The value of an additional hypoechoic lesion-directed biopsy core for detecting prostate cancer.

OBJECTIVE: To determine the value of a hypoechoic lesion (HL)-directed biopsy in addition to a systematic sextant biopsy for detecting prostate cancer. SUBJECTS AND METHODS: Within the European Randomized study of Screening for Prostate Cancer, 37 627 assays for prostate-specific antigen (PSA) were done in men aged 55-75 years (screening round 1-3, interval 4 years). A PSA level of >or=3.0 ng/mL prompted a systematic transrectal ultrasonography (TRUS)-guided lateralized sextant biopsy (4986 biopsy sessions were evaluated). If there was a HL, an additional lesion-directed biopsy was taken. RESULTS: At the initial screening, 1840 men were biopsied and 532 cancers were detected (28.9%). Of the men biopsied, 436 had a HL and an additional biopsy (23.7%). In these men, 230 cancers were detected (52.8%). In 3.5% (eight of 230) only the HL-directed core showed malignancy. At the repeat and third screening, respectively, 19.3% and 18.9% of the men biopsied had prostate cancer, 16.8% and 9.3% had an HL and the additional core detected two (2.2%) and one (5.9%) cancers. At the first screen most cancers found by the additional core were clinically relevant. In later screens these cancers seemed to be minimal. CONCLUSION: The performance of TRUS as a screening tool is poor. The value of the additional core was limited as only 3.5% of the visible cancers were detected solely by the additional biopsy (round 1). However, a substantial part of these cancers were clinically relevant and would have been missed without the additional biopsy. This finding was less clear in screening round 2 and 3, even in men who were not previously biopsied.

Digital rectal examination and the diagnosis of prostate cancer--a study based on 8 years and three screenings within the European Randomized Study of Screening for Prostate Cancer (ERSPC), Rotterdam.

BACKGROUND: Evidence indicates that an abnormal digital rectal examination (DRE) is a risk factor for high-grade prostate cancer (PC). OBJECTIVE: To determine whether men with an initially suspicious DRE, a prostate-specific antigen (PSA) level > or = 3.0 ng/ml, and a benign prostate biopsy are at higher risk for significant PC at rescreening than men with an initially normal DRE, and whether an adaptation of the rescreening interval is warranted for this group. DESIGN, SETTING, AND PARTICIPANTS: Within the European Randomized Study of Screening for Prostate Cancer (ERSPC), Rotterdam, 2218 men underwent biopsy of the prostate (from 1993 to 2000) with a benign result at initial screening. The serum PSA was determined every 4 yr. A PSA level of > or = 3.0 ng/ml prompted a DRE and a lateralised sextant biopsy. MEASUREMENTS: Number and characteristics of PCs found at repeat screenings and as interval cancers (ICs) were compared between men with or without a suspicious DRE result at initial screening. Multivariate logistic regression analyses were performed to evaluate if an initially suspicious DRE was a significant predictor for detecting cancer at consecutive screenings. RESULTS AND LIMITATIONS: After 4 yr, the total number of PCs detected in men with and without an initially suspicious DRE was, respectively, 27 (6%) versus 103 (6%) (p=0.99). After 8 yr these numbers increased, respectively, to 45 (10%) versus 167 (10%) (p=0.88). The proportion of clinically significant PCs was 2% and 3%, respectively, for the group with initially normal and abnormal DRE after 8 yr. Having a suspicious DRE result at initial screening was not a significant predictor for detecting PC after 4 yr [odds ratio (OR)=1.15, p=0.59) or 8 yr (OR=1.41, p=0.43)]. A limitation of this study is the relatively short follow-up of 8 yr. CONCLUSIONS: During a follow-up of 8 yr after initial cancer-negative biopsy, an initially suspicious DRE did not influence the chance for detection of cancer or significant cancer at later screens. An adaptation of the rescreening interval on the basis of the initial DRE-outcome is not warranted in future population-based screening for prostate cancer.

The role of the digital rectal examination in subsequent screening visits in the European randomized study of screening for prostate cancer (ERSPC), Rotterdam.

BACKGROUND: The value of digital rectal examination (DRE) as a screening test for prostate cancer (PC) is controversial in the current prostate-specific antigen (PSA) era. OBJECTIVES: To determine (1) the additional value of a suspicious DRE for the detection of PC in men with an elevated PSA level in subsequent screenings and (2) the tumour characteristics of PCs detected in men with a suspicious DRE. DESIGN, SETTING, PARTICIPANTS: Within the screening study, from 1997-2006 men aged 55-75 years were invited for an every 4-yr PSA determination. A PSA level > or =3.0ng/ml prompted a DRE and a transrectal ultrasound (TRUS)-guided, lateralized sextant biopsy. Throughout the three screenings of the ERSPC, Rotterdam, 5040 biopsy sessions were evaluated. MEASUREMENTS: We determined the positive predictive values (PPVs) of a suspicious DRE and normal DRE, which entailed, respectively, the proportion of PCs detected in men with a suspicious DRE or normal DRE divided by, respectively, all biopsied men with a suspicious DRE or normal DRE. RESULTS AND LIMITATIONS: At initial screening, the PPV of a suspicious DRE, in conjunction with an elevated PSA level, to detect PC was 48.6% compared to 22.4% for men with a normal DRE. Both PPVs decreased in consecutive screens: respectively, 29.9% versus 17.1% (screen 2) and 21.2% versus 18.2% (screen 3). Respectively, 71.0% (p<0.001), 68.8% (p<0.001), and 85.7% (p=0.002) of all PCs with a Gleason score >7 were detected in men with a suspicious DRE at screens 1, 2, and 3. A limitation is that only biopsied men were evaluated. CONCLUSIONS: At initial and subsequent screenings, the chance of having cancer at biopsy was higher in men with a suspicious DRE compared to men with a normal DRE (to a lesser extent in subsequent screenings), and the combination of a PSA level > or =3.0ng/ml with a suspicious DRE resulted in detecting significantly more PCs with Gleason score >7. DRE may be useful in more selective screening procedures to decrease unnecessary biopsies and overdiagnosis.

Early detection of prostate cancer in 2007. Part 1: PSA and PSA kinetics.

OBJECTIVE: This is the first of two review papers attempting to clarify the best way to detect prostate cancer (PCa) in 2007. Screening for PCa has not yet been shown to lower PCa mortality. Still, opportunistic screening is wide spread in Europe and in most other parts of the world. METHODS: Current literature and data from screening studies are reviewed and discussed. Prostate-specific antigen (PSA) has been and remains one of the corner stones of early detection of PCa. Traditionally used cut-off values cannot be applied in an uncritical fashion after it was shown that a significant amount of overdiagnosis and that large proportions of cancers and poorly differentiated cancers are present in the low PSA ranges. The paper addresses the continued relevance of PSA cut-off values. The diagnostic value of PSA velocity is reviewed in conjunction with PSA cut-off values and as a possible replacement of total PSA. A need for more selective screening in the low PSA ranges is pointed out. RESULTS AND CONCLUSIONS: The data show that men presenting initially with PSA values below 1 do not have to be rescreened for a period of 8 yr. In the PSA range 1-2.9 ng/ml, new parameters are needed that improve specificity and are selective for screening for aggressive lesions. PSA velocity so far has not been shown to be useful in the early detection of PCa but may be useful in detecting aggressive PCa selectively. For the time being, it seems sensible to continue using PSA cut-off values such as 3.0 or 4.0 ng/ml provided overtreatment is decreased by using available nomograms.

Screening for prostate cancer at low PSA range: the impact of digital rectal examination on tumor incidence and tumor characteristics.

OBJECTIVES: To compare tumor characteristics of screen-detected prostate cancers (PCs) either by digital rectal examination (DRE) or by prostate-specific antigen (PSA) as biopsy indication at low PSA. METHODS: Two populations with PSA between 2.0 and 3.9 ng/ml were studied. Group-1 was biopsied if DRE was suspicious (1st screening round, N = 1877). In group-2 all men were offered biopsy, regardless of DRE result (side-study in 2nd screening-round, N = 801). We compared cancer detection rates (CDRs) and tumor characteristics. RESULTS: In group-1 abnormal DRE prompted biopsy in 253 (13.5%) men (236 (93.3%) actually biopsied). Forty-nine PCs were detected, CDR 49/1877 = 2.6%. In group-2 we found 120 cancers in 666 (83.1%) men actually biopsied, CDR = 120/801 = 15.0%. Of all cancers detected, organ confinement (clinical T2) was found in 77.5% (group-1) and 96.6% (group-2; of which 99 T1c). Of all PCs 46.9% in group-1 and 15.0% in group-2 had biopsy Gleason score (GS) > or = 7. In the latter, 15.2% of T1cs were classified GS > or = 7. Considering only PCs with organ confinement or GS > or = 7 for each group, CDRs amounted to 2.0% versus 14.5% and 1.2% versus 2.3% for group-1 and group-2, respectively. CONCLUSIONS: PSA-based screening detected a considerable amount (15.2%) of potentially aggressive tumors as T1cs, but in addition large numbers of possibly insignificant cancers (T1c, GS = 6) were diagnosed. DRE seemed to detect more selectively high-grade cancers, but also missed many of these. Considering both populations and the need to detect aggressive but confined cancers, PSA as biopsy indication outperformed DRE at the price of more biopsies (13.5% vs. 100% if all would comply).

Active surveillance for prostate cancers detected in three subsequent rounds of a screening trial: characteristics, PSA doubling times, and outcome.

OBJECTIVES: To study active surveillance as a management option for the important number of prostate cancer patients who would not have been diagnosed in the absence of screening. PATIENTS AND METHODS: We analyzed baseline characteristics and outcome parameters of all men on active surveillance who were screen-detected in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC). Recruitment and surveillance of men were not guided by a protocol but depended on individual decisions of patients and their physicians. RESULTS: Active surveillance was applied in 278 men detected by screening from 1993 to 2006. At diagnosis, their median age was 69.8 yr (25-75p; 66.1-72.8); median PSA 3.6 ng/ml (25-75p; 3.1-4.8), and the clinical stage was T1c in 220 (79.1%) and T2 in 58 (20.9%). During the follow-up of median 3.4 yr, 103 men (44.2%) had a PSA doubling time that was negative (ie, half-life) or longer than 10 yr. Men detected at rescreening were significantly more likely to be on active surveillance, and they had more beneficial characteristics. Deferred treatment was elected in 82 cases (29.0%). Overall survival was 89% after 8 yr; the cause-specific survival was 100%. CONCLUSIONS: This report shows a beneficial, although preliminary, outcome of screen-detected men managed on active surveillance. Men were more likely to be on active surveillance if the disease was detected at repeated screening. The report also shows that an important proportion of men have prolonged PSA doubling times, although the value of this parameter has not been established in untreated men.

Feasibility study of adjustment for contamination and non-compliance in a prostate cancer screening trial.

BACKGROUND: The use of PSA as a screening test has become increasingly prevalent in the general population and therefore also in the control arm of the European Randomized study of Screening for Prostate Cancer (ERSPC). We present a feasibility study and impact simulation of a secondary analysis, which imitates a situation where all participants in the study are managed according to their random assignment. METHODS: The results of the Rotterdam section of the ERSPC were adjusted for contamination and non-compliance according to Cuzick et al. [Stat Med 1997; 16:1017-1029]. Endpoints of this analysis were simulated reductions in prostate cancer mortality. RESULTS: Of the men allocated to the screen arm, 27.1% were non-compliant. In the control arm 30.7% had their PSA-level measured by a general practitioner (GP) (i.e., contamination). For a scenario in which the intention-to-screen analysis was assumed to give a decrease in the mortality in the men randomized to screening of 6.7%, the secondary analysis resulted in a decrease of 16.1% for those actually screened. CONCLUSION: Although the definition of contamination as "PSA ever tested" gives an indication of the proportion of contamination, it will be important to differentiate the screening use of PSA from its diagnostic use. For the rest, adjustment for non-compliance and contamination was shown to be feasible in this prostate cancer screening trial. It can therefore be used to carry out a secondary analysis on the definitive outcome of the ERSPC and will provide accurate information for those men who are in fact screened.

Biochemical progression rates in the screen arm compared to the control arm of the Rotterdam Section of the European Randomized Study of Screening for Prostate Cancer (ERSPC).

BACKGROUND: The European Randomized study of Screening for Prostate Cancer (ERSPC) investigates the feasibility of population-based screening. This report compares the preliminary outcome of cancers detected in the screen and the control arm of its Rotterdam section, by means of biochemical progression rates. METHODS: In the screen arm of this study (21,210 men), screening was applied according to well-established protocols, and a 4-year screen interval was chosen. Widely accepted biochemical progression-criteria were used to evaluate the diagnosed cancers over time. RESULTS: Although more cancers were detected in the screen than in the control arm (1,339 vs. 298, P < 0.001), their clinico-pathological features were more favorable. Furthermore, screened men had higher 5-year survival rates for biochemical progression after surgery (84.4% vs. 58.9% in controls), radiotherapy (71.0% vs. 58.0%), and endocrine therapy (40.5% vs. 16.3%). CONCLUSIONS: The higher biochemical progression-free survival can at least in part be explained by lead and length-time. How screening will effect the mortality remains unclear.

Metastatic disease of screen-detected prostate cancer : characteristics at diagnosis.

BACKGROUND: Screening for prostate cancer has not only led to a stage migration, but also to a higher incidence of the disease. A decrease in mortality has occurred in several countries during the same time period. Risk stratification of screen-detected cancers at diagnosis has become more important for the anticipation and interpretation of changing incidence/mortality ratios. METHODS: From 1993 to 1998, 633 men were diagnosed with nonmetastatic prostate cancer in the prevalence screen of the Rotterdam section of the European Randomized study of Screening for Prostate Cancer (ERSPC). The characteristics at diagnosis of men who developed metastatic disease were compared with men without evidence of metastases during follow-up. RESULTS: During the median follow-up of 7.5 years, 41 men developed metastatic disease. After 10 years the metastasis-free survival rate was 89.6%, the overall survival 64.7%. In a Cox-model 2logPSA (prostate-specific antigen), biopsy Gleason score and the number of biopsy cores with prostate cancer were independent predictors for the development of metastases; the latter only predicted metastases that presented within 60 months of follow-up. CONCLUSIONS: The metastasis-free survival of men with prostate cancer detected in a prevalence screening was very high. Whether this was related to the beneficial effects of screening or to overdiagnosis due to screening (or both) remains unclear. The prognostic factors known for clinically diagnosed disease also hold for screen-detected disease.

Management and survival of screen-detected prostate cancer patients who might have been suitable for active surveillance.

OBJECTIVE: Screening practices for prostate cancer have resulted in an increasing incidence of prostate cancers. Our knowledge about which prostate cancers are life threatening and which are not is limited. Thus, for ethical, medical, and economic reasons we need to define which patients can be managed by active surveillance. METHODS: From 1993 through 1999, men from the Rotterdam section of the European Randomized study of Screening for Prostate Cancer (ERSPC) were screened by two strict protocols, which were based on prostate-specific antigen (PSA), digital rectal examination, and transrectal ultrasound. For this study, men with criteria that reflect current active surveillance studies were selected: those with a biopsy Gleason score < or =3+3 in two or fewer cores, with a PSA density <0.2 and a maximum PSA-level of 15 ng/ml. Clinical stage had to be T1C or T2. RESULTS: Of the 1,014 prostate cancers detected in the prevalence screen, 293 men (28.9%) met the criteria for active surveillance. Their mean age was 65.7 and the mean PSA level was 4.8 ng/ml. Radical prostatectomy was elected by 136 men (46.4%), radiotherapy by 91 (31.1%), and watchful waiting by 64 (21.8%). The mean follow-up was 80.8 months. The eight-year prostate cancer-specific survival was 99.2%; the overall survival was 85.4%. Nineteen men who chose watchful waiting changed to definitive treatment during follow-up. CONCLUSION: Only three men died of prostate cancer, none of whom were on watchful waiting. Our observations provide preliminary validation of the arbitrary selection criteria for active surveillance.

Prevalence, treatment modalities and prognosis of familial prostate cancer in a screened population.

PURPOSE: A family history of prostate cancer is an important risk factor for this disease. The clinical presentation and prognosis of familial disease remain uncertain. In this study these entities are evaluated in the first and second rounds of a screening program in The Netherlands. MATERIALS AND METHODS: Of all men randomized in the Rotterdam section of the ERSPC, 19,970 men were eligible for screening. Information regarding the family history was obtained by a self-administered questionnaire at baseline. RESULTS: In the prevalence screen the cancer detection rate in 1,364 men (7.1%) with a positive family history was 7.7% (106 cancers in 1,364 screened men with a positive family history) while the positive predictive value of the biopsies was 32.2% (154 cancers of 532 biopsies). In 12,803 sporadic cases the detection rate was 4.7% and the positive predictive value was 23.6% (p <0.0001 and 0.003, RR 1.63). No clinicopathological differences were found in the 1,559 men diagnosed in the first and second rounds. The overall biochemical-free survival rate after a mean followup of 56.8 months (range 0 to 129.9) was 76.8%, and was not significantly different in familial and sporadic cases (p = 0.840). These findings were consistent for the specific treatment modalities as well. CONCLUSIONS: Although screened men 55 to 75 years old with a father or a brother having prostate cancer themselves are at a substantially greater risk for the disease, the clinical presentation, treatment modalities and prognosis by biochemical progression are not different compared to sporadic cases.

Screening for prostate cancer without digital rectal examination and transrectal ultrasound: results after four years in the European Randomized Study of Screening for Prostate Cancer (ERSPC), Rotterdam.

BACKGROUND: Omission of DRE/TRUS as biopsy indication results in fewer unnecessary biopsies, but may increase the risk of missing potentially aggressive prostate cancers (PCs). In 1997, the biopsy indication within the ERSPC was changed from a PSA cut-off of 4.0 ng/ml and/or abnormal DRE/TRUS (group-1) to solely a PSA cut-off of 3.0 ng/ml (group-2). We estimated the effect of omitting DRE/TRUS by comparing the results of a re-screening 4 years after initial screening to the original policy. METHODS: We compared rate and characteristics of detected PCs in the second round in men initially screened in group-1 (N=5,957) or group-2 (N=8,044). Additionally, we compared the rate of interval cancers (ICs) after screening with and without DRE/TRUS. RESULTS: There was no significant difference in second round cancer-detection-rates (group-1, 3.0%; group-2, 2.7%), positive-predictive-values (group-1, 23.9%; group-2, 26.3%), and number of poorly-differentiated tumors (group-1, 2.6%; group-2, 3.8%). Most PCs were clinically confined to the prostate. Eleven ICs were detected in each group (0.18 and 0.14%). CONCLUSIONS: Omitting DRE/TRUS did not result in an increased IC- or PC-detection. However, considering the natural history of PC, the 4-year follow-up may be too short to draw a definitive conclusion.

Prevalence and characteristics of screen-detected prostate carcinomas at low prostate-specific antigen levels: aggressive or insignificant?

Screening for prostate cancer at low prostate-specific antigen (PSA) levels (