71
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      HPV testing on self collected cervicovaginal lavage specimens as screening method for women who do not attend cervical screening: cohort study

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Objective To determine whether offering self sampling of cervicovaginal material for high risk human papillomavirus (HPV) testing is an effective screening method for women who do not attend regular cervical screening programmes.

          Design Cohort study (the PROHTECT trial).

          Settings Noord-Holland and Flevoland regions of the Netherlands, December 2006 to December 2007, including 13 laboratories, gynaecologists, and more than 800 general practitioners.

          Participants 28 073 women who had not responded to two invitations to the regular cervical screening programme: 27 792 women were assigned to the self sampling group and invited to submit a self collected cervicovaginal sample for HPV testing; 281 were assigned to the recall control group and received a second re-invitation for conventional cytology.

          Intervention Women with a positive result on the high risk HPV test on their self sample material were referred to their general practitioner. Women with abnormal results on cytology were referred for colposcopy. Women with normal results on cytology were re-evaluated after one year by cytology and high risk HPV testing and referred for colposcopy if either result was positive.

          Main outcome measures Attendance rate in both groups and yield of cervical intraepithelial neoplasia grade II/III or worse (≥CIN II/≥CIN III) in self sampling responders.

          Results The compliance rate in the self sampling group was significantly higher than in the control group (crude 26.6% v 16.4%, P<0.001; adjusted 27.5% v 16.6%, P<0.001). The number of detected ≥CIN II and ≥CIN III lesions in self sampling responders was 99 (1.3%) and 76 (1.0%), respectively. Self sampling responders who had not participated in the previous round of screening (43%) had increased relative risks of ≥CIN II (2.04, 95% confidence interval 1.27 to 3.28) and ≥CIN III (2.28, 1.31 to 3.96) compared with self sampling women who had been screened in the previous round (57%).

          Conclusions Offering self sampling by sending a device for collecting cervicovaginal specimens for high risk HPV testing to women who did not attend regular screening is a feasible and effective method of increasing coverage in a screening programme. The response rate and the yield of high grade lesions support implementation of this method for such women.

          Trial registration ISRCTN45527158.

          Related collections

          Most cited references26

          • Record: found
          • Abstract: found
          • Article: not found

          Pathology Databanking and Biobanking in The Netherlands, a Central Role for PALGA, the Nationwide Histopathology and Cytopathology Data Network and Archive

          Since 1991, a nationwide histopathology and cytopathology network and archive is in operation in The Netherlands under the name PALGA, encompassing all sixty-four pathology laboratories in The Netherlands. The overall system comprises decentralized systems at the participating laboratories, a central databank, and a dedicated communication and information exchange tool. Excerpts of all histopathology and cytopathology reports are generated automatically at the participating laboratories and transferred to the central databank. Both the decentralized systems and the central system perform checks on the quality and completeness of excerpts. Currently, about 42 million records on almost 10 million patients are stored in the central databank. Each excerpt contains patient identifiers, including demographic data and the so-called PALGA diagnosis. The latter is structured along five classification axes: topography, morphology, function, procedure, and diseases. All data transfer and communication occurs electronically with encryption of patient and laboratory identifiers. All excerpts are continuously available to all participating pathology laboratories, thus contributing to the quality of daily patient care. In addition, external parties may obtain permission to use data from the PALGA system, either on an ongoing basis or on the basis of a specific permission. Annually, 40 to 60 applications for permission to use PALGA data are submitted. Among external users are the Dutch cancer registry, population-based screening programs for cancer of the uterine cervix and breast cancer in The Netherlands, and individual investigators addressing a range of research questions. Many scientific papers and theses incorporating PALGA data have been published already. In conclusion, the PALGA system is a unique system that requires a minimal effort on the part of the participating laboratories, while providing them a powerful tool in their daily practices.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Human papillomavirus DNA testing for the detection of cervical intraepithelial neoplasia grade 3 and cancer: 5-year follow-up of a randomised controlled implementation trial.

            Tests for the DNA of high-risk types of human papillomavirus (HPV) have a higher sensitivity for cervical intraepithelial neoplasia grade 3 or worse (CIN3+) than does cytological testing, but the necessity of such testing in cervical screening has been debated. Our aim was to determine whether the effectiveness of cervical screening improves when HPV DNA testing is implemented. Women aged 29-56 years who were participating in the regular cervical screening programme in the Netherlands were randomly assigned to combined cytological and HPV DNA testing or to conventional cytological testing only. After 5 years, combined cytological and HPV DNA testing were done in both groups. The primary outcome measure was the number of CIN3+ lesions detected. Analyses were done by intention to treat. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN20781131. 8575 women in the intervention group and 8580 in the control group were recruited, followed up for sufficient time (> or =6.5 years), and met eligibility criteria for our analyses. More CIN3+ lesions were detected at baseline in the intervention group than in the control group (68/8575 vs 40/8580, 70% increase, 95% CI 15-151; p=0.007). The number of CIN3+ lesions detected in the subsequent round was lower in the intervention group than in the control group (24/8413 vs 54/8456, 55% decrease, 95% CI 28-72; p=0.001). The number of CIN3+ lesions over the two rounds did not differ between groups. The implementation of HPV DNA testing in cervical screening leads to earlier detection of CIN3+ lesions. Earlier detection of such lesions could permit an extension of the screening interval.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Benefit of cervical screening at different ages: evidence from the UK audit of screening histories

              While most experts agree that cervical screening is effective, there remains controversy over the most appropriate screening interval. Annual screening is common in North America (even in women who have been screened several times previously), while 5-yearly screening is provided by some European countries. Here, we estimate the benefits of screening at different intervals and at different ages from a large population-based case–control study. Following the relaunch of the National Cervical Screening Programmes in the United Kingdom in 1988, we initiated a protocol to monitor its effectiveness. Originally under the auspices of the National Coordinating Network and more recently with the support of the National Screening Office, we have been collecting data on the screening histories of all women from self-selected Health Authorities and Health Boards (HAs) with newly diagnosed cancer and a small control of sample women without cervical cancer. We previously reported results on 5 years of screening in 1025 women, including 348 with cancer (Sasieni et al, 1996). The full data set now has over 2500 women with cancer. Here we analyse data on 1305 women diagnosed with stage 1B or worse cervical cancer between the ages of 20 and 69 years, and 2532 controls with a total of approximately 40 000 women-years of screening (35 000 since 1988). Approximately 90% of cases in this report were not included in the previous report. The rationale for restricting attention to frankly invasive cancer is that ideally these should all be prevented by screening, whereas microinvasive cancers are mostly screen-detected and have an extremely good cure rate. MATERIALS AND METHODS The methods have been described previously (Sasieni et al, 1996). The participating HAs have changed over the years due to boundary changes and changes in personnel. Areas that contributed data and the years for which they contributed are listed in the Acknowledgements. Data were collected by local coordinators as part of audit. Cases were identified from pathology laboratories and confirmed to have been resident in the HA at diagnosis. Data recorded included the date of diagnosis and, where possible, the stage and histology of the cancers. Age-matched controls, for each case, were identified from among women (not known to have had a hysterectomy) registered with a group practice (GP) in the same area. One control was selected from the same GP, the other from another GP in the same area. Screening histories (including the dates and results of all smears) were downloaded from the Exeter computer system and checked against information held by cytology laboratories. The Exeter system is used to run the screening programme and stores screening histories of all women registered with a GP. All smears in this study were prepared by conventional (as opposed to liquid-based) cytology and classified according to a version of the British Society for Clinical Cytology (BSCC) system (Johnson and Patnick, 2000). In all analyses, a case's date of diagnosis was used as a pseudo-date of diagnosis for her matched controls, and only smears taken prior to that date were considered. All smears in teenagers were excluded because they are not part of the screening programme and are likely to identify a high-risk group. Odds ratios and their confidence intervals (CIs) were estimated by conditional logistic regression (Breslow and Day, 1980). As cervical cancer is a rare disease, odds ratios are interpreted as relative risks (RRs) and are referred to as such. Age groups refer to the age at diagnosis, not the age at which the smear was taken. One measure of exposure is the time between the last ‘operationally’ negative smear and (pseudo-) diagnosis. An operationally negative smear is defined as a negative smear not preceded by an abnormal smear (borderline or worse) within the previous 12 months. A second measure of exposure is the time prior to diagnosis of the most recent adequate screening smear (regardless of result) ignoring all smears within 6 months of diagnosis. A screening smear is defined here to be one that was not preceded (at any time) by an abnormal smear. An adequate smear is one that was not classed as inadequate (for making a good cytological classification). To estimate the protection from frankly invasive cervical cancer by being screened once every 3 years, we calculate the mean of the RRs for 0.5–1.5, 1.5–2.5 and 2.5–3.5 years, and similarly for 5 years. For ‘time since last negative’, the first interval is 0–1.5 years and is weighted accordingly when calculating the mean. The proportion preventable is one minus the mean RR. RESULTS The database includes 2753 women with invasive cervical cancer diagnosed between 1990 and 2001 (91% between 1992 and 1998). Their age distribution (Table 1 Table 1 Age distribution of invasive, microinvasive and unknown stage cases from this audit compared to all UK cervical cancer registrations   Stage     Age group (years) 1A 1B+ Unknown Total Registrations for UK 1993–1997 (%) 6 years 4.1 3.6 Never 18.4 16.3       Total 2532 1305 Time measure from date of (pseudo-) diagnosis. ). Half of all cases had a smear within 3 months of diagnosis compared to just 5% 6–12 months prior to diagnosis. In fact, the 6-month exclusion (used in Table 4) is not long enough to take account of all ‘diagnostic smears’ – the relative proportions last screened 6–12 months, compared to 1–6 years, prediagnosis is greater in cases than controls (P=0.002). Another difficulty with identifying the last screening test is that once a woman has been treated for a cervical lesion, she could be put on indefinite annual follow-up. Our solution of censoring screening histories at the first abnormal smear is not ideal and it potentially introduces a small bias in favour of screening. Further, the fact that the RRs (in Table 4) are greater in the first time period than the second suggests that the 6-month exclusion is not quite sufficient and that these RRs should not be overinterpreted. Despite these caveats, we believe that this approach does provide reasonable estimates of the efficacy of 3- and 5-yearly (but not annual) screening (Table 5). In younger women, the risk of disease in those whose last smear was more than 5.5 years ago was greater than in those who had no smears (Table 3 and 4). This suggests that those who opt out of screening altogether are at a lower underlying risk of cervical cancer than those who are screened occasionally. Opportunistic screening of women seeking contraceptive advice and those attending STD clinics could account for such a trend. What then is the appropriate baseline for estimating the RRs? We have used those with no smears, but use of those with no recent smear would have made the estimated effect of screening considerably greater in young women. The RR in women aged 20–39 years, whose most recent operationally negative smear was 3.5–4.5 years ago, was 1.06 relative to those with no such smear (Table 3). However, relative to those whose most recent negative smear was more than 6.5 years ago, it is 0.45 (=1.06/2.37). In our opinion, such adjusted RRs are inappropriate: (ignoring the effect of screening) it is more likely that those who were last screened many years ago form a high-risk subgroup than that those who are never screened are at low risk. But this needs to be tested by a larger, more detailed study in young women in which risk factors for the acquisition and persistence of HPV infection are collected along with screening histories. POLICY CONSIDERATIONS Policy should be determined by balancing costs against benefits. Although there are fixed overheads, the main cost is proportional to the number of screening tests. Thus, 3-yearly screening will cost 60–66% more than 5-yearly screening. This is partly offset by not having to pay for the treatment of cancers prevented, but the financial saving is modest. The main benefits are in terms of cancers prevented and lives saved and the latter can be converted into years of life saved. There are also ‘negative benefits’ such as unnecessary treatment and anxiety caused by abnormal smears. Icelandic data show that the amount of low-grade disease (and hence, presumably, the number of women made anxious) is inversely proportional to the screening interval (Sigurdsson and Adalsteinsson, 2001). One can try to combine these factors in an overall measure of quality of life, but it is difficult to balance the low level of anxiety provoked in many women against the prevention of cancer in a few. It is also unclear whether giving one woman an extra 30 years of life is equivalent to giving an extra week to 1500 women. Our results clearly show that cytological screening is less effective at preventing frankly invasive cervical cancer in women under the age of 40 than it is in women aged over 40 years. They also suggest that cervical cancer develops more rapidly in young women so that the incidence rate of cervical cancer 3 years after a negative smears is the same as that in unscreened women. It is possible that although screening is not very effective at preventing cancer in young women, it saves lives through early diagnosis. Indeed, in this series of 747 staged cancers in women aged 20–39 years, 41% were microinvasive. Our results in young women differ from those reported by IARC (1986). That paper summarised the results from three cohort studies with a total of 148 cases aged under 35 years and found that the protection, relative to historical incidence rates, was similar to that seen in older women. Cases in that study were restricted to those with squamous cancer, but included stage 1A tumours (including any that were screen-detected). It is thus possible that differences in the design of the studies could explain the different results. The RR associated with various screening intervals estimated here will help formulate policy, but there will be other considerations such as the underlying age-specific incidence rates, the numbers of years of cancer-free life gained and the age-specific rates of cytological abnormalities. Our own recommendations are given in Table 7 Table 7 Provisional screening recommendations for the UK Age group (years) Frequency of cytological screening Under 25 Do not screen 25–49 3-yearly screening 50–64 5-yearly screening 65+ Only screen those who have not been screened since age 50 Note that these age groups are shifted by 5 years from those elsewhere in this paper to allow for the time from screening to cancer diagnosis in Tables 3–5. . Under the age of 25 years, invasive cancer is extremely rare, but cytological abnormalities are common (Department of Health, 2001). Although lesions treated in very young women may prevent cancers from developing many years later, the results of this paper would suggest that it is enough to begin screening around age 25 – lesions that are destined to progress will still be screen-detectable and those that would regress will no longer be a source of anxiety. Nationally, only 1.7% of cervical cancer in women aged 20–69 occur under the age of 25, corresponding to an incidence rate of 2.5 per 100 000 women-years. In our study, 26 out of the 34 women with cervical cancer aged 20–24 years had a previous (operationally) negative smear, suggesting that cytology is not very sensitive for these tumours. A review of the screening histories of the 13 women with stage 1B+ cervical cancer aged 20–24 indicates that six of these cases were symptomatic, of which five were stage 1B and the other was stage 3. In the UK, cervical cancer rates between the ages of 25 and 40 years are only slightly lower than in older women, so effective screening in this group is essential. However, most cancers still occur in older women, so resources also have to be allocated to ensure that a high proportion of women continue to be screened (albeit less frequently) at older ages.
                Bookmark

                Author and article information

                Contributors
                Role: research fellow
                Role: molecular biologist
                Role: surgical pathologist
                Role: medical statistician
                Role: surgical pathologist
                Role: gynaecologist
                Role: gynaecologist
                Role: senior researcher
                Role: manager of regional screening organisation
                Role: medical biologist
                Role: surgical pathologist
                Journal
                BMJ
                bmj
                BMJ : British Medical Journal
                BMJ Publishing Group Ltd.
                0959-8138
                1468-5833
                2010
                2010
                11 March 2010
                : 340
                : c1040
                Affiliations
                [1 ]Department of Pathology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, Netherlands
                [2 ]Epidemiology and Biostatistics, VU University Medical Center, Amsterdam
                [3 ]Obstetrics and Gynaecology, VU University Medical Center, Amsterdam
                [4 ]Regional Screening Organisation, Hoogoorddreef 54e 1101 BE Amsterdam, Netherlands
                Author notes
                Correspondence to: C J L M Meijer cjlm.meijer@ 123456vumc.nl
                Article
                gokm683060
                10.1136/bmj.c1040
                2837143
                20223872
                5bf46eac-3282-453f-81c5-995a9c99c908
                © Gök et al 2010

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.

                History
                : 25 January 2010
                Categories
                Research
                Epidemiologic studies
                General practice / family medicine
                Cervical cancer
                Cervical screening
                Gynecological cancer
                Screening (oncology)
                Surgical diagnostic tests
                General surgery
                Screening (epidemiology)
                Screening (public health)

                Medicine
                Medicine

                Comments

                Comment on this article