Matti Hakama

Routine cervical screening with primary HPV testing and cytology triage protocol in a randomised setting.

The role of high-risk human papillomavirus (hrHPV) testing in primary cervical screening has not been established. We generated a randomised evaluation design ultimately to clarify whether primary hrHPV testing implemented into routine screening can bring increase in the programme effectiveness. The aim of the present report on first-year results was to assess the cross-sectional relative validity parameters for routine hrHPV screening, in comparison with conventional screening. An equal number of women invited to routine screening was randomly allocated to primary hrHPV screening (n=7060) and to cytological screening (n=7089). In the hrHPV screening arm, after a single positive hrHPV test result, the need of colposcopy referral was determined by a cytological triage test. Compared with the conventional arm, more colposcopy referrals were made in the hrHPV screening arm (relative risk 1.51, confidence interval 95% 1.03–2.22). Specificity of the primary screening with sole hrHPV test (91.5–92.1%) was much lower than that with the cytology triage (98.7–99.3%), which was not quite as specific as screening with conventional cytology (99.2–99.6%). Compared with conventional cytology, primary screening with hrHPV test results in increased cross-sectional relative sensitivity at the level of all positive lesions at the cost of substantial loss in specificity. With cytology triage, the specificity improves to the level of conventional cytology.

European randomized study of prostate cancer screening: first-year results of the Finnish trial.

SummaryApproximately 20 000 men 55–67 years of age from two areas in Finland were identified from the Population Registry and randomized either to the screening arm (1/3) or the control arm (2/3) of a prostate cancer screening trial. In the first round, the participation rate in the screening arm was 69%. Of the 5053 screened participants, 428 (8.5%) had a serum prostate-specific antigen (PSA) concentration of 4.0 ng/ml or higher, and diagnostic examinations were performed on 399 of them. A total of 106 cancers were detected among them corresponding to a positive predictive value of 27%, which is comparable with mammography screening for breast cancer. The prostate cancer detection rate based on a serum PSA concentration of 4.0 ng ml–1 or higher was 2.1%. Approximately nine out of ten screen-detected prostate cancers were localized (85% clinical stage T1–T2) and well or moderately differentiated (42% World Health Organization (WHO) grade I and 50% grade II), which suggests a higher proportion of curable cancers compared with cases detected by other means.

A randomized trial of choice of treatment in prostate cancer: the effect of intervention on the treatment chosen

To determine whether different approaches in the choice of treatment affect the treatment chosen by the patient for prostate cancer.

Smoking and risk of colorectal cancer

Tobacco smoking was studied in relation to colorectal cancer in 56 973 Finnish men and women initially free from cancer. Smoking status was determined by a health questionnaire. During a follow-up period of 28 years, from the baseline in 1966-72 to the end of 1994, 457 cases of colorectal cancer occurred. There was no significant association between baseline smoking status and colorectal cancer risk over the total follow-up period. The sex- and age-adjusted relative risk of colorectal cancer between smokers and non-smokers was 1.06 (95% confidence interval 0.84-1.33). For follow-up periods of 11-20 years, however, the relative risk was 1.57 (95% confidence interval 1.09-2.24). In a subgroup in which smoking habits were assessed twice, the relative risk of colorectal cancer among persistent smokers was 1.71 (95% confidence interval 1.09-2.68) compared with others. The results of the present prospective study are consistent with the possibility that smoking increases the risk of colorectal cancer after a relatively long induction period. To clarify the role of smoking in colorectal cancer development, further cohort studies are needed with long follow-up periods and allowing for control of dietary and other potential confounding factors.

VALIDITY OF THE PROSTATE SPECIFIC ANTIGEN TEST FOR PROSTATE CANCER SCREENING: FOLLOWUP STUDY WITH A BANK OF 21,000 SERA IN FINLAND

PURPOSE We investigate the validity of prostate specific antigen (PSA) as a screening test for prostate cancer. MATERIALS AND METHODS A registry of serum samples drawn from 1968 to 1976 from 21,387 men was linked to the Finnish Cancer Registry. During followup from 1968 to 1991, 104 prostate cancers were identified. A matched case control design with incidence density sampling and nested in the serum sample bank was applied, and PSA was assessed. RESULTS The estimated sensitivity of the test was 44% and specificity 94% at a cutoff of 4.0 microg./l. in the total material. The sensitivity had improved to 86% in patients diagnosed in 5 years after the sample drawing. The test had a better sensitivity (93%) and specificity (96%) in men younger than 65 years at the time of the sample drawing compared to those older. The sensitivity further improved to 100% with a cutoff of 2.5 microg./l. CONCLUSIONS PSA is a valid screening test for prostate cancer, which compares favorably with mammography for breast cancer. However, until an effect on mortality has been shown, routine screening cannot be recommended.

Detection rates of precancerous and cancerous cervical lesions within one screening round of primary human papillomavirus DNA testing: prospective randomised trial in Finland

Objective To compare the detection rates of precancerous and cancerous cervical lesions by human papillomavirus (HPV) DNA testing and by conventional cytology screening. Design Prospective randomised trial. Two cohorts were followed over one screening round of five years, screened initially by primary HPV DNA testing or by primary Pap test. Setting Population based programme for cervical cancer screening in Finland. Participants Women aged 25-65 years invited for screening in 2003-07 (101 678 in HPV arm; 101 747 in conventional cytology arm). Intervention Women were randomly allocated (1:1) to primary HPV DNA screening followed by cytology triage if they had positive results, or to primary cytology screening. Screening method was disclosed at the screening visit. Trial personnel involved were aware of all test results. Main outcome measures Cumulative detection rates of cervical intraepithelial neoplasia (CIN), adenocarcinoma in situ (AIS), and invasive cervical cancer before the second screening (after five years) or before 31 December 2008. Lesions detected at screening and during the five year interval were included. Results 1010 and 701 precancerous or cancerous lesions were detected during an average follow-up of 3.6 years in the HPV and cytology arms, respectively. Among invited women, the hazard ratio was 1.53 (95% confidence interval l.28 to 1.84) for CIN grade 1, 1.54 (1.33 to 1.78) for CIN 2, 1.32 (1.09 to 1.59) for CIN 3 or AIS, and 0.81 (0.48 to 1.37) for cervical cancer. In 25-34 year old participants, the cumulative hazard (or cumulative detection rate) was 0.0057 (0.0045 to 0.0072) for HPV screening versus 0.0046 (0.0035 to 0.0059) for conventional screening; corresponding data for women aged 35 years and older were 0.0022 (0.0019 to 0.0026) and 0.0017 (0.0014 to 0.0021), respectively. Conclusions Primary HPV DNA screening detects more cervical lesions than primary cytology within one screening round of five years. Even if the detection rate of CIN 3 or AIS increased in the HPV arm in both age groups, the absolute difference in cumulative rates in women aged 35 years or older was small. By carefully selecting age groups and screening intervals, HPV screening could increase the overall detection rate of cervical precancerous lesions only slightly. However, these findings should be interpreted in the context of the high level of opportunistic screening that occurs in Finland. Trial registration International Standard Randomised Controlled Trial ISRCTN23885553.

Cardiovascular drug use and the incidence of erectile dysfunction

It is unclear whether high blood pressure per se or antihypertensive drug use causes erectile dysfunction (ED). The aim of this study was to investigate the effect of cardiovascular diseases and their concomitant medications use on the incidence of ED. The target population consisted of men aged 55, 65 or 75 years old residing in the study area in Finland in 1999. Questionnaires were mailed to 2837 men in 1999 and to 2510 of them 5 years later. The follow-up sample consisted of 1665 men (66% of those eligible) who responded to both baseline and follow-up questionnaires. Men free of moderate or severe ED at baseline (N=1000) were included in the study. ED was assessed by two questions on subject ability to achieve or maintain an erection sufficient for intercourse. Poisson regression model was used in the multivariable analyses. The risk of ED was higher in men suffering from treated hypertension or heart disease than in those with the untreated condition. The risk of ED was higher in men using calcium channel inhibitor (adjusted relative risk (RR)=1.6, 95% confidence interval (CI) 1.0–2.4), angiotensin II antagonist (RR=2.2, 95% CI 1.0–4.7), non-selective β-blocker (RR=1.7, 95% CI 0.9–3.2) or diuretic (RR=1.3, CI 0.7–2.4) compared with non-users. ED was not associated with using organic nitrates, angiotensin-converting enzyme inhibitors, selective β-blockers and serum lipid-lowering agents. In summary, calcium channel inhibitors, angiotensin II antagonists, non-selective β-blockers and diuretics may increase the risk of ED.

The HPV test has similar sensitivity but more overdiagnosis than the Pap test—A randomised health services study on cervical cancer screening in Finland

We compared test sensitivity (in terms of prevented cancers) and overdiagnosis (in terms of non‐progressive pre‐invasive lesions) between the human papillomavirus test (HPV test, Hybrid Capture 2) and the traditional Pap test in routine screening for cervical cancer. The design was a randomised (1:1) health services study in Finland with intake between 2003 and 2007. We estimated sensitivity by the incidence method within one screening round. Overdiagnosis was based on the rate of cervical intraepithelial Grade 3 (CIN3) lesions diagnosed at screen and during the following interval. Out of 203,788 randomised women 132,298 attended (65% in both study arms) and 600,753 person‐years accumulated among attenders up to the end of 2010. In all attenders, 34 invasive cervical cancers and 288 CIN3 lesions were diagnosed at screen or during the following interval. The interval cancer incidence was 2.5/105 person‐years (sensitivity 0.87) and 1.4 (sensitivity 0.93) in the HPV arm and Pap test arm, respectively. The rate of CIN3 lesions was 57.1 and 38.8, respectively. In conclusion, sensitivity of HPV testing was similar to that of Pap testing but caused more overdiagnosis. Therefore, implementation of HPV testing needs to be reconsidered especially in countries with well organised programmes.

Prostate cancer screening within a prostate specific antigen range of 3 to 3.9 ng./ml.: a comparison of digital rectal examination and free prostate specific antigen as supplemental screening tests.

PURPOSE Performing biopsy in all men with a serum prostate specific antigen (PSA) of 3 to 3.9 ng./ml. increases the sensitivity of prostate cancer screening compared with a PSA cutoff of 4 ng./ml. but decreases specificity and may contribute to over diagnosis. Therefore, we evaluated the detection rate and specificity attributable to digital rectal examination and percent free PSA within the PSA range of 3 to 3.9 ng./ml. MATERIALS AND METHODS Serum PSA was determined in 20,716 participants in the Finnish population based screening trial. Supplementary digital rectal examination was offered to men with a PSA of 3 to 3.9 ng./ml. during 1996 to 1998 (protocol 1). Those with a suspicious digital rectal examination finding were referred for biopsy. The screening algorithm was modified by substituting percent free PSA for digital rectal examination with a cutoff of 16% as a biopsy criterion in 1999 (protocol 2). In addition, biopsies were performed in all men with PSA 4 ng./ml. or greater. RESULTS A total of 23 cancers (2.9%) were detected by digital rectal examination among 801 men, while percent-free PSA resulted in the diagnosis of 13 cases (4.8%) among 270 men with a PSA of 3 to 3.9 ng./ml. The detection rate of tumors with a Gleason score of 5 or greater increased from 1.6% (13 of 801 cases) to 4.4% (12 of 270) in the modified screening program. The PSA cutoff of 3 ng./ml. alone showed 88.6% and 87.5% specificity in protocols 1 and 2 but specificity increased to 93.3% and 91.7% using digital rectal examination and percent free PSA, respectively. CONCLUSIONS Using percent free PSA increased the detection rate of aggressive disease compared with digital rectal examination and provided higher specificity than PSA alone.

Risk of Breast Cancer and Changes in Mammographic Parenchymal Patterns Over Time

The relationship between sequential mammographic parenchymal patterns and breast cancer was estimated and the results were applied to selective screening. In a pilot screening program 4163 Finnish women aged 40-47 years at entry were invited to be screened every second year from 1982 to 1990. Mammographic parenchymal patterns (Wolfes classification) were recorded at each screening round. The follow-up ended in 1993 and up until that time 68 new breast cancers were diagnosed. The age-adjusted relative risk of breast cancer was 2.5 (95% CI 1.5-4.0) among women with high-risk mammographic parenchymal patterns (P2,DY) at the screenings preceding cancer diagnosis compared with those with low-risk patterns (N1,P1). After further adjustment for body mass index, number of pregnancies and size of the breast, the relative risk increased to 2.8 (95% CI 1.7-4.9). The mammographic parenchymal pattern is an independent risk factor of breast cancer but not strong enough to be used as a criterion for selective screening.