Bengt Andrae

Screening-Preventable Cervical Cancer Risks : Evidence From a Nationwide Audit in Sweden

BACKGROUND The effectiveness of cervical cancer screening programs differs widely in different populations. The reasons for these differences are unclear. Routine and comprehensive audits have been proposed as an ethically required component of screening. We performed a nationwide audit of the effectiveness of the Swedish cervical cancer screening program. METHODS We identified all invasive cervical cancer cases that were diagnosed in Sweden from January 1, 1999, through December 31, 2001, and had been reported to the Swedish Cancer Registry (n = 1230 cases). We verified the diagnoses by histopathologic rereview and matched each case subject to five (population-based) age-matched control subjects who were identified from the National Population Register. The Pap smear screening histories for case and control subjects were reviewed for a 6-year period using the National Cervical Cancer Screening Register, which contains data on essentially all relevant cytological and histological diagnoses in Sweden. Odds ratios (ORs), and their 95% confidence intervals (CIs), of cervical cancer according to screening history were calculated in conditional logistic regression models. All statistical tests were two-sided. RESULTS Women who had not had a Pap smear within the recommended screening interval had higher risk of cervical cancer than women who had been screened (OR = 2.52, 95% CI = 2.19 to 2.91). This risk was similarly increased for all age groups (P(homogeneity) = .96). The risk for non-squamous cell cervical cancers (OR = 1.59, 95% CI = 1.20 to 2.11) was also increased. Women who had not had a Pap smear within the recommended screening interval had a particularly high risk of advanced cancers (OR = 4.82, 95% CI = 3.61 to 6.44). Among women who had been screened within the recommended interval, those with abnormal Pap smears had a higher risk of cervical cancer than those with normal smears (OR = 7.55, 95% CI = 5.88 to 9.69) and constituted 11.5% of all women with cervical cancer. CONCLUSIONS Nonadherence to screening intervals was the major reason for cervical cancer morbidity. The screening program was equally effective for women of all ages and was also effective against non-squamous cancers.

The challenges of organising cervical screening programmes in the 15 old member states of the European Union

Cervical cancer incidence and mortality can be reduced substantially by organised cytological screening at 3 to 5 year intervals, as was demonstrated in the Nordic countries, the United Kingdom, the Netherlands and parts of Italy. Opportunistic screening, often proposed at yearly schedules, has also reduced the burden of cervical cancer in some, but not all, of the other old member states (belonging to the European Union since 1995) but at a cost that is several times greater. Well organised screening programmes have the potential to achieve greater participation of the target population at regular intervals, equity of access and high quality. Despite the consistent evidence that organised screening is more efficient than non-organised screening, and in spite of the Cancer Screening Recommendations of the European Council, health authorities of eight old member states (Austria, Belgium, France, Germany, Greece, Luxembourg, Portugal and Spain) have not yet started national organised implementation of screening for cervical cancer. A decision was made by the Irish government to extend their pilot programme nationally while new regional programmes commenced in Portugal and Spain. Introduction of new methods of prevention, such as HPV screening and prophylactic HPV vaccination, can reduce the burden further, but this will require a high level of organisation with particular attention needed for the maximisation of population coverage, compliance with evidence-based guidelines, monitoring of data enabling continued evaluation and improvement of the preventive programmes.

Screening and cervical cancer cure : population based cohort study

Objective To determine whether detection of invasive cervical cancer by screening results in better prognosis or merely increases the lead time until death. Design Nationwide population based cohort study. Setting Sweden. Participants All 1230 women with cervical cancer diagnosed during 1999-2001 in Sweden prospectively followed up for an average of 8.5 years. Main outcome measures Cure proportions and five year relative survival ratios, stratified by screening history, mode of detection, age, histopathological type, and FIGO (International Federation of Gynecology and Obstetrics) stage. Results In the screening ages, the cure proportion for women with screen detected invasive cancer was 92% (95% confidence interval 75% to 98%) and for symptomatic women was 66% (62% to 70%), a statistically significant difference in cure of 26% (16% to 36%). Among symptomatic women, the cure proportion was significantly higher for those who had been screened according to recommendations (interval cancers) than among those overdue for screening: difference in cure 14% (95% confidence interval 6% to 23%). Cure proportions were similar for all histopathological types except small cell carcinomas and were closely related to FIGO stage. A significantly higher cure proportion for screen detected cancers remained after adjustment for stage at diagnosis (difference 15%, 7% to 22%). Conclusions Screening is associated with improved cure of cervical cancer. Confounding cannot be ruled out, but the effect was not attributable to lead time bias and was larger than what is reflected by down-staging. Evaluations of screening programmes should consider the assessment of cure proportions.

Trust versus concerns : how parents reason when they accept HPV vaccination for their young daughter

Abstract Background. From spring of 2012, human papillomavirus (HPV) vaccine against cervical cancer is offered free of charge to all girls aged 10–12 years through a school-based vaccination programme in Sweden. The aim of this study was to explore how parents reason when they accept HPV vaccination for their young daughter and also their views on HPV-related information. Methods. Individual interviews with parents (n = 27) of 11–12-year-old girls. The interviews were recorded, transcribed verbatim, and analysed using thematic content analysis. Results. Three themes emerged through the analysis: Trust versus concern, Responsibility to protect against severe disease, and Information about HPV and HPV vaccination is important. The parents expressed trust in recommendations from authorities and thought it was convenient with school-based vaccination. They believed that cervical cancer was a severe disease and felt a responsibility to protect their daughter from it. Some had certain concerns regarding side effects and vaccine safety, and wished for a dialogue with the school nurse to bridge the information gaps. Conclusions. Trust in the recommendations from authorities and a wish to protect their daughter from a severe disease outweighed concerns about side effects. A school-based vaccination programme is convenient for parents, and the school nurse has an important role in bridging information gaps. The findings from this qualitative study cannot be generalized; however, it can provide a better understanding of how parents might reason when they accept the HPV vaccination for their daughter.

School-based intervention for the prevention of HPV among adolescents: a cluster randomised controlled study

Objective To improve primary prevention of human papillomavirus (HPV) infection by promoting vaccination and increased condom use among upper secondary school students. Design Cluster randomised controlled trial. Setting 18 upper secondary schools in Sweden. Participants Schools were first randomised to the intervention or the control group, after which individual classes were randomised so as to be included or not. Of the 832 students aged 16 years invited to participate during the regular individual health interview with the school nurse, 751 (90.2%) agreed to participate and 741 (89.1%) students completed the study. Interventions The intervention was based on the Health Belief Model (HBM). According to HBM, a persons health behaviour can be explained by individual beliefs regarding health actions. School nurses delivered 30 min face-to-face structured information about HPV, including cancer risks and HPV prevention, by propagating condom use and HPV vaccination. Students in the intervention and the control groups completed questionnaires at baseline and after 3 months. Main outcome measures Intention to use condom with a new partner and beliefs about primary prevention of HPV, and also specifically vaccination status and increased condom use. Results All statistical analyses were performed at the individual level. The intervention had a significant effect on the intention to use condom (p=0.004). There was also a significant effect on HBM total score (p=0.003), with a 2.559 points higher score for the intervention group compared to the controls. The influence on the HBM parameters susceptibility and severity was also significant (p<0.001 for both variables). The intervention also influenced behaviour: girls in the intervention group chose to have themselves vaccinated to a significantly higher degree than the controls (p=0.02). No harms were reported. Conclusions The school-based intervention had favourable effects on the beliefs about primary prevention of HPV, and increased the HPV vaccination rates in a diverse population of adolescents. Trial registration number NCT02280967; Results.

Risk of invasive cervical cancer after atypical glandular cells in cervical screening: nationwide cohort study

Objectives To investigate the risks of invasive cervical cancer after detection of atypical glandular cells (AGC) during cervical screening. Design Nationwide population based cohort study. Setting Cancer and population registries in Sweden. Participants 3 054 328 women living in Sweden at any time between 1 January 1980 and 1 July 2011 who had any record of cervical cytological testing at ages 23-59. Of these, 2 899 968 women had normal cytology results at the first screening record. The first recorded abnormal result was atypical glandular cells (AGC) in 14 625, high grade squamous intraepithelial lesion (HSIL) in 65 633, and low grade squamous intraepithelial lesions (LSIL) in 244 168. Main outcome measures Cumulative incidence of invasive cervical cancer over 15.5 years; proportion of invasive cervical cancer within six months of abnormality (prevalence); crude incidence rates for invasive cervical cancer over 0.5-15.5 years of follow-up; incidence rate ratios compared with women with normal cytology, estimated with Poisson regression adjusted for age and stratified by histopathology of cancer; distribution of clinical assessment within six months after the abnormality. Results The prevalence of cervical cancer was 1.4% for women with AGC, which was lower than for women with HSIL (2.5%) but higher than for women with LSIL (0.2%); adenocarcinoma accounted for 73.2% of the prevalent cases associated with AGC. The incidence rate of invasive cervical cancer after AGC was significantly higher than for women with normal results on cytology for up to 15.5 years and higher than HSIL and LSIL for up to 6.5 years. The incidence rate of adenocarcinoma was 61 times higher than for women with normal results on cytology in the first screening round after AGC, and remained nine times higher for up to 15.5 years. Incidence and prevalence of invasive cervical cancer was highest when AGC was found at ages 30-39. Only 54% of women with AGC underwent histology assessment within six months, much less than after HSIL (86%). Among women with histology assessment within six months, the incidence rate of cervical cancer after AGC was significantly higher than that after HSIL for up to 6.5 years. Conclusions AGC found at cervical screening is associated with a high and persistent risk of cervical cancer for up to 15 years, particularly for cervical adenocarcinoma and women with AGC at age 30-39. Compared with the reduction in risk of cancer seen after HSIL management, management of AGC seems to have been suboptimal in preventing cervical cancer. Research to optimise management is needed, and a more aggressive assessment strategy is warranted.

Risk of invasive cervical cancer in relation to management of abnormal Pap smear results

OBJECTIVE We sought to evaluate the management of women with abnormal cytology in terms of subsequent risk of invasive cervical cancer. STUDY DESIGN The screening histories of all invasive cervical cancer cases diagnosed in Sweden 1999-2001 and of 5 population-based controls per case were reviewed. In all, 159 patients and 258 control subjects aged < 67 years had an abnormal smear result 0.5-6.5 years prior to cancer diagnosis. The cervical cancer risk was estimated in relation to management by calculating odds ratios. RESULTS Histologic assessment of low-grade squamous abnormalities strongly reduced the risk compared to repeated cytology (odds ratio, 0.46; 95% confidence interval, 0.24-0.89). Delaying histologic assessment was also associated with a higher risk (odds ratio, 5.65; 95% confidence interval, 1.39-23.05). After high-grade squamous atypia, absence of any cytologic or histologic specimen was a major determinant of cancer risk (odds ratio, 12.52; 95% confidence interval, 1.42-infinitive). CONCLUSION For adequate protection against invasive cervical cancer, further assessment with histology must be recommended also for women with low-grade squamous abnormalities.

Effectiveness of cervical screening after age 60 years according to screening history: Nationwide cohort study in Sweden

Background The relatively high incidence of cervical cancer in women at older ages is a continuing concern in countries with long-established cervical screening. Controversy remains on when and how to cease screening. Existing population-based studies on the effectiveness of cervical screening at older ages have not considered women’s screening history. We performed a nationwide cohort study to investigate the incidence of cervical cancer after age 60 years and its association with cervical screening at age 61–65, stratified by screening history at age 51–60. Methods and findings Using the Total Population Register, we identified 569,132 women born between 1 January 1919 and 31 December 1945, resident in Sweden since age 51. Women’s cytological screening records, cervical cancer occurrence, and FIGO stage (for those diagnosed with cancer) were retrieved from national registers and medical charts. We calculated the cumulative incidence of cervical cancer from age 61 to age 80 using a survival function considering competing risk, and estimated the hazard ratio (HR) of cervical cancer in relation to screening status at age 61–65 from Cox models, adjusted for birth cohort and level of education, conditioning on women’s screening history in their 50s. In women unscreened in their 50s, the cumulative incidence up to age 80 was 5.0 per 1,000 women, and screening at age 61–65 was associated with a lower risk for cervical cancer (HR = 0.42, 95% CI 0.24–0.72), corresponding to a decrease of 3.3 cancer cases per 1,000 women. A higher cumulative incidence and similarly statistically significant risk decrease was seen for women with abnormal smears in their 50s. In women adequately or inadequately screened with only normal results between age 51 and age 60, the cumulative incidence of cervical cancer from age 61 to 80 was 1.6 and 2.5 per 1,000 women, respectively, and further screening at age 61–65 was not associated with statistically significant decreases of cervical cancer risk up to age 80, but with fewer cancer cases of advanced stages at age 61–65. Adjustment for potential lifestyle confounders was limited. Conclusions In this study, cervical screening with cytology at age 61–65 was associated with a statistically significant reduction of subsequent cervical cancer risk for women who were unscreened, or screened with abnormalities, in their 50s. In women screened with normal results in their 50s, the risk for future cancer was not sizeable, and the risk reduction associated with continued screening appeared limited. These findings should inform the current debate regarding age and criteria to discontinue cervical screening.

Follow-up of women with cervical cytological abnormalities showing atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion: a nationwide cohort study

BACKGROUND: Atypical squamous cells of undetermined significance or low‐grade squamous intraepithelial lesion in abnormal cervical cytology among young women in cervical cancer screening is an increasing health burden, and comparative effectiveness studies of different management options for such diagnoses are needed. OBJECTIVE: The objective of the study was to compare the incidence of invasive cervical cancer, following different management options pursued after an atypical squamous cells of undetermined significance/low‐grade squamous intraepithelial lesion index smear. STUDY DESIGN: In this nationwide cohort study, we included all women aged 22‐50 years and resident in Sweden 1989–2011 and with at least 1 cervical smear registered during the study period (n = 2,466,671). Follow‐up of a first atypical squamous cells of undetermined significance/low‐grade squamous intraepithelial lesion cytological diagnosis within 25 months was classified as repeat cytology, colposcopy/biopsy, or without further assessment. Incidence rate ratios and 95% confidence intervals of subsequent cervical cancer within 6.5 years following atypical squamous cells of undetermined significance/low‐grade squamous intraepithelial lesion were estimated using Poisson regression by age group and management strategy. RESULTS: Women managed with repeat cytology within 6 months after atypical squamous cells of undetermined significance or low‐grade squamous intraepithelial lesion cytology had a similar risk of cervical cancer compared with colposcopy/biopsy (incidence rate ratio, 1.1, 95% confidence interval, 0.5–2.5, and incidence rate ratio, 2.0, 95% confidence interval, 0.6–6.5, respectively) among women aged 22–27 years. For women aged 28 years and older, women managed with repeat cytology had a higher risk for cervical cancer than women managed with colposcopy/biopsy. CONCLUSION: Our findings suggest that women with a first cytological diagnosis of atypical squamous cells of undetermined significance/low‐grade squamous intraepithelial lesion up to age 27 years may indeed be safely followed up with repeat cytology within 6 months. A large amount of colposcopies that are currently performed in this group, therefore, could safely be discontinued.

High-risk human papillomavirus status and prognosis in invasive cervical cancer: A nationwide cohort study

Background High-risk human papillomavirus (hrHPV) infection is established as the major cause of invasive cervical cancer (ICC). However, whether hrHPV status in the tumor is associated with subsequent prognosis of ICC is controversial. We aim to evaluate the association between tumor hrHPV status and ICC prognosis using national registers and comprehensive human papillomavirus (HPV) genotyping. Methods and findings In this nationwide population-based cohort study, we identified all ICC diagnosed in Sweden during the years 2002–2011 (4,254 confirmed cases), requested all archival formalin-fixed paraffin-embedded blocks, and performed HPV genotyping. Twenty out of 25 pathology biobanks agreed to the study, yielding a total of 2,845 confirmed cases with valid HPV results. Cases were prospectively followed up from date of cancer diagnosis to 31 December 2015, migration from Sweden, or death, whichever occurred first. The main exposure was tumor hrHPV status classified as hrHPV-positive and hrHPV-negative. The primary outcome was all-cause mortality by 31 December 2015. Five-year relative survival ratios (RSRs) were calculated, and excess hazard ratios (EHRs) with 95% confidence intervals (CIs) were estimated using Poisson regression, adjusting for education, time since cancer diagnosis, and clinical factors including age at cancer diagnosis and International Federation of Gynecology and Obstetrics (FIGO) stage. Of the 2,845 included cases, hrHPV was detected in 2,293 (80.6%), and we observed 1,131 (39.8%) deaths during an average of 6.2 years follow-up. The majority of ICC cases were diagnosed at age 30–59 years (57.5%) and classified as stage IB (40.7%). hrHPV positivity was significantly associated with screen-detected tumors, young age, high education level, and early stage at diagnosis (p < 0.001). The 5-year RSR compared to the general female population was 0.74 (95% CI 0.72–0.76) for hrHPV-positive cases and 0.54 (95% CI 0.50–0.59) for hrHPV-negative cases, yielding a crude EHR of 0.45 (95% CI 0.38–0.52) and an adjusted EHR of 0.61 (95% CI 0.52–0.71). Risk of all-cause mortality as measured by EHR was consistently and statistically significantly lower for cases with hrHPV-positive tumors for each age group above 29 years and each FIGO stage above IA. The difference in prognosis by hrHPV status was highly robust, regardless of the clinical, histological, and educational characteristics of the cases. The main limitation was that, except for education, we were not able to adjust for lifestyle factors or other unmeasured confounders. Conclusions In this study, women with hrHPV-positive cervical tumors had a substantially better prognosis than women with hrHPV-negative tumors. hrHPV appears to be a biomarker for better prognosis in cervical cancer independent of age, FIGO stage, and histological type, extending information from already established prognostic factors. The underlying biological mechanisms relating lack of detectable tumor hrHPV to considerably worse prognosis are not known and should be further investigated.