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Arbyn M.,Scientific Institute of Public Health | Ronco G.,Centro per la prevenzione Oncologica | Anttila A.,Mass Screening Registry | M. Meijer C.J.,VU University Amsterdam | And 6 more authors.
Vaccine | Year: 2012

More than ever, clinicians need regularly updated reviews given the continuously increasing amount of new information regarding innovative cervical cancer prevention methods. A summary is given from recent meta-analyses and systematic reviews on 3 possible clinical applications of human papillomavirus (HPV) testing: triage of women with equivocal or low-grade cytologic abnormalities; prediction of the therapeutic outcome after treatment of cervical intraepithelial neoplasia (CIN) lesions, and last not but not least, primary screening for cervical cancer and pre-cancer. Consistent evidence is available indicating that HPV-triage with the Hybrid Capture® 2 assay (Qiagen Gaithersburg, Inc., MD, USA [previously Digene Corp.] (HC2) is more accurate (higher sensitivity, similar specificity) than repeat cytology to triage women with equivocal Pap smear results. Several other tests show at least similar accuracy but mRNA testing with the APTIMA® (Gen-Probe Inc., San Diego, CA, USA) test is similarly sensitive but more specific compared to HC2. In triage of low-grade squamous intraepithelial lesions (LSIL), HC2 is more sensitive but its specificity is substantially lower compared to repeat cytology. The APTIMA® test is more specific than HC2 without showing a loss in sensitivity. Identification of DNA of HPV types 16 and/or 18, or RNA from the five most carcinogenic HPV types allow selecting women at highest risk for CIN3+ but the sensitivity and negative predictive value of these markers are lower than full-range high-risk HPV (hrHPV) testing. After conservative treatment of cervical pre-cancer, HPV testing picks up more quickly, with higher sensitivity and not lower specificity, residual or recurrent high-grade CIN than follow-up cytology. Primary screening for hrHPV generally detects more CIN2, CIN3 or cancer compared to cytology at cut-off atypical squamous cells of undetermined significance (ASC-US) or LSIL, but is less specific. Combined HPV and cytology screening provides a further small gain in sensitivity at the expense of a considerable loss in specificity if positive by either test is referred to colposcopy, in comparison with HPV testing only. Randomised trials and follow-up of cohort studies consistently demonstrate a significantly lower cumulative incidence of CIN3+ and even of cancer, in women aged 30 years or older, who were at enrollment hrHPV DNA negative compared to those who were cytologically negative. The difference in cumulative risk of CIN3+ or cancer for double negative (cytology & HPV) versus only HPV-negative women is small. HC2, GP5+/6+ PCR (polymerase chain reaction), cobas® 4800 PCR (Roche Molecular Systems Inc., Alameda, CA, USA) and Real Time PCR (Abbott Molecular, Des Plaines, IL, USA) can be considered as clinically validated for use in primary screening. The loss in specificity associated with primary HPV-based screening can be compensated by appropriate algorithms involving reflex cytology and/or HPV genotyping for HPV16 or 18. There exists a substantial evidence base to support that HPV testing is advantageous both in triage of women with equivocal abnormal cytology, in surveillance after treatment of CIN lesions and in primary screening of women aged 30 years or older. However, the possible advantages offered by HPV-based screening require a well organised program with good compliance with screening and triage policies. © 2012 Marc Arbyn.


Anttila A.,Mass Screening Registry | Pokhrel A.,Finnish Cancer Registry | Kotaniemi-Talonen L.,Mass Screening Registry | Hakama M.,Mass Screening Registry | And 4 more authors.
International Journal of Cancer | Year: 2011

The purpose was to evaluate alternative cytological screening methods in population-based screening for cervical cancer up to cancer incidence and mortality outcome. Automation-assisted screening was compared to conventional cytological screening in a randomized design. The study was based on follow-up of 503,391 women invited in the Finnish cervical cancer screening program during 1999-2003. The endpoints were incident cervical cancer, severe intraepithelial neoplasia and deaths from cervical cancer. One third of the women had been randomly allocated to automation-assisted screening and two thirds to conventional cytology. Information on cervical cancer and severe neoplasia were obtained through 1999-2007 from a linkage between screening and cancer registry files. There were altogether 3.2 million woman-years at risk, and the average follow-up time was 6.3 years. There was no difference in the risk of cervical cancer between the automation-assisted and conventional screening methods; the relative risk (RR) of cervical cancer between the study and control arm was 1.00 (95% confidence interval [CI] = 0.76-1.29) among all invited and 1.08 (95% CI = 0.76-1.51) among women who were test negative at entry. Comparing women who were test negative with nonscreened, RR of cervical cancer incidence was 0.26, 95% CI = 0.19-0.36 and of mortality 0.24 (0.13-0.43). Both methods were valid for screening. Because cervical cancer is rare in our country, we cannot rule out small differences between methods. Evidence on alternative methods for cervical cancer screening is increasing and it is thus feasible to evaluate new methods in large-scale population-based screening programs up to cancer outcome. © 2010 UICC.


Virtanen A.,Mass Screening Registry | Nieminen P.,University of Helsinki | Niironen M.,Mass Screening Registry | Luostarinen T.,Finnish Cancer Registry | Anttila A.,Mass Screening Registry
Gynecologic Oncology | Year: 2014

Objective. High coverage and attendance is essential to positive cervical cancer screening results. Offering self-sampling for HPV-testing to the non-attendees of the program may improve attendance rates. Information on women's perceptions and experiences with self-sampling (acceptability) is needed to further optimize attendance by this method. Methods. A questionnaire study focusing on women's experiences on the screening method was embedded in a trial investigating the effects and feasibility of self-sampling among non-attendees of cervical screening in 31 Finnish municipalities in 2011-2012 (n = 4688). Reasons for non-attendance in routine screening were also surveyed. Results. Response rate to the questionnaire was 98.8% (909/920) among women who performed self-sampling. Self-sampling participants reported mainly good experiences. Negative experiences (difficulties in sample taking, pain, fear, anxiety, insecurity) were reported rarely, but more commonly among women with a mother tongue other than Finnish or Swedish (immigrants). Most common reason for non-attendance in routine screening was a recent Pap-smear elsewhere (opportunistic screening). Practical reasons (pregnancy, scheduling difficulties) were reported by 42%, emotional or attitudinal reasons by 17%, and 16% forgot to take part. Response yield to questionnaire was unsatisfactory among those women who declined the self-sampling option. Conclusions. Optimizing the practical aspects of screening and offering a self-sampling option to non-attendees can help to overcome a large variety of both practical and emotional barriers to traditional screening. More research is needed among the non-attendees to routine screening who decline also the self-sampling option. © 2014 Elsevier Inc. All rights reserved.


Booth N.,University of Tampere | Rissanen P.,University of Tampere | Tammela T.L.J.,University of Tampere | Maattanen L.,Mass Screening Registry | And 2 more authors.
European Urology | Year: 2014

Background: Evidence of the potential impact of systematic screening for prostate cancer (PCa) on health-related quality of life (HRQoL) at a population-based level is currently scarce. Objective: This study aims to quantify the long-term HRQoL impact associated with screening for PCa. Design, setting, and participants: Postal questionnaire surveys were conducted in 1998, 2000, 2004, and 2011 among men in the Finnish PCa screening trial diagnosed with PCa (total n = 7011) and among a random subsample of the trial population (n = 2200). In 2011, for example, 1587 responses were received from men with PCa in the screening arm and 1706 from men in the control arm. In addition, from the trial subsample, 549 men in the screening arm and 539 in the control arm provided responses. Outcome measurements and statistical analysis: Health-state-value scores were compared between the intervention and control arms using three distinct HRQoL measures (15D, EQ-5D, and SF-6D), and statistical significance was assessed using t tests. In addition, differences over repeated assessments of HRQoL between groups were evaluated using generalised estimating equations. Results and limitations: In the 2011 survey, a small but statistically significant difference emerged between the trial arms among men diagnosed with PCa (mean scores, screening vs control arm: 15D: 0.872 vs 0.866, p = 0.14; EQ-5D: 0.852 vs 0.831, p = 0.03; and SF-6D: 0.763 vs 0.756, p = 0.06). Such differences in favour of the screening arm were not found among the sample of men from the trial (15D: 0.889 vs 0.892, p = 0.62; EQ-5D: 0.831 vs 0.852, p = 0.08; and SF-6D: 0.775 vs 0.777, p = 0.88). The slight advantage with screening among men with PCa was reasonably consistent across time in the longitudinal analysis and was strongest among men with early-stage disease. Conclusions: These results show some long-term HRQoL benefit from screening for men with PCa but suggest little impact overall in the trial population. © 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.


Kalliala I.,Mass Screening Registry | Dyba T.,Mass Screening Registry | Nieminen P.,University of Helsinki | Hakulinen T.,Mass Screening Registry | Anttila A.,Mass Screening Registry
International Journal of Cancer | Year: 2010

After treatment of the cervical intraepithelial neoplasia (CIN) cervical cancer incidence remains elevated at least for 20 years. Whether the overall or cervical cancer mortality after treatment of CIN is elevated is unknown. The aim of this study was to determine the long-term survival and cause-specific mortality among women treated for CIN. The study population consisted of 7,104 women treated for CIN between 1974 and 2001 and 35,437 individually matched controls. The follow-up of mortality was based on nationwide registries and closed at death, emigration or December 31, 2005. The possible differences in mortality were assessed using Cox proportional hazard model. With follow-up time of approximately 630,000 woman-years, overall 2,781 deaths were observed, 530 among women treated for CIN and 2,251 among reference population (HR 1.1, 95% CI 1.0-1.3). Mortality from any cancer (HR 1.4, 95% CI 1.2-1.7), lung cancer (HR 2.7, 95% CI 1.8-4.1) and HPV-related anogenital cancer (HR 3.1, 95% CI 1.1-8.6) was higher among CIN patients, but mortality from cervical cancer was not (HR 1.0, 95% CI 0.3-4.0). Elevated cervical cancer incidence after treatment of CIN, documented earlier, did not predict elevation in cervical cancer mortality. This suggests high effectiveness of CIN management. Most of the excess mortality observed among CIN patients was due to increased risk of other cancers. These long-term mortality patterns should be considered when planning and evaluating the management of CIN lesions and related cervical or other cancer prevention activity. © 2009 UICC.


Virtanen A.,Mass Screening Registry | Anttila A.,Mass Screening Registry | Luostarinen T.,Mass Screening Registry | Nieminen P.,University of Helsinki
International Journal of Cancer | Year: 2011

Optimizing attendance and coverage of organized screening is needed to reduce cervical cancer incidence to previous lower levels. In our study, all nonparticipants in organized cervical cancer screening in 2008 in Espoo, Finland were randomized to receive a self-sampling kit (1,130 women) or a reminder letter (3,030 women). Effects on screening coverage were assessed according to the self-reported previous Pap smear history of the participants. Participation rate in the self-sampling arm, 29.8%, was significantly higher than in the reminder letter arm, 26.2% (adjusted relative risk for participation 1.13). Total participation in Espoo in 2008 rose significantly after the two interventions from 64.0 to 75.4%. In both arms, ∼ 20% of the participants after second intervention could be considered under screened (previous Pap smear ≥5 years ago) and thus increased screening coverage. Respectively, for 70-75%, the second intervention only provided overscreening. Participation was lowest among young age groups and immigrants, after primary invitation and after interventions. Our study shows that a second intervention for nonattendees after the first invitation is needed to optimize the attendance rates. Self-sampling might be slightly more successful in this, but the effects on screening coverage were similar in both groups. © 2010 UICC.


Virtanen A.,Mass Screening Registry | Anttila A.,Mass Screening Registry | Nieminen P.,University of Helsinki
BMC Women's Health | Year: 2015

Background: Offering self-sampling to non-attendees of cervical screening increases screening attendance. Methods: We used observations from two Finnish studies on the use of self-sampling among the non-attendees to estimate in a hypothetical screening population of 100,000 women the possible costs per extra screened woman and costs per extra detected and treated CIN2+ with three intervention strategies; 1) a primary invitation and a reminder letter, 2) a primary invitation and a mailed self-sampling kit and 3) two invitation letters and a self-sampling kit. The program costs were derived from actual performance and costs in the original studies and a national estimate on management costs of HPV related diseases. Results: The price per extra participant and price per detected and treated CIN2+ lesion was lower with a reminder letter than by self-sampling as a first reminder. When self-sampling was used as a second reminder with a low sampler price and a triage Pap-smear as a follow-up test for HPV-positive women instead of direct colposcopy referral, the eradication of a CIN2+ lesion by self-sampling was not more expensive than in routine screening, and the addition of two reminders to the invitation protocol did not increase the price of an treated CIN2+ lesion in the entire screened population. Conclusions: As a first reminder, a reminder letter is most likely a better choice. As second reminder, the higher costs of self-sampling might be compensated by the higher prevalence of CIN2+ in the originally non-attending population. © 2015 Virtanen et al.


Virtanen A.,Mass Screening Registry | Nieminen P.,University of Helsinki | Luostarinen T.,Mass Screening Registry | Anttila A.,Mass Screening Registry
Cancer Epidemiology Biomarkers and Prevention | Year: 2011

Background: Attendance in screening is an important determinant of cervical cancer. Previous experience on high-risk human papillomavirus (hrHPV) DNA testing on patient-obtained samples suggests a good effect among nonattendees of screening. We assessed the effects of self-sampling on attendance in the Finnish screening program. Methods: Nonattendees after the primary invitation in one municipality (Espoo) were randomized to receive either a self-sampling kit (2,397 women) or an extra invitation (6,302 women). One fourth (1,315 women) of reminder letter arm nonattendees also received a self-sampling kit as a third intervention. Main outcomes were increases in screening attendance and coverage. Results: The adjusted relative risk for participation by self-sampling as a second intervention in comparison to a reminder letter arm was 1.21 (95% CI: 1.13-1.30). Total attendance increased from 65% to 76% by self-sampling and from 65% to 74% with a reminder letter. Combining the interventions (reminder letter and then self-sampling) increased total attendance from 63% to 78%. One fifth of the participants in all three groups increased screening coverage (previous Pap smear ≥5 years ago or never). Self-obtained samples were more often HPV positive than provider-obtained ones (participants after primary invitation and reminder letter), 12% to 13% versus 7%. Conclusions: Self-sampling is a feasible option in enhancing the attendance at organized screening, particularly as an addition to a reminder letter. Impact: If self-sampling is used as a third intervention after two written invitations, the overall attendance in Finland could most likely reach the desired 80% to 85%. ©2011 AACR.


Singh D.,University of Tampere | Malila N.,University of Tampere | Pokhrel A.,Mass Screening Registry | Anttila A.,Mass Screening Registry
International Journal of Cancer | Year: 2015

The study purpose was to assess association of symptoms at screening visits with detection of breast cancer among women aged 50-69 years during the period 2006-2010. Altogether 1.2 million screening visits were made and symptoms (lump, retraction, secretion etc.) were reported either by women or radiographer. Breast cancer risk was calculated for each symptom separately using logistic regression [odds ratio (OR)] and 95% confidence intervals (CIs). Of the 1,198,410 screening visits symptoms were reported in 298,220 (25%) visits. Breast cancer detection rate for women with and without symptoms was 7.8 per 1,000 and 4.7 per 1,000 screening visits, respectively, whereas lump detected 32 cancers per 1,000 screens. Women with lump or retraction had an increased risk of breast cancer, OR = 6.47, 95% CI 5.89-7.09 and OR = 2.19, 95% CI 1.92-2.49, respectively. The sensitivity of symptoms in detecting breast carcinoma was 35.5% overall. Individual symptoms sensitivity and specificity ranged from, 0.66 to 14.8% and 87.4 to 99.7%, respectively. Of 5,541 invasive breast cancers, 1,993 (36%) reported symptoms at screen. Breast cancer risk among women with lump or retraction was higher in large size tumors (OR = 9.20, 95% CI 8.08-10.5) with poorly differentiated grades (OR = 5.91, 95% CI 5.03-6.94) and regional lymph nodes involvement (OR = 6.47, 95% CI 5.67-7.38). This study was done in a setting where breast tumors size is generally small, and symptoms sensitivity and specificity in diagnosing breast tumors were limited. Importance of breast cancer symptoms in the cancer prevention and control strategy needs to be evaluated also in other settings. © 2014 The Authors. Published by Wiley Periodicals Inc. on behalf of UICC.


Arbyn M.,Scientific Institute of Public Health | Anttila A.,Mass Screening Registry | Jordan J.,Birmingham Womens Hospital | Ronco G.,Cancer Epidemiology Unit | And 5 more authors.
Annals of Oncology | Year: 2010

European Guidelines for Quality Assurance in Cervical Cancer Screening have been initiated in the Europe Against Cancer Programme. The first edition established the principles of organised population-based screening and stimulated numerous pilot projects. The second multidisciplinary edition was published in 2008 and comprises ~250 pages divided into seven chapters prepared by 48 authors and contributors. Considerable attention has been devoted to organised, population-based programme policies which minimise adverse effects and maximise benefits of screening. It is hoped that this expanded guidelines edition will have a greater impact on countries in which screening programmes are still lacking and in which opportunistic screening has been preferred in the past. Other methodological aspects such as future prospects of human papillomavirus testing and vaccination in cervical cancer control have also been examined in the second edition; recommendations for integration of the latter technologies into European guidelines are currently under development in a related project supported by the European Union Health Programme. An overview of the fundamental points and principles that should support any quality-assured screening programme and key performance indicators are presented here in a summary document of the second guidelines edition in order to make these principles and standards known to a wider scientific community. © The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

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