BRIEF COMMUNICATION

Three-Year Results of the Finnish Prostate Cancer Screening Trial

Liisa Määttänen, Anssi Auvinen, Ulf-Håkan Stenman, Teuvo Tammela, Sakari Rannikko, Jussi Aro, Harri Juusela, Matti Hakama

Affiliations of authors: L. Määttänen, Finnish Cancer Registry, Helsinki, Finland; A. Auvinen, Tampere School of Public Health, University of Tampere, Finland; U.-H. Stenman, Department of Clinical Chemistry, Helsinki University Hospital; T. Tammela, Department of Urology, Tampere University Hospital; S. Rannikko, Department of Urology, Helsinki University Hospital; J. Aro, Department of Surgery, Helsinki City Hospital; H. Juusela, Department of Surgery, Jorvi Hospital, Espoo, Finland; M. Hakama, Finnish Cancer Registry and Tampere School of Public Health, University of Tampere.

Correspondence to: Liisa Määttänen, M.P.H., Finnish Cancer Registry, Liisankatu 21 B, 00170 Helsinki, Finland (e-mail: liisa.maattanen{at}cancer.fi).

Prostate cancer screening is increasing despite lack of demonstrated effectiveness (1). Large randomized, controlled trials with long-term follow-up are ongoing in Europe and North America to assess the effects of screening on mortality and quality of life (2).

The Finnish trial is a part of the European Randomized Study of Screening for Prostate Cancer, a multicenter trial with eight participating centers (3). The common core protocol includes enrollment of men at age 55–67 years and a screening test to assay the concentration of prostate-specific antigen (PSA) in serum, with a PSA cutoff point of 4.0 ng/mL.

We report here the attendance rate, the specificity, and the detection rate of prostate cancer during the first 3 years of the prevalence screening round. These parameters are intermediate indicators and thus are necessary, but are not sufficient, conditions for effective screening.

The target population of the Finnish prostate cancer screening trial consists of men born during the period from 1929 through 1944 who reside in the metropolitan areas of Helsinki or Tampere, Finland. During the first 3 years of the study (1996–1998), 60 211 men aged 55–67 years were identified from the Population Registry of Finland. Information on prostate cancers was obtained through a record linkage with the Finnish Cancer Registry, and men with prevalent prostate cancer were excluded from the study before randomization (n = 238).

Annually, 8000 men were randomly assigned to the screening arm, and the roughly 12 000 men remaining in the target population (a total of 35 973) were randomly assigned to the control arm. Men in the screening arm were recruited by invitations that were mailed in four batches annually. Men who were deceased, had moved outside the study area, or had prohibited the use of their addresses between randomization and the date of mailing were considered to be ineligible (n = 1268). After written informed consent was obtained from the men, a blood sample was drawn from the men in the screening group. The concentration of PSA in serum was determined with the Tandem-E assay (Hybritech, San Diego, CA) or, in case of equipment malfunction, with another assay calibrated to the Tandem-E assay.

Men with a serum PSA concentration of 4.0 ng/mL or higher were referred to diagnostic examinations. These examinations consisted of digital rectal examination (DRE), transrectal ultrasound, and transrectal prostate biopsy examination.

Men with a PSA concentration of 3.0–3.9 ng/mL were offered a DRE by a urologist. Initially, 119 men with a PSA concentration of 2.0–2.9 ng/mL were also offered a DRE, but this was soon discontinued because of its poor efficiency and high cost. Men with a suspicious DRE finding, however, were referred to the other diagnostic examinations described above.

The positive predictive value (PPV) was estimated as the number of cancers detected among men with defined PSA concentrations, divided by the number of men within the PSA range. The detection rate was calculated as the prevalence of screening-detected cancers, i.e., the number of cancers among men with given criteria, relative to the number of men fulfilling those criteria. Specificity was estimated as the proportion of men with negative screening test results among men without prostate cancer.

The study protocol was approved by an ethical committee in each participating hospital.

Of the 22 732 eligible men in the screening arm, 69% (15 685 men) participated (Table 1Go). The participation rate did not vary substantially by age. The serum PSA concentration was 3.0 ng/mL or greater in 14% (2143 men) of the participants in the screening arm. As expected, the PSA concentration increased with age. At baseline, 10% (1334 of 13 802 men, 1883 with missing information) reported prior PSA screening and 5% (719 of 13 240 men, 2445 with missing information) reported a first-degree relative affected with prostate cancer.


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Table 1. Number of eligible men, participation, and serum prostate-specific antigen (PSA) concentration by age in the Finnish prostate cancer screening trial, 1996–1998
 
The overall detection rate of the screening program was 2.6% (Table 2Go). The detection rates ranged from 1% at 55 years of age to 5% at 67 years of age. The detection rate was 2.1% for cancers of Gleason grades 2–6 and 0.4% for cancers of Gleason grades 7–10. (The Gleason grade was unavailable for seven patients with prostate cancer.)


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Table 2. Cumulative number of men and prostate cancers, specificity (with 95% confidence interval [CI]) and detection rate (with 95% CI) by serum concentration of prostate-specific antigen (PSA) in the Finnish prostate cancer screening trial, 1996–1998
 
The specificity of the PSA test increased rapidly with increasing cutoff level. Of the 1342 men with a PSA concentration of 4.0 ng/mL or greater, 1236 (92%) underwent diagnostic examinations. A total of 386 men with a PSA concentration of 4.0 ng/mL or greater were diagnosed with prostate cancer. The detection rate attributable to a PSA concentration of 4.0 ng/mL or greater was 2.5%, and the specificity was 93%. A PSA cutoff point of 10 ng/mL gave a higher specificity (99%), but the detection rate was only 0.9%. The PPV was 22% for the PSA range of 4.0–9.9 ng/mL and 62% for a PSA concentration of 10 ng/mL or higher. A DRE was offered to 801 men with a PSA concentration of 3.0–3.9 ng/mL, 92% (733) of them complied, and 22 cancers were detected. This practice contributed modestly to the detection rate (0.1%) and lowered specificity (from 93% to 88%).

The Finnish prostate cancer screening trial is population based. Hence, the results are generalizable to screening as a public health policy, unlike results from volunteer-based efficacy trials. The high participation rate (69%) indicates that, in Finland, prostate cancer screening will be feasible, if it is found to be effective. At baseline, opportunistic screening was relatively low in Finland and does not seem to jeopardize the trial.

Specificity determines the costs and acceptability of a prostate cancer screening program. To increase specificity, we used a screening algorithm with a relatively high PSA cutoff point and few auxiliary interventions. Specificity and PPV increased rapidly with increasing concentrations of serum PSA, indicating less harm and lower costs per screen-detected cancer at higher cutoff levels. We found a PPV for serum PSA concentrations of 4.0 ng/mL or greater of 29%, i.e., 3.5 biopsy examinations per cancer. Lowering the PSA cutoff point to 3 ng/mL and abandoning the DRE would have increased referral to diagnostic examinations by 5%, in addition to the 9% of men with a PSA concentration of 4 ng/mL or greater.

The detection rate for cancers of Gleason grades 7–10 was 0.4%, which indicates that the screening program also is able to detect clinically significant cancers. However, information on interval cancer incidence and the detection rate at a second screening round are required for assessment of overdiagnosis and sensitivity.

In summary, the Finnish prostate cancer screening trial demonstrates that screening is acceptable for the target population, the performance of the screening test is adequate, and the detection rate of aggressive, potentially lethal cancer is reasonable. These results pertaining to intermediate indicators provide necessary, but not sufficient, indication for the effectiveness of prostate cancer screening.

NOTES

Supported by the Academy of Finland, the Cancer Society of Finland, the Helsingin Sanomat Centenarian Foundation, the Tampere University Hospital Research Fund, the Finnish Cultural Fund, the Hybritech Corporation, and the Europe Against Cancer Program.

We are grateful to the Pirkanmaa Cancer Society (Tampere, Finland) and the Aleksi Medical Center (Helsinki, Finland) for drawing the blood samples for the study, to Mr. Jarkko Koivuniemi for programming, and to Ms. Minna Heikkilä for data management.

REFERENCES

1 The International Prostate Screening Trial Evaluation Group. Rationale for randomised trials of prostate cancer screening. Eur J Cancer 1999;35:262–71.[Medline]

2 Auvinen A, Rietbergen JB, Denis LJ, Schroder FH, Prorok PC. Prospective evaluation plan for randomised trials of prostate cancer screening. The International Prostate Cancer Screening Trial Evaluation Group. J Med Screen 1996;3:97–104.[Medline]

3 Maattanen L, Auvinen A, Stenman UH, Rannikko S, Tammela T, Aro J, et al. European randomized study of prostate cancer screening: first-year results of the Finnish trial. Br J Cancer 1999;79:1210–4.[Medline]

Manuscript received September 18, 2000; revised November 8, 2000; accepted January 23, 2001.


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