Sven Törnberg

Efficacy of HPV DNA Testing With Cytology Triage and/or Repeat HPV DNA Testing in Primary Cervical Cancer Screening

BACKGROUNDnPrimary cervical screening with both human papillomavirus (HPV) DNA testing and cytological examination of cervical cells with a Pap test (cytology) has been evaluated in randomized clinical trials. Because the vast majority of women with positive cytology are also HPV DNA positive, screening strategies that use HPV DNA testing as the primary screening test may be more effective.nnnMETHODSnWe used the database from the intervention arm (n = 6,257 women) of a population-based randomized trial of double screening with cytology and HPV DNA testing to evaluate the efficacy of 11 possible cervical screening strategies that are based on HPV DNA testing alone, cytology alone, and HPV DNA testing combined with cytology among women aged 32-38 years. The main outcome measures were sensitivity for detection of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) within 6 months of enrollment or at colposcopy for women with a persistent type-specific HPV infection and the number of screening tests and positive predictive value (PPV) for each screening strategy. All statistical tests were two-sided.nnnRESULTSnCompared with screening by cytology alone, double testing with cytology and for type-specific HPV persistence resulted in a 35% (95% confidence interval [CI] = 15% to 60%) increase in sensitivity to detect CIN3+, without a statistically significant reduction in the PPV (relative PPV = 0.76, 95% CI = 0.52 to 1.10), but with more than twice as many screening tests needed. Several strategies that incorporated screening for high-risk HPV subtypes were explored, but they resulted in reduced PPV compared with cytology. Compared with cytology, primary screening with HPV DNA testing followed by cytological triage and repeat HPV DNA testing of HPV DNA-positive women with normal cytology increased the CIN3+ sensitivity by 30% (95% CI = 9% to 54%), maintained a high PPV (relative PPV = 0.87, 95% CI = 0.60 to 1.26), and resulted in a mere 12% increase in the number of screening tests (from 6,257 to 7,019 tests).nnnCONCLUSIONSnPrimary HPV DNA-based screening with cytology triage and repeat HPV DNA testing of cytology-negative women appears to be the most feasible cervical screening strategy.

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

BACKGROUNDnThe 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.nnnMETHODSnWe 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.nnnRESULTSnWomen 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.nnnCONCLUSIONSnNonadherence 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.

Chlamydia trachomatis infection and persistence of human papillomavirus

Human papillomavirus (HPV) persistence is the major cause of cervical cancer, but most HPV infections will not persist and risk factors for HPV persistence are not well known. Chlamydia (C.) trachomatis infection seems to also be associated with cervical cancer. We investigated whether C. trachomatis infection is a risk factor for HPV persistence. In a cohort of 12,527 women participating in a population‐based HPV screening trial in Sweden, 6,418 women completed testing for HPV DNA by general primer PCR and typing by reverse dot blot hybridization. On average 19 months later, 303 women that had been HPV‐positive and had normal cytology at enrollment completed a new HPV test. Environmental exposures were assessed by an 87‐item questionnaire. Previous sexually transmitted infections were also investigated by serology. At follow‐up, 44% of the women were positive for the same type of HPV DNA as at enrollment. Persistence correlated with length of follow‐up (p < 0.01) and condom use seemed to protect against HPV persistence (p < 0.05). The most significant risk factor for persistent presence of HPV DNA was self‐reported history of previous C. trachomatis infection (relative risk in multivariate model = 2.09; 95% confidence interval = 1.05–4.18). We conclude that persistence of oncogenic HPV infections is more likely among women with a previous C. trachomatis infection.

BREAST CANCER RISK IN RELATION TO SERUM CHOLESTEROL, SERUM BETA-LIPOPROTEIN, HEIGHT, WEIGHT, AND BLOOD PRESSURE

The relation between breast cancer risk and serum levels of cholesterol and beta-lipoprotein (BLP), height, weight, Quetelets index and blood pressure was studied in a cohort of 46,570 Swedish women less than 75 years of age. The cohort was examined between 1963 and 1965 and followed up in the Swedish Cancer Registry until 1983. During this period 1,182 cases of breast cancer were reported. Of those, 196 were reported among women less than 50 years of age. Statistically significant positive associations were observed between height, weight, and systolic blood pressure and breast cancer risk. No clear trend in cancer risk related to serum cholesterol or BLP was seen in the total material. In a stepwise Cox multiple regression analysis only the associations with height and blood pressure remained significant. Among women, having their cancer diagnosed before the age of 50, higher Quetelets index was associated with a lower cancer risk, whereas a positive correlation was seen among women greater than or equal to 50 years. In the group of younger women a high BLP level was associated with an increased risk of breast cancer. This relation became even stronger when studied in a multivariate analysis, which also showed a negative correlation between serum cholesterol and cancer risk.

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.

Risks of cancer of the colon and rectum in relation to serum cholesterol and beta-lipoprotein.

We studied the risk of colorectal cancer in relation to serum cholesterol and beta-lipoprotein in more than 92,000 Swedish subjects less than 75 years old. The cohort was examined between 1963 and 1965 and followed by means of the Swedish Cancer Register until 1979. During this period, 528 colon cancers and 311 rectal cancers developed. A positive association was observed between the serum cholesterol level and the risk of rectal cancer among men (P less than 0.05), with a relative risk of 1.65 in men with levels greater than or equal to 276 mg per deciliter (7.1 mmol per liter). An association was also observed between the serum beta-lipoprotein level and the risk of rectal cancer among men (P less than 0.05). When cholesterol and beta-lipoprotein levels were considered together, they were associated with both rectal and colon cancer in men. The relative risk in men with both cholesterol greater than or equal to 250 mg per deciliter (6.5 mmol per liter) and beta-lipoprotein greater than or equal to 12 units (2.2 g per liter) was 1.62 for colon cancer (95 percent confidence interval, 1.18 to 2.22) and 1.70 for rectal cancer (1.18 to 2.44). Similar trends were observed in women, although they were not statistically significant.

HPV type-specific risks of high-grade CIN during 4 years of follow-up: A population-based prospective study

We followed a population-based cohort of 5696 women, 32–38 years of age, by registry linkage with cytology and pathology registries during a mean follow-up time of 4.1 years to assess the importance for CIN2+ development of type-specific HPV DNA positivity at baseline. HPV 16, 31 and 33 conveyed the highest risks and were responsible for 33.1, 18.3 and 7.7% of CIN2+ cases, respectively. Women infected with HPV 18, 35, 39, 45, 51, 52, 56, 58, 59 and 66 had significantly lower risks of CIN2+ than women infected with HPV 16. After adjustment for infection with other HPV types, HPV types 35, 45, 59 and 66 had no detectable association with CIN2+. In summary, the different HPV types found in cervical cancer show distinctly different CIN2+ risks, with high risks being restricted to HPV 16 and its close relatives HPV 31 and HPV 33.

European guidelines for quality assurance in cervical cancer screening. Summary of the supplements on HPV screening and vaccination

In a project coordinated by the International Agency for Research on Cancer (IARC) 31 experts from 11 European countries and IARC have developed supplements to the current European guidelines for quality assurance in cervical cancer screening. The supplements take into account the potential of primary testing for human papillomavirus (HPV) and vaccination against HPV infection to improve cervical cancer prevention and control and will be published by the European Commission in book format. They include 62 recommendations or conclusions for which the strength of the evidence and the respective recommendations is graded. While acknowledging the available evidence for more efficacious screening using HPV primary testing compared to screening based on cytology, the authors and editors of the supplements emphasize that appropriate policy and programme organization remain essential to achieve an acceptable balance between benefit and harm of any screening or vaccination programme. A summary of the supplements and all of the graded recommendations are presented here in journal format to make key aspects of the updated and expanded guidelines known to a wider professional and scientific community.

'I got a letter ...' a qualitative study of women's reasoning about attendance in a cervical cancer screening programme in urban Sweden

This explorative study aims at investigating how ‘healthy’ women describe and reason about participation in a cervical cancer screening programme in Sweden. The study is part of a multidisciplinary research project studying a population‐based cervical cancer‐screening programme from the perspective of different actors.

Service screening with mammography in Sweden : Evaluation of effects of screening on breast cancer mortality in age group 40-49 years

The aim of the study was to develop a model for estimating the effect of the nation-wide service screening program with mammography on breast cancer mortality in Sweden. In 1997, the introduction of population-based service screening had been completed in all 26 counties. In approximately half of the counties suitable for evaluation, the lower age limit for invitation was 40 years (study population) and in the other half the age limit was 50 years (control population). The numbers of females aged 40-49 years for the two populations were 202 152 and 237 279, respectively (1988). The study and control populations were compared for the period 1986-1996 with regard to refined breast cancer mortality. To adjust for geographical differences, the period 1976-1986 was used as reference. With a mean follow-up time of 8 years, the estimated relative risk of breast cancer death in relation to invitation to service screening among women aged 40-49 years at breast cancer diagnosis was 0.91 (95% confidence interval 0.72-1.15). These findings were compatible with those presented in the previous overview of the Swedish randomized studies.The aim of the study was to develop a model for estimating the effect of the nation-wide service screening program with mammography on breast cancer mortality in Sweden. In 1997, the introduction of population-based service screening had been completed in all 26 counties. In approximately half of the counties suitable for evaluation, the lower age limit for invitation was 40 years (study population) and in the other half the age limit was 50 years (control population). The numbers of females aged 40 49 years for the two populations were 202,152 and 237,279, respectively (1988). The study and control populations were compared for the period 1986-1996 with regard to refined breast cancer mortality. To adjust for geographical differences, the period 1976 1986 was used as reference. With a mean follow-up time of 8 years, the estimated relative risk of breast cancer death in relation to invitation to service screening among women aged 40-49 years at breast cancer diagnosis was 0.91 (95% confidence interval 0.72-1.15). These findings were compatible with those presented in the previous overview of the Swedish randomized studies.