Cervical Cancer Screening in the Developing WorldCHAPTER 1

Cervical cancer is a leading cause of morbidity, mortality and premature death among middle-aged women in many developing countries. Although prevention, early detection and treatment have all proven to be effective in controlling cervical cancer, these are yet to be fully applied and utilized in developing countries, leading to a great disparity in risk and suffering as compared to developed nations.

Cervical cancer is caused by persistent infection with one or more of the oncogenic types of human papillomaviruses (HPV).⁴ The peak risk of HPV infection is soon after the onset of sexual activity, usually between the ages of 14 and 20 years. In most infected women, HPV infection usually resolves spontaneously, but it may persist in a proportion of infected women leading to the occurrence, persistence and progression of precancerous lesions such as cervical intraepithelial neoplasia (CIN), particularly CIN 3 and adenocarcinoma in situ in some women. If untreated, these precursor lesions may progress to invasive cervical cancer over a period of 5-15 years. While early detection of occult, asymptomatic precancerous lesions by screening and their effective treatment leads to the prevention of invasive cervical cancer and premature death from it, prevention of oncogenic HPV infection by vaccination provides an important emerging avenue for cervical cancer prevention. Early clinical diagnosis constitutes a third approach to disease control where the emphasis is on rapid identification of early stages of invasive cancer and offering effective treatment. The lack of effective screening programs and the high prevalence of oncogenic HPV infection (>10% in women aged 30 years or more) are primarily responsible for the high burden of cervical cancer in many developing countries.^3,5,6 We review the current status and future prospects for controlling cervical cancer by screening in developing countries in this chapter. The opportunities emerging from recent research on screening and the potential difficulties, challenges and possible solutions to overcome these obstacles in the context of developing countries are also briefly discussed.

The objective of cervical screening is to prevent the occurrence of and death from invasive cervical cancer by detecting and treating women with high-grade CIN 2 and 3 lesions. Screening is the most time tested method to prevent cervical cancer and offers the greatest immediate potential to reduce cervical cancer burden throughout the world. The effectiveness of screening is evaluated by the extent of reduction in cervical cancer incidence and mortality following screening. Screening tests such as conventional cytology, liquid-based cytology, visual inspection with acetic acid (VIA), visual inspection with Lugol's iodine (VILI) and HPV testing have a high accuracy of identifying women with CIN as well as early, asymptomatic, preclinical invasive cancer, if these tests are carried out with quality assurance and by well trained providers. Effective outpatient treatment methods for precancerous lesions include cryotherapy, electrocoagulation, laser ablation, loop electrosurgical excision procedure (LEEP), laser conization and cold knife conization. Colposcopy is a useful diagnostic tool to triage women with positive tests, to assess the nature and extent of lesions and to direct biopsies. Treatment of lesions are usually carried out under colposcopy control in many clinical settings.

Screening in developed countries involves repeated rounds at yearly (e.g. Germany, USA) or three-yearly (e.g. France, Norway) or five-yearly (Finland, UK) intervals involving sexually active women across a wide age range beginning from early twenties to late sixties. The conventional diagnostic and treatment algorithms following a positive cytology screening test in western and other healthcare settings include three visits for colposcopy, diagnostic confirmation and treatment. Such regimes are not feasible and multiple visits following screening will result in substantial nonparticipation by women in developing countries for various reasons.

Conventional cytology is the most widely used and evaluated cervical screening test. It is the current workhorse in screening programs throughout the world. The substantial reductions in cervical cancer burden in developed countries followed large scale cytology screening since the 1950s. The strengths and deficiencies of cytology have become much evident with long experience with this remarkable screening test.

The optimum accuracy is achieved when cytology is scored positive at atypical cells of uncertain significance (ASCUS) threshold.

Visual inspection after application of 3-5% acetic acid (VIA), also known as direct visual inspection (DVI), or as acetic acid test (AAT), is the most widely studied visual screening test.

VIA involves naked eye inspection of the cervix, using a bright torch light or a halogen focus lamp, 1 minute after the application of 3-5% acetic acid using a cotton swab or a spray.²² A positive test is characterized by well-defined acetowhite areas close to the squamocolumnar junction (SCJ) or to the external os or the entire cervix or a cervical growth turning acetowhite (Fig. 1.2).²² It is a simple, affordable test that can be rapidly taught to providers such as primary health workers, nurses and doctors, and gives immediate results to permit a ‘single visit’ approach for diagnosis and treatment.¹¹ Providers can be rapidly taught VIA in short training courses of 4-10 days with the help of manuals and hands-on training.^22,23 Quality assurance procedures for VIA are yet to be standardized. Assuring consistent high performance can be challenging under field conditions and requires constant monitoring and frequent re-training of test providers. The useful quality assurance procedures include use of 5% freshly prepared acetic acid on daily basis, periodic re-training of providers and reproducibility studies and monitoring the following process measures regularly: test positivity rates between 7-12%, positive predictive value for any grade of CIN not less than 20%, positive predictive value for CIN 2-3 lesions not less than 10%, and inter-observer agreement exceeding 70%.

8When conventional cytology was concurrently evaluated in these studies, the sensitivity of VIA was found to be higher than or similar to that of cytology, but had lower specificity.¹⁸ The results from a multicenter Indian cross-sectional studies in given in Table 1.4. It is a fair assessment that the reported sensitivities for VIA in most studies are likely to be overestimates. The wide range in accuracy parameters of VIA in different studies underscore the subjective nature of the test as well as the range in the validity, completeness and accuracy of the reference standard established in different studies. A high correlation with colposcopy and VIA may result in overestimation of VIA sensitivity in studies relying on colposcopically directed biopsy to establish the final diagnosis.²⁵ When the criterion standard was changed from colposcopically directed biopsy, random biopsy, plus ECC to colposcopically directed biopsy in a study in China, the sensitivity of VIA for CIN 2 or worse increased from 75.9 to 85.5%.²⁵ It appears that a quality assured single VIA has an average sensitivity around 60% and specificity around 85% to detect high-grade CIN in study settings. Low level of magnification has shown that low-level magnification does not improve the test performance of naked eye visualization after acetic acid application.¹⁸

Visual inspection with Lugol's iodine (VILI) involves naked eye examination of the cervix, to identify mustard-yellow lesions in the transformation zone of the cervix, after application of Lugol's iodine. The results are reported immediately after application of iodine. A positive result is based on the appearance of definite mustard-yellow area on the cervix close to the SCJ or the os or on a cervical growth²² (Fig. 1.3). VILI has been investigated in fewer studies than VIA. The sensitivity of VILI varied between 44-92% and specificity between 75-85% in cross-sectional studies in India, Africa and Latin America (Table 1.2).^18,26–28 It seems that concurrent use of both VIA and VILI is advisable when individual women seek screening or early diagnostic services.

HPV testing is the most objective and reproducible of all currently available cervical screening tests. The sensitivity of HPV testing in detecting CIN 2 and 3 lesions varied from 66-100% and the specificity varied from 62-96% in cross-sectional studies in developing countries (Table 1.2).^6,17,29 In most studies it had a higher sensitivity, but lower specificity, than cytology in detecting high-grade lesions. The sensitivity of HPV testing when specimens have been taken and/or analyzed in developing country settings has generally been lower than that where the entire specimen chain (collection/testing) was completed in a developed country.^6,29 A consistently higher sensitivity for high-grade CIN was demonstrated for HPV testing in North American and European studies (pooled average 98%), whereas the sensitivity in India and Zimbabwe was lower (range 50-88%).²⁹ A certain amount of bias in reference diagnosis due to the use of colposcopic biopsy based gold standard for final diagnosis cannot be ruled out for this discrepancy. In recently reported randomized trials from Sweden, the Netherlands and Canada, HPV testing has greater sensitivity for the detection of CIN as compared with Pap testing.^30–32 Although self-sampling for HPV DNA testing seems to be a potentially promising for use in underresourced areas or for women who are reluctant to participate in screening programs, further definitive research is needed to provide a solid evidence base to inform the use of self-sampling.³³

Efforts are now underway to develop simple, affordable, rapid and accurate HPV testing methods for use in low- and medium-resource settings and it is expected that a rapid HPV test, giving results in 3 hours, at affordable costs will be available for use soon.

Cytology screening has been largely responsible for the substantial decline in cervical cancer incidence and mortality in developed countries of Europe, North America, Japan, Australia and New Zealand by early detection and effective treatment of cervical precancerous lesions in the last 5 decades.^3,6,11 Cytology screening is yet to be effectively implemented in many developing countries in South and East Asia. Only Japan, Taiwan, Hong Kong, South Korea, Singapore and Thailand in Asia have mass cytology screening for cervical cancer in Asia. More than 60% of the women between 30 and 60 years have received at least a single round of screening in these countries with the exception of Thailand. Colposcopy and treatment (LEEP, laser, cryotherapy) services for CIN are more extensively available in these countries than elsewhere in Asia. Cervical cancer incidence rates have declined in Japan, Taiwan, Hong Kong and Singapore. Mass cytology screening programs do not exist anywhere in mainland Africa, although South Africa has plans to introduce a cytology screening program, it is yet to be realized on a large scale. Although cytology screening is widespread in Mauritius, screen-positive women are seldom diagnosed and treated, with the net effect of no appreciable impact on disease burden over the last three decades.

Although a large amount of accuracy and reproducibility data are available for visual and HPV tests, these alone will not make sufficient case for their efficacy in preventing cervical cancer and for their introduction in routine mass screening programs. Accuracy studies will always be viewed in the context of the uncertainties on the reference standard investigations and completeness and validity of final reference diagnoses. Moreover, high accuracy of a given test to detect CIN need not automatically indicate a lowered incidence and mortality as the tests may miss real precursors progressing to invasive cancer. In other words, a high accuracy is not a surrogate for efficacy for reducing disease burden. For these reasons, it is important to generate evidence from randomized controlled trials, if incidence and mortality reductions will follow if these new tests are implemented in screening programs as compared to standard cytology screening or no screening which is the case in many countries. Cost-effectiveness data will further contribute to public health decisions on implementing alternative tests to cytology. We will briefly review the evidence base for visual and HPV tests from randomized controlled trials in developing countries.

After 8 years from the beginning of screening, women in the HPV group experienced a significant 53% reduction in the incidence rate of stage II or worse stages of invasive cervical cancer (hazard ratio 0.47 [95% CI: 0.32-0.69]) and a significant 48% reduction in cervical cancer mortality (hazard ratio 0.52 [95% CI 0.33-0.83]) compared to those in the control group.⁹ The reduction in cervical cancer mortality observed in the cytology (hazard ratio 0.89 [95% CI: 0.62-1.27]) and in the VIA (hazard ratio: 0.86% [95% CI: 0.60-1.25]) groups as compared to the control group did not reach statistical significance. During the 8-year follow-up period, 8 of the 24,380 HPV-negative women developed cervical cancer as opposed to 22 of 23,762 Pap smear negative and 25 of 23,032 VIA-negative women, indicating that HPV testing more accurately identified women at risk for developing cervical cancer and it is a more effective screening test than Pap smear or VIA.

Cryotherapy provided by nurses in field conditions in India, Thailand and South Africa has been safe, acceptable and effective.^12–14,35 In a study involving 1879 women treated, adapting ‘see and treat’ procedure involving VIA screening, colposcopy, directed biopsy and double-freeze cryotherapy by trained nurses in a single -visit in field clinics supervised by a doctor, four-fifths of the women with CIN were cured; cure rates were 81.4% (752/924) for women with CIN 1; 71.4% (55/77) for CIN 2 and 68.0% (17/25) for CIN 3 cases.³⁰ Minor side-effects and complications were documented in less than 3% of women. In a screening trial in Osmanabad district, 94% of 574 women with CIN treated with cryotherapy by nurses were cured; cure rates were 96.4% (451/468) for women with CIN 1; 82.1% for CIN 2 and 3 lesions (55/67 and 32/39, respectively); minor side-effects and complications were documented in 5.2% of women.³⁶ Of the 488 women with CIN treated with LEEP in a screening trial in Osmanabad district, India, cure rates were 98.1% (253/258) for women with CIN 1; 93.6% (103/110) for CIN 2 and 85.0% (102/120) for CIN 3; minor side-effects and complications were documented in 12.1% of women in this study.³⁷ LEEP provided by newly trained doctors in this field screening study was associated with similar cure rates and complications reported in the gynecological literature.^38,39 In Kerala, India, of the 283 evaluable women with CIN treated with LEEP, 248 (87.6%) had no evidence of CIN at follow-up; cure rates were 93.0% (145/156) for women with CIN 1; 85.5% (71/83) for CIN 2 and 72.7% (32/44) for CIN 3. Minor side-effects were documented in 34 (12.0%) and complications in 5 (1.8%) of women.⁴⁰ These experiences are similar to the results reported from developed countries where these procedures were carried out by experienced doctors.^38,39

The cost-effectiveness of a variety of cervical-cancer screening strategies in India, Kenya, Peru, South Africa, and Thailand, were assessed using computer-based models.⁴¹ Outcomes included the lifetime risk of cancer, years of life saved, lifetime costs, and cost-effectiveness ratios (cost per year of life saved). 12The most cost-effective strategies were those that required the fewest visits, resulting in improved follow-up testing and treatment. Screening women once in their lifetime, at the age of 35 years, with a one-visit or two-visit screening strategy involving visual inspection of the cervix with acetic acid or HPV testing in cervical cell samples, reduced the lifetime risk of cancer by approximately 25 to 36 percent, and cost less than 500 dollars per year of life saved. Relative risk of cancer declined by an additional 40 percent with two screenings (at 35 and 40 years of age), resulting in a cost per year of life saved that was less than each country's per capita gross domestic product–a very cost-effective result, according to the Commission on Macroeconomics and Health. These results indicate that cervical-cancer screening strategies incorporating visual inspection of the cervix with acetic acid or DNA testing for HPV in one or two clinical visits are cost-effective alternatives to cytology screening programs in resource-poor settings.

Clinical early diagnosis differs from screening in the sense that the emphasis is rapid identification and prompt reporting of symptoms to health professionals whose onus is to diagnose disease early in symptomatic women and offer appropriate treatment to prevent death due to disease. Education and awareness are critical for the success of this approach. Programs focused on achieving earlier diagnosis of symptomatic disease offer great potential with minor investment to reduce the burden of disease in settings where mass screening is not feasible. Clinical early diagnosis has been responsible for the reduction in mortality from cervical cancer achieved in developed countries before cervical screening programs were introduced.^42,43 However, diagnostic and treatment facilities should be in place if clinical early diagnosis has to work. Unfortunately, this is not the case in several sub-Saharan African countries, some countries in Central Asia and some Asian and Latin American countries. Thus, considerable investments in cancer health care infrastructure and human resources must be made in these countries for clinical early diagnosis and screening to become a reality in these countries.

Cervical cancer reflects striking global health inequity, resulting in deaths of women in their most productive years, with a devastating effect on the society at large. It is the largest single cause of years of life lost to cancer in the developing world. Fortunately, we have a large evidence and experience base now to implement screening programs based on cytology, visual screening tests or HPV testing and such an action has the potential for profound public health benefit if appropriate screening policies are implemented at the right earnest. It is time to focus attention on putting in place the important programmatic components related education, participation, good quality testing, diagnosis, treatment, follow-up care and evaluation.

To screen successfully in low-resource settings the following requirements must be met: