Cervical cancer remains the most common cancer among women living in developing countries, largely because of the failure either to initiate or sustain effective cervical-cancer screening programmes. This potentially preventable and curable cancer continues to cause high mortality among relatively young women residing in low-resource countries. Cytology as a screening test, linked with a robust healthcare infrastructure, has significantly affected cervical cancer prevention in countries that have had sufficient resources to establish and sustain well-conducted programmes. The failure to establish such programmes has stimulated a large body of research into alternative screening tests and approaches to cervical-cancer prevention. Two of the most recent research methods have been visual inspection with acetic acid and molecular testing for high-risk types of human papillomavirus deoxyribonucleic acid. Visual inspection with acetic acid has shown a great deal of promise in cross-sectional studies; however, in randomised-controlled trials, it has been shown to be significantly less effective in reducing cervical cancer or its precursors. The development of point-of-care human papillomavirus or other highly sensitive tests for the prevention of cervical cancer is imperative. It has also been clearly shown that linking testing or screening to treatment (so-called ‘screen and treat’) without the intervention of colposcopy or the need for sophisticated laboratories may potentially prevent cervical cancer in large numbers of women.
Introduction
Worldwide, cervical cancer is the third most common cancer among women and the fourth leading cause of cancer death in women worldwide. It is estimated that annually there are about 529,828 cases and 275,125 deaths from cervical cancer globally ( Table 1 ). The numbers of cases and deaths from cervical cancer, however, underestimates its global effect, as cervical cancer occurs in relatively young women. Each death from invasive cervical cancer occurring before the age of 70 years accounts for an average of 17 potential years of life lost. Globally, the mortality : incidence ratio is 52%. About 3.4 million women-years of life before age 70 years are lost annually from cervical cancer worldwide. Marked global disparities exist in both the incidence of, and mortality from, cervical cancer. More than 85% of the cases of cervical cancer occur in developing countries where it accounts for 13% of all cancers in women ( Table 1 ). Highest risk regions include Eastern and Western Africa, where the age-standardised incidence rates are over 30 per 100,000 ( Fig. 1 ). Other high-risk regions with age-standardised incidence rates of over 20 per 100,000 include South Africa, South-Central Asia, South America, Melanesia, Middle Africa, Central America and the Caribbean. Rates are lowest in Western Asia, Australia and New Zealand, and Northern America, where the age-standardised incidence rates are less than 6 per 100,000. India, the second most populous country in the world, accounts for 27% of all cervical cancer deaths globally. In large part, these global disparities in the burden of cervical cancer reflect differences in cervical cancer screening rates as well as rates of infection with high-risk types of HPV. Few developing countries have organised and quality assured cervical cancer-prevention programmes that allow the detection of high-grade cervical cancer precursors (referred to as cervical intraepithelial neoplasia (CIN) grade 2 and 3) and early invasive cervical cancers before the development of advanced disease.
| Region | Cases | Deaths |
|---|---|---|
| World | 529,828 | 275,125 |
| More developed regions | 76,000 | 32,000 |
| Less developed regions | 453,000 | 242,000 |
| WHO Africa Region | 75,000 | 50,000 |
| WHO Americas Region | 80,000 | 36,000 |
| European Union | 31,000 | 13,000 |
| United States | 11,000 | 3,000 |
| China | 75,000 | 33,000 |
| India | 134,000 | 72,000 |
Requirements for a successful cytology-based screening program and barriers found in low-resource settings
Since the introduction of cervical cytology (e.g. the Papanicolaou test) in the 1950s, the approach to cervical cancer prevention in most developed countries has been to screen women for CIN 2,3 lesions and early invasive cervical cancers using cervical cytology. Screening is followed by an evaluation using colposcopy and cervical biopsy for women with cytological abnormalities. If a CIN 2,3 lesion or early invasive cancer is detected on the cervical biopsy, treatment is provided. This approach works because it takes on average more than 10 years for a CIN 2,3 lesion to progress to an invasive cervical cancer, giving ample opportunity to detect and treat the precursor lesion and prevent the development of invasive cancer. In developed countries that have established screening programmes, and in which women are repetitively screened at relatively frequent intervals, cytology-based cervical cancer prevention has proven to be the single most successful cancer prevention programme.
Unfortunately, although simple in concept, cytology-based prevention programmes have proven extremely difficult to implement in low-resource settings. Bishop et al. described many of the challenges faced in implementing and sustaining cytology-based cervical-cancer prevention programmes in low-resource settings. Typically, the major barrier to cervical cancer prevention is not the cost of the screening test, which is relatively inexpensive; instead it is the cost and complexity of providing the infrastructure required for the screening programme. Not only must quality-assured cytology laboratories be established, but the healthcare systems must also put into place the infrastructure and capacity to track women with abnormal cytology as well as to provide quality assured colposcopy, pathology, and treatment services. Each of these associated services has its own highly specific infrastructure requirements. Cervical cytology is a good example of how complex a seemingly simple test can be. Obtaining and evaluating the cytology specimen first requires that patients and clinicians be made aware that screening is available and beneficial. Supplies need to be made available where screening is carried out, and providers must be trained in speculum exams and obtaining the specimens. Once the cytology specimen is collected, it has to be transported to the cytology laboratory and stained. It then has to be screened by a trained cytotechnologist, whose training in most developed countries takes about 2 years. Trained pathologists also need to be available who can review specimens classified as abnormal by the cytotechnologists and make a final diagnosis. Maintaining a high-quality cytology laboratory requires rigorous quality control mechanisms to assure that positive smears are not inadvertently missed and that negative smears are correctly diagnosed as being negative. These controls, in and of themselves, require extensive training, follow up, and oversight. Finally, once a cytology result is available, the patient must be made aware of the result and whether or not colposcopy is needed. This requires an infrastructure for patient tracking and follow up. This example serves to simply illustrate the complex training and infrastructure requirements for obtaining and evaluating the Pap smear. The other components of an effective cervical cancer-prevention programme include maintaining registries of women who have been screened; providing invitations to attend screening; providing colposcopic services for evaluating women with abnormal screening test results; treating women with preinvasive lesions; and finally providing medical, surgical, and terminal care for women with invasive cervical cancer identified through the screening process. All have their own infrastructure requirements.
Competing public health priorities are a major barrier to developing the infrastructure and capacity described above, which is needed for cytology-based cervical cancer prevention programmes. For example, in sub-Saharan Africa, other conditions such as communicable diseases including human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS), tuberculosis and malaria, combined with maternal or perinatal complications, accounted for 70% of deaths in women in 1995. Despite the fact that the global AIDS epidemic seems to have stabilised and the annual number of new HIV infections has been steadily declining since the late 1990s, the effort required to handle the HIV and AIDS epidemic in sub-Saharan Africa has drained limited healthcare resources. It was estimated that, in 2009, 5% of all adults aged 15–49 years living in sub-Saharan Africa were infected with HIV and required ongoing and expensive care. High rates of communicable diseases are compounded by widespread poverty in many developing countries. The United Nations Children’s Fund estimates that almost 50% of the developing world’s population (2.5 billion people) lack improved sanitation facilities, and over 884 million people still use unsafe drinking water sources. Primary healthcare facilities, which are where preventative healthcare services, including cervical cancer screening, should be situated, are poorly resourced and over-burdened in most developing countries. Finally, an urban–rural bias exists in health-care service provision in developing countries, which means that large segments of the population lack access to health care. For example, in sub-Saharan Africa 87% of the urban population has access to a health care, but over 50% of the region’s population is non-urban and lives more than 10 km from a primary healthcare facility.
It should also be stressed that even if a developing country found the resources to establish a high-quality cytology laboratory and had the capacity for follow up and treatment of abnormal results, the programme would be only moderately effective in reducing death from invasive cervical cancer if women were screened only once or twice in their lifetime. This is because the sensitivity of a single cervical cytology is relatively low. Meta-analyses of the performance of single cervical cytology find a sensitivity of 49–51% for CIN 2 and 3 and cancer (CIN2+). Although these meta-analyses can been criticised because they include a number of older studies, recent large screening studies that have used contemporary high-quality cytology laboratories have confirmed that the sensitivity of a single cervical cytology for CIN2+ is only 53–57%.
Requirements for a successful cytology-based screening program and barriers found in low-resource settings
Since the introduction of cervical cytology (e.g. the Papanicolaou test) in the 1950s, the approach to cervical cancer prevention in most developed countries has been to screen women for CIN 2,3 lesions and early invasive cervical cancers using cervical cytology. Screening is followed by an evaluation using colposcopy and cervical biopsy for women with cytological abnormalities. If a CIN 2,3 lesion or early invasive cancer is detected on the cervical biopsy, treatment is provided. This approach works because it takes on average more than 10 years for a CIN 2,3 lesion to progress to an invasive cervical cancer, giving ample opportunity to detect and treat the precursor lesion and prevent the development of invasive cancer. In developed countries that have established screening programmes, and in which women are repetitively screened at relatively frequent intervals, cytology-based cervical cancer prevention has proven to be the single most successful cancer prevention programme.
Unfortunately, although simple in concept, cytology-based prevention programmes have proven extremely difficult to implement in low-resource settings. Bishop et al. described many of the challenges faced in implementing and sustaining cytology-based cervical-cancer prevention programmes in low-resource settings. Typically, the major barrier to cervical cancer prevention is not the cost of the screening test, which is relatively inexpensive; instead it is the cost and complexity of providing the infrastructure required for the screening programme. Not only must quality-assured cytology laboratories be established, but the healthcare systems must also put into place the infrastructure and capacity to track women with abnormal cytology as well as to provide quality assured colposcopy, pathology, and treatment services. Each of these associated services has its own highly specific infrastructure requirements. Cervical cytology is a good example of how complex a seemingly simple test can be. Obtaining and evaluating the cytology specimen first requires that patients and clinicians be made aware that screening is available and beneficial. Supplies need to be made available where screening is carried out, and providers must be trained in speculum exams and obtaining the specimens. Once the cytology specimen is collected, it has to be transported to the cytology laboratory and stained. It then has to be screened by a trained cytotechnologist, whose training in most developed countries takes about 2 years. Trained pathologists also need to be available who can review specimens classified as abnormal by the cytotechnologists and make a final diagnosis. Maintaining a high-quality cytology laboratory requires rigorous quality control mechanisms to assure that positive smears are not inadvertently missed and that negative smears are correctly diagnosed as being negative. These controls, in and of themselves, require extensive training, follow up, and oversight. Finally, once a cytology result is available, the patient must be made aware of the result and whether or not colposcopy is needed. This requires an infrastructure for patient tracking and follow up. This example serves to simply illustrate the complex training and infrastructure requirements for obtaining and evaluating the Pap smear. The other components of an effective cervical cancer-prevention programme include maintaining registries of women who have been screened; providing invitations to attend screening; providing colposcopic services for evaluating women with abnormal screening test results; treating women with preinvasive lesions; and finally providing medical, surgical, and terminal care for women with invasive cervical cancer identified through the screening process. All have their own infrastructure requirements.
Competing public health priorities are a major barrier to developing the infrastructure and capacity described above, which is needed for cytology-based cervical cancer prevention programmes. For example, in sub-Saharan Africa, other conditions such as communicable diseases including human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS), tuberculosis and malaria, combined with maternal or perinatal complications, accounted for 70% of deaths in women in 1995. Despite the fact that the global AIDS epidemic seems to have stabilised and the annual number of new HIV infections has been steadily declining since the late 1990s, the effort required to handle the HIV and AIDS epidemic in sub-Saharan Africa has drained limited healthcare resources. It was estimated that, in 2009, 5% of all adults aged 15–49 years living in sub-Saharan Africa were infected with HIV and required ongoing and expensive care. High rates of communicable diseases are compounded by widespread poverty in many developing countries. The United Nations Children’s Fund estimates that almost 50% of the developing world’s population (2.5 billion people) lack improved sanitation facilities, and over 884 million people still use unsafe drinking water sources. Primary healthcare facilities, which are where preventative healthcare services, including cervical cancer screening, should be situated, are poorly resourced and over-burdened in most developing countries. Finally, an urban–rural bias exists in health-care service provision in developing countries, which means that large segments of the population lack access to health care. For example, in sub-Saharan Africa 87% of the urban population has access to a health care, but over 50% of the region’s population is non-urban and lives more than 10 km from a primary healthcare facility.
It should also be stressed that even if a developing country found the resources to establish a high-quality cytology laboratory and had the capacity for follow up and treatment of abnormal results, the programme would be only moderately effective in reducing death from invasive cervical cancer if women were screened only once or twice in their lifetime. This is because the sensitivity of a single cervical cytology is relatively low. Meta-analyses of the performance of single cervical cytology find a sensitivity of 49–51% for CIN 2 and 3 and cancer (CIN2+). Although these meta-analyses can been criticised because they include a number of older studies, recent large screening studies that have used contemporary high-quality cytology laboratories have confirmed that the sensitivity of a single cervical cytology for CIN2+ is only 53–57%.
Alternative approaches to cervical cancer prevention
Because cytology-based cervical cancer prevention programmes have proven so difficult to establish in low-resource settings, over the past 15 years there has been considerable interest in the global health community in developing new strategies for cervical cancer prevention specifically for low-resource settings. These include changing the screening test that is used as well as simplifying how we evaluate and treat screen-positive women.
Alternative screening tests
Visual inspection with acetic acid
Two alternatives to cervical cytology have been evaluated in large studies in developing countries. These are visual inspection with acetic acid (VIA) and molecular testing for high-risk types of human papillomavirus (HPV). Visual inspection with acetic acid is the simplest, and the low unit cost and the cost of the test itself makes it the least inexpensive screening test. Visual inspection with acetic acid is based on the principle that most CIN 2,3 lesions are acetowhite (i.e. they develop a white colour when vinegar or 5% acetic acid is applied to the cervical epithelium that harbors preinvasive lesions). This means that mid-level providers can screen for CIN 2 and 3 lesions by conducting a speculum examination to visualise the cervix, applying vinegar to the cervix, and looking for areas of acetowhitening. Normal cervical epithelium is pink, but most CIN 2 and 3 lesions will be white. The clinician conducting the test then classifies a woman as screen positive (she has an acetowhite lesion); screen negative, (she has no acetowhite lesions); or as suspicious for invasive cervical cancer if a necrotic, ulcerated, or exophytic cervical lesion is found. Although this sounds quite simple, it is actually more complicated than it appears. First, acetowhitening is a relatively non-specific cervical finding. Many women without CIN 2 and 3 lesions have acetowhitening of the cervix owing to areas of immature squamous metaplasia or reparative conditions. This can lead to a considerable degree of over-referral and over-treatment of women who do not have CIN2+ lesions. To minimise the amount of over-referral and over-treatment of women with CIN2+, over the years a number of criteria have been developed to try and improve the specificity of VIA, and comprehensive training guides have been developed for mid-level providers. Training typically takes 1–2 weeks and is competency based. The recommended courses for providers allow the participants to learn by doing, and focuses on specific knowledge, attitudes, and skills needed to perform VIA in low-resource settings. At the end of the training, a competency-based performance evaluation is used to assess the participants’ performance in VIA.
The performance of VIA has been evaluated in numerous cross-sectional and prospective studies, as well as in a meta-analysis. A recent large meta-analysis of VIA studies published through 2010 divided the studies based on patient population (e.g. asymptomatic women undergoing screening versus symptomatic women) and whether or not all women underwent a gold standard of colposcopy and histology. A total of 26 studies enrolled only asymptomatic women and all screened women underwent colposcopy and histology. In these studies the pooled sensitivity of VIA for CIN2+ was 80% and the specificity was 92%, with a positive predictive value (PPV) of 10% and a negative predictive value (NPV) of 99%.
When interpreting the results of the VIA studies, it is important to recognise that most studies were large screening studies conducted in low-resource settings and many used local pathologists to diagnose the cervical biopsies. In addition, many of the pathologists were not blinded to the colposcopic findings. This can lead to quite significant problems in measuring the performance of a screening test, as a combination of colposcopy and cervical biopsy is an imperfect gold standard. It is now recognised that a single colposcopy examination misses about one-third of CIN 2 and 3 lesions. In addition, the pathological interpretation of cervical biopsies is highly subjective, and studies have shown poor inter-observer and intra-observer reproducibilty of a diagnosis of CIN 2,3. When an imperfect gold standard is used to determine disease status, significant bias can be introduced into measures of a test’s performance. The direction of the bias is determined by whether or not the imperfect gold standard and the test being evaluated tend to err in the same patients. If a test and the imperfect standard have a tendency to err in the same patients, the test’s performance characteristics can be significantly overestimated. Previously, we have shown that that classification errors occurring with VIA correlate with histopathologic classification errors. What happens is that women with areas of immature squamous metaplasia are classified as VIA positive, as these areas are frequently acetowhite. When colposcopy is carried out, these areas of immature squamous metaplasia are frequently biopsied, again because they are acetowhite. Unfortunately, as pathologists can also find it difficult to differentiate between immature squamous metaplasia and CIN 2 and 3 on the biopsy, some of the biopsies from areas of immature squamous metaplasia are misclassified as CIN 2 and 3. The correlation between the VIA result and the erroneous biopsy result would increase the sensitivity of VIA and decrease the sensitivity of cytology and HPV deoxyribonucleic acid (DNA) testing. In another study, it was shown that the sensitivity of VIA was overestimated by 20% when colposcopy-directed, rather than random cervical biopsies were used as the gold standard.
A high degree of variability is found in different studies that have measured the sensitivity of VIA. For example, in one study of 11 separate screening studies conducted by the International Agency for Research in Cancer, the sensitivity of VIA for CIN 2 and 3 varied from 56.1% and 58% in Kolkata and Mumbai, respectively, to 93.9% and 90.3% in Burkina Faso and Guinea, respectively. In this same study, specificity of VIA for CIN 2 and 3 varied from 75.1% and 76.6% in Jaipur and Congo, respectively, to 93.2% and 93.8% in Guinea and Niger, respectively. This high degree of variation occurred despite the fact that all of the providers conducting VIA underwent a similar intensive training course. In two different South African screening studies in which providers who underwent similar intensive training and were supervised by the same clinician carried out VIA in both, the sensitivity of VIA for CIN 2+ was found to be 55% and 73%.
Although it is difficult to know what the real performance will be of VIA when used in a developing country screening programme, considerable evidence currently shows that VIA should be considered as a reasonable alternative to cervical cytology. The advantages of VIA compared with cytology are that it seems to be somewhat more sensitive (about 50–70%) sensitivity for VIA compared with about 50% for cytology; it is a point-of-care test, which means that women can be immediately informed if they are screening test positive; and it does not require a cytopathology laboratory. The disadvantages of VIA compared with cytology are that it is much more difficult to provide quality control with VIA than it is with cytology, as rescreening is not easily done; it requires that a considerable number of providers be trained in VIA, whereas cytology requires only a limited number of cytotechnologists; its performance declines substantially in women aged 40 years and older ; and its specificity is lower than that of cytology. The variability in the performance of VIA observed in different studies, however, does not seem to be any greater than that of cervical cytology.
High-risk human papillomavirus testing
It is now accepted that infection with one of 14 oncogenic HPV genotypes (referred to as ‘high-risk’ genotypes) is required for the development of CIN 2 and 3 and invasive cervical cancer. This underlying causal association has spurred considerable interest in using high-risk HPV (hrHPV) testing to improved cervical-cancer screening, and has resulted in commercially available sensitive molecular tests to detect hrHPV genotypes in clinical specimens. A number of large clinical trials and cost-effectiveness analyses have firmly established the clinical utility of using hrHPV testing to improve the sensitivity of cervical screening in women aged 30 years and over undergoing routine screening. Multiple studies have convincingly shown that hrHPV testing is more sensitive and more reproducible than cervical cytology. Moreover, because of the high negative predictive value of hrHPV testing, women who are hrHPV negative do not need to be rescreened before 6 years. Over the past several years, evidence has grown that HPV DNA testing should be considered as an adjunct to cervical cytology when screening, and also as a true replacement for cervical cytology. Several large screening trials conducted in Europe and the USA have shown that combining cervical cytology with hrHPV testing adds little compared with using hrHPV testing alone. Recently, an Italian screening study showed a lower occurrence of invasive cervical cancer in women screened using hrHPV testing compared with cytology alone. Currently, several European countries are beginning to transition from a cytology-based screening programme to a hrHPV-based one. A potential advantage of hrHPV testing over other screening methods for developing countries is that testing can be done on self-collected vaginal swabs. In 2007, Petignat et al. conducted a systematic review of studies that compared the prevalence of HPV infection detected with cervical versus self-collected vaginal swabs and concluded that the two methods produced comparable results. More recently, Gravitt et al. conducted another systematic review and reached the same conclusion. In our South African experience, however, we have uniformily found that hrHPV testing of self-collected samples has both a lower sensitivity and lower specificity for CIN 2 and 3 compared with clinician-collected samples. In these studies, the sensitivity of hrHPV testing using a self-collected specimen is roughly equivalent to that of cervical cytology.
The greatest issues in hrHPV testing for developing countries are the unit cost of the test, the sophistication of the laboratories that are needed for carrying out current versions of the test, and the fact that a point-of-care hrHPV test is not yet available. The current generation of commercially available hrHPV assays use various amplification methods for detecting either hrHPV DNA or RNA. Globally, the most widely used hrHPV test is the Hybrid Capture ® 2 HPV Assay (HC2) (Qiagen, Gaithersburg, MD, USA). Hybrid Capture ® 2 HPV uses signal amplification methodology to detect 13 hrHPV genotypes (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68) as a pooled mixture. It was developed over several years and, during development, it underwent clinical validation in large clinical trials in developed and developing countries. As a result of these trials, the sensitivity of HC2 was adjusted to provide a reasonable trade-off between sensitivity for CIN3+ lesions and positivity in women without cervical disease. The latter is extremely important in reducing unnecessary or redundant follow-up procedures for women who are hrHPV positive without cervical disease. Therefore, the performance of HC2 in a screening setting is widely viewed by experts in Europe and North America as the benchmark by which other hrHPV tests should be judged. It has been proposed that any other candidate hrHPV test should have a sensitivity for CIN2+ of 90% that of HC2 as assessed by a non-inferiority score test. Furthermore, the candidate hrHPV test should have at least 98% of the specificity of HC2 as assessed by a non-inferiority test. Recently, several genomic amplification hrHPV tests have become commercially available. These tests use either the polymerase chain reaction or other techniques to amplify DNA or RNA. Provided the tests have been clinically validated in a sufficiently large general screening population, and been shown to have a sensitivity and specificity comparable to that of HC2, there is no reason that these newer tests should not perform reasonably for cervical cancer screening.
A new hrHPV test that is modelled on HC2 has been developed in collaboration between Qiagen (the company that makes HC2), the Bill and Melinda Gates Foundation, and PATH (a NGO based in Seattle, WA). This test that is called careHPV™, and is specifically designed for use in low-resource settings. It does not require reagent refrigeration, can be carried out in a clinic setting by a healthcare worker with minimal laboratory training, and takes only 2.5 h or less to complete. In 2008, careHPV™ was directly compared with HC2 and was shown to have a somewhat lower sensitivity for CIN2+ than HC2 (90% v 97%). The specificity of the two tests, however, was equivalent (84% v 86%). It is expected that careHPV™ will be made available to countries introducing nationwide HPV-based screening programmes at a much lower cost than other hrHPV tests. When this occurs, it will overcome one of the major barriers to the introduction of HPV-based cervical cancer screening programmes in low-resource settings. careHPV™ is expected to become available in 2012.
Alternative approaches to managing screen-positive women
The approach used in most developed countries to manage screen-positive women is to initially carry out colposcopy and obtain cervical biopsies of all lesions. If the biopsies are found to have CIN2+, the woman undergoes treatment. Treatment for CIN 2 and 3 is typically loop electrosurgical excision procedure or large loop excision of the transformation zone, whereas treatment for early invasive cancers is generally surgical. Many developing countries do not have the capacity to carry out colposcopy on screen-positive women. Moreover, many have a limited number of pathology laboratories and pathologists to process and evaluate cervical biopsies. In rural settings, the need to track and recall screen-positive women to provide them with their test results is also a barrier. Therefore, an alternative approach to managing screen-positive women is needed if large-scale screening programmes are going to be expanded into developing countries. These alternative approaches to managing screen-positive women in developing countries have to take into account two competing priorities. One is assuring that the cervical cancer prevention programme is as effective as possible in reducing death from invasive cervical cancer. The other is to minimise over-treatment of women without CIN2+ lesions. Unfortunately, at the current time, none of the current approaches are suitable for low-resource settings that can fulfill both priorities. Therefore, public health authorities have to decide which priority is most important in a given setting: preventing as many deaths as possible from cervical cancer or minimising over-treatment of women without CIN2+ lesions.
The simplest approach would be to use the most sensitive screening test possible and ablate the transformation zone in all women in whom the screening test is positive. Ablation of the transformation zone is typically achieved using cryotherapy, and is generally considered to be quite safe and to have only minor complications. This approach is referred to as ‘screen-and-treat’. The advantages of ‘screen-and-treat’ are that it produces the greatest reduction in CIN2+. The reduction in CIN 2 and 3 to be expected from a ‘screen-and-treat’ programme is simply the (sensitivity of the screening test) x (success rate of the ablative method in eliminating CIN 2,3). Therefore, if a highly sensitive screening test such as hrHPV testing is used that has a sensitivity of 90% for CIN 2 and 3 lesions, and this test is coupled with cryotherapy to ablate the transformation zone in all screen-positive women (which eliminates about 80% of CIN 2 and 3 lesions), the overall reduction in CIN 2 and 3 achieved with the programme would be about 72%. Another advantage of ‘screen-and-treat’ is that, if a point-of-care screening test is used, the entire process can be completed in a single visit and there is no need to establish a track and recall system for patients. The major disadvantage of ‘screen-and-treat’ is that, depending on the specificity of the screening test, 5–20% of all women without CIN 2 and 3 lesions will undergo unnecessary treatment.
In order to reduce the over-treatment of women without CIN 2 and 3, many demonstration projects are using either colposcopy or, if hrHPV is used as the screening test, VIA to identify a subset of screen-positive women for treatment who are at highest risk for having CIN2+. We have previously referred to this approach as a ‘two-stage screening approach’. The expected reduction in CIN 2 and 3 to be expected from a ‘two-stage’ screening programme that incorporates an intermediate triage step to select a subset of screen-positive women for treatment is (sensitivity of the screening test) x (sensitivity of the triage method for detecting CIN 2 and 3) x (success rate of the ablative method in eliminating CIN 2 and 3). Therefore, if hrHPV testing is used to screen and then hrHPV positive women then undergo VIA, which has a sensitivity of 60% for CIN 2 and 3 to select a subset of women for cryotherapy, the overall reduction in CIN 2 and 3 of the programme would be only 43%. Thus, the reduction in CIN 2 and 3 achieved with a ‘two-stage’ screening programme is greatly reduced compared with a ‘screen-and-treat’ programme. The ‘two-stage’ screening approach does reduce unnecessary treatments. It is important for policy makers to recognise that the sensitivity of colposcopy is considerably lower than previously thought. Most studies have found that a single colposcopic examination misses about one-third of CIN 2 and 3 lesions. Therefore, colposcopy seems to offer little advantage over VIA as a triage approach for screen-positive women.
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