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Introduction: We report head-to-head comparison of the bivalent and quadrivalent HPV vaccine efficacies against immediate precursors of cervical cancer from 15 years' country-wide cancer registry follow-up of phase III trial cohorts and an age-aligned cohort of unvaccinated women., Methods: These individually and/or clusterrandomized cohorts of HPV6/11/16/18- and HPV16/18-vaccinated and unvaccinated women were enrolled, respectively, in 2002, 2004, and 2003/2005. The trial cohorts comprised initially 16- to 17-year-old HPV6/11/16/18-vaccinated FUTURE II (NCT00092534) participants (866) and HPV16/18-vaccinated PATRICIA (NCT00122681) and 012 trial (NCT00169494) participants (2,465), and 16,526 initially 16- to 19-year-old unvaccinated controls. After active 4-year clinical follow-up, passive, country-wide Finnish Cancer Registry (FCR) follow-up for cervical intraepithelial neoplasia grade 3 (CIN3) and adenocarcinoma in situ (AIS) was based on consented use of unique personal identifiers and started 6 months after the end of the FUTURE II and PATRICIA trials in 2007 and 2009, and ended at the end of 2019. The follow-up with altogether 229,020 follow-up years was age-aligned to ensure that similarly aged cohorts were passively followed up for 15 years post=vaccination for the intention-to-treat analyses of vaccine efficacy., Results: Overall, we identified 5 and 16 CIN3 (no AIS) cases in the HPV6/11/16/18 and HPV16/18 cohorts, respectively, during the FCR-based follow-up. In the unvaccinated cohort, we identified 281 CIN3 cases, 20 AIS cases, and 13 cases with invasive cervical cancer. Vaccine efficacies against CIN3+ were 68.4% and 64.5% for the quadrivalent and the bivalent vaccines, respectively, with overlapping confidence intervals., Discussion: Long-term follow-up of randomized, initially adolescent HPV-vaccinated and unvaccinated cohorts shows, in this head-to-head setting, that the bivalent and quadrivalent HPV vaccines are equally effective against immediate precursors of cervical cancer., Competing Interests: DA, JD, ML, and JPaa have received grants for their HPV vaccination studies from Merck&Co. Inc. DA, JD, ML, and JPaa and GSK Biologicals DA, ML, JPaa. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lehtinen, Gray, Luostarinen, Eriksson, Apter, Bly, Harjula, Heikkilä, Hokkanen, Kuortti, Nieminen, Nummela, Paavonen, Palmroth, Petäjä, Pimenoff, Pukkala and Dillner.)

Background: Human papillomavirus (HPV) vaccination protects against HPV, a necessary risk factor for cervical cancer. We now report results from population-based follow-up of randomised cohorts that vaccination provides HPV-type-specific protection against invasive cancer., Methods: Individually and/or cluster randomised cohorts of HPV-vaccinated and non-vaccinated women were enrolled in 2002-2005. HPV vaccine cohorts comprised originally 16-17 year-old HPV 16/18-vaccinated PATRICIA (NCT00122681) and 012 trial (NCT00169494) participants (2465) and HPV6/11/16/18-vaccinated FUTURE II (NCT00092534) participants (866). Altogether, 3341 vaccines were followed by the Finnish Cancer Registry in the same way as 16 526 non-HPV-vaccinated controls. The control cohort stemmed from 15 665 originally 18-19 years-old women enrolled in 2003 (6499) or 2005 (9166) and 861 placebo recipients of the FUTURE II trial. The follow-up started 6 months after the clinical trials in 2007 and 2009 and ended in 2019. It was age aligned for the cohorts., Findings: During a follow-up time of up to 11 years, we identified 17 HPV-positive invasive cancer cases (14 cervical cancers, 1 vaginal cancer, 1 vulvar cancer and 1 tongue cancer) in the non-HPV-vaccinated cohorts and no cases in the HPV-vaccinated cohorts. HPV typing of diagnostic tumour blocks found HPV16 in nine cervical cancer cases, HPV18, HPV33 and HPV52 each in two cases and HPV45 in one cervical cancer case. The vaginal, vulvar and tongue cancer cases were, respectively, positive for HPV16, HPV52/66 and HPV213. Intention-to-treat vaccine efficacy against all HPV-positive cancers was 100% (95% CI 2 to 100, p<0.05)., Interpretation: Vaccination is effective against invasive HPV-positive cancer., Trial Registration Number: NCT00122681, Post-results; NCT00169494, Post-results; NCT00092534, Post-results., Competing Interests: Competing interests: We declare that ML, DA, JD and JPaa have received grants from Merck & Co. Inc. and/or from the GSK group of companies through their respective employers. GSK Biologicals SA was provided the opportunity to review this manuscript but the authors are solely responsible for final content and interpretation., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: We conducted a community-randomized trial (NCTBLINDED) in Finland to assess gender-neutral and girls-only vaccination strategies with the AS04-adjuvanted human papillomavirus (HPV)-16/18 (AS04-HPV-16/18)vaccine., Methods: Girls and boys (12-15 years) were invited. We randomized 33 communities (1:1:1 ratio): Arm A: 90% of randomly selected girls and boys received AS04-HPV-16/18 vaccine and 10% received hepatitis B vaccine (HBV); Arm B: 90% of randomly selected girls received AS04-HPV-16/18 vaccine, 10% of girls received HBV, and all boys received HBV; Arm C: all participants received HBV. Effectiveness measurements against prevalence of HPV-16/18 cervical infection were estimated in girls at 18.5 years. The main measures were: (1) overall effectiveness comparing Arms A or B, regardless of vaccination status, vs Arm C; (2) total effectiveness comparing AS04-HPV-16/18 vaccinated girls in pooled Arms A/B vs Arm C; (3) indirect effectiveness (herd effect) comparing girls receiving HBV or unvaccinated in Arm A vs Arm C. Co-primary objectives were overall effectiveness following gender-neutral or girls-only vaccination., Results: Of 80,272 adolescents invited, 34,412 were enrolled. Overall effectiveness was 23.8% (95% confidence interval: -19.0, 51.1; P = 0.232) with gender-neutral vaccination. Following girls-only vaccination, overall effectiveness was 49.6% (20.1, 68.2; P = 0.004). Total effectiveness was over 90% regardless of vaccination strategy. No herd effect was found. Immunogenicity of the AS04-HPV-16/18 vaccine was high in both sexes., Conclusions: This study illustrates the difficulty in conducting community randomized trials. It is not plausible that vaccinating boys would reduce overall effectiveness, and the apparent lack of herd effect was unexpected given findings from other studies. This analysis was likely confounded by several factors but confirms the vaccine's high total effectiveness as in clinical trials., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Human papillomavirus (HPV) vaccine is efficacious but the real-life effectiveness of gender-neutral and girls-only vaccination strategies is unknown. We report a community-randomized trial on the protective effectiveness [(PE) = vaccine efficacy (VE) + herd effect (HE)] of the two strategies among females in virtually HPV vaccination naïve population. We randomized 33 Finnish communities into Arm A) gender-neutral vaccination with AS04-adjuvanted HPV16/18 vaccine (11 communities), Arm B) HPV vaccination of girls and hepatitis B-virus (HBV) vaccination of boys (11 communities) or Arm C) gender-neutral HBV vaccination (11 communities). All resident 39,420 females and 40,852 males born 1992-95 were invited in 2007-09. Virtually all (99%) 12- to 15-year-old participating males (11,662) and females (20,513) received three doses resulting in uniform 20-30% male and 50% female vaccination coverage by birth cohort. Four years later (2010-14) 11,396 cervicovaginal samples obtained from 18.5 year-old women were tested for HPV DNA, and prevalence of cervical HPV infections by trial arm and birth cohort was the main outcome measure. VEs against HPV16/18 varied between 89.2% and 95.2% across birth cohorts in arms A and B. The VEs against non-vaccine types consistent with cross-protection were highest in those born 1994-95 for HPV45 (VE A 82.8%; VE B 86.1%) and for HPV31 (VE A 77.6%, VE B 84.6%). The HEs in the non HPV-vaccinated were statistically significant in those born 1994-95 for HPV18 (HE A 51.0%; 95% CI 8.3-73.8, HE B 47.2%; 6.5-70.2) and for HPV31/33 in arm A (HE A 53.7%; 22.1-72.5). For HPV16 and 45 no significant herd effects were detected. PE estimates against HPV16/18 were similar by both strategies (PE A 58.1%; 45.1-69.4; PE B 55.7%; 42.9-66.6). PE estimates against HPV31/33 were higher by the gender-neutral vaccination (PE A 60.5%; 43.6-73.4; PE B 44.5%; 24.9-60.6). In conclusion, while gender-neutral strategy enhanced the effectiveness of HPV vaccination for cross-protected HPV types with low to moderate coverage, high coverage in males appears to be key to providing a substantial public health benefit also to unvaccinated females. Trial registration www.clinicaltrials.gov.com NCT000534638., (© 2017 UICC.)

Objective: Due to long lag time between infection/cancer diagnoses human papillomavirus (HPV) vaccination programs will deliver vaccine efficacy (VE) estimates against cancer end-points late. Cancer registry follow-up of population-based, randomised trial cohorts of vaccinated and unvaccinated women was undertaken for the estimation of VE against cervical intraepithelial neoplasia grade three and invasive cancer (CIN3+)., Methods: We report interim results with 98 561 person years of Finnish Cancer Registry -based follow-up of individually and/or cluster randomised cohorts of HPV-16/18 vaccinated and unvaccinated adolescent women enrolled in June 2003/2005, and between May 2004 and April 2005, respectively. The cohorts comprised 15 627 18- to 19-year-old unvaccinated women (NCT01393470), and 2 401 and 64 16- to 17-year-old HPV-16/18 vaccinated women participating the PATRICIA (NCT00122681) and HPV-012 (NCT00169494) trials, respectively. The age-aligned passive follow-up started 6 months after the clinical trials' end., Results: During the follow-up of 4.5 to 10 years post enrolment we identified 75 cases of cervical intraepithelial neoplasia grade 3 (CIN3) and 4 cases of invasive cervical cancer (ICC) in the unvaccinated cohort, and 4 CIN3 cases in the HPV-16/18 vaccinated women. Diagnostic blocks were available for HPV typing from 87% of the cases. CIN3+ lesions were detectable in 54 cases. HPV16 was found in 26 of 50 unvaccinated CIN3+ cases, and in 3 CIN3+ cases in the HPV-16/18 vaccinated women. The latter were all baseline positive for cervical HPV16 DNA. Baseline data was not available for the unvaccinated women. Intention-to-treat VE against any CIN3+ was 66% (95% CI 8, 88)., Conclusions: Ten years post vaccination the AS04-adjuvanted HPV-16/18 vaccine shows continued efficacy against CIN3+ irrespectively of HPV type. Vaccine efficacy was not observed in baseline HPV16 DNA positive subjects., Trial Registration Number: NCT01393470., Competing Interests: Competing interests: DA, ML, JP and JD have received grants from GSK group of companies and/or Merck & Co. Inc. through their employers (DA, Family Federation Finland; ML; University of Tampere; JP and PN University of Helsinki; JD and ML, Karolinska Institute) for HPV vaccination studies. GD was and FS is employee of GSK group of companies. FS has received shares and stock options from the GSK group of companies., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

To further understand the risk of stomach cancer after fractionated high-dose radiotherapy, we pooled individual-level data from three recent stomach cancer case-control studies. These studies were nested in cohorts of five-year survivors of first primary Hodgkin lymphoma (HL), testicular cancer (TC) or cervical cancer (CX) from seven countries. Detailed data were abstracted from patient records and radiation doses were reconstructed to the site of the stomach cancer for cases and to the corresponding sites for matched controls. Among 327 cases and 678 controls, mean doses to the stomach were 15.3 Gy, 24.7 Gy and 1.9 Gy, respectively, for Hodgkin lymphoma, testicular cancer and cervical cancer survivors, with an overall mean dose of 10.3 Gy. Risk increased with increasing radiation dose to the stomach cancer site (P < 0.001) with no evidence of nonlinearity or of a downturn at the highest doses (≥35 Gy). The pooled excess odds ratio per Gy (EOR/Gy) was 0.091 [95% confidence interval (CI): 0.036-0.20] with estimates of 0.049 (95% CI: 0.007-0.16) for Hodgkin lymphoma, 0.27 (95% CI: 0.054-1.44) for testicular cancer and 0.096 (95% CI: -0.002-0.39) for cervical cancer (P homogeneity = 0.25). The EOR/Gy increased with time since exposure (P trend = 0.004), with an EOR/Gy of 0.38 (95% CI: 0.12-1.04) for stomach cancer occurring ≥20 years postirradiation corresponding to odds ratios of 4.8 and 10.5 at radiation doses to the stomach of 10 and 25 Gy, respectively. Of 111 stomach cancers occurring ≥20 years after radiotherapy, 63.8 (57%) could be attributed to radiotherapy. Our findings differ from those based on Japanese atomic-bomb survivors, where the overall EOR/Gy was higher and where there was no evidence of an increase with time since exposure. By pooling data from three studies, we demonstrated a clear increase in stomach cancer risk over a wide range of doses from fractionated radiotherapy with the highest risks occurring many years after exposure. These findings highlight the need to directly evaluate the health effects of high-dose fractionated radiotherapy rather than relying on the data of persons exposed at low and moderate acute doses.

Purpose: To assess the dose-response relationship for stomach cancer after radiation therapy for cervical cancer., Methods and Materials: We conducted a nested, matched case-control study of 201 cases and 378 controls among 53,547 5-year survivors of cervical cancer diagnosed from 1943 to 1995, from 5 international, population-based cancer registries. We estimated individual radiation doses to the site of the stomach cancer for all cases and to corresponding sites for the matched controls (overall mean stomach tumor dose, 2.56 Gy, range 0.03-46.1 and after parallel opposed pelvic fields, 1.63 Gy, range 0.12-6.3)., Results: More than 90% of women received radiation therapy, mostly with external beam therapy in combination with brachytherapy. Stomach cancer risk was nonsignificantly increased (odds ratio 1.27-2.28) for women receiving between 0.5 and 4.9 Gy to the stomach cancer site and significantly increased at doses ≥ 5 Gy (odds ratio 4.20, 95% confidence interval 1.41-13.4, Ptrend=.047) compared with nonirradiated women. A highly significant radiation dose-response relationship was evident when analyses were restricted to the 131 cases (251 controls) whose stomach cancer was located in the middle and lower portions of the stomach (Ptrend=.003), whereas there was no indication of increasing risk with increasing dose for 30 cases (57 controls) whose cancer was located in the upper stomach (Ptrend=.23)., Conclusions: Our findings show for the first time a significant linear dose-response relationship for risk of stomach cancer in long-term survivors of cervical cancer., (Published by Elsevier Inc.)

Phase III clinical trials of human papilloma virus (HPV) vaccination have shown ≥95% efficacy against HPV16/18 associated cervical intraepithelial neoplasia (CIN) Grade 2/3. Long-term surveillance is, however, needed to determine the overall vaccine efficacy (VE) against CIN3 and invasive cervical carcinoma (ICC). During population-based recruitment between September 2002 and March 2003, 1,749 16- to 17-year old Finns participated in a multi-national randomized Phase III HPV6/11/16/18 vaccine (FUTURE II) trial for the determination of VE against HPV16/18 positive CIN2/3. The passive follow-up started at the country-wide, population-based Finnish Cancer Registry (FCR) six months after the active follow-up and voluntary cross-vaccination in April 2007. A cluster randomized, population-based reference cohort of 15,744 unvaccinated, originally 18-19 year old Finns was established in two phases in 2003 and 2005 after the FUTURE II recruitment. We linked these cohorts with the FCR in 2007-2011 (HPV vaccine and placebo cohorts) and 2006-2010 and 2008-2012 (unvaccinated reference cohorts 1 and 2) to compare their incidences of CIN3 and ICC. The four years passive follow-up resulted in 3,464, 3,444 and 62,876 person years for the HPV6/11/16/18, original placebo and reference cohorts, after excluding cases discovered during the clinical follow-up and individuals not at risk. The numbers of CIN3 and ICC cases identified were 0 and 0, 3 and 0, 59 and 3 for the HPV6/11/16/18, placebo and the unvaccinated reference cohorts. The corresponding CIN3 incidence rates were 0/100,000 (95% confidence interval 0.0-106.5), 87.1/100,000 (95% CI 17.9-254.5) and 93.8/100,000 (95% CI 71.4-121), respectively. Long-term surveillance up to 8 years (and longer) post vaccination of the HPV6/11/16/18 vaccine and placebo cohorts, and the unvaccinated reference cohort (not exposed to interventions) for the most stringent efficacy end-points by passive cancer registry-based follow-up is feasible., (Copyright © 2012 UICC.)

The aim of this study was to evaluate the association of postmenopausal estradiol-progestagen therapy (EPT) with the risk for precancerous lesions, squamous cell carcinoma and adenocarcinoma of the uterine cervix. All Finnish women who had used EPT in 1994-2008 for at least 6 months (n = 243,857) at the age of 50 years or more were identified from the national Medical Reimbursement Registry and linked to the Finnish Cancer Registry. The incidence of cervical precancerous or cancerous lesions among EPT users was compared to that in the background population. There were 210 EPT users with squamous lesions (178 with precancerous and 32 with cancer) and 79 EPT users with glandular lesions (14 precancerous and 65 adenocarcinomas). The ever use of EPT did not associate with the incidence of precancerous lesions, but the risk for squamous cell carcinoma decreased (standardized incidence ratio 0.41; 95% confidence interval 0.28-0.58) and that for adenocarcinoma increased (1.31; 1.01-1.67). After the use of EPT for 5 years, the risk for squamous cell carcinoma decreased (0.34; 0.16-0.65), and the risk for adenocarcinomas increased (1.83; 1.24-2.59). The prolonged use of EPT is associated with the occurrence of cervical malignancies. If the association would be a causal one, the use for 5+ years among 10,000 women followed for 10 years would mean about two to three fewer cases of cervical squamous cell carcinoma but about two extra cases with adenocarcinoma., (Copyright © 2011 UICC.)

Aims: The efficacy of human papillomavirus (HPV) type 16 and 18 vaccines against cervical intraepithelial neoplasia grade II (CIN2+) has been verified, but the active follow-up of studies with invasive cervical cancer or cervical intraepithelial neoplasia grade III (CIN3) as primary end points are ethically not possible. Furthermore, ongoing registry-based passive follow-up studies with invasive cervical cancer as the end point will take time., Materials & Methods: To evaluate the feasibility of CIN3 as a surrogate end point, we compared high-risk (hr) HPV-associated relative risk and population attributable fraction (PAF) of CIN3 and/or squamous cell carcinoma (SCC) estimated in a large serological case-cohort HPV study. Our case-cohort comprised 83 SCC and 389 CIN3 cases and a subcohort of 7862 out of 230,998 Finnish women, who at baseline were under 32 years of age and had undergone a minimum of two pregnancies within 5 years during 1983-1997., Results: PAFs of the case-cohort, approach-based, serologically defined and misclassification-corrected HPV16 and hrHPV (HPV types 16, 18, 31 and 33) exposures in the SCC samples were 61% (95% CI: 18-85) and 73% (95% CI: 13-93), respectively. Considerably lower HPV16 and hrHPV PAF estimates in CIN3 of 6% (95% CI: -19-35) and 36% (95% CI: -5-65), respectively, were obtained. A meta-analysis-derived, PCR-based, hrHPV-associated relative risk estimate of 20.3 in CIN2/3+ yielded a PAF estimate for hrHPV in CIN2/3+ of 86% (90% CI: 63-95) in our study population. The former, hrHPV serology-based CIN3 PAF estimates were biased owing to low sensitivity of HPV16 and/or HPV16/18/31/33 serology, most notably in cervical cancer precursor lesions, but the latter estimate overlapped with our hrHPV serology-based cervical cancer PAF estimate., Conclusion: CIN3 may be a valid surrogate efficacy end point for HPV vaccination studies, but the associated causality of multiple hrHPV exposures needs to be unambigously defined.

Introduction: We studied variation in incidence of cervix cancer during 1971-1995 among Finnish women born in 1906 to 1945 by social class and cell type., Material and Methods: The Finnish Cancer Registry data were linked to the 1970 Population Census, which included social class data. There were 0.8 million individuals in the cohort under follow-up, with 5,102 squamous cell cancers and 573 cases of cervical adenocarcinoma diagnosed after the census date., Results: Incidence of squamous cell cancer was more than two-fold in the lowest social class (standardized incidence ratio (SIR) 1.29, 95% CI 1.21-1.36) as compared with the highest one (SIR 0.59, 0.51-0.66), while there was no association between social class and risk on adenocarcinoma (SIR 1.07, 0.87-1.28 and 1.08, 0.79-1.45, respectively)., Discussion: Oncogenic HPV is regarded as the necessary cause of all types of cervix cancer. Sexually transmitted diseases and social status are correlated. Lack of association between adenocarcinoma and social class makes the HPV-etiology of this cell type less credible than that of squamous cell cancer.

Purpose: Although cervical squamous cell carcinoma (SCC) and adenocarcinoma (AC) are both caused by human papillomavirus (HPV) infection, they differ in cofactors such as cigarette smoking. We assessed whether these cofactor differences translate into differences in second cancer risk., Patients and Methods: We assessed second cancer risk among 85,109 cervical SCC and 10,280 AC survivors reported to population-based cancer registries in Denmark, Finland, Norway, Sweden, and the United States. Risks compared to the general population were assessed using standardized incidence ratios (SIR)., Results: Overall cancer risk was significantly increased among both cervical SCC survivors (n = 10,559 second cancers; SIR, 1.31; 95% CI, 1.29 to 1.34) and AC survivors (n = 920 second cancers; SIR, 1.29; 95% CI, 1.22 to 1.38). Risks of HPV-related and radiation-related cancers were increased to a similar extent among cervical SCC and AC survivors. Although significantly increased in both groups when compared with the general population, risk of smoking-related cancers was significantly higher among cervical SCC than AC survivors (P = .015; SIR for cervical SCC = 2.07 v AC = 1.78). This difference was limited to lung cancer (SIR for cervical SCC = 2.69 v AC = 2.18; P = .026). The increased lung cancer risk among cervical AC survivors was observed for both lung SCC and lung AC. SIRs for second cancers of the colon, soft tissue, melanoma, and non-Hodgkin's lymphoma were significantly higher among cervical AC than SCC survivors., Conclusion: The second cancer profiles among cervical SCC and AC survivors mirror the similarities and differences in cofactors for these two histologies. Because smoking is not a cofactor for cervical AC, the increased lung cancer risk suggests a role for additional factors.

In many industrialized countries, with some degree of screening, cervical cancer nowadays is most frequent among women of lower socioeconomic status (SES), partly owing to their lower participation in screening. This study aims to provide support for specification of mass screening policy for cervical cancer by describing relationships between sociodemographic factors and the incidence of cervical cancer in the Netherlands based on geographical differences and by analysing the relationship between SES of neighbourhood and individual tumour characteristics. Municipality-specific, age-adjusted incidence rates for cervical cancer were calculated from the Netherlands Cancer Registry, and data on sociodemographic factors were obtained from Statistics Netherlands. Logistic regression analysis was performed to investigate determinants of variations in incidence at the ecological level. An additional analysis linked individual tumour characteristics to SES estimates at the postal code level by calculating relative risks (RR). The incidence was higher in municipalities with a high prevalence of immigrants [odds ratios 7.9, 1.4-47 95% confidence intervals (CI)] and with more individuals on welfare (odds ratios 8.6, 1.7-43 95% CI). Patients residing in neighbourhoods with lower SES had higher Federation of Gynecology and Obstetrics stages (RR 1.4, 1.2-1.6 95% CI) and fewer adenocarcinomas (RR 0.7, 0.6-0.9 95% CI), and were younger at diagnosis (P<0.001). Cervical cancer is more common among women of lower SES and immigrant women. This, together with the finding that lower SES is associated with more advanced cancer and consequently worse survival, emphasizes the importance of future cervical cancer prevention programmes targeted at women of lower SES who do not participate in opportunistic screening.

With respect to cervical cancer management, Finland and the Netherlands are comparable in relevant characteristics, e.g., fertility rate, age-of-mother at first birth and a national screening programme for several years. The aim of this study is to compare trends in incidence of and mortality from cervical cancer in Finland and the Netherlands in relation to the introduction and intensity of the screening programmes. Therefore, incidence and mortality rates were calculated using the Cancer Registries of Finland and the Netherlands. Data on screening intensity were obtained from the Finnish Cancer Registry and the Dutch evaluation centre at ErasmusMC-Rotterdam. Women aged 30-60 have been screened every 5 years, in Finland since 1992 and in the Netherlands since 1996. Screening protocols for smear taking and referral to the gynaecologist are comparable. Incidence and mortality rates have declined more in Finland. In 2003, age-adjusted incidence and mortality in Finland were 4.0 and 0.9 and in the Netherlands 4.9 and 1.4 per 100,000 woman-years, respectively. Excess smear use in the Netherlands was estimated to be 24 per 1,000 women during a 5-year interval compared to 121 in Finland. The decline in mortality in Finland seems to be almost completely related to the screening programme whereas in the Netherlands it was initially considered to be a natural decline. Differences in risk factors might also play a role: the Netherlands has higher population density and higher percentages of immigrants and (female) smokers. The greater excess smear use in Finland might also have affected incidence.

Background: Given the extended survival of patients diagnosed with cervical cancer, the large number of these women treated with radiotherapy, and the presence in this population of established cancer risk factors such as human papillomavirus (HPV) infection and cigarette smoking, it is important to clarify long-term trends in second cancer risk., Methods: Using data from 104,760 one-year survivors of cervical cancer reported to 13 population-based cancer registries in Denmark, Finland, Norway, Sweden, and the United States, we calculated standardized incidence ratios (SIRs) for second cancers overall and cancers at particular sites among women with cervical cancer, including cervical cancer patients who were treated or not treated with radiation, over more than 40 years of follow-up. Cox regression models were used to assess the time-varying association of radiotherapy with risk of second cancers and to assess the interaction of radiation treatment with age at diagnosis. All statistical tests were two-sided., Results: Among 104,760 one-year survivors of cervical cancer, the risk of all second cancers taken together was increased to a statistically significant extent (n = 12,496; SIR = 1.30; 95% confidence interval [CI] = 1.28 to 1.33). Compared with the general population, in both radiotherapy (N = 52,613) and no-radiotherapy groups (N = 27,382), risks for HPV-related cancers (of the pharynx, genital sites, and rectum/anus) and smoking-related cancers (of the pharynx, trachea/bronchus/lung, pancreas, and urinary bladder) were elevated to a statistically significant extent. Cervical cancer patients treated with radiotherapy, but not those who did not receive radiotherapy, were at increased risk for all second cancers and cancers at heavily irradiated sites (colon, rectum/anus, urinary bladder, ovary, and genital sites) beyond 40 years of follow-up compared with women in the general population. The association of radiotherapy with second cancer risk was modified by age at cervical cancer diagnosis for rectum/anus, genital sites, and urinary bladder, with higher hazard ratios for second cancer at younger ages of cervical cancer. After adjustment for competing mortality, the 40-year cumulative risk of any second cancer was higher among women diagnosed with cervical cancer before age 50 (22.2%; 95% CI = 21.5% to 22.8%) than among women diagnosed after age 50 (16.4%; 95% CI = 16.1% to 16.9%)., Conclusion: Cervical cancer patients treated with radiotherapy are at increased risk of second cancers at sites in close proximity to the cervix beyond 40 years of follow-up.

Cervical cancer (CxCa) is a long-term sequelae caused by persistent human papillomavirus (HPV) infection. Genetic susceptibility to the persistent infection and CxCa is associated with certain human leucocyte antigen (HLA) types. The same susceptibility genes may also determine whether a woman will be protected against the persistent infection and against CxCa by HPV vaccination or not. A systematic review of literature identified following HLAs to be associated with CxCa: A11 (odds ratio [OR] = 1.4, 95% confidence interval [CI] 1.1-2.0); B7 (1.5, 1.1-2.0); B15 (0.6, 0.4-0.8); DR2 (1.2, 1.1-1.4) and DR6 (0.6, 0.5-0.8). In the Caucasian population, HLA-B7 and DR6, and DR2 and B15 antigens showed at least borderline associations. In view of a bone marrow donor registry at the Finnish Red Cross and the Finnish Cancer Registry, we created geographic distribution maps of index HLA frequencies and CxCa incidence in the fertile-aged Finnish population. Increased incidence of CxCa was found in a region of western coastal Finland, where frequency of two CxCa susceptibility genes (HLA-DR2 and B7) was increased, and frequency of one CxCa resistance gene (HLA-B15) was decreased. Whether or not HLA type determines also regional susceptibility to persistent HPV infection, and the success of HPV vaccination in preventing both the persistent infection and CxCa warrants further investigation.

Objective: Cervical cancer is one of the most lethal cancers among women worldwide. Women are treated and followed-up in several different manners. Long-term studies of cancer or death risks after different methods of treatment or after different initial histology are scarce., Methods: A retrospective cohort study with 7466 women treated of CIN between 1974 and 2001 in Helsinki University Hospital followed-up until the end of 2003. The Cox model was used to determine differences in cancer free or overall survival between women treated of CIN with different methods or after different initial grade of CIN., Results: Twenty-two cases of invasive cervical cancer (ICC) and 57 cases of CIN 3 after treatment of CIN were observed. There were no statistically significant differences in ICC free survival between different treatment methods or initial grade of CIN. In CIN 3 free survival, the hazard ratios for the 57 cases of CIN 3, when cold knife coagulation (CKC) was set as the reference, were 0.22 for laser, 0.55 for cryotherapy and 0.31 for LEEP. In CIN 3+ (CIN 3 or ICC) free survival, the hazard ratios of 79 CIN 3+ cases (CKC reference) were 0.25 for laser, 0.50 for cryotherapy and 0.27 for LEEP. There were no differences in overall survival between different grades of initial CIN., Conclusions: The CKC seems to be the least favorable in terms of both further cancer and CIN 3 risk. The follow-up has to be well organized because the post-treatment cancer risk is independent of the initial grade of CIN.

Phase III trials have demonstrated the efficacy of human papillomavirus (HPV) vaccines in preventing transient and persistent high-risk (hr) HPV infection and precancerous lesions. A mathematical model of HPV type 16 infection and progression to cervical cancer, parameterised to represent the infection in Finland, was used to explore the optimal age at vaccination and pattern of vaccine introduction. In the long term, the annual proportion of cervical cancer cases prevented is much higher when early adolescents are targeted. Vaccinating against hr HPV generates greater long-term benefits if vaccine is delivered before the age at first sexual intercourse. However, vaccinating 12 year olds delays the predicted decrease in cervical cancer, compared to vaccinating older adolescents or young adults. Vaccinating males as well as females has more impact on the proportion of cases prevented when vaccinating at younger ages. Implementing catch-up vaccination at the start of a vaccination programme would increase the speed with which a decrease in HPV and cervical cancer incidence is observed.

Human papillomaviruses (HPVs, most notably types 16 and 18) cause cervical carcinoma, the second most common cancer among women. Vaccination of adolescents against HPV16/18 might prevent large proportion of cervical and other anogenital cancers. However, because of ethical reasons this cannot be proven by clinical studies. To determine the long-term vaccine efficacy (VE) of HPV16/18 virus-like-particle (VLP) vaccine against cervical carcinoma in situ (CIS+) and invasive cervical carcinoma, the following three population-based cohorts of adolescent women have been enrolled: (1) women vaccinated with the HPV vaccine; (2) women vaccinated with hepatitis A control vaccine; and (3) unvaccinated control women. These cohorts will be passively followed for cumulative incidence of CIS+ endpoints by population-based cancer registry. Overall 24,046 16- to 17-year-old adolescent women from 18 cities in Finland were invited between May 2004 and June 2005 to participate in a phase III trial with bivalent HPV16/18 VLP vaccine. A total of 58,996 18- to 19-year-old women were invited in May 2005 to participate as unvaccinated controls. Women who reported their willingness to participate in an HPV vaccination trial had they been 1-2 years younger were eligible. Cumulative incidence (CI) of CIS+ in our cohorts over 15 years is approximately 0.45%. VE of 70% against CIS+ with 80% power requires 3357-3189 HPV16/18 vaccine recipients, 3357-3189 other vaccine recipients, and 6714-9567 unvaccinated controls. We have now enrolled 2404 HPV16/18 vaccine recipients, 2404 hepatitis A-vaccine recipients, and 5130 unvaccinated controls. This enrolment in addition to our earlier enrolment in another phase III trial guarantees enough power so that by 2020 we can ultimately provide data on the efficacy of HPV16/18 vaccination against CIS+.

Objective: To study the long term risk of cervical and other cancers after treatment for cervical intraepithelial neoplasia., Design: Retrospective cohort study., Setting: University Hospital, Helsinki, Finland., Participants: 7564 women treated for cervical intraepithelial neoplasia during 1974 and 2001 and followed up through the Finnish cancer registry until 2003., Main Outcome Measures: Standardised incidence ratio for cervical cancer and other cancers., Results: During follow-up 22 cases of invasive cervical cancer occurred in women treated for cervical intraepithelial neoplasia (standardised incidence ratio 2.8, 95% confidence interval 1.7 to 4.2). The highest risk was during the second decade (10 cases observed: 3.1, 1.5 to 5.7). The standardised incidence ratio for cervical intraepithelial cancer type 1 was 3.1 (1.4 to 6.2) and for type 2 was 3.7 (0.9 to 10.7)., Conclusions: The risk of cervical cancer in the first 20 years after treatment for cervical intraepithelial neoplasia is higher than in the average population. The risk of smoking related cancers is also increased.

The hysterectomy-corrected age-adjusted incidence rate of endometrial cancer was 29%, and for cervical cancer 11% higher than the uncorrected rate. Correction factors for such cancer sites are recommended for regular use. The levelling-off of the incidence of endometrial cancer appears to be an artefact caused by the increasing prevalence of hysterectomy.

This case-control study based in Nordic serum banks evaluated the joint effects of infections with genital human papillomavirus (HPV) types, and Chlamydia trachomatis in the aetiology of cervical squamous cell carcinoma. Through a linkage with the cancer registries, 144 cases were identified and 420 controls matched to them. Exposure to past infections was defined by the presence of specific IgG antibodies. The odds ratio (OR) for the second-order interaction of HPV16, HPV6/11 and C. trachomatis was small (1.0) compared to the expected multiplicative OR, 57, and the additive OR, 11. The interactions were not materially different among HPV16 DNA-positive squamous cell carcinomas. When HPV16 was replaced with HPV18/33 in the analysis of second-order interactions with HPV6/11 and C. trachomatis, there was no evidence of interaction, the joint effect being close to the expected additive OR. Possible explanations for the observed antagonism include misclassification, selection bias or a true biological phenomenon with HPV6/11 and C. trachomatis exposures antagonizing the carcinogenic effects of HPV16.

Previous studies suggest that high parity increases the risk of cervical cancer. We studied the risk of cervical cancer (CC) and cervical intraepithelial neoplasia (CIN3) in a Finnish cohort of grand multiparous (GM) women (at least five children) with low prevalence of sexually transmitted infections (STI). The Finnish Cancer Registry data revealed 220 CC and 178 CIN3 cases among 86 978 GM women. Standardised incidence ratios (SIR) were calculated from the numbers of observed and expected cases. Interval analyses by parity, age at first birth and average birth interval were done using multivariate Poisson regression. Seroprevalence of human papillomavirus (HPV) 16 and Chlamydia trachomatis was tested among 561 GM women and 5703 women with 2-4 pregnancies. The incidence among GM women was slightly above the national average for squamous cell carcinoma of cervix uteri (SIR 1.21, 95% CI 1.05-1.40) and CIN3 (1.37, 95% CI 1.17-1.58), but lower for adenocarcinoma (SIR 0.77, 95% CI 0.52-1.10). The seroprevalence of HPV16 and Chlamydia trachomatis among GM women was lower than in the reference population, except among those women who had their child under age 19. Age under 20 years at first birth increased the risk of CC and CIN3 especially in premenopausal GM women, while increasing parity had no effect. The small relative risks of CC and CIN3 among GM women in our study as compared to studies from other countries can be explained by the exceptionally low prevalence of STIs in Finnish GM women. The observed SIRs between 1.2 and 1.4 should be interpreted to represent increased risk attributable to grand multiparity. The increased incidence of CC and CIN3 among young GM women suggests causal association to HPV 16 and Chlamydia trachomatis infections.

Objective: Infection with oncogenic human papillomaviruses (HPVs) is the most important cause of cervical cancer worldwide. After infection there is a long latency period of at least 10 to 15 years during which cervical cancer develops in a small proportion of originally infected women. Up to 50% of these women have at diagnosis antibodies to the HPV oncoproteins E6 and E7, which are rarely found among healthy women. Our purpose was to evaluate whether antibodies to HPV16 and HPV18 E6 and E7 proteins are useful for early diagnosis of cervical cancer by measuring the antibody response in women in whom cervical cancer later developed., Study Design: A joint serum bank of 550,000 Swedish, Norwegian, and Finnish women was followed up for 0.5 to 20 years, after which 178 invasive cervical carcinoma (ICC) cases, 150 of whom had squamous cell carcinoma (SCC), and 527 controls were identified. Antibodies to HPV16 and HPV18 E6 and E7 proteins were determined by tag enzyme-linked immunoassays., Results: HPV16/18 E6 and E7 antibodies were detected infrequently (7.0%) in women in whom SCC later developed and yielded a moderately increased estimate of associated relative risk (odds ratio 2.7, 95% CI 1.1-6.4). Sensitivity of the combined antibody tests for the detection of occult SCC varied between 6% and 14% but was not related to time lag between serum sampling and cancer diagnosis., Conclusion: HPV16/18 E6 and E7 antibody responses are not sensitive markers of occult cervical cancer.

Background: Endometrial cancer incidence rates are low in Asia and Africa and high in North America and Northern Europe. Cervical cancer is often the most common female cancer in developing countries, and infection with human papillomavirus (HPV) is its main risk factor. However, other factors, such as occupational exposures may modify the HPV-related risk. We conducted an exploratory register-linkage study in Finland to assess the role of occupational exposures on incidence rates of cancers of the endometrium and cervix uteri., Methods: Occupational risk factors for endometrial and cervical cancers were explored in a 25-year follow-up of female workers born 1906-1945 (N = 413,877) identified through the Population Census of Finland of 1970. Job titles in census records were converted to exposures of 31 occupational agents through a job-exposure matrix. Poisson regression models estimated relative risks (RR) for each agent, standardized for birth cohort, follow-up period, and socio-economic status. For each agent, the product of level and probability of exposure was calculated and subdivided in three categories: zero, low, and medium/high. Adjustment at the job title level was done for the turnover rate (endometrial and cervical cancers), mean parity, and age at first birth (endometrial cancer)., Results: Endometrial cancer (2,833 cases) was associated with exposure to animal dust (RR 1.2, low level, 174 cases) and sedentary work (RR 1.3, high level, 145 cases). Cervical cancer (1,101 cases) was associated with exposure to aliphatic and alicyclic (RR 1.3, low level, 91 cases), aromatic (RR 1.2, low level, 318 cases; RR 1.4, high level, 41 cases), and chlorinated hydrocarbon solvents (RR 1.3, low level, 50 cases), silica dust (RR 1.2, low level, 251 cases), and wood dust (RR 1.2, low level, 249 cases)., Conclusions: This study suggests that occupational exposures may be associated with increased risk of endometrial and cervical cancers., (Copyright 2001 Wiley-Liss, Inc.)

Context: Human papillomavirus (HPV) infection has been established as a cause of cervical cancer. Epidemiologic studies suggest that Chlamydia trachomatis infection also confers increased risk for cervical squamous cell carcinoma (SCC). Whether this risk is serotype-specific is unknown., Objective: To study the association between exposure to different C trachomatis serotypes and subsequent development of cervical SCC., Design and Setting: Longitudinal, nested case-control study within a cohort of 530 000 women who provided samples to serum banks in Finland, Norway, and Sweden. The data files were linked to respective national cancer registries., Subjects: One hundred twenty-eight women who had developed invasive cervical SCC at least 12 months following serum donation. Each case had 3 matched controls., Main Outcome Measure: Risk for the development of cervical SCC by IgG antibodies to 10 different C trachomatis serotypes, adjusted for antibodies to HPV types 16, 18, and 33 and for serum cotinine levels., Results: Of specific C trachomatis serotypes, serotype G was most strongly associated with SCC (adjusted odds ratio [OR], 6.6; 95% confidence interval [CI], 1. 6-27.0). Other serotypes associated with SCC were I (OR, 3.8; 95% CI, 1.3-11.0) and D (OR, 2.7; 95% CI, 1.3-5.6). Presence of serum IgG antibodies to more than 1 serotype increased the adjusted ORs for SCC (P<.001 for trend)., Conclusions: Chlamydia trachomatis serotype G is most strongly associated with subsequent development of cervical SCC. Increasing numbers of exposures to different C trachomatis serotypes also increases risk. Our results strengthen the evidence that there is a link between past C trachomatis infection and cervical SCC.

Background: oncogenic, i.e. high risk human papillomavirus (hrHPV) types are the major cause of invasive cervical cancer (ICC). Putatively licensable vaccines against the hrHPVs have been developed and are approaching clinical phase III trials that use persistent HPV infection as end point. Direct extension of the phase III trials towards long-term end points (ICC and its immediate precursors: carcinoma in situ and severe dysplasia, i.e. cervical intraepithelial neoplasia grade III, CINIII) is important, to avoid early contamination of the target population by opportunistic use of licensed HPV vaccines. Country-wide registration on population and health events in a stable population of 25 million make Estonia and the Nordic countries a unique venue for long-term evaluation of cervical cancer control measures. Mass-screening programmes exist in all Nordic countries, but not in Estonia., Aim: design of phase III-IV trials for evaluation of protection against ICC and CINIII by preventive HPV vaccines based on cancer registry follow-up., Results: in the Nordic countries, population based randomisation of all 15-year-old women to the vaccination (vaccine and placebo) and reference cohorts entering conventional Pap-smear screening after a clinical phase III trial would assure comparability of the cohorts. Enrollment of 10094 vaccinees +10094 placebo vaccinees +30282 other hrHPV negative women without vaccination at the age of 16 would give 80% power for the demonstration of 70% vaccine efficacy (VE) against ICC in 20 years by cancer registry follow-up. On the other hand, vaccination of 8303 Estonian hrHPV negative women among the entire 15-year-old female birth cohort (about 10000 women) with an already licensed HPV vaccine would enable demonstration of 70% VE against ICC by 20 years of registry follow-up of these and comparable 16606 women identified among the 16-19-year-old birth cohorts., Conclusions: evaluation of the protective effect of an HPV vaccine against ICC is possible both in countries with or without mass-screening. The effects of vaccination on spread of different HPVs in the population would need to be monitored, especially in Estonia. Ethical aspects, cost-benefit evaluation and comparisons with other new means of cervical cancer control warrant further investigation.

Background: The purpose of the study was to estimate subsequent incidence of cervical cancer among women with positive cytology followed by negative histology., Methods: This was a longitudinal cohort study involving about 80,000 women with class II, III, IV or V cytology at the organized mass screening in Finland in 1971 1990. Follow-up through the Finnish Cancer Registry started from the fifth month following the initial screening and ended on December 31, 1995., Results: Standardized incidence ratios (SIR) of invasive cervical cancer varied from 2.2 (class II) to 19 (class V), and SIRs of preinvasive lesion varied from 3.0 (class II) to 20 (class V) compared to the risk among the total Finnish female population of same age and calendar period. The relative risk was greatest during first years of follow-up for both preinvasive and invasive cervical lesions, and it remained significantly high over 5 years of follow-up. For women with class II cytology there were peaks in relative risk in the years of subsequent rescreenings., Conclusion: Women with positive cytology have a high relative risk of cervical cancer even when excluding the cancers found at screening; the high relative risk is persistent for more than 5 years, and therefore these women should be kept under close surveillance and repeated smears should be taken with relatively short intervals.

Background: Identification of human papillomavirus type 16 (HPV16) as the major risk factor for cervical neoplasia, and mass production of DNA free HPV capsids have paved the way to preventive vaccination trials. Design of such trials requires reliable attack rate data., Objective: Determination of (1) HPV16 and (2) cervical neoplasia attack rates in primiparous women. Estimation of actuarial sample sizes for HPV16 vaccination phase IV trials., Design: A longitudinal cohort study., Methods: Population based Finnish Maternity Cohort (FMC) and Finnish Cancer Registry (FCR) were linked for the identification of two cohorts of primiparous women: (1) a random subsample of the FMC: 1656 women with two pregnancies between 1983-9 or 1990-6 and living in the Helsinki metropolitan area, and (2) all 72,791 primiparous women living in the same area during 1983-94. Attack rate for persistent HPV16 infection (1) was estimated in 1279 seronegative women by proportion of seroconversions between the first and the second pregnancy. Comparable 10 year cumulative incidence rate (CR) of cervical intraepithelial neoplasia grade III and cervical cancer (CIN III+) (2) was estimated based on cases registered at the FCR during 1991-4., Results: The HPV16 attack rates were 13.8% (< 18 years), 7.0% (18-19 years), 2.3% (21 years), 2.4% (23 years), and 4.5% (< 25 years). Number of vaccinees required for a 5 year efficacy trial with persistent HPV16 infection as the end point ranged between 1000 and 3900, assuming 80% power, 90%-70% vaccine efficacy (VE), and misclassification. The CRs of CIN III+ were 0.33% (< 18 years), 0.44% (18-19 years), 0.21% (20-24 years), and 0.28% (< 25 years). Number of vaccinees required for a 10 year efficacy trial with HPV16 positive CIN III+ as the end point was 15,000 assuming 80% power, 90% VE, and 75% aetiological fraction of CIN III+ for HPV16., Conclusions: The attack rates of HPV16 and CIN III+ identify primiparous women under 25 years of age among target populations for postnatal HPV vaccination at phase II/III trials.

A longitudinal cohort study was carried out to determine whether gynaecological infections other than human papillomavirus (HPV) are also related to the subsequent increased risk of cervical neoplasia. The study comprised 19114 women attending the organized mass screening in Finland in 1985-1990 with cytologically detected HPV, Actinomyces, herpes simplex, Trichomonas vaginalis, or yeast. The women were followed-up for subsequent preinvasive lesions and invasive cancers until the end of 1994 by linkage to the nation-wide Cancer Registry. Standardized incidence ratios (SIR) with rates for the whole of Finland as reference and 95% confidence intervals (CI) were estimated. Trichomonas vaginalis and HPV were associated with a high relative risk of cervical cancer, SIR 6.4 (CI 3.7-10, preinvasive lesion and invasive cancer combined) and SIR 5.5 (CI 4.2 7.2, preinvasive lesion and invasive cancer combined), respectively. Herpes simplex was rarely detected, but the highest and statistically most significant point estimate was observed (SIR 12, CI 2.4-34, preinvasive lesion and invasive cancer combined). Neither Actinomyces nor yeast was associated with a significantly increased risk of cervical cancer. None of these results could be accounted for by the confounding effect of the other infections. Our results, based on a prospective design, lead us to propose that Trichomonas vaginalis and herpes simplex virus are also predictors for cervical neoplasia.

Cervical carcinoma is a sexually transmitted disease most strongly linked with human-papillomavirus (HPV) infection. We conducted a prospective sero-epidemiologic study to evaluate the role of Chlamydia trachomatis infection in the development of cervical carcinoma, with invasive cancer as an end point. A nested case-control study within a cohort of 530000 Nordic women was performed. Linking data files of 3 Nordic serum banks and the cancer registries of Finland, Norway and Sweden identified 182 women with invasive cervical carcinoma diagnosed during a mean follow-up of 5 years after serum sampling. The serum samples of the cases and matched cancer-free controls were analyzed for IgG antibodies to C. trachomatis, C. pneumoniae (a control microbe) and HPV types 16, 18 and 33, as well as for serum cotinine (an indicator of tobacco smoking). Serum antibodies to C. trachomatis were associated with an increased risk for cervical squamous-cell carcinoma (HPV- and smoking-adjusted OR, 2.2; 95% CI, 1.3-3.5). The association remained also after adjustment for smoking both in HPV16-seronegative and -seropositive cases (OR, 3.0; 95% CI, 1.8-5.1; OR, 2.3, 95% CI, 0. 8-7.0 respectively). No such association was found for C. pneumoniae. Our prospective study provides sero-epidemiologic evidence that infection with C. trachomatis confers an increased risk for subsequent development of invasive squamous-cell carcinoma of the uterine cervix., (Copyright 2000 Wiley-Liss, Inc.)

A nation-wide screening programme for cervical cancer started in Finland gradually from 1963 onwards. By the beginning of the 1990s, there had been a decrease of 80% both in the age-adjusted incidence of and mortality from cervical cancer. To describe the recent patterns in cervical cancer incidence and mortality and evaluate their differentials in relation with the organised screening activities, we have updated the material on the cervical cancer incidence and mortality as well as mass-screening activities up to the year 1995. Based on the files of the Finnish Cancer Registry, there is a striking increase of about 60% in the incidence of cervical cancer during the last 4 years of the study period among women below 55 years of age. The mortality rates are still decreasing. There is no overall decrease over recent years in the coverage of the programme invitations or smears taken. Incidence of invasive cancer and of moderate and severe dysplasia as detected in mass screening have increased. As to the interpretation, changes in the risk factors, such as in sexual behaviour and smoking habits, over the decades might partly explain increasing trends in cervical cancer incidence. As the change in incidence was relatively abrupt, inadequacies or changes in the effectiveness in the screening programme, particularly among young women, may also have contributed. Expanding the coverage of and attendance in the pap-screening programme among women in young target ages would still be effective. Increasing emphasis on quality assessment in screening is also needed., (Copyright 1999 Wiley-Liss, Inc.)

Human papillomavirus (HPV) types 16 and 18 are the major risk factors for cervical carcinoma, whereas HPV types 6 and 11 cause benign genital lesions. We wanted to study the joint effect of simultaneous infections with the oncogenic and non-oncogenic HPV types on risk of subsequent development of cervical carcinoma. A cohort of 530,000 women who had donated blood samples to Nordic serum banks between 1973 and 1994 was followed up by linkage to national cancer registries. We identified 182 prospective cases with invasive cervical carcinoma and selected 538 matched controls at random. HPV 6, 11, 16, 18 and 33 seropositivity was used as a marker for the different HPV infections, and seropositivity for Chlamydia trachomatis and cotinine were used as markers for risk-taking sexual behavior and smoking respectively. The adjusted odds ratio (OR) of cervical squamous-cell carcinoma (SCC) was 2.2 for HPV6/11 among HPV16 seronegatives and 5.5 for HPV16 among HPV6/11 seronegatives. Assuming multiplicative joint effect, the expected OR for seropositivity to both HPV6/11 and HPV16 would have been 12, but the observed OR was 1.0. The antagonistic interaction was statistically significant (p = 0.001) and present also under deterministic considerations of possible misclassification bias. Antagonistic interactions were also detected for combinations of HPV16 and HPV18 and of HPV16 and HPV33. The results are in line with the concept that HPV-specific immunity protects against SCC and support primary prevention of SCC by vaccination against the HPVs.

Objective: To evaluate whether five years is an appropriate screening interval for cervical cancer for the improvement of public health., Setting: Finland., Methods: 45,572 women with a cytological class I smear attending the mass screening programme organised every five years in Finland during 1971 to 1976 and followed up until the end of 1994. The data from the Nationwide Mass Screening Registry were linked to the Finnish Cancer Registry. Standardised incidence ratios of preinvasive and invasive cervical cancer with 95% confidence intervals (CI) were estimated, with rates for the total Finnish population as reference., Results: The standardised incidence ratio estimates were low initially after screening and then gradually increased up to the time of the next smear five years later. This pattern was repeated after each screening. The risk was persistently low for invasive cervical cancer even after 10 years of follow up, whereas the low risk for preinvasive lesions was of a shorter duration. The low risk associated with a negative smear became even lower with advancing age., Conclusions: Women who attend organised screening programmes and have a negative smear have a low risk of cervical cancer for over 10 years. Also, the relative risk of a preinvasive lesion after an initial negative smear is decreased for more than five years. Therefore, the five year screening interval in Finland is appropriate and effective in reducing the risk of invasive cervical cancer.

Background: The purpose of our study was to find out whether bleeding symptoms are predictive factors of subsequent gynecological or urinary cancers among women screened negative., Methods: The data stemmed from the Finnish Mass Screening Registry, and were linked to the National Cancer Registry: 37,596 screening negative women in the nationwide population-based mass screening program for cervical cancer were classified by their bleeding symptom (bloody discharge, coital bleeding, irregular bleeding, postmenopausal bleeding) at the time of screening (1985-1990) and followed up (1985-1994) in order to assess the subsequent risk of cancer., Results: Bleeding symptoms with prevalence of 5.9% were more likely to be signs of preinvasive than invasive cervical cancer with the exception of coital bleeding, nevertheless relative risk of cervical cancer (SIR 1.1, 95% CI 0.8-1.4) was not significantly increased during the total follow-up of maximum 10 years. Women with any bleeding symptom had increased risk of cancer of the corpus uteri (SIR 2.1, 95% CI 1.6-2.6), postmenopausal bleeding was the strongest symptom (RR 3.6, 95% CI 2.0-6.0). None of the bleeding symptoms increased subsequent risk of ovarian, vaginal or vulvar carcinoma. The risk of kidney cancer was increased (SIR 1.7, 95% CI 1.0-2.6)., Conclusions: The prevalence of bleeding symptoms was small and relative risks for cancers were low for them to be suitable as predictive factors of cancer neither in clinical practice nor for public health purposes, e.g. in developing selective screening based on this high risk group. Only 34 gynecological cancers during 220,000 person-years in women with bleeding symptoms were attributable to bleeding. Relative risks remained increased only for a short time after screening. Therefore, short term surveillance is important, but due to the fact that relative risks approached unity during the follow-up, reassurance of a woman that she is cancer-free should be emphasized more in the long term after the bleeding symptoms.

Background: The pattern of second cancers after treatment for cervical cancer provides important information on the risk of radiation-induced malignancies. Large numbers of women survive many years and can be studied for late effects., Methods: Incident second cancers in 86,193 patients with cervical cancer reported to 13 population-based cancer registries in 5 countries were evaluated to estimate the risk of second cancer among very long term survivors., Results: Overall, 7543 second cancers were observed versus 6015 cancers expected based on population rates (observed/expected = 1.2). Lung cancer accounted for nearly half of the excess cancers. Among the 49,828 women treated with radiation, 3750 survived 30 or more years and a two-fold risk of cancers of heavily irradiated organs was seen. Most of the excess cancers were of the rectum, vagina, vulva, ovary, and bladder. Patterns of risk over time since treatment were consistent with a radiation etiology. Significant increases of nonchronic lymphocytic leukemia and cancers of the bone and kidney were also linked to radiotherapy. Women treated surgically were also at significant risk of second cancers, in all likelihood related to cigarette smoking and risk factors similar to those of cervical cancer., Conclusions: Curative therapy for cervical cancer results in large numbers of long term survivors who develop second cancers very late in life. Radiation is an important cause of this increase and there is no evidence that risk returns to normal levels.

Long term trends in the incidence of and mortality from invasive cervical cancer have been studied in Finland (1953-1987) and Estonia (1968-1987). The analyses are based on the data from the Finnish and Estonian Cancer Registries. An organised nationwide screening programme for cervical cancer was started in Finland in the early 1960s. In Estonia, no cytological screening programme has been introduced, and cervical malignancies are diagnosed in routine gynaecological practice. During 1968-1987, both the incidence of and mortality from cervical cancer were considerably higher in Estonia than in Finland. A decrease has taken place in the cervical cancer incidence and mortality in both countries since the mid-1960s, but whereas in Finland the decrease has been marked, in Estonia it has been less pronounced and levelled off in the 1980s. In 1987, the age-standardised (world population) incidence rate per 100,000 women was 14.0 in Estonia and 3.8 in Finland, and the age-standardised mortality rate was 6.0 and 1.6 per 100,000, respectively. The difference in the incidence of the disease in the two neighbouring countries can be partially attributed to socioeconomic factors. The main reason for the different slopes of the trend curves for cervical cancer is probably the difference in public health policies: an effective mass screening programme is being conducted in Finland but not in Estonia.

Using data taken from the organised mass screening system in Finland, risk indicators of cervical cancer were identified in order to define a high-risk group which could then be used for selective screening of cervical cancer. Single risk factors classified at best 39% of the cases into a high-risk group of 8%. A combination of risk factors by different statistical methods was applied, but the results were essentially the same. In order to find a high-risk group small enough to yield a reduction in costs, the number of cases originating from the low-risk group was increased. Theoretical calculations showed that for selective screening to be effective, the risk of disease in the high-risk group relative to that in the low-risk group must be greater than that implied by current knowledge of cervical cancer epidemiology. It was concluded that selective screening has only a limited applicability.

Ecologic and individual risk indicators were derived from the population censuses of Finland Cancer Registry. The years covered in the study were 1955-1974 for the ecologic analysis and 1971-1975 for the analysis on individuals. The incidence of both diseases was high in an urban environment with high standard of living. The individuals with high risk of breast cancer were of high socioeconomic status and were well educated, whereas cervical cancer was common among women of low socioeconomic status and with less education. Conceptually similar indicators used on both the ecologic and individual levels characterize different aspects of risk; for example, a woman with a low standard of living in a well-to-do environment has a high risk of cervical cancer.

Names of women eligible to be screened for cervical cancer are taken from the national population registry and the women are invited by a personal letter. The data, from these mass screenings are analysed and stored at the screening registry. To reduced the costs of the system and to increase the yield of preinvasive lesions the idea of selective screening was considered. Tt was decided that if people were selected according to their risk factors, as recorded in the national population registry, the screening would be ineffective as many cases of invasive cancer were found in the low risk groups. High risk factors were determined from anamnestic data on systems and from previous cytological diagnoses. The proportion of women with symptoms of bleeding or the class II-V smears without positive histological results constituted fewer than 10% of the participants, but 20% and 40% respectively of invasive carcinomas were found in these groups during the subsequent follow-up period. Thus it is suggested that selective screening apart from that based on age has a limited application and should be restricted mainly to the interval between the organised screenings, which in Finland is five years.