Estimating bias in causes of death ascertainment in the Finnish Randomized Study of Screening for Prostate Cancer.

BACKGROUND: Precise cause of death (CoD) ascertainment is crucial in any cancer screening trial to avoid bias from misclassification due to excessive recording of diagnosed cancer as a CoD in death certificates instead of non-cancer disease that actually caused death. We estimated whether there was bias in CoD determination between screening (SA) and control arms (CA) in a population-based prostate cancer (PCa) screening trial. METHODS: Our trial is the largest component of the European Randomized Study of Screening for Prostate Cancer with more than 80,000 men. Randomly selected deaths in men with PCa (N=442/2568 cases, 17.2%) were reviewed by an independent CoD committee. Median follow-up was 16.8 years in both arms. RESULTS: Overdiagnosis of PCa was present in the SA as the risk ratio for PCa incidence was 1.19 (95% confidence interval (CI) 1.14-1.24). The hazard ratio (HR) for PCa mortality was 0.94 (95%CI 0.82-1.08) in favor of the SA. Agreement with official CoD registry was 94.6% (κ=0.88) in the SA and 95.4% (κ=0.91) in the CA. Altogether 14 PCa deaths were estimated as false-positive in both arms and exclusion of these resulted in HR 0.92 (95% CI 0.80-1.06). CONCLUSIONS: A small differential misclassification bias in ascertainment of CoD was present, most likely due to attribution bias (overdiagnosis in the SA). Maximum precision in CoD ascertainment can only be achieved with independent review of all deaths in the diseased population. However, this is cumbersome and expensive and may provide little benefit compared to random sampling.

Prostate cancer screening: a survey of attitudes and practices among Finnish physicians in 1999 and 2007.

OBJECTIVE: To evaluate the attitudes and practices related to prostate-specific antigen (PSA) screening for prostate cancer (PC) among Finnish physicians in 1999 and 2007. MATERIALS AND METHODS: The first questionnaire survey was conducted in 1999 with a mailing to 102 urologists, 679 community physicians and 684 occupational health physicians identified from the membership files of three medical associations. The area of residence was divided into the study area of the Finnish PC screening trial and the rest of Finland. The second survey was carried out in 2007 targeting 168 urologists, 1039 community physicians and 938 occupational health physicians. RESULTS: The response proportion was 48% in 1999 and 50% in 2007. In both rounds, urologists regarded PC as a more important public health issue than other physicians. On the other hand, the non-urologists considered early diagnosis and screening more important than the urologists. PC was rated by all physicians as a less important public health problem in 2007 than in 1999. A smaller proportion of urologists found routine PSA testing indicated for asymptomatic men, compared with other physicians (40% versus 74-60% in 1999, P < 0.001 and 35% versus 44-37% in 2007, P = 0.005). The proportion of physicians reporting regular PSA screening in asymptomatic men was reduced from 1999 to 2007 (from 18% to 9%, P < 0.0001). CONCLUSION: Based on reported practices of Finnish urologists, community physicians and occupational health physicians, popularity of PSA testing declined between 1999 and 2007. Urologists found PSA testing among asymptomatic men justified less frequently than the other physicians.

Prognostic grouping of metastatic prostate cancer using conventional pretreatment prognostic factors.

OBJECTIVE: To develop three prognostic groups for disease specific mortality based on the binary classified pretreatment variables age, haemoglobin concentration (Hb), erythrocyte sedimentation rate (ESR), alkaline phosphatase (ALP), prostate-specific antigen (PSA), plasma testosterone and estradiol level in hormonally treated patients with metastatic prostate cancer (PCa). MATERIAL AND METHODS: The present study comprised 200 Finnprostate 6 study patients, but data on all variables were not known for every patient. The patients were divided into three prognostic risk groups (Rgs) using the prognostically best set of pretreatment variables. The best set was found by backward stepwise selection and the effect of every excluded variable on the binary classification cut-off points of the remaining variables was checked and corrected when needed. RESULTS: The best group of variables was ALP, PSA, ESR and age. All data were known in 142 patients. Patients were given one risk point each for ALP > 180 U/l (normal value 60-275 U/l), PSA > 35 microg/l, ESR > 80 mm/h and age < 60 years. Three risk groups were formed: Rg-a (0-1 risk points), Rg-b (2 risk points) and Rg-c (3-4 risk points). The risk of death from PCa increased statistically significantly with advancing prognostic group. CONCLUSION: Patients with metastatic PCa can be divided into three statistically significantly different prognostic risk groups for PCa-specific mortality by using the binary classified pretreatment variables ALP, PSA, ESR and age.

A high pretreatment plasma oestradiol level is associated with a low risk of acute myocardial infarction in parenteral oestrogen therapy for locally advanced prostate cancer.

OBJECTIVE: To evaluate the relationship of pretreatment plasma oestradiol (ppE2) and testosterone (ppT) level to acute myocardial infarction (AMI) in patients with locally advanced prostate cancer primarily treated with parenteral polyoestradiol phosphate (PEP) or orchidectomy, considering the effect of age, performance status, pretreatment diseases and medication, and tumour stage and grade. PATIENTS AND METHODS: The present Finnprostate 6 study comprised 234 patients randomized to oestradiol or intramuscularly administered PEP (240 mg/month) therapy. Each patient was followed until the end of the primary therapy (up to 10 years) or until the first AMI (lethal or not). RESULTS: The risk of AMI, when the PEP and orchidectomy groups were analysed together, was lower in patients with a high ppE2 level, and this risk was independent of the ppT level, pretreatment diseases, medication, age, performance status, disease stage or grade. In the PEP therapy group the risk of AMI was statistically significantly lower in patients with a high ppE2 level (>or=93 pmol/L) than in those with a low ppE2 level (<93 pmol/L; risk ratio 0.28, 95% confidence interval 0.10-0.84, P = 0.022). There was no such difference in the orchidectomy group. The ppT level had no association with the risk of AMI. CONCLUSIONS: A high ppE2 level is associated with a low risk of AMI in patients with locally advanced prostate cancer treated with PEP; there was no such association for ppT level. In the orchidectomy group the ppE2 or ppT level was not statistically significantly associated with the risk of AMI.

Assessment of causes of death in a prostate cancer screening trial.

Accurate assessment of the causes of death is crucial for a conclusive evaluation of the ongoing prostate cancer screening trials. Here, we report the validity of the official causes of death as compared with an independent expert review in the Finnish prostate cancer screening trial. Because nearly 80,000 men were involved, death-cause evaluation was restricted to men diagnosed for prostate cancer. Medical charts were retrieved and the cause of death was assigned by an expert review panel for all deaths among men with prostate cancer during the study period, 1996-2003. The panel decision was compared with both death certificates and the official causes of death as assigned by Statistics Finland. Of a total of 315 deaths, the review panel attributed 127 (41%) to prostate cancer and 184 (59%) to other causes, the corresponding figures in death certificates being 124 (40%) and 187 (60%). Four cases were excluded because of insufficient information. The death-certificate data were in agreement with the panel's assessment in 305 out of 311 cases (overall agreement 97.7%, kappa = 0.95). The overall agreement between the official causes of death and the panel's decision was 97.4% (304/311, kappa = 0.95). The sensitivity of the certificates in identifying prostate cancer deaths was 96.1% (panel as golden standard). Correspondingly, specificity was 98.9%. The official causes of death thus provide an accurate means for evaluating disease-specific mortality in a large population-based prostate-cancer screening trial in Finland.

Ten-year survival and cardiovascular mortality in patients with advanced prostate cancer primarily treated by intramuscular polyestradiol phosphate or orchiectomy.

BACKGROUND: The aim of the study was to evaluate overall and prostate cancer (PCa) specific survival with special attention to cardiovascular (CV) mortality in patients primarily treated by parenteral polyestradiol phosphate (PEP) 240 mg/month or with orchiectomy (OE), taking into account the effect of pretreatment diseases and medication, and later PCa therapies. METHODS: The present Finnprostate 6 study (10-year follow-up) consisted of 244 patients with locally advanced PCa (T3-4 M0) and 200 patients with metastatic PCa (T1-4 M1). Patients were randomized to OE or PEP therapy. The T3-4 M0 and T1-4 M1 patients were analyzed separately. RESULTS: There was no difference in overall or PCa specific survival between the primary therapy groups in T3-4 M0 or T1-4 M1 patients. In the T3-4 M0 patients the primary treatment (PEP vs. OE) was statistically significantly associated with a risk of CV deaths (P = 0.001). Such an association was not found in the T1-4 M1 patients. CONCLUSIONS: The primary PEP and OE therapies are equal in terms of overall and PCa specific survival in patients with T3-4 M0 or T1-4 M1 disease. In T3-4 M0 patients PEP increases the risk of CV deaths compared to OE but not in T1-4 M1 patients.

Cardiovascular complications in patients with advanced prostatic cancer treated by means of orchiectomy or polyestradiol phosphate.

OBJECTIVE: To evaluate the cardiovascular (CV) complications associated with orchiectomy (OE) and parenteral polyestradiol phosphate (PEP) therapy (240 mg/month), taking into account the effect of pretreatment diseases and pretreatment medication. MATERIAL AND METHODS: A total of 244 T3-4 M0 patients and 200 T1-4 M1 patients were randomized to either OE or PEP therapy. The two groups of patients were analyzed separately. The follow-up period was 36 months. The effect of pretreatment vascular and other diseases and pretreatment medication which may be associated with a risk of CV complications was evaluated. RESULTS: In the T3-4 M0 patients, the treatment (PEP versus OE) and the presence of pretreatment vascular diseases were statistically significantly associated with a risk of CV complications (p=0.01 and 0.003, respectively). In the T1-4 M1 patients, such an association was not found. No association was observed between pretreatment medication and CV complications. There was no difference in progression-free time between the therapy groups in either the T3-4 M0 or T1-4 M1 patients. CONCLUSION: In patients with locally advanced prostatic cancer, PEP therapy is associated with a statistically significantly higher risk of CV complications compared to OE.

Test sensitivity of prostate-specific antigen in the Finnish randomised prostate cancer screening trial.

We estimated the sensitivity of serum prostate-specific antigen (PSA) as a screening test for prostate cancer in the Finnish randomised, population-based prostate cancer screening trial. The study population consisted of 80,458 men aged 55-67 years identified from the national population registry and randomised to the screening or control arm of the trial. The screening algorithm was based on determination of serum PSA concentration. Test sensitivity was estimated based on interval cancer incidence during the first 4 years of follow-up among screening participants with a negative screening test. Interval cancers were defined as those occurring among men with a negative screening test. Altogether, 19 interval cancers were detected among 17,897 men with serum PSA < 3 ng/ml during the first screening interval. A further 5 cases were diagnosed among 811 men with PSA 3.0-3.9 ng/ml with a benign digital rectal examination or free total PSA ratio > or = 0.16. Test sensitivity based on serum PSA of 3 ng/ml was estimated to be 0.89 (95% confidence interval 0.84-0.93) and that based on PSA of 4 ng/ml combined with an ancillary test (digital rectal examination or free total PSA ratio in the PSA range 3.0-3.9) was 0.87 (0.82-0.92). Test sensitivity achieved with serum PSA in prostate cancer screening appears excellent in the context of a population-based effectiveness trial.

Second round results of the Finnish population-based prostate cancer screening trial.

PURPOSE: Large randomized trials provide the only valid means of quantifying the benefits and drawbacks of prostate-specific antigen (PSA) screening, but the follow-up of ongoing studies is still too short to allow evaluation of mortality. We report here the intermediate indicators of screening efficacy from the second round of the Finnish trial. EXPERIMENTAL DESIGN: The Finnish trial, with approximately 80,000 men in the target population, is the largest component in the European Randomized Study of Screening for Prostate Cancer. The first round was completed in 1996-1999. Each year 8,000 men 55-67 years of age were randomly assigned to the screening arm, and the rest formed the control arm. Men randomized to the screening arm in 1996 were reinvited 4 years later, in 2000, and PSA was determined. RESULTS: Of the eligible 6415 men, 4407 (69%) eventually participated in the second round of screening. Of the first-round participants, up to 84% (3833 of 4556) attended rescreening. A total of 461 screenees (10.5%) had PSA levels of > or = 4 microg/liter. Altogether, 97 cancers were found, yielding an overall detection rate of 2.2% (97 of 4407). Seventy-nine cases were found among the 3833 second-time screenees (detection rate 2.1%) and 18 in those 574 men (3.1%) who had not participated previously. A PSA of > or = 4 microg/liter, but negative biopsy in the first screening round was associated with an up to 9-fold risk of cancer in rescreening relative to those with lower PSA levels at baseline. Ninety-one (94%) of all of the detected cancers were clinically localized. CONCLUSIONS: As surrogate measures of an effective screening program, both compliance as well as the overall and advanced prostate cancer detection rates remained acceptable. Men defined as screen-positive but with a negative confirmation of cancer at prevalence screen formed a high-risk group at rescreening.

Tumor characteristics in a population-based prostate cancer screening trial with prostate-specific antigen.

PURPOSE: Early diagnosis of prostate cancer is a necessary, but not sufficient, prerequisite for an effective screening program aiming at mortality reduction. We compared tumor characteristics between the screening and control arms in the Finnish population-based screening trial. EXPERIMENTAL DESIGN: The Finnish trial is the largest component in the European Randomized Study of Screening for Prostate Cancer. A total of 24,000 men aged 55-67 years were randomized to the screening arm, whereas 35,973 men formed the control arm during the first three screening years. At the time of invitation, 22,732 men were eligible for screening, and 15,685 (69%) participated. A prostate-specific antigen (PSA) concentration of > or ==" BORDER="0">4 micro g/liter was defined as a screening-positive finding. RESULTS: The detection rate among screenees was 2.4% (377 of 15,685), whereas 0.6% (40 of 7,047) of nonparticipants in the screening arm and 0.3% (112 of 35,973) of the controls were diagnosed with prostate cancer during the first postrandomization year in the absence of screening. In the screening arm, 82% of the cancers were clinically organ confined compared with 65% in the control arm. Yet, both the absolute number and cumulative incidence of advanced cancer were higher in the screening arm. No differences were seen in the WHO grade distribution between the study groups. The median PSA was substantially lower among screen-detected cases (7.1 micro g/liter) than among nonattenders (15.7 micro g/liter) and controls (13.2 micro g/liter). CONCLUSIONS: Our findings on intermediate indicators of PSA screening provide encouraging, yet inconclusive evidence for eventual mortality reduction.

Family history and prostate cancer screening with prostate-specific antigen.

PURPOSE: Early detection of prostate cancer has been recommended for men with affected first-degree relatives despite the lack of evidence for mortality reduction. We therefore evaluated the impact of family history in the Finnish prostate cancer screening trial. PATIENTS AND METHODS: Approximately 80,000 men were identified from the population register for the first screening round. Of the 32,000 men randomized to the screening arm, 30,403 were eligible at the time of invitation. A blood sample was drawn from the participants (n = 20,716), and serum prostate-specific antigen (PSA) was determined. Men with a PSA level > or = 4.0 ng/mL were referred for prostate biopsy. Information on family history was obtained through a self-administered questionnaire at baseline. RESULTS: A total of 964 (5%) of the 20,716 screening participants had a positive family history, and 105 (11%) were screening-positive. Twenty-nine tumors were diagnosed, corresponding to a detection rate of 3.0% (29 of 964) and a positive predictive value of 28% (29 of 105). Of the 19,347 men without a family history, 1,487 (8%) had a PSA level > or = 4.0 ng/mL. The detection rate was 2.4% (462 of 19,347) and the positive predictive value was 31% (462 of 1,487). The risk associated with a positive family history was not substantially increased (rate ratio, 1.3; 95% confidence interval, 0.9 to 1.8). The results were not affected by the age of the screenee or age at diagnosis of the affected relative. The program sensitivity was 6% (29 of 491) (ie, selective screening policy would have missed 94% of cancers in the population). No differences were seen in the characteristics of screen-detected cancers by family history. CONCLUSION: Our findings provide no support for selective screening among men with affected relatives.

Estimation of prostate cancer risk on the basis of total and free prostate-specific antigen, prostate volume and digital rectal examination.

BACKGROUND AND OBJECTIVE: Approximately 70% of the men with an elevated serum prostate-specific antigen (PSA) identified in prostate cancer screening do not have prostate cancer. Other available diagnostic variables may be utilized to reduce the number of false positive PSA results, but few algorithms for calculation of the combined impact of multiple variables are available. The objective of this study was to establish nomograms showing the probability of detecting prostate cancer at biopsy on the basis of total PSA, and the percentage of free PSA in serum, prostate volume and digital rectal examination (DRE) findings. METHODS: In a randomized, population-based prostate cancer screening trial 10284 men aged 55-67 years were screened during 1996 and 1997 in two metropolitan areas in Finland. Results for men (n=758) with a serum PSA of 4-20 microg/l were used to establish the risk nomograms. Of these 200 (26%) had prostate cancer at biopsy. RESULTS: Prostate cancer probability depended most strongly on the percentage of free PSA. Total PSA, prostate volume, and DRE also contributed to prostate cancer probability, whereas age and family history of prostate cancer did not. More false positive PSA results could be eliminated by using the multivariate risk model rather than the percentage of free PSA (p<0.001) or PSA density (p=0.003) alone. CONCLUSIONS: Wide variation in probability of detecting prostate cancer among screened men with a serum PSA of 4-20 microg/l was observed. The nomograms established can be used to avoid or defer biopsy in men with a low prostate cancer probability in spite of a serum PSA level exceeding 4 microg/l.

Lead-time in prostate cancer screening (Finland).

OBJECTIVE: Lead-time in prostate cancer screening was estimated using data from the Finnish randomized, population-based trial. METHODS: Lead-time was defined as the duration of follow-up needed to accrue the same expected number of incident prostate cancer cases in the absence of screening as detected in the initial screening round. Expected numbers were calculated using an age-cohort model. RESULTS: Based on findings among 10,000 men screened in 1996-1997 with 292 screen-detected cancers, lead-time was estimated as approximately 5-7 years, depending on the reference rates used. This corresponds to a mean duration of the detectable preclinical phase (DPCP) of 10-14 years, given that the cancers were detected on average at the midpoint of the DPCP. CONCLUSIONS: The findings suggest that a screening interval substantially longer than the 2 years generally used for mammography screening is unlikely to cause a substantial loss of sensitivity. A long screening interval is further justified in order to diminish the extent of overdiagnosis, until mortality effects can be evaluated.