Björn Strander

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

BACKGROUND Primary 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. METHODS We 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. RESULTS Compared 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). CONCLUSIONS Primary 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

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.

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.

Long term risk of invasive cancer after treatment for cervical intraepithelial neoplasia grade 3: population based cohort study

Objective To study the long term risk of invasive cancer of the cervix or vagina after treatment for cervical intraepithelial neoplasia grade 3. Design Prospective cohort study. Setting Swedish cancer registry. Participants All women in Sweden with severe dysplasia or cervical carcinoma in situ (equivalent to cervical intraepithelial neoplasia grade 3) treated during 1958-2002 (n=132 493) contributing 2 315 724 woman years. Main outcome measures Standardised incidence ratios with risk of cancer in the Swedish general female population as reference, and relative risks in multivariable log-linear regression model, with internal references. Results Women with previous cervical intraepithelial neoplasia grade 3 had an increased risk of invasive cervical cancer compared with the general female population (standardised incidence ratio 2.34, 95% confidence interval 2.18 to 2.50). The increased risk showed a decreasing trend with time since diagnosis for women treated later than 1970 but the risk was still increased after 25 years. An effect of age was found, with an accentuated increase in risk for women aged more than 50. The excess risk for cervical cancer associated with previous cervical intraepithelial neoplasia grade 3 has steadily increased since 1958. For vaginal cancer the standardised incidence ratio was 6.82 (5.61 to 8.21) but this decreased to 2.65 after 25 years. Adjustments in the multivariable log-linear regression model did not substantially alter these results. Conclusions Women previously treated for cervical intraepithelial neoplasia grade 3 are at an increased risk of developing invasive cervical cancer and vaginal cancer. This risk has increased since the 1960s and is accentuated in women aged more than 50. The risk is still increased 25 years after treatment.

Liquid-based cytology versus conventional Papanicolaou smear in an organized screening program : a prospective randomized study.

The objective of this study was to evaluate whether liquid‐based cytology (LBC) can improve high‐standard cervical cancer screening cytology further. The primary endpoint was histopathologic high‐grade lesions in current and subsequent screening rounds. The secondary endpoints were cytologic diagnosis and inadequate samples.

Increasing participation in cervical cancer screening: Offering a HPV self-test to long-term non-attendees as part of RACOMIP, a Swedish randomized controlled trial

RACOMIP is a population‐based, randomized trial of the effectiveness and cost‐effectiveness of different interventions aimed at increasing participation in a well‐run cervical cancer screening program in western Sweden. In this article, we report results from one intervention, offering non‐attendees a high‐risk human papillomavirus (HPV) self‐test. Comparison was made with standard screening invitation routine or standard routine plus a telephone call. Women (8,800), aged 30–62, were randomly selected among women without a registered Pap smear in the two latest screening rounds. These women were randomized 1:5:5 to one of three arms: 800 were offered a high‐risk HPV self‐test, 4,000 were randomized to a telephone call (reported previously) and 4,000 constituted a control group (standard screening invitation routine). Results were based on intention to treat analysis and cost‐effectiveness was calculated as marginal cost per cancer case prevented. The endpoint was the frequency of testing. The total response rate in the self‐testing arm was 24.5%, significantly higher than in the telephone arm (18%, RR 1.36, 95% CI 1.19–1.57) and the control group (10.6%, RR 2.33, 95% CI 2.00–2.71). All nine women who tested positive for high‐risk HPV attended for a cervical smear and colposcopy. From the health‐care sector perspective, the intervention will most likely lead to no additional cost. Offering a self‐test for HPV as an alternative to Pap smears increases participation among long‐term non‐attendees. Offering various screening options can be a successful method for increasing participation in this group.

The performance of a new scoring system for colposcopy in detecting high‐grade dysplasia in the uterine cervix

Objective.  To construct a simple scoring system for colposcopic examination that can facilitate education of colposcopists and increase the accuracy of evaluation.

Effect of ageing on cervical or vaginal cancer in Swedish women previously treated for cervical intraepithelial neoplasia grade 3: population based cohort study of long term incidence and mortality

Objective To determine factors influencing long term risks for acquiring or dying from invasive cervical or vaginal cancer in women previously treated for cervical intraepithelial neoplasia grade 3 (CIN3). Design Population based cohort study conducted in 1958-2008, followed up until 2009 in the Swedish Cancer Registry and Swedish Cause of Death Register, linked to the Swedish Population Register. Standardised incidence and mortality ratios were calculated for the risk of acquiring or dying from vaginal or cervical cancer, with the general female population in Sweden as reference. Relative risks in multivariable regression models were also calculated, adjusting for follow-up duration, treatment period, and age at CIN3 treatment or attained age. Setting Entire female population of Sweden. Participants 150 883 women in Sweden diagnosed and treated with CIN3 and followed up for invasive cervical or vaginal cancer, and related mortality. The cohort comprised 3 148 222 woman years. Main outcome measures Standardised incidence and mortality ratios, stratified by period for treatment. Relative standardised incidence ratios and standardised mortality ratios for age at acquiring or dying from cervical or vaginal cancer (attained age), adjusted for preset variables. Results Women previously diagnosed with CIN3 had an increased risk of dying from invasive cervical or vaginal cancer, compared with the general female population (standardised mortality ratio 2.35, 95% confidence interval 2.11 to 2.61). After age 60 years, these women had an accelerated increased risk of acquiring invasive cancer; a similar steep increase in mortality risk was seen after age 70. Regression analyses indicated that the increase in risk over time is highly attributable to ageing. Conclusions Women previously treated for CIN3 are at increased risk of developing and dying from cervical or vaginal cancer, compared with the general female population. The risk accelerates above age 60 years, suggesting a need for lifelong surveillance of these women.

Increasing participation in cervical cancer screening: telephone contact with long-term non-attendees in Sweden. Results from RACOMIP, a randomized controlled trial

Non‐participation is the foremost screening‐related risk factor for cervical cancer. We studied the effectiveness and cost‐effectiveness of an intervention to increase participation in the context of a well‐run screening program. Telephone contact with non‐attendees, offering an appointment to take a smear, was compared with a control group in a population‐based randomized trial in western Sweden. Of 8,800 randomly selected women aged 30–62, without a registered Pap smear in the two latest screening rounds, 4,000 were randomized to a telephone arm, another 800 were offered a high‐risk human papillomavirus (HPV) self‐test by mail (not reported in this article) and 4,000 constituted a control group. Endpoints were frequency of testing, frequency of abnormal smears and further assessment of abnormal tests. Participation during the following 12 months was significantly higher in the telephone arm than in the control group, 718 (18.0%) versus 422 (10.6%) [RR: 1.70, 95% confidence interval (CI): 1.52–1.90]. The number of detected abnormal smears was 39 and 19, respectively (RR: 2.05, 95% CI: 1.19–3.55). The respective numbers of further assessed abnormalities were 34 and 18 (RR: 1.89, 95% CI: 1.07–3.34). Twice as many high‐grade intraepithelial neoplasia (CIN2+) were detected and treated in the telephone arm: 14 and 7, respectively. Telephone contact with women who have abstained from cervical cancer screening for long time increases participation and leads to a significant increase in detection of atypical smears. Cost calculations indicate that this intervention is unlikely to be cost‐generating and this strategy is feasible in the context of a screening program.

Safety of modern treatment for cervical pre-cancer.

Most women can be reassured about future pregnancies