Report on consensus conference on cervical cancer screening and management

During the present meeting, the participants reviewed the state of the art on screening for cervical cancer, and considered a number of promising new developments. Four key areas comprised a major focus of the discussions, programmatic issues, cervical cytology, alternative methods of screening and diagnosis and treatment of dysplasia. Worldwide, cervical cancer comprises approximately 12% of all cancers in women. It is the 2nd most common cancer in women worldwide and the most common in developing countries. The global estimates are for 452,000 new cases and more than 234,000 deaths from cervical cancer each year around 2000 (Ferlay et al., 1998; Parkin et al., 1999). Eighty percent of these cases are found in developing countries with only 5% of global cancer resources. Cervical cancer is both preventable and curable. Widespread comprehensive cervical cancer control programs have helped some developed countries to achieve up to an 80% reduction in incidence and mortality from cervical cancer. In developing countries, 60–80% of cases are seen in advanced stages (III and IV), if ever diagnosed, with a low probability of long-term survival (Sankaranarayanan et al., 1998a). In most developing countries, cytological screening is not currently available for population-based screening programs, and will not be possible for several decades. In a few countries where it is available, it is of suboptimal quality. Several studies are being conducted worldwide to evaluate alternative, feasible techniques for cervical cancer in comparison to cytology. Consideration of these studies comprised one of the main features of this consensus conference. The participants considered cervical screening projects and programs from Brazil, Chile, Finland, India, Iran, South Africa, Sri Lanka, Tunisia and Zimbabwe. These programs are in highly varied stages of evolution (from pilot studies to highly successful nationwide efforts) from areas of the world with major differences in incidence rates of cervical cancer and varied levels of economic development. The program in Finland is the model for organized programs of screening by cervical cytology worldwide. This program began in 1960 with 5 yearly screening for women age 30 to 59, invited through the national population register (Hakama and Louhivuori, 1988). Considerable attention was devoted to education of the population, fast feedback of screening results to women, a cost-effective system for referral of women with abnormalities, histological confirmation of diagnoses and continuous quality control (Syrjänen, 1995; Hristova and Hakama, 1997). Recent data show much greater efficacy following smears conducted in the organized program than opportunistic smears. The programs under development in Tunisia and Iran illustrate the relatively low risk of cervical cancer in Islamic populations. Nevertheless, in Tunisia, cervical cancer is the second most common cancer in women, therefore mass screening for women over the age of 35 is being developed. In Iran, a national program to screen by cytology all married females between 20 and 65 years every 3 years was proposed. This achieved a coverage of 61% in urban areas in 1997 but only 16% in rural areas. It is proposed to change the program to start at 25 or 30 years of age, and to screen every 5 years. Further development of organized approaches should help to reduce excessive expenditure on screening low-risk women, with little impact on the disease. In contrast, the experience in high incidence countries in Africa and South America confirms the need to ensure that those at risk are incorporated into programs. In many such settings, alternative approaches to screening must be evaluated if a major impact on the disease is to be achieved. In South Africa, where in some settings the sensitivity of the Pap smear is low, alternative approaches such as visual inspection with acetic acid (VIA), speculoscopy and human papilloma virus (HPV) DNA testing are being evaluated. Data from several studies suggest that most of these approaches have similar sensitivities to cytology. Similar data are being obtained in a study in Brazil. However, in South Africa, VIA has lower specificity than cytology. Further, in India and Zimbabwe, although studies have shown that VIA performed substantially better at identifying true disease than a Pap smear, the reverse was true for specificity (Chirenje et al., 1999; Sankaranarayanan et al., 1998b, Sankaranarayanan et al., 1999). This has substantial implications for treatment policies such as “see and treat” as there will be considerable overtreatment of women who in fact have a false positive finding. Combinations of screening tests or a simple immediately applied diagnostic test may help to resolve this. A once in a lifetime test would need to be of high sensitivity to be effective. Currently, an organized program involving 3 smears in a lifetime (starting at age 30) is being piloted as national policy in South Africa. Chile illustrates the difficulties in introducing organized programs. A national program was introduced in 1985, but initially appeared to have little impact. Therefore, concentration was devoted to the metropolitan area of Santiago. The lessons learnt there were extended to the rest of the country. Recently, an emerging impact in terms of declining incidence, improving proportions of cases diagnosed in stage I and declining mortality from the disease has been noted. Chile is, in practice, the only country in Latin America that has so far shown a decline in mortality from cancer of the cervix. Although there is every hope that a prophylactic vaccine against the oncogenic types of HPV will eradicate cervical cancer in the future, the likely time course for such a scenario to unfold will be prolonged. Once a “perfect” HPV prophylactic vaccine is synthesized, 3 years will be required for completion of all 3 phases of clinical trial. Another 2–4 years will be required to collect short-term results (i.e., prevention of HPV infection in vaccinated subjects). Information regarding the prevention of high-grade precancerous lesions (high-grade squamous intraepithelial neoplastic lesions or HSIL) in vaccinated individuals will not be available for 20–30 years after the completion of phase 3 clinical trials. Finally, acceptance and introduction of such a vaccine can be expected to take at least another 10 years once efficacy in prevention of HSIL has been established. It was noted in this context that the hepatitis B vaccine has been administered to less than 1% of children worldwide, despite the decades that have elapsed since the successful development of that vaccine. Several approaches to HPV DNA testing are available, including hybrid capture, PCR and in situ hybridization tests. Some are being piloted as alternatives to cervical cytology, or in terms of their clinical utility in the management of women with an abnormal Pap smear. The sensitivity of hybrid capture is very high for oncogenic types of HPV. Information regarding cervical cancer screening in women co-infected with human immunodeficiency virus (HIV) or other sexually transmitted diseases (STD) and HPV was also presented. Women with HIV infection tend to show high prevalence of both low-grade squamous intraepithelial neoplastic lesions (LSIL) and HSIL, and most of these test positive for infection with oncogenic types of HPV. Given what is known about the natural histories of cervical dysplasia and of HIV-induced disease, it is unclear whether screening for cervical cancer will improve health outcomes of women infected with HIV, particularly in light of the high rates of treatment failure for high-grade cervical disease in HIV-positive women. It was questioned whether cervical screening constitutes an effective allocation of scarce medical resources in areas of the world with high prevalence rates of HIV infection. Approaches are being made to improve the efficacy of cervical cytology. One promising approach is the liquid-based test (Thin Prep). In one evaluation in a developed country, a triage protocol involving a combination of the liquid-based test and an HPV DNA test has been evaluated. Attempts at automating cervical cytology reading are also encouraging in developed countries, in terms of reducing dependence on cytotechnicians and facilitating reduction of false negatives. However, there have been some difficulties in extending their use to developing countries, where maintenance of high technology approaches could prove to be difficult. The success of cervical cancer screening will depend on the program, from education to screening to acting on results, being acceptable to women themselves. Thus, the methods and activities of the program will have to respect the dignity, privacy and autonomy of women. It is more likely that this will be achieved if women and women's health and rights advocates are involved in the development of the program. The greatest burden of disease in terms of the rates of cervical cancer and the absolute number of women with cervical cancer occurs in countries and countries with in Thus, of are proposed as a to the number of women of cervical cancer The of the program must focus on the possible coverage such as number of women as to number of Pap smears should be of programs should be it is that cervical cancer is an disease the country. The should be to up national organized screening programs (Hakama et al., It is more as it is less to opportunistic screening than to a population-based involving a comprehensive program, including all the in an area of high is as a of This should for national and the to from education program to the of and of health of of smear and cytology reading and quality control of their of smear and cytology of screening of to cytological and a system to ensure quality control in these for the of cytological smears and the of results as as of referral for and of treatment that can treatment for of a system for with advanced disease, in the scenario would and for women with disease. of an system that for evaluation of the program such that data can be at the as as the national for including for each and at each of these is and to an impact on cervical cancer incidence, and the health model of cervical screening to each of these is to the of a screening program. The of the and the is a for program The health model for cervical cancer education is by who have experience in this area and resources should be to and test and effective methods of education to coverage and of to at both and women should be attention must be to women, the required for each of smear smear should be and methods of that this is and of the quality of must be in of to each of these will be by resources. It is from pilot programs that and of the quality of the than their are Pap by women. Pap by cytotechnicians under of by although if by and or attention must be to and other required to and smears to up for of quality of the smear is very Therefore, in to ensure smear and smear reading is highly These should be in such a as to ensure coverage of the have been to be very successful in many countries. However, should be the is the most risk in cervical cancer and screening should to women. A would be to at the incidence of cervical cancer and screening at 5 years to this In most countries, this will be at about years of age and can to about years of resources will national programs are developed. It is that women who have a Pap smear and who are than years of age should have Pap smear Data that women who have smears and are about years of age are at very low risk of developing cervical cancer and can the screening program at this should for at least Pap smear in Once this has been the should be smears. would be but only resources resources will this for each country. The should ensure feedback to on the of the smears A of with a of and quality should be up Data at least to prevalence by age and treatment and up should be to treatment and up are of the program and to ensure their at the and to this at the national must be A may be in in highly The should also be seen in the context prevention for cervical cancer should that age at women control over their particularly their to have and with that against women and children is Cervical cancer from in other immunodeficiency and programs and women that by cervical cytology has to be most successful in reducing the incidence and mortality from cervical cancer et al., other approaches to control of cancer of the must be evaluated in to this However, only 5% of women in developing countries, where approximately 80% of new cases of cervical cancer have a cervical cytology smear. Therefore, one of the key the must be to evaluate whether cervical control in these countries is achieved by the for cervical cytology in developing countries. It is that resources are relatively only an organized program of cervical cytology screening can achieve the expected reduction in incidence and mortality from cancer of the et al., achieve such an attention has to be to a number of The following on quality control and are proposed to countries to a comprehensive and organized cytology and smear must be experience with the of available A with should be This will be for the and of a successful cytology This should be at an of in Cervical with the of the of The of should must and The should be and to long-term with the new may be through the by to may be by national or or if are should be the approaches a screening of will by this During the will be by the should similar as for The of should be approximately The will be expected to The of has an for The could a in the quality of smear A for Pap can be by a who is in and Pap smear must this should be in medical In countries where such was not will have to be other health will also be A could be to at the and to as a quality control should be with a if resources are and may be obtained through may be through to the or to the at the national or of the is the as far as should use a data system and be to Pap smear results, results and must ensure of Pap smear to smear to more than is a number of Pap smears to be in each should be is one an The policy of of smears should be by in an organized quality control should cervical smear to the as as and ensure in should feedback regarding with the of smears to the may be and by of by of or should every with may be by of and should every with may be by of squamous of intraepithelial neoplastic and or The of a cytology screening program should be to screen each between the of 30 and at least once screening at 5 to should only be resources of the can be for Pap smear However, this system is for of cervical smears. It should not be to as there are to be made with the et al., et al., 1999). smear may be the system as to experience and Women with Pap smears as HSIL or of must be for evaluation as as women with Pap smears as or there is consensus regarding the most it is possible with referral and cytology after is an et al., 1999). It is that currently available and liquid-based cytology screening will be cost-effective in developing countries. The considered the currently available on the of the following alternative methods to cervical cytology as screening tests in the of high-grade cervical neoplastic and HPV DNA The these approaches in The data available on the of the tests to high-grade cervical lesions with that of cervical cytology were considered to at the following consensus on the of the as screening The noted the of data on the of incidence or mortality reduction with the approaches and the of of the acetic acid under light by health who the as or abnormal with an abnormal need to be would cytology settings where cytology are or by a cytology is this is the ever alternative approach proposed to be evaluated in low settings et al., Data from studies in India that the test would in referral of of women for cytology or evaluation by et al., et al., et al., et al., 1997). This was not for the of disease but for the diagnosis of cervical cancer. However, the approach has a low and low specificity to disease. Further, the or treatment for management of cervical cancer in settings where is to be as a screening test in low This approach the for in visual This test visual of the after the of acetic It has been to have a sensitivity to that of cytological screening to high-grade lesions (Chirenje et al., 1999; Sankaranarayanan et al., 1998b, Sankaranarayanan et al., 1999). Therefore, this test should be considered as a screening in settings where quality cervical cytology is not However, the specificity is lower than that of cervical cytology. Further evaluation is required to to improve the specificity and to reduce the number of women who from outcomes VIA is with In quality control in the of the test need to be evaluation can be in or in trials. This test visual in a of the acetic to with by a light in the of the and specificity to be to that of However, in of the resources it is an as a screening test in developing countries. This test of of the acetic cervix. is lower than that of cytology and VIA to high-grade although specificity is to that of cytology. a screening it is an in developing countries. HPV DNA testing with methods for the HPV types has been shown to have similar or sensitivity to high-grade disease than that of cytology. However, the specificity is lower than that of cervical cytology, as the prevalence of HPV DNA in women cervical and may be particularly high in women. Currently, the of the test is a to in developing countries. the can be HPV DNA testing should be considered as a screening in women over the age of but evaluation is required to in high HPV prevalence populations. can be in programs or in trials. The has not on possible of screening tests in of In involving alternative the high-grade disease as the for disease. Further evaluation in terms of incidence mortality reduction from cervical cancer as as of the screening approaches need to be Although programmatic with screening approaches are to be the as those for cervical cytology, may with to the A number of new are being evaluated. One in the of a to a an diagnosis of cervical neoplastic disease. It on the fact that cervical has and that can be with their by of an are that the sensitivity is to cytology but evaluation is from such screening programs to a the referral should be by with It is that in less than will not be these referral treatment should be in the or or in an an or system should be in by medical or It should be possible to women to a for long-term in the of high-grade be between 5 and 10 years. The of at reducing the and mortality of cervical cancer will have all these in and The management of cervical on the of both the low and high-grade of the disease. cancer is In up to of women with low-grade cytology, a high-grade the cervix. in women with an smear, will such a high-grade However, occurs in up to of low-grade Therefore, with a diagnosis of low-grade cytology, or it is that referral to a be organized only after the of 3 smears over an and smears over a such smears will the of the lesions that are likely to to so the smear. Women between with an smear that is with a of an HPV DNA would the of oncogenic However, in this the smear would have to be after year the of a positive smear could the of disease. of an abnormal smear is a referral for a should be women over 35 with an or a positive HPV test on should the need for a by will a or to the of an A state that of the be it or is the the to the the Therefore, of disease in the be should be histological of is treatment should be and the the is less than 3 of the the can be in time may have the is and 3 or more of the disease in the of low-grade cytology, there may be a high-grade present this These are the cases that may be by HPV DNA In of the risk of high-grade disease being treatment should be the “see and treat” a is to be high in the of low-grade cytology and this high is a treatment would be In women over 35 who have an test for oncogenic virus in the of an treatment has been so as to a possible high-grade in and 3 could also be or However, must be for the of these must be of disease or there must be there should be between diagnosis and cytological the must be to treatment is by or techniques can be performed under with or under control in an may in developing countries, is not In such treatment of women with a high-grade cytological diagnosis by of or will in approximately The of treatment can be by acetic acid to the is there may be an cancer It would be to use or to a of the cervix. Thus, if 3 or more are to be after or a is not on the a should be performed of or available, the use of HPV DNA testing for the of oncogenic virus would the specificity in respect to high-grade lesions in women is available, a similar protocol to that for low-grade cytology should be treatment may be with and the of the for management as is not available, of the with a than the should be A may be with 3 of the being and It is with a to the in that is a is However, of these may be in respect to as a can be a or The most common of treatment is by This can be as a and with diagnosis and treatment being performed at the or the diagnostic of the is with treatment at a the diagnostic can be from or must be for In up to of there is of or with the Although this would in the true as by a positive smear at is less than 5% of women. The protocol for with and the of is as are the has and a smear at The is to if cervical it smears must be with an the smear is a smear, or an HPV DNA is at and HPV DNA testing in such the the are involved with high-grade disease, as a is a smear is at that time the smear is a or should be A smear as in the the has of disease stage a is at after has it of more as is Recent of cancer has into the of to in lesions that less than 3 into the a diagnosed only by with are stage The should not be more than 5 in and more than in The should be from the of the or from it or not the disease is only for comprehensive diagnosis once a or has been the features need to be by a can treatment be This is as a with of more than in and or less in The diagnosis should made on a evaluation of a and not on a of risk of The treatment are simple or of the cervix. The treatment would be on the to This is as of more than but less than in and not than The risk of with lesions of this is between The treatment with or is in women of who have a to a new of treatment for advanced stage or stage disease with is being at several lesions between 5% and of all cervical neoplastic lesions are diagnosed an cytology diagnostic is Once disease has been diagnosed on cytology, the must be for a number of of have been but these are to is the only of all the is the of the of the It is that between and of be of disease to is may be by of but this is In the major have been made in of approaches to control cancer of the by The cervical cytology smear is the by all other approaches are as it is the only one that has been shown to reduce cervical cancer incidence and inspection of the with acetic acid (VIA), but methods are required to improve the specificity of and the of HPV DNA testing also but the of specificity in women that it be considered for screening in women under the age of However, it may help to improve the of disease that must be in women. are evaluation and may all if their of an and reading is after However, all programs will it is possible to women with abnormal screening tests to for diagnosis and and for treatment are Considerable attention is, required to these programmatic issues, and that is such an of this consensus conference.