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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) ≥ 7. In the latter, 15.2% of T1cs were classified GS ≥ 7. Considering only PCs with organ confinement or GS ≥ 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). Prostate © 2006 Wiley-Liss, Inc.

Prostate cancer screening using prostate-specific antigen (PSA) is highly controversial. In this Q & A, Guest Editors for BMC Medicine's 'Spotlight on Prostate Cancer' article collection, Sigrid Carlsson and Andrew Vickers, invite some of the world's key opinion leaders to discuss who, and when, to screen for prostate cancer. In response to the points of view from the invited experts, the Guest Editors summarize the experts' views and give their own personal opinions on PSA screening.

From its early use as a marker of prostate cancer progression, prostate-specific antigen (PSA) has matured into a screening test used by many millions of men to aid prostate cancer detection. Despite criticism over its sensitivity/specificity profile, PSA remains the most readily available and most optimal biomarker for prostate cancer. New evidence also suggests that it is a better marker of more aggressive disease, aiding detection of cancers that most urgently require intervention. While we await the outcomes of large-scale, randomised studies to determine the long-term impact of PSA screening on prostate cancer mortality, there is still substantive evidence from nonrandomised data that PSA testing has a positive impact in shifting the presentation of prostate cancer to earlier stages. What is less clear is how a PSA-based screening programme should be implemented and whether the cost-benefit profile is acceptable in some or all countries. Although lowering of the PSA threshold from 4.0 or 3.0ng/ml has been advocated, the high false-negative rate has real implications at a population level. Furthermore, the burden of increased intervention for early prostate cancer, with its low overall mortality, represents a significant issue for individual men and society alike. It is becoming evident that we need to take a more flexible approach to threshold values, taking into account the age at which screening starts, and using different thresholds and screening intervals to ensure that, first, the lag time to diagnosis is minimised and, second, that "over-testing" is minimised.

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.

Epidemiologic studies have repeatedly associated a high intake of lycopene and vitamin E with reduced prostate cancer risk. The present study examined the ability of the 2 compounds to reduce tumor growth and prostate-specific antigen (PSA) plasma levels in the PC-346C orthotopic mouse model of human prostate cancer. Three days after intraprostatic tumor injection, NMRI nu/nu mice were administered a daily oral dose of synthetic lycopene [5 or 50 mg/kg body weight (BW)], vitamin E in the form of alpha-tocopheryl acetate (5 or 50 mg/kg BW), a mixture of lycopene and vitamin E (5 mg/kg BW each), or vehicle. Intraprostatic tumor volume and plasma PSA concentrations were measured at regular intervals. Mice were killed when the tumor load exceeded 1000 mm(3) or on d 95 when the study was terminated. Prostate and liver were analyzed by HPLC for lycopene isomers and alpha- and gamma, delta-tocopherol concentrations. None of the single treatments significantly reduced tumor volume. In contrast, combined treatment with lycopene and vitamin E, at 5 mg/kg BW each, suppressed orthotopic growth of PC-346C prostate tumors by 73% at d 42 (P < 0.05) and increased median survival time by 40% from 47 to 66 d (P = 0.02). The PSA index (PSA:tumor volume ratio) did not differ between experimental groups, indicating that PSA levels were not selectively affected. Lycopene was detected only in mice supplemented with lycopene. As in humans, most tissue lycopene was in the cis-isomer conformation, whereas 77% trans-lycopene was used in the dosing material. Liver alpha-tocopherol concentrations were increased in mice supplemented with both 50 mg/kg (226%, P < 0.05) and 5 mg/kg vitamin E (41%, P < 0.05), whereas prostate alpha-tocopherol concentrations were increased only by the higher dose (83%, P < 0.05). Our data provide evidence that lycopene combined with vitamin E may inhibit the growth of prostate cancer and that PSA can serve as a biomarker of tumor response for this treatment regimen.

This part II of a paper on the “dilemma of PSA” is a continuation of part I which appeared in the first issue of the EAU-EBU update series. The paper deals with the two dilemma's of PSA: (1) the decreased prediction of PSA as a diagnostic tool in pre-screened populations. (2) the fact that even at in very low PSA ranges large proportions of biopsy detectable cancers are present and that Gleason 7 or higher cancers have a low but possibly clinically relevant prevalence in these populations. In the first place the issue of test performance of PSA is addressed. It is pointed out that we cannot really calculate test sensitivity and specificity as long as we do not know the prevalence of those cancers we wish to put into the denominator of the equation. Any calculation of sensitivity which uses a “gold standard” leads to erroneous numbers. The discussion of this issue concludes that clinically the most useful denominator in calculating sensitivity would be the rate of aggressive cancers which do not include those indolent cases which are most likely to contribute to overdiagnosis.

To document anxiety and depression from pretreatment till 5-year follow-up in 299 men with localized prostate cancer. To assess, if baseline scores were predictive for anxiety and depression at 1-year follow-up. Respondents completed four assessments (pretreatment, at 6 and 12 months, and at 5-year follow-up) on anxiety, depression and mental health. Respondents were subdivided according to therapy (prostatectomy or radiotherapy) and high vs low-anxiety. Pretreatment 28% of all patients were classified as ‘high-anxiety'; their average anxiety scores decreased significantly post-treatment, that is towards less anxiety. At all assessments, high-anxiety men treated by prostatectomy reported less depression than high-anxiety men treated by radiotherapy. Of men treated by radiotherapy, 27% reported clinical significant levels of depression while 20% is expected in a general population. The improvement in mental health at 6-months follow-up was statistically significant and clinically meaningful in all respondent groups. Sensitivity of anxiety at baseline as a screening tool was 71% for anxiety and 60% for symptoms of depression. We recommend clinicians to attempt early detection of patients at risk of high levels of anxiety and depression after prostate cancer diagnosis since prevalence is high. STAI-State can be a useful screening tool but needs further development.

PSA has been shown to be a powerful tool to detect prostate cancer in men at risk due to their age. Catalona et al. [1] used a PSA cut-off value of 4 ng/mL in a group of 1653 men in age groups at risk as a biopsy indication. 37 cancers (2.3%) were detected. 16 of the 37 cancers would have been missed by rectal examination alone. With increasing use of PSA it then emerged that the prostate cancers detected in excess of rectal examination had a more favourable distribution of prognostic factors. This was again shown early on in a prospective setting by Catalona et al. [2] . Recent developments have cast doubt on the use of the traditional PSA cut-off of 4.0 ng/mL and on the value of PSA levels in general and specifically in heavily pre-screened populations. It seems that recent findings, which will be subject to review in this paper, have made the role of PSA in diagnosing prostate cancer more uncertain than ever before. While lowering PSA cut-off levels leads to a higher detection rate of prostate cancer, it also leads to an increase of the diagnosis of cancers which might otherwise never bother their carrier (overdiagnosis). In addition, potentially aggressive cancers as defined by Gleason scores above 7 cannot be identified by appropriate PSA cut-off levels. Even with PSA values below 3.0 ng/mL 10–15% of cancers identified have been shown to have aggressive features. The high rate of overdiagnosis makes strategies desirable, which identify aggressive but still curable cancers with an acceptable accuracy. This unfortunately is still impossible. Potentially valid approaches, which include the use of PSA kinetics over time, are in the process of being evaluated. The best way of making use of PSA in the future for diagnosing prostate cancer and its role in differentiating between aggressive and less aggressive tumours seems uncertain at this time. Further research in this field is urgently needed and directions are outlined. For the time being, arbitrary cut-off levels will remain the best option even in repeat screening.

The prostate-specific antigen (PSA) is the most studied marker of prostate cancer. It is used for screening and as indicator of disease evolution for individual patients. PSA being a prognostic factor is however not sufficient to justify using PSA-derived endpoints as surrogate for definitive survival endpoint in phase III trials. First, we clarify the terminology and requirements for a marker to be a valid surrogate endpoint. We then review the published literature pertaining to the validation of PSA endpoints as surrogate in all disease stages. We discuss the limitations of these studies and conclude that so far, PSA is not a validated surrogate endpoint in any of the disease settings and treatment conditions considered. We give some recommendations for the planning of trials that would use PSA endpoints (in hormone refractory disease) and for the early stop of (endocrine treatment) trials on the basis of intermediate results based on PSA.

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.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.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% (p0.0001 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.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.

International audience; Pathological staging and surgical margin status of radical prostatectomy specimens are next to grading the most important prognosticators for recurrence. A central review of pathological stage and surgical margin status was performed on a series of 552 radical prostatectomy specimens of patients, participating in the European Organisation for Research and Treatment of Cancer trial 22911. Inclusion criteria of the trial were pathological stage pT3 and/or positive surgical margin at local pathology. All specimens were totally embedded. Data of the central review were compared with those of local pathologists and related to clinical follow-up. Although a high concordance between review pathology and local pathologists existed for seminal vesicle invasion (94%, kappa=0.83), agreement was much less for extraprostatic extension (57.5%, kappa=0.33) and for surgical margin status (69.4%, kappa=0.45). Review pathology of surgical margin status was a stronger predictor of biochemical progression-free survival in univariate analysis [hazard ratio (HR)=2.16 and p=0.0002] than local pathology (HR=1.08 and p>0.1). The review pathology demonstrated a significant difference between those with and without extraprostatic extension (HR=1.83 and p=0.0017), while local pathology failed to do so (HR=1.05 and p>0.8). The observations suggest that review of pathological stage and surgical margin of radical prostatectomy strongly improves their prognostic impact in multi-institutional studies or trials.

Screening for prostate cancer using prostate-specific antigen (PSA) tests has led to a stage and grade shift as compared to the pre-PSA era. Effectiveness of screening for prostate cancer should be manifested by a reduction in detection rate of aggressive cancers during subsequent screening. In 6 centers of the European Randomized Screening study for Prostate Cancer, a total of 58,710 men were tested for prostate cancer. Screening centers differed with regard to age-range, screening interval and biopsy indications. During the 2nd visit, the proportion of Gleason score 6 cancers increased from 62.5 to 75%, mainly at the expense of Gleason score 7 cancers. High-grade (Gleason score 8-10) cancer detection rates varied per screening center during the 1st visit from 5.1 to 41.1, and during the 2nd visit from 6.4 to 29.3/10,000 men. The overall detection rate of high-grade cancers showed a reduction during the 2nd visit from 26 to 12/10,000 men, an effect mainly attributable to the screening center with the highest cancer detection rate (i.e. 507/10,000 men). Variations in detection rates among screening centers related among others to biopsy compliance and age range.

PSA-driven screening has been applied to a large part of the male population in many countries. An elevated PSA in secondary screens may indicate benign enlargement of the prostate rather than prostate cancer. In such cases the yearly rate of increase of PSA (PSA velocity [PSAV]) may improve the test characteristics of PSA. Materials and Methods Data from the European Randomized Study of Screening for Prostate Cancer Rotterdam are used to study the issue. Relative sensitivity, relative specificity, and positive predictive value (PPV) are calculated. Logistic regression analysis is used to compare odds ratios for positive biopsies. The relationship between PSAV and parameters of tumour aggressiveness is investigated. Results Five hundred eighty-eight consecutive participants were identified who presented at their first screening with PSA values 4.0ng/ml four years later. None were biopsied in round one, all were biopsied in round two. Relative sensitivity and specificity depend strongly on PSAV cut-offs of 0.25–1.0ng/ml/yr. The use of PSAV cut-offs does not improve the PPV of the PSA cut-off of 4.0ng/ml, nor do any of the PSAV cut-offs improve the odds ratio for identifying prostate cancer with respect to the cut-off value of 4.0ng/ml. The rate of aggressive cancers seems to increase with increasing PSAV. Conclusions PSAV does not improve the detection characteristics of a PSA cut-off of 4.0ng/ml in secondary screening after four years.

The European Randomized study of Screening for Prostate Cancer (ERSPC) has shown a disease-specific mortality reduction of prostate-specific antigen (PSA) screening for prostate cancer (1). After eleven years of follow-up, prostate cancer mortality was reduced by 29% after adjustment for noncompliance. In terms of absolute effect, 37 cancers would need to be detected to avert one prostate cancer death (1). Some of the screen-detected prostate tumors (23% to 42%) might never give rise to clinical symptoms and would not lead to death from prostate cancer (2). These overdetected cancers reduce quality of life and result in higher costs because of overtreatment (3), affecting the balance of benefits and harms as well as cost-effectiveness of PSA testing for prostate cancer. In our recent study, we demonstrated that the introduction of a screening program between the ages of 55 to 70 with a four-year interval would result in a gain of 52 life-years and 41 quality-adjusted life-years (QALYs) per 1000 men over their life span (a 23% negative impact on the life-years gained because of quality of life [4]). Very recently the American Urological Association (AUA) recommended shared decision-making for men age 55 to 69 years who are considering PSA screening, but they gave no clear indication of the screen interval. In the ERSPC, the Swedish center used a two-year screening interval, whereas the other centers used four-year intervals (1). In the United States, annual screening is more common. There are no trials comparing different screening intervals, and such empirical studies are highly unlikely to be conducted because of the immense resources required. Few recent cost-effectiveness studies have been published using QALYs gained. Most cost-effectiveness studies for prostate cancer screening have been performed before large screening trial results had been published and showed very inconsistent results (5,6). The aim of this study was to assess the cost-effectiveness of prostate cancer screening. Based on data of the ERSPC trial various prostate cancer screening strategies were modeled to find the optimal screening intervals and ages.

Objectives To assess the prognostic significance of a positive surgical margin in the radical prostatectomy specimen, and to test for the presence of statistically significant interactions between surgical margin status and select pathologic stage variables. Methods We combined prospectively collected data from 7816 consecutive patients treated with radical prostatectomy at eight institutions. The pretreatment serum prostate-specific antigen level, pathologic Gleason sum, surgical margin status (positive versus negative), presence of extracapsular extension, seminal vesicle involvement, and pelvic lymph node status were examined as predictors of the rate of biochemical progression in 5831 patients with complete records. Results In multivariate Cox regression models, a positive surgical margin was associated with a 3.7-fold greater risk of progression (P = 0.001). Moreover, a statistically significant interaction was found between surgical margin status and Gleason sum 7 to 10 (P = 0.008) and lymph node invasion (P Conclusions The presence of a positive surgical margin in the radical prostatectomy specimen has an adverse effect on prognosis. The greatest risk of biochemical recurrence may be expected if a positive surgical margin is present with Gleason sum 7 to 10 disease or lymph node invasion.

An overview is given of serum and urine prostate cancer markers that are currently under investigation and subsequently the P-Mark project is introduced. There are many markers showing promise to overcome the limitations of prostate specific antigen (PSA). Eventually, these markers should be able to increase the specificity in diagnosis, differentiate between harmless and aggressive disease and identify progression towards androgen independence at an early stage. In the P-Mark project, several recently developed, promising markers will be evaluated using clinically well-defined biorepositories. Following successful evaluation, these markers will be validated on a sample set derived from two large, European, prostate cancer studies and used for the identification of special risk groups in the general population. In addition, novel markers will be identified in the same biorepositories by different mass spectrometry techniques.

Objectives To evaluate the adjuvant clinical use of [−2] precursor prostate-specific antigen ([−2]pPSA), which is associated with prostate cancer (PCa), and “benign” PSA, related to benign prostatic hyperplasia, in selecting a treatment strategy in patients with screen-detected PCa. Methods Research-use immunoassays (Beckman Coulter) were used to measure [−2]pPSA, sum [−7, −5, −4, and −2]pPSA, and benign PSA from the frozen serum of participants from the screen arm of the European Randomized Study of Screening for Prostate Cancer, section Rotterdam, diagnosed with PCa with a serum PSA level lower than 15 ng/mL. We compared men with relatively benign PCa (Epstein’s criteria; group 1) and men with arbitrarily defined aggressive PCa characteristics (Gleason score greater than 4 + 4 and more than four cores with PCa invasion or pT3C disease; group 2). Results The data of 61 patients were evaluated. The median age in both groups was 68 years. Total PSA performed best in a univariate analysis, although in the multivariate analysis, the combination of pPSA and percent free PSA could correctly predict 95.5% of group 1 and 82.4% of group 2. The pPSA and percent free PSA forms remained statistically significant in the multivariate analysis of a subgroup of 30 participants normalized for PSA level and prostate volume; combined they correctly identified 89.5% and 54.5% of patients identified as having relatively favorable and aggressive PCa characteristics, respectively. Conclusions Adjuvant clinical use of pPSA over traditional parameters in selecting treatment strategies for men with PCa cannot yet be definitely determined. However, the promising results in a subgroup analysis warrant further investigation.

BACKGROUND Focal carcinoma detected by needle biopsy has been a common finding since prostate-specific antigen (PSA)-based screening was introduced. Clinicopathologic features in patients with focal prostate carcinoma who underwent radical prostatectomy (RP) or who were treated with watchful waiting (WW) were analyzed to detect clinical predictors for disease progression during follow-up. METHODS Patients were selected from the European Randomized Screening study for Prostate Cancer. Focal carcinoma on sextant biopsy was defined as ≤ 3.0 mm involvement by tumor in 1 biopsy core lacking Gleason pattern 4 or 5. PSA doubling time was used in the WW group as a marker of disease progression. RESULTS The proportion of patients with focal prostate carcinoma increased significantly from 16% in the first screening round to 29% in the second screening round. One hundred eighteen men underwent RP, and 108 men were treated with WW. The median tumor volume was 0.13 mL. PSA level and prostate volume were predictive for tumor volume in a multivariate regression analysis. A PSA density cut-off level of ≤ 0.1 ng/mL/cm3 predicted organ-confined tumor (< 0.5 mL) in 94% of patients. Positive surgical margins were predictive for PSA recurrence. Four patients in the RP group had PSA recurrence at follow-up. PSA doubling times < 2 years, < 3 years, and < 4 years were noted in 4.9%, 14.6%, and 22.0% of patients in the WW group, respectively. CONCLUSIONS The median tumor volume was small (0.13 mL). A comparison between PSA recurrence in the RP group and PSA doubling time in the WW group showed a significantly more favorable outcome after RP if a PSA doubling time of < 3 years or < 4 years was chosen as a marker for disease progression in the WW group. A WW policy with delayed curative intent may be recommended in patients ages 55–75 years with focal carcinoma and PSA density < 0.1 ng/mL/cm3. Cancer 2005. © 2005 American Cancer Society.

Objectives To evaluate whether the incidence of atrophy reported on sextant biopsies is associated with subsequent prostate cancer detection and to obtain a more thorough analysis of the different categories and extent of atrophy, we performed a review of benign biopsy cores. Methods In the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer, 4117 and 1840 men underwent sextant biopsy in the first and second screening round (4-year interval), respectively. Sextant biopsy was prompted by elevated prostate-specific antigen levels. For review, randomly taken benign sextant biopsies (n = 202) with a follow-up of at least 8 years were chosen. Results Before review, atrophy was reported in the biopsies of 11.4% and 8.7% of the first and second round, respectively. The prostate cancer incidence during 8 years of follow-up after an initial diagnosis of atrophy was 10.4%, which was not significantly different than the 12.3% of cancers detected after a benign diagnosis without reference to atrophy. After review, the incidence of simple atrophy, post-atrophic hyperplasia, and sclerotic atrophy in sextant biopsies was 91%, 47%, and 9%, respectively. Extensive atrophy was observed in 5% of biopsies. Only 2 men (4.7%) in the reviewed group had a subsequent diagnosis of prostate cancer in the 8 years of follow-up. Additionally, prostatic intraepithelial neoplasia was diagnosed in 3 men (7.0%) in the second screening round. Conclusions Atrophy, especially its simple form, is a very common lesion in prostate biopsy cores (94%). Atrophy in an asymptomatic population undergoing screening was not associated with a greater prostate cancer or prostatic intraepithelial neoplasia incidence during subsequent screening rounds.

Contains fulltext : 48847schalken.pdf (Publisher’s version ) (Closed access) Recent developments in the field of molecular techniques have provided new tools that have led to the discovery of many new promising biomarkers for prostate cancer. These biomarkers may be instrumental in the development of new tests that will have a high specificity for the diagnosis and prognosis of prostate cancer. A biomarker is defined as a molecular test that provides additional information to currently available clinical and pathological tests. Biomarkers should be reproducible (both within and between institutes) and have an impact on clinical management. For diagnostic purposes it is important that potential biomarkers are tested in terms of tissue specificity and their discrimination potential between prostate cancer, normal prostate and benign prostatic hyperplasia. The results of (multiple) biomarker-based assays may enhance the specificity of cancer detection. There is an urgent need for molecular prognostic biomarkers for predicting the biological behavior and outcome of cancer.

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

The European Randomized Study of Screening for Prostate Cancer investigates the impact of screening on prostate cancer mortality and contributes to a better understanding of available screening tests. The present study evaluates the predictive value of a prostate specific antigen (PSA) increase to PSA 3.0 ng/ml or greater in a 4-year period in men who present with low PSA values (less than 3.0 ng/ml) at first screen.A total of 42,376 men were randomized to screening vs control in Rotterdam. Of 6,467 men 5,771 had PSA values of less than 3.0 ng/ml, did not undergo biopsy at baseline and were rescreened after 4 years with PSA 3.0 ng/ml or greater as biopsy indication. PSA progression in a 4-year interscreening interval is evaluated by determining the positive predictive values, detection rates and parameters of aggressiveness of round 2 cancers.PSA progression to more than 3.0 ng/ml occurred in 0.9%, 9.3% and 48.6% of men who presented with PSA values less than 1.0, 1 to 1.9 and 2 to 2.9 ng/ml, respectively, in round 1. Their respective positive predictive values amounted to 19.0%, 23.8% and 27.9%. Cancer detection rates increased with increasing PSA values in round 1. The distribution of low, moderate and high risk cancers depends on round 2 but not on round 1 PSA ranges.PSA progression to the (arbitrary) cutoff value of 3.0 ng/ml and the diagnosis of prostate cancer in round 2 screening with a 4-year interval depends strongly on PSA values at the time of the 1st screen. These observations will be helpful to design future screening procedures. With levels less than 2.0 ng/ml PSA progression to levels of 3.0 ng/ml or greater is rare as it was seen only in 4.8% of all men.

Objectives Epidemiological studies have shown significant relationships between the use of dietary components and prostate cancer incidence and mortality. Large studies of primary prevention, which confirm these findings, are desirable but costly and difficult to design. The present tertiary prevention study reports on the effect of a dietary supplement in comparison with placebo on the rate of increase of prostate-specific antigen (PSA). Methods 49 patients with a history of prostate cancer and rising PSA levels after radical prostatectomy ( n =34) or radiotherapy ( n =15) participated in a randomised, double-blind, placebo-controlled crossover study of a dietary supplement. Ethical approval of the protocol was obtained. Treatment periods of 10 weeks were separated by a 4-week washout period. The supplement consisted of soy, isoflavones, lycopene, silymarin and antioxidants as main ingredients. Changes in the rate of increase of PSA (PSA slope and doubling time) were the primary parameters of efficacy. Analyses according to intention to treat (ITT) and per protocol (PP) were carried out. Results Baseline parameters did not differ between randomised groups. Five participants were lost to follow-up, however 46 could be evaluated in an ITT analysis. PP analysis could be performed in 42 men with at least 5 PSA measurements. Per protocol analysis showed a significant decrease in PSA slope ( p =0.030) and 2 log PSA slope ( p =0.041). This translates into a 2.6 fold increase in the PSA doubling time from 445 to 1150 days for the supplement and placebo periods. No treatment-based changes in safety parameters were observed during the study. Conclusions The soy-based dietary supplement utilised in this study was shown to delay PSA progression after potentially curative treatment in a significant fashion. More extensive studies of the supplement may be indicated.

The objective of this study was to show or to exclude an effect of dietary supplement on rising prostate-specific antigen (PSA) levels. We have studied the effect of a dietary supplement (verum, administered for 6 weeks) containing plant estrogens, antioxidants, including carotenoids, selenium and other putative prostate cancer inhibiting substances in a randomized placebo-controlled double-blind crossover study in 37 hormonally untreated men with prostate cancer and increasing PSA levels. Outcome measures were changes in the rates of change of serum concentrations of total and free PSA and changes in male sex hormone levels. Male sex hormone levels were significantly lower during the verum phase (DHT: -0.11 nmol/L, p = 0.005; testosterone: -1 nmol/L, p = 0.02). Total PSA doubling time was unaffected. Free PSA, which increased during the placebo phase (average doubling time of 68 weeks), decreased during the verum period (average half-life of 13 weeks; p = 0.02). In those men in whom the free androgen index decreased (21 out of 32), a significant decrease in the slopes of both total and free PSA was observed (p = 0.04). Overall total PSA doubling times did not increase significantly during verum. However, the study demonstrates that this dietary intervention reduces DHT and testosterone levels and increases free PSA doubling time (and total PSA doubling time in a relevant subgroup). If future studies confirm that these observations translate into a slowing of disease progression, a dietary intervention may become an attractive option for prostate cancer treatment and prevention.

for cancer. I was one of the architects of the National Health Service Breast Screening Programme (NHSBSP) in the United Kingdom in the late 1980s and also have enjoyed the privilege of acting as independent chairman of the Prostate Testing for Cancer and Treatment (ProtecT) trial of PCa screening in the United Kingdom for the last 12 yr [3]. I was also one of the first to break ranks with the NHSBSP as emergingdata started to suggest that breast cancer screening was failing to liveup to itspromise.Most recently, I published a paper in the BMJ inwhich I returned to basics and posed the question in the introduction of the editorial, ‘‘Does screening for breast cancer improve LoL andorQoL?’’ The answerwas a resounding no [4]. If we are not to repeat the errors of the past, then all cancer-screening trials must be reported using absolute numbers, numbers needed to screen to avoid a causespecific death, all-cause mortality, and some measure of QoL. Impotence and incontinence might be good surrogates for the latter. Some biostatisticians get very cross with me when they argue that the trials were not powered to determine any impact on all-cause deaths. Yet hundreds of thousands of men have been randomised in screening trials, so if the signal has been lost in the background noise, it must be a very small signal. If that is indeed the case, there is the issue of opportunity costs when the same money might be used with greater wisdom to save more lives. I am confident that the ProtecT trial will not repeat the mistakes of the past.

Background/Aim: Retention of crystals in the kidney ultimately leads to renal stone formation. Hyaluronan (HA) has been identified as binding molecule for calcium oxalate monohydrate crystals. The association of high molecular mass (Mr) HA with cell surface receptors such as CD44 gives rise to pericellular matrix (PCM) formation by many eukaryotic cells in culture. Here, we study the ability of several renal tubular cell lines to assemble PCMs and to synthesize high-Mr HA during proliferation in relation to crystal retention. Methods: PCM assembly by MDCK-I, MDCK-II, and LLC-PK1 cells was visualized by particle exclusion assay. Metabolic labeling studies were performed to estimate the cellular production of HA. The expression of CD44 and HA was studied using fluorescent probes, and crystal binding was quantified with radiolabeled calcium oxalate monohydrate. Results: PCMs were formed, and HA was expressed by most MDCK-I and some MDCK-II, but not by LLC-PK1 cells. All cell types expressed CD44 at their apical surface. MDCK-I and MDCK-II cells secreted, respectively, 14.7 ± 1.6 and 0.5 ± 0.2 pmol [3H]glucosamine incorporated in high-Mr HA, whereas LLC-PK1 cells did not secrete HA. Streptomyces hyaluronidase treatment significantly decreased crystal binding (µg/cm2) to MDCK-I cells (from 8.6 ± 0.4 to 3.9 ± 0.9), but hardly to MDCK-II cells (from 10.2 ± 0.2 to 9.6 ± 0.1) or LLC-PK1 cells (from 10.2 ± 0.8 to 9.9 ± 0.3). Conclusions: There are various forms of crystal binding to renal tubular cells in culture. Crystal attachment to MDCK-I and some MDCK-II cells involves PCM assembly that requires high-Mr HA synthesis. HA production and PCM formation do not play a role in crystal binding to LLC-PK1 and the majority of MDCK-II cells. It remains to be determined which form of binding is involved in renal stone disease.

Purpose: We evaluated the positive predictive value and cancer detection rate in the prostate specific antigen (PSA) range of 2.0 to 3.9 ng/ml and assessed the value of percent free (F) PSA (FPSA) on tumor detection and tumor aggressiveness in this low PSA range. Materials and Methods: Of 3,623 men who were attending the second round of screening within the European Randomized Study of Screening for Prostate Cancer, section Rotterdam 883 had PSA values of 2.0 to 3.9 ng/ml. These men were offered laterally directed sextant biopsy. FPSA was prospectively determined from pretreatment serum. Cancers were classified as prognostically favorable and unfavorable using biopsy results and other pretreatment diagnostic features. Results: Using the PSA range of 2.0 to 3.9 ng/ml as a biopsy indication 126 cancers were detected, resulting in a positive predictive value of 17.1% and a cancer detection rate of 14.3%. By using percent FPSA and setting relative sensitivity at 95% 9% of biopsies could have been avoided. Unfavorable tumor characteristics were found in 46.9% of the men with T1C tumors. Mean percent FPSA was significantly lower in such men compared to men with favorable tumor characteristics. Of the men with percent FPSA lower than 10% 90% had unfavorable tumor characteristics. Conclusions: The PSA range 2.0 to 3.9 ng/ml is accessible for prostate cancer screening. Percent FPSA is of moderate value in avoiding unnecessary biopsies in the PSA range of 2.0 to 3.9 ng/ml. However, when assessing tumor aggressiveness in biopsy results, percent FPSA is predictive and can be used to select treatment options, such as watchful waiting.

BACKGROUND We evaluated the incidence of prostate cancer, high-grade prostatic intraepithelial neoplasia (PIN) and lesions suspicious for prostate cancer (LSPC) in sextant biopsies in two subsequent screening rounds at a 4-year interval and their predictive value for subsequent prostate cancer detection. METHODS In the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC), 4,117 men underwent sextant biopsy in the 1st screening round. The 2nd round was performed at a 4-year interval and biopsies were taken in 1,840 men. RESULTS The incidences of prostate cancer, LSPC and PIN in the 1st, respectively 2nd round were 24.6, resp. 19.9% (P = 0.001), 2.7, resp. 2.8% and 0.8, resp. 2.5% (P

OBJECTIVE To assess the value of the precursor form (-7,5pro) of prostate-specific antigen (PSA) and human kallikrein-2 (hK2) for detecting and grading prostate cancer, as better serum markers with improved specificity are needed in men with lower ranges of total (t)PSA. PATIENTS AND METHODS tPSA, free PSA (fPSA), the precursor (-7,5)proPSA and hK2 were measured in a subset of participants of the European Randomised Study of Screening of Prostate Cancer. In a pilot study, sera from 143 men biopsied but with no prostate cancer, 142 with BPH, and 146 with prostate cancer were analysed to determine the relative value of serum markers for differentiating between the groups. Then, in 141 men with prostate cancer who had a radical prostatectomy, these serum markers were related to the pathological grading to analyse their value as prognostic variables. RESULTS Levels of (-7,5)proPSA, hK2 and fPSA could be used to distinguish between BPH and cancer, but proPSA and hK2, alone or combined, did not improve the specificity of fPSA for discriminating BPH and cancer. There was also no correlation between these serum markers and pathological tumour grade. CONCLUSION The clinical effect of using (-7,5)proPSA or hK2 for detecting and grading prostate cancer remains limited.

Objectives: This trial was designed to compare the efficacy of Flutamide (FLU) versus Cyproterone acetate (CPA) in men with metastatic prostate cancer and favourable prognostic factors. The primary endpoint of the trial was overall survival, disease specific survival, time to progression and side effects were secondary endpoints. The results pertaining to sexual function were already reported [Br J Cancer 82(2) (2000) 283]. Material and Methods: The trial was designed to detect a 50% improvement in median overall survival with 80% power. At the time of the present report, the trial provides 88% power to detect the planned difference of 50% with a 2-sided Logrank test and 80% power to detect a difference of 43% in median survival. Results: 310 patients were randomized to treatment by FLU (250mg t.i.d. p.o.) or CPA (100mg t.i.d. p.o.). Of the 310 patients, 12 (3.9%) were ineligible. The baseline characteristcs of the two groups were similar except for age which was significantly younger in the CPA group and for the presence of soft tissue metastases which were absent in the FLU group and present in 6 patients in the CPA group. The median follow-up was 8.6 years, 245 patients died, 158 (64.5%) of prostate cancer. There was no significant difference between the treatment arms with respect to overall survival, specific survival nor time to progression. Side effect profiles were studied and found to be more favourable for CPA overall and in particular with respect to gynecomastia, diarrhea and nausea. Conclusions: The trial shows no significant differences in efficacy between Flutamide and CPA monotherapy. The number of patients who died of prostate cancer up to this time is insufficient for a definitive analysis of specific survival. Erectile function and sexual activity are not preserved with FLU but decay slowly with both antiandrogens, toxicity is more pronounced with FLU.

BACKGROUND At the Rotterdam branch of the European Randomized Study of Screening for Prostate Cancer, a cohort of 19,970 men ages 55–75 years is screened at an interval of 4 years. Screening includes systematic sextant needle biopsy for men with elevated prostate-specific antigen (PSA) levels and/or positive findings on digital rectal examination or transrectal ultrasound. Detection during the second screening round of a large number of high-grade (Gleason Grade 4 or 5) malignancies and/or a large number of malignancies in general could be considered the result of a failure to identify these malignancies at an early stage, during prevalence screening. METHODS Men diagnosed during the second screening round with potentially advanced carcinoma (PAC), characterized by a biopsy Gleason score of 7 (4 + 3, or 3 + 4 with > 30% malignant involvement) or a biopsy Gleason score of 8–10, were identified. Clinical data, including PSA values on prevalence screening, biopsy history, clinical stage, and follow-up data, were retrieved for these patients. Tumor features were further analyzed in radical prostatectomy specimens. RESULTS During the second screening round, 503 malignancies, including 30 (6.0%) with features of PAC on diagnostic biopsy, were detected in 11,210 patients. Curative treatment was offered to 26 patients. Prostatectomy demonstrated the presence of organ-confined disease in 11 of 12 specimens, and tumor volume ranged from 0.11–7.93 cm3 (median, 1.05 cm3). PSA failure was noted in 6 of 22 patients who were offered curative therapy. CONCLUSIONS PAC is a rare finding in the second round of screening after a 4-year interval, and a substantial proportion of PAC cases detected in the second screening round represent organ-confined disease. The findings of the current study suggest that the screening protocol used is sufficiently effective for detecting > 95% of malignancies before they develop features that would make them incurable. Cancer 2004;100:968–75. © 2004 American Cancer Society.

Objectives. To study retrospectively whether the prostate-specific antigen (PSA) velocity, that is, the change in PSA level over time, might serve as a screening tool in this PSA range. It is estimated that 40% of detectable prostate cancers are present in men with a PSA level of 4.0 ng/mL or less. Digital rectal examination and/or transrectal ultrasonography have been used as screening tools at these low PSA levels, but this approach is not very efficient. Methods. The possible predictors (including PSA velocity) for biopsy outcome were studied using univariate and multivariate logistic regression analysis in 774 men who underwent biopsy between November 1997 and January 2002 in the second screening round of the European Randomised Study of Screening for Prostate Cancer (ERSPC). The clinical stage of the tumors was determined, and the Gleason scores of the biopsies were studied. Results. A total of 149 cancers were found (positive predictive value 19.2%). The odds ratio for the PSA velocity determined by univariate logistic regression analysis was 2.2 (95% confidence interval 0.7 to 6.9, P = 0.19) and was 0.73 (95% confidence interval 0.20 to 2.6, P = 0.64) by multivariate analysis. The distribution of the clinical stage of the detected tumors was 64.4% T1c, 32.2% T2, and 3.4% T3. The biopsy Gleason score was 6 in 84.5%, 7 in 14.2%, and 8 in 1.3%. Conclusions. The number of cancers detected in this study and the distribution of clinical stage and biopsy Gleason score confirmed that a relatively large proportion of potentially curable cancers can be found in the low PSA ranges. The PSA velocity did not appear to be a useful screening tool for the identification of these cancers.

We evaluated prostate cancer (PCa) characteristics at diagnosis and changes in prostatic specific antigen (PSA) with time in males with screening detected PCa that was initially managed with a watchful waiting policy.Patients with histologically proven PCa and PSA less than 10 ng/ml were selected from the European Randomized Study of Screening for Prostate Cancer, section Rotterdam. The choice of initiating a watchful waiting policy was patient desire or physician advice. PSA slope and PSA doubling time (PSADT) were calculated in patients with 3 or more PSA tests results available.A total of 191 patients were included. Mean age at diagnosis was 69 years and mean PSA was 3.9 ng/ml. Of the patients 92.6% had a Gleason score of 3 + 3 or lower, 133 had a followup of greater than 12 months (mean 40) and 35 (29.2%) had a negative PSA slope. Mean PSADT was 9.7 years (range 0.3 to 155) in 85 males with a positive PSA slope. During followup 30 patients changed therapy.Watchful waiting remains a controversial prostate cancer treatment strategy. In select screening detected patients with PCa there appears to be a subgroup with stable or even decreasing PSA values with time. These males could profit from a watchful waiting policy with possible deferred treatment. Together with conventional tumor parameters at diagnosis PSADT and PSA slope during followup could be used to monitor tumor activity and possibly aid in determining the time of deferred treatment. Further followup is mandatory to validate these results.

The timing of endocrine treatment for prostate cancer remains controversial. The issue is addressed in protocol 30846 of the European Organisation for Research and Treatment of Cancer for patients with lymph node positive cancer without local treatment of the primary tumor. A total of 302 patients with metastatic regional lymph nodes who had not received local treatment for the primary tumor were included in the trial, of whom 234 were randomized to immediate vs delayed endocrine treatment. Endocrine treatment consisted of an luteinizing hormone-releasing hormone agonist and 1 month of antiandrogen treatment or surgical castration. The main end point of the trial was overall survival. Analysis followed the intent to treat principle. At a median followup of 9.6 years (8.7 in the randomized sample) 190 patients (62.9%) had died, including 76% of prostate cancer. In the randomized sample the HR for survival on delayed vs immediate treatment was 1.23 (95% CI 0.88 to 1.71), indicating a 23% nonsignificant trend in favor of early treatment. However, the wide CI showed that results remained compatible with true effects, ranging from a 12% benefit in favor of delayed treatment to a 71% detriment for the same treatment approach. While this study suggests an advantage for early treatment, it is under powered to show equivalence or superiority for the early or delayed approach. When dealing with individual patients, the potential survival advantage on early treatment must be balanced against potential advantages in quality of life on delayed treatment

Recent studies have reported that serum IGF-I levels in the highest quartile of the normal range and IGF binding protein-3 (IGFBP-3) in the lowest quartile of the normal range are associated with an increased risk of future prostate cancer and/or presence of prostate cancer. It has also been suggested that the measurement of circulating total IGF-I concentrations might be a useful tool for the early detection of prostate cancer in men with moderately increased prostate-specific antigen (PSA) levels. To determine whether circulating free IGF-I, total IGF-I, and IGFBP-3 levels can predict future prostate cancer risk, we prospectively studied prostate cancer characteristics in a cohort of men during two rounds (mean interval, 4 yr) of a population-based screening study for prostate cancer. Two hundred one prostate cancer cases were detected at the second-round screening (aged 55-70 yr), and all these subjects were enrolled in the case group for the present study. Prostate cancer had been confirmed by biopsy in all cases. These 201 subjects were matched with the 201 nonprostate cancer cases by age, serum PSA range at the first-round screening (PSA < 2 ng/ml, n = 67; PSA = 2-3 ng/ml, n = 67; and PSA = 3-4 ng/ml, n = 67), and residence area. At baseline, total IGF-I, free IGF-I, and IGFBP-3 levels and prostate volume of cases with prostate cancer were not different from those of healthy controls. PSA velocity was significantly different between cases and controls (P < 0.001).Stepwise forward logistic regression analysis showed that only PSA levels at baseline and PSA at round 2 after 4 yr are good predictors of prostate cancer, whereas total IGF-I, free IGF-I, and IGFBP-3 did not predict the development of prostate cancer. Only one of the 201 subjects with prostate cancer had metastases. Within the subjects with prostate cancer, there were no differences of IGF-I parameters with different tumor node metastasis categories and/or Gleason scores. Our study suggests that the measurement of serum IGF-I and/or IGFBP-3 concentrations in addition to PSA does not improve the identification of men at high risk to develop early stages of prostate cancer. In addition, our results indicate that the endocrine IGF-I system is not directly involved in the growth of the early stages of prostate cancer.

Prostate cancer is the most commonly diagnosed non-cutaneous neoplasm among American males and is the second leading cause of cancer-related death. Prostate specific antigen screening has resulted in earlier disease detection, yet approximately 30% of men will die of metastatic disease. Slow disease progression, an aging population and associated morbidity and mortality underscore the need for improved disease classification and therapies. To address these issues, we analyzed a cohort of patients using array comparative genomic hybridization (aCGH). The cohort comprises 64 patients, half of whom recurred postoperatively. Analysis of the aCGH profiles revealed numerous recurrent genomic copy number aberrations. Specific loss at 8p23.2 was associated with advanced stage disease, and gain at 11q13.1 was found to be predictive of postoperative recurrence independent of stage and grade. Moreover, comparison with an independent set of metastases revealed approximately 40 candidate markers associated with metastatic potential. Copy number aberrations at these loci may define metastatic genotypes.

OBJECTIVE To compare a series of 121 sextant needle biopsy sets with their corresponding radical prostatectomy specimens in screened participants in the European Randomized study of Screening for Prostate Cancer (ERSPC), investigating the effect of screening for prostate cancer on disease-specific mortality and quality of life, as the clinical significance of a small focus of well-differentiated prostate cancer on biopsy is unclear. PATIENTS AND METHODS The expected clinical significance of the discovered tumours was estimated using an arbitrary model combining volume, grade, and stage characteristics. RESULTS Of 34 patients who had a small focus (

textabstractBACKGROUND: The interval cancer rate is an important parameter for determining the sensitivity of a screening procedure and the screening interval. We evaluated the time and mechanism of detection and the stage distribution of interval prostate cancers diagnosed during a 4-year screening interval. METHODS: We determined the rate of interval cancers and the sensitivity of the screening protocol (involving prostate-specific antigen, digital rectal and transrectal ultrasound examinations) in a cohort of 17 226 men (8350 on the screened arm, 8876 on the control arm) enrolled consecutively on the European Randomized Study of Screening for Prostate Cancer-Rotterdam. Men on the screened arm received a first screen between October 1993 and December 1996 and a scheduled second screen 4 years later. Prostate cancers detected in men enrolled on the control arm over the same 4-year period and, between screens, in men on the screened arm, were identified by linkage to the Dutch national cancer registry. RESULTS: During the first screen, 412 prostate cancers were detected. During the subsequent 4-year period, 135 cancers were diagnosed in men in the control arm and 25 cancers were diagnosed in men in the screened arm. Seven of the 25 cancers were diagnosed in men who had refused a recommended biopsy at their initial screen. Of the remaining 18 cancers, all were classified as stage T1A-C or T2A and none were poorly differentiated or metastatic. The rate of interval cancers relative to the number of cancers in the control group was 18.5% (25/135), or 13.3% (18/135), if the seven who refused an initial biopsy were excluded. The sensitivity of the screening protocol was 79.8% when considering all 25 interval cancers and 85.5% when considering 18 interval cancers. CONCLUSION: The interval cancer rate with a 4-year screening interval was low, confirming that the screening procedure has a high sensitivity and that the 4-year screening interval is reasonable.

Internalization of calcium oxalate crystals by renal tubular cells: A nephron segment–specific process? Background Crystal retention in the kidney is caused by the interaction between crystals and the cells lining the renal tubules. These interactions involve crystal attachment, followed by internalization or not. Here, we studied the ability of various renal tubular cell lines to internalize calcium oxalate monohydrate (COM) crystals. Methods Crystal-cell interactions are studied by light-, electron-, and confocal microscopy with cells resembling the renal proximal tubule [porcine kidney (LLC-PK 1 )], proximal/distal tubule [Madin-Darby canine kidney II (MDCK-II)], and distal tubule and/or collecting ducts [(Madin-Darby canine kidney I (MDCK-I), rat cortical collecting duct 1 (RCCD 1 )]. Crystal-binding strength and internalization are characterized and quantified with radiolabeled COM. Results Microscopy studies showed that crystals were firmly embedded in the membranes of LLC-PK 1 and MDCK-II cells to be subsequently internalized. On the other hand, crystals bound only loosely to MDCK-I and RCCD 1 and were not taken up by these cells. Crystal uptake by LLC-PK 1 and MDCK-II, expressed in μg/10 6 cells, is temperature-dependent and gradually increases from 0.88 and 0.15 in 30 minutes, respectively, to 4.70 and 3.85, respectively, after five hours, whereas these values never exceeded background levels in MDCK-I and RCCD 1 cells. Conclusion The adherence of COM crystals to renal cells with properties of the proximal tubule is inevitable and actively followed by their uptake, whereas crystals attached to cells resembling the distal tubule and/or collecting duct are not internalized. Since crystal formation usually occurs in segments beyond the renal proximal tubule, crystal uptake may be of less importance in the etiology of idiopathic calcium oxalate stone disease.

textabstractBACKGROUND: Screening for prostate cancer advances the time of diagnosis (lead time) and detects cancers that would not have been diagnosed in the absence of screening (overdetection). Both consequences have considerable impact on the net benefits of screening. METHODS: We developed simulation models based on results of the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC), which enrolled 42,376 men and in which 1498 cases of prostate cancer were identified, and on baseline prostate cancer incidence and stage distribution data. The models were used to predict mean lead times, overdetection rates, and ranges (corresponding to approximate 95% confidence intervals) associated with different screening programs. RESULTS: Mean lead times and rates of overdetection depended on a man's age at screening. For a single screening test at age 55, the estimated mean lead time was 12.3 years (range = 11.6-14.1 years) and the overdetection rate was 27% (range = 24%-37%); at age 75, the estimates were 6.0 years (range = 5.8-6.3 years) and 56% (range = 53%-61%), respectively. For a screening program with a 4-year screening interval from age 55 to 67, the estimated mean lead time was 11.2 years (range = 10.8-12.1 years), and the overdetection rate was 48% (range = 44%-55%). This screening program raised the lifetime risk of a prostate cancer diagnosis from 6.4% to 10.6%, a relative increase of 65% (range = 56%-87%). In annual screening from age 55 to 67, the estimated overdetection rate was 50% (range = 46%-57%) and the lifetime prostate cancer risk was increased by 80% (range = 69%-116%). Extending annual or quadrennial screening to the age of 75 would result in at least two cases of overdetection for every clinically relevant cancer detected. CONCLUSIONS: These model-based lead-time estimates support a prostate cancer screening interval of more than 1 year.

Over-representation of sequences on chromosome 7 and 8 have been reported to be associated with aggressive behavior of prostate cancer. In this study we have performed a molecular cytogenetic survey by comparative genomic hybridization of a cohort of 40 prostate cancer patients, consisting of 20 progressors and 20 nonprogressors, after radical surgery for localized adenocarcinoma. Progression was defined as a biochemical relapse, ie, an elevation in prostate-specific antigen level in the serum. The mean follow-up after prostatectomy for the progressor group was 10.6 years, for the nonprogressor group, 9.1 years. Using comparative genomic hybridization, we found that progressors harbored on average more aberrations than nonprogressors. Gains were especially more prominent among progressors (p < 0.05), whereas a statistical trend was detected for losses (p = 0.10). As a consequence we examined all chromosome arms separately. The frequencies of loss for areas known to be frequently deleted in prostate cancer, such as 6q, 8p, or 13q, were not different between the two groups. A tendency was observed for more frequent gain on 3q in the progressor group (p = 0.09). However, gain of 8q (minimal overlapping region at 8q24-qter) was significantly more frequent in the progressor group (p = 0.04). This biomarker retained its significance when adjusted for the factors age, tumor grade, tumor stage, resection margin status, and preoperative prostate-specific antigen level. In conclusion we have created a map of genetic changes in progressive and nonprogressive prostatic carcinomas. Importantly, the presence of gain of distal 8q markedly reduced the progression-free survival, suggesting a clinical role for 8q gain in assessing the malignant potential of localized prostatic adenocarcinoma.

The extent of effective prostate-specific antigen (PSA) contamination in the Rotterdam section of the ongoing European Randomized Study of Screening for Prostate Cancer (ERSPC) trial was evaluated and defined as when opportunistic PSA testing of ≥ 3.0 ng/ml was followed by biopsy, similar to the regular procedure within the trial. Records of participants aged 55–74 years at entry were linked to the regional database of the general practitioner (GP) laboratory to obtain PSA tests requested by GPs in the period 1 July 1997 to 31 May 2000 (2.9 years), and to the national pathology database to quantify the number of biopsies. All men randomized were included, only those with prostate cancer screen-detected or clinically diagnosed before July 1997 were omitted from the analyses. 2,895 out of the 14,349 men (20.2%) in the control arm and 1,981 out of the 14,052 men (14.1%) in the screening arm were PSA-tested, at an average annual rate of 73 and 52 per 1,000 person-years, respectively. These rates were higher than those recorded at the national and regional levels, 33 and 38 per 1,000 person-years, respectively. Opportunistic PSA testing in the control arm reached a peak within the first months of randomization, after which it decreased to around 70 per 1,000 person-years. An opposite pattern was observed in the screening arm, where participants already had received the scheduled screening within the trial. The proportion of men in the control arm with PSA ≥ 3.0 ng/ml followed by biopsy and prostate cancer was 7–8% and 3%, respectively (3% and 0.4–0.6% in the screening arm), over the whole study period. Over a 4-year rescreening interval, the average PSA and effective contamination amount were approximately 28% and 10%, respectively. PSA testing in the control arm in the Rotterdam ERSPC section is high, but was not followed by a substantial increase in prostate biopsies. Although the reasons for ordering PSA test or indicating biopsy are unknown, effective PSA contamination in the Rotterdam ERSPC section is low and not likely to jeopardize the power of the trial. © 2003 Wiley-Liss, Inc.