PSA, the net number of years of life does not favour screening.

OBJECTIVE

• ? To evaluate the impact of the implementation a prostate‐specific antigen (PSA) screening programme using the European Randomized Study of Screening for Prostate Cancer (ERSPC) results and taking into account the impact of prostate biopsy and over‐treatment on mortality.

MATERIALS AND METHODS

• ? We used a model based on the number of years of life gained and lost owing to screening, using data reported in the ERSPC.
• ? We conducted a critical evaluation of the ERSPC results and of the Swedish arm of the study.

RESULTS

• ? Accounting for biopsy‐specific mortality and for over‐treatment, the balance of number of years of life was negative in the ERSPC study, with an estimated loss of 3.6 years of life per avoided death.
• ? The number of years of life becomes positive (real gain) only when fewer than 666 screened individuals are required to avoid one death.
• ? We found that in the Swedish arm of the ERSPC there was a biopsy rate of 40% compared with 27% in the ERSPC overall. The over‐treatment rate was also greater with 4.1% compared with 3.4% overall.
• ? For the last 20 years, there has been a marked difference in prostate cancer‐specific mortality between Sweden and the rest of Europe: in 2005, for the age group 65–74 the rate was 140 per 100 000 person years in Sweden and ～80 per 100 000 for the rest of Europe.

CONCLUSION

• ? Overall, PSA testing in Europe is associated with a loss in years of life and should thus not be recommended.

     

Screening for prostate cancer: an updated Cochrane systematic review

OBJECTIVE

? To determine whether screening for prostate cancer reduces prostate cancer‐specific mortality, impact on all‐cause mortality and patient health‐related quality of life.

MATERIALS AND METHODS

? An update to our 2006 Cochrane systematic review was performed by re‐running an updated search of several databases, including MEDLINE and the Cochrane CENTRAL Register of Controlled Trials. ? Articles were included if they were a randomized controlled trial (RCT) examining screening vs no screening for prostate cancer. Data was collected and analysed according to the methods outlined in the Cochrane Handbook for Systematic Reviews of Interventions.

RESULTS

? Five RCTs with a total of 341 351 participants were included in this updated Cochrane systematic review. All involved PSA testing, although the interval and threshold for further evaluation varied across trials. The age of participants was 50–74 years, with durations of patient follow‐up of 7–15 years. ? The methodological quality of three of the studies was assessed as posing a high risk of bias. ? Meta‐analysis of the five included studies indicated no statistically significant difference in prostate cancer‐specific mortality between men randomized to screening and control [relative risk (RR) 0.95, 95% CI 0.85–1.07]. Sub‐group analyses indicated that prostate cancer‐specific mortality was not affected by age at which participants were screened. A pre‐planned analysis of a ‘core’ age group of men aged 55–69 years from the largest RCT (European Randomised Study of Screening for Prostate Cancer) reported a significant 20% relative reduction in prostate cancer‐specific mortality; (95% CI 0.65–0.98; absolute risk 0.71 per 1000 men). The number of men diagnosed with prostate cancer was significantly greater in men randomized to screening, compared with those randomized to control (RR 1.35, 95% CI 1.06–1.72). ? Harms of screening included high rates of false‐positive results for the PSA test, over‐diagnosis and adverse events associated with transrectal ultrasonography guided biopsies such as infection, bleeding and pain.

CONCLUSIONS

? Prostate cancer screening did not significantly decrease all‐cause or prostate cancer‐specific mortality in a combined meta‐analysis of five RCTs. ? Any benefits from prostate cancer screening may take >10 years to accrue; therefore, men who have a life expectancy of <10–15 years should be informed that screening for prostate cancer is not beneficial and has harms.     

Usefulness of prostate-specific antigen (PSA) rise as a marker of prostate cancer in men treated with dutasteride: lessons from the REDUCE study

Study Type – Prognostic (RCT) Level of Evidence 1b What's known on the subject? and What does the study add? Previous studies used the decrease in PSA after 6 months of dutasteride treatment as a new ‘baseline’ PSA value from which subsequent rises may serve as a warning for prostate cancer; however, PSA tends to continue to decrease as dutasteride treatment continues. By comparing positive biopsy rates in the REDUCE study using any rise from nadir in the dutasteride arm and standard PSA decision criteria (NCCN) in the placebo arm, we demonstrated that the ability to detect prostate cancer and high grade prostate cancer is maintained with dutasteride treatment.

OBJECTIVES

? To determine if dutasteride‐treated men can be monitored safely and adequately for prostate cancer based on data from the Reduction by Dutasteride in Prostate Cancer Events (REDUCE) study. ? To analyse whether the use of treatment‐specific criteria for repeat biopsy maintains the usefulness of prostate‐specific antigen (PSA) level for detecting high grade cancers.

PATIENTS AND METHODS

? The REDUCE study was a randomized, double‐blind, placebo‐controlled investigation of whether dutasteride (0.5 mg/day) reduced the risk of biopsy‐detectable prostate cancer in men with a previous negative biopsy. ? The usefulness of PSA was evaluated using biopsy thresholds defined by National Comprehensive Cancer Network guidelines in the placebo group and any rise in PSA from nadir (the lowest PSA level achieved while in the study) in the dutasteride group. ? The number of cancers detected on biopsy in the absence of increased/suspicious PSA level as well as sensitivity, specificity, positive predictive value and negative predictive value for high grade prostate cancer detection were analysed by treatment group. ? Prostate cancer pathological characteristics were compared between men who did and did not meet biopsy thresholds.

RESULTS

? Of 8231 men randomized, 3305 (dutasteride) and 3424 (placebo) underwent at least one prostate biopsy during the study and were included in the analysis. ? If only men meeting biopsy thresholds underwent biopsy, 25% (47/191) of Gleason 7 and 24% (7/29) of Gleason 8–10 cancers would have been missed in the dutasteride group, and 37% (78/209) of Gleason 7 and 22% (4/18) Gleason 8–10 cancers would have been missed in the placebo group. ? In both groups, the incidence of Gleason 7 and Gleason 8–10 cancers generally increased with greater rises in PSA. ? Sensitivity of PSA kinetics was higher and specificity was lower for the detection of Gleason 7–10 cancers in men treated with dutasteride vs placebo. ? Men with Gleason 7 and Gleason 8–10 cancer meeting biopsy thresholds had greater numbers of positive cores, percent core involvement, and biopsy cancer volume vs men not meeting thresholds.

CONCLUSION

? Using treatment‐specific biopsy thresholds, the present study shows that the ability of PSA kinetics to detect high grade prostate cancer is maintained with dutasteride compared with placebo in men with a previous negative biopsy. ? The sensitivity of PSA kinetics with dutasteride was similar to (Gleason 8–10) or higher than (Gleason 7–10) the placebo group; however, biopsy decisions based on a single increased PSA measurement from nadir in the dutasteride group resulted in a lower specificity compared with using a comparable biopsy threshold in the placebo group, indicating the importance of confirmation of PSA measurements.     

Population‐based prostate‐specific antigen testing in the UK leads to a stage migration of prostate cancer

OBJECTIVE

To determine, within the UK, the stage and grade of prostate cancers that would be found through population‐based prostate specific antigen (PSA) testing and biopsy.

SUBJECTS AND METHODS

In the ‘Prostate Testing for Cancer and Treatment’ trial (ProtecT), men aged 50–69 years were recruited from nine cities in the UK and from randomly selected practices of general practitioners. Those with a PSA level of >3 ng/mL were offered a prostate biopsy. Age, PSA, stage and grade at diagnosis of ProtecT participants with cancer were compared with contemporaneous incident cases aged 50–69 years (age‐restricted Cancer Registry cases) registered with the Eastern Cancer Registration and Information Centre (ECRIC).

RESULTS

Within ProtecT, 94 427 men agreed to be tested (50% of men contacted), 8807 (≈9%) had a raised PSA level and 2022 (23%) had prostate cancer; 229 (≈12%) had locally advanced (T3 or T4) or metastatic cancers, the rest having clinically localized (T1c or T2) disease. Within ECRIC, 12 661 cancers were recorded over the same period; 3714 were men aged 50–69 years at diagnosis. Men in ProtecT had a lower age distribution and PSA level, and the cancers were of lower stage and grade (P < 0.001 for all comparisons). If population‐based PSA testing were introduced in the UK, ≈2660 men per 100 000 aged 50–69 years would be found to have prostate cancer, compared to current rates of ≈130 per 100 000. If half of men accepted PSA testing, ≈160 000 cancers would be found, compared to 30 000 diagnosed each year at present.

CONCLUSIONS

Population‐based PSA testing resulted in a significant downward stage and grade migration, and most such cancers were of low stage and grade, which could lead to risks of over‐treatment for some men.     

Radical prostatectomy vs radiation therapy and androgen-suppression therapy in high-risk prostate cancer

Study Type – Therapy (retrospective cohort analysis) Level of Evidence 2b What's known on the subject? and What does the study add? Prostate cancer is generally considered to be high risk when the prostate‐specific antigen (PSA) concentration is >20 ng/mL, the Gleason score is ≥8 or the American Joint Commission on Cancer (AJCC) tumour (T) category is ≥2c. There is no consensus on the best treatment for men with prostate cancer that includes these high‐risk features. Options include external beam radiation therapy (EBRT) with androgen suppression therapy (AST), treatment with a combination of brachytherapy, EBRT and AST termed combined‐modality therapy (CMT) or radical prostatectomy (RP) followed by adjuvant RT in cases where there are unfavourable pathological features, e.g. positive surgical margin, extracapsular extension and seminal vesicle invasion. While outcomes for both approaches have been published independently these treatments have not been compared in the setting of a prospective RCT where confounding factors related to patient selection for RP or CMT would be minimised. These factors include age, known prostate cancer prognostic factors and comorbidity. RCTs that compare RP to radiation‐based regimens have been attempted but failed to accrue.

OBJECTIVE

• ? To assess the risk of prostate cancer‐specific mortality after therapy with radical prostatectomy (RP) or combined‐modality therapy (CMT) with brachytherapy, external beam radiation therapy (EBRT) and androgen‐suppression therapy (AST) in men with Gleason score 8–10 prostate cancer.

PATIENTS AND METHODS

• ? Men with localised high‐risk prostate cancer based on a Gleason score of 8–10 were selected for study from Duke University (285 men), treated between January 1988 and October 2008 with RP or from the Chicago Prostate Cancer Center or within the 21st Century Oncology establishment (372) treated between August 1991 and November 2005 with CMT.
• ? Fine and Gray multivariable regression was used to assess whether the risk of prostate cancer‐specific mortality differed after RP as compared with CMT adjusting for age, cardiac comorbidity and year of treatment, and known prostate cancer prognostic factors.

RESULTS

• ? As of January 2009, with a median (interquartile range) follow‐up of 4.62 (2.4–8.2) years, there were 21 prostate cancer‐specific deaths.
• ? Treatment with RP was not associated with an increased risk of prostate cancer‐specific mortality compared with CMT (adjusted hazard ratio [HR] 1.8, 95% confidence interval [CI] 0.6–5.6, P= 0.3).
• ? Factors associated with an increased risk of prostate cancer‐specific mortality were a PSA concentration of <4 ng/mL (adjusted HR 6.1, 95% CI 2.3–16, P < 0.001) as compared with ≥4 ng/mL, and clinical category T2b, c (adjusted HR 2.9; 95% CI 1.1–7.2; P= 0.03) as compared with T1c, 2a.

CONCLUSION

• ? Initial treatment with RP as compared with CMT was not associated with an increased risk of prostate cancer‐specific mortality in men with Gleason score 8–10 prostate cancer.

     

Clinical and pathological features of screen vs non‐screen‐detected prostate cancers: is there a difference?

OBJECTIVE

To evaluate the clinical and pathological characteristics of screen vs non‐screen‐detected prostate cancers, to determine if there is a difference in the same prostate‐specific antigen (PSA) range.

PATIENTS AND METHODS

In all, 997 patients who had had a radical prostatectomy were evaluated; 806 were Tyrolean screening volunteers, and 191 were from outside Tyrol, representing the ‘referred prostate cancer’ group. PSA level, age, prostate volume and pathological characteristics were assessed, as was the amount of over‐ and under‐diagnosis.

RESULTS

There were no statistically significant differences in patient age or PSA levels in the two groups. Even in the same PSA range there were statistically significantly more extraprostatic cancers in the referral group, at 31.7% and 17.4%, respectively. In the referred and screening groups there was over‐diagnosis in 7.9% and 16.8%, and under‐diagnosis in 40.8% and 27.8%, respectively.

CONCLUSION

This study suggests that screening volunteers have a statistically significantly higher rate of organ‐confined prostate cancers, and a statistically significantly lower rate of extracapsular extension and positive surgical margins than their counterparts in the referral group even in the same PSA range. As the pathological stage and surgical margin status are significant predictors of recurrence, these findings support the concept of PSA screening.     

Detection rate and factors predictive the presence of prostate cancer in patients undergoing ultrasonography‐guided transperineal saturation biopsies of the prostate

Study Type – Diagnostic (case series)
Level of Evidence 4

OBJECTIVES

To assess the prostate cancer detection rate and predictive factors for prostate cancer after transrectal ultrasonography (TRUS)‐guided transperineal saturation re‐biopsies of the prostate, using a 24‐core scheme.

PATIENTS AND METHODS

We evaluated 143 consecutive patients undergoing TRUS‐guided transperineal saturation re‐biopsy of the prostate using a 24‐core scheme. The inclusion criteria were a previous negative biopsy and a prostate‐specific antigen (PSA) level of ≥10.0 ng/mL, or of 4.0–10.0 ng/mL with a free/total ratio of <20% or an abnormal digital rectal examination or previous high‐grade prostatic intraepithelial neoplasia (HGPIN) or atypical small acinar proliferation (ASAP).

RESULTS

The mean (sd ) age of the patients was 66.5 (6.1) years and the median (interquartile range) PSA level was 9.0 (6.1–12.8) ng/mL. The number of previous biopsies was one in 59% of patients, two in 26% and three or more in 15%. We detected prostate cancer in 26%, ASAP in 5.6% and HGPIN in 2.1%. The cancer detection rate was 47%, 25.5% and 14% for prostate volumes of <40, 40–60 and ≥60 mL, respectively (P = 0.002). On a multivariate analysis the total prostate volume (40–60 vs <40 mL, hazard ratio 5.683; >60 vs <40 mL, hazard ratio 6.965; P = 0.01) was the only significant predictor of prostate cancer at saturation biopsy.

CONCLUSIONS

TRUS‐guided transperineal saturation re‐biopsy of the prostate using a 24‐core scheme resulted in a high cancer detection rate also in patients who had had two or more previous biopsies. The total prostate volume was the only predictor of prostate cancer.     

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.     

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.     

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.     

Evaluation of the serum testosterone to prostate‐specific antigen ratio as a predictor of prostate cancer risk

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

OBJECTIVE

To analyse the ratio of serum testosterone (sT) to prostate‐specific antigen (PSA) as a predictor of prostate cancer risk, as low levels of sT have been related to a greater risk of prostate cancer, and its ratio with serum PSA level was recently proposed as a new tool to increase the specificity of PSA.

PATIENTS AND METHODS

In all, 439 consecutive men with a normal digital rectal examination and a serum PSA level of 4.1–20 ng/mL had a transrectal ultrasonography‐guided biopsy using a 10‐core scheme, with an additional 1–8 cores according to prostate volume and patient age. The sT level was determined before the procedure using a chemiluminescent assay, and the ratio of sT to PSA (sT/PSA) was calculated after transforming sT measurements from ng/dL to ng/mL. The percentage free PSA (%fPSA) and PSA density were also included in this analysis.

RESULTS

The overall cancer detection rate was 42.1%. The median sT level was 469 ng/dL in men with cancer and 499 ng/dL in those without (P = 0.521). The median sT/PSA was 0.68 and 0.74, respectively (P = 0.215). However, the median %fPSA was 14 in men with cancer and 17 in men without (P < 0.001) and the median PSA density was 0.22 and 0.16, respectively (P < 0.001). The multivariate analysis confirmed the independent predictive value only for %fPSA (odds ratio 0.94, 95% confidence interval 0.91–0.98) and PSA density (5.8, 3.42–19.8).

CONCLUSION

These results do not support the use of sT/PSA for predicting the risk of prostate cancer and to increase the specificity of PSA.     

The prostate cancer gene 3 (PCA3) urine test in men with previous negative biopsies: does free‐to‐total prostate‐specific antigen ratio influence the performance of the PCA3 score in predicting positive biopsies?

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

OBJECTIVE

To determine the performance characteristics of the prostate cancer gene 3 (PCA3) score on the outcome of biopsy relative to different ranges of free‐to‐total prostate‐specific antigen (PSA) ratio (f/tPSA) in men with a previous negative biopsy and a PSA level of 2.5–10 ng/mL, as urine tests like PCA3 are currently under investigation in order to improve prostate cancer diagnosis and to decrease the rate of unnecessary rebiopsies.

PATIENTS AND METHODS

Data from the previous prospective European multicentre study were reviewed. Only patients with a PSA level of 2.5–10 ng/mL were included in the present study. In all, 301 patients had complete data. The diagnostic accuracy of the PCA3 score for predicting a positive biopsy outcome was studied using sensitivity, specificity, negative and positive predictive values. The PCA3 performance was evaluated relative to three different subgroups of f/tPSA, as follows: >20% (group 1), 10–20% (group 2) and <10% (group 3).

RESULTS

The prostate cancer detection rates were 18.8%, 23.9% and 34.8% in groups 1, 2 and 3, respectively. The area under the receiver operating characteristic curve of the PCA3 score, total PSA and f/tPSA was 0.688, 0.553 and 0.571, respectively. The percentage of men with positive biopsies was 30.6%, 37.0% and 44.4% in those with a PCA3 score of >30, vs 10.3%, 15.5% and 28.6% when the PCA3 score was <30, in groups 1, 2 and 3, respectively. The difference was significant only in groups 1 and 2. In men with a f/tPSA of ≤10% the difference in detection rates relative to the PCA3 score was not statistically significant regardless of which PCA3 threshold was used. A high PCA3 score was significantly associated with age, clinical T2 stage and positive biopsy (P < 0.001, 0.013 and <0.001, respectively). In bivariate analysis accounting for the PCA3 score and the f/tPSA, a PCA3 score of >30 was a significant independent predictor of positive biopsies (odds ratio 3.01; 95% confidence interval 1.74–5.23; P < 0.001).

CONCLUSIONS

PCA3 remained a better predictor of prostate cancer than f/tPSA. In men with a f/tPSA of >10%, the use of the PCA3 score was highly correlated with the risk of having cancer on re‐biopsy, and could prevent unnecessary prostate biopsies if the value is low.