Screening for cervical cancer in developing countries

Screening for cervical cancer in developing countries

International Journal of Gynecology and Obstetrics 84 (2004) 101–108 Review article Screening for cervical cancer in developing countries ´ H.S. Cro...

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International Journal of Gynecology and Obstetrics 84 (2004) 101–108

Review article

Screening for cervical cancer in developing countries ´ H.S. Cronje* Department of Obstetrics and Gynecology, University of the Free State, Bloemfontein, South Africa Received 15 August 2003; accepted 30 September 2003

Abstract Cervical cancer is the most common malignancy amongst females in developing countries, mainly due to a lack of precursor screening. This absence of screening is the result of inherent disadvantages of the Pap smear: high cost, low sensitivity, the need for a laboratory with high human expertise and a complex screening program logistic system. The prerequisites for screening in a developing country include a screening method that is affordable, which can be effectively applied once in a lifetime at the age of 30–35 years, provide an immediate result and thereby allowing for on-site treatment of positive cases. None of the current screening methods comply with these prerequisites. More research is necessary into different combinations of tests, which improve sensitivity. On-site human papillomavirus (HPV) identification, alone or in combination with other tests, is promising. Another promising development is immunization against HPV infection, either as a preventative measure or for stimulating immunity in infected women. 䊚 2003 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Cervix; Cancer; Neoplasia; Screening; Developing countries

1. Introduction Cervical cancer is the most common malignancy in women of developing countries. According to the South African National Cancer Registry, the lifetime risk for a woman to develop cancer of the cervix is 1 in 26 w1x. Table 1 lists the number of patients with gynecological cancer admitted to our institution during the past 5 years, showing the predominance of cervical cancer. Of these patients, 85% were already in FIGO stages III and IV on *Tel.: q27-51-405-3444; fax: q27-51-444-2660. E-mail address: [email protected] ´ (H.S. Cronje).

admission. This situation is true for most developing countries. In the Free State province of South Africa, less than 1% of women dependent on public health services have been screened for cervical neoplasia w2x. In two studies from this province the histological prevalence of disease has been documented as follows: cervical intra-epithelial neoplasia grade 1 (CIN 1) as 18%, CIN 2 and 3 as 8%, and infiltrating cancer as 0.8% w3,4x. This cancer commonly affects women in their late forties and fifties. During these decades, they fulfill a crucial role within their family structures. As a result, cervical cancer can be extremely disruptive to the stability of the social structure

0020-7292/04/$30.00 䊚 2003 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijgo.2003.09.009

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Table 1 Admissions for gynecological cancer to the Departments of Obstetrics and Gynecology, and Oncology, University of the Free State Cancer site

a

Cervix Endometrium Ovary Vulva a

Year 1996

1997

1998

1999

2000

391 30 40 21

407 31 53 17

399 25 44 16

402 29 39 14

532 54 44 17

Cervical cancer comprised 81.8% of the total.

within a community. Therefore, the control of this disease in developing countries is of paramount importance. 2. Natural history of the disease Cervical cancer develops over a prolonged period covering two to three decades (Fig. 1) w5x. During adolescence, lesions are usually low-grade in nature. The majority of these will regress back to normal spontaneously. A small proportion will continue to develop into true cancer precursors, known as cervical intra-epithelial neoplasia (CIN), which is divided into grades 1, 2, and 3. The median ages of patients with these different precursor grades are 25, 29 and 34 years, respectively w6x. At least two-thirds of CIN I lesions will regress to normal, half of CIN 2 lesions and a third of CIN 3 lesions. Ultimately, a small proportion will

develop into infiltrating cancer, usually from the age of 45 years onwards. At the age of 30–35 years, most of the minor lesions (koilocytes, atypia and CIN 1) would have regressed, leaving behind a larger portion of CIN 2 and 3 (high grade lesions). Therefore, this age interval seems to be an ideal time for screening. According to the South African National Cancer Registry, only 8% of cervical cancers will occur under the age of 30 years w1x. Presumably, most of these cases will be immune compromised. 3. The Papanicolaou (PAP) smear Globally the Pap smear is the preferred screening method for cervical cancer precursors. Generally it is believed to consist of a high sensitivity of over 70% w7x. Three recent articles, however, carefully studied the methods by which the sensitivity was calculated in a large number of publications and concluded that the sensitivity was approximately 50% w8–10x. Our own material confirmed a sensitivity of 53% using CIN 2 as a threshold and only 23% when CIN 1 was used as threshold w3,4x. It seemed that the sensitivity of the Pap smear increased with both the degree of precursor and the patient’s age as long as she was pre-menopausal w3,4,10x. New technologies in cytology such as fluid based techniques and computerized screening and re-screening were associated with higher sensitivities, reaching the 70% level w9,10x. Unfortunately, these techniques are

Fig. 1. Natural history of cervical neoplasia.

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Table 2 Prevalence of cervical neoplasia based on cytology from South African studies Study

CIN 2 & 3 (%)

Infiltrating cancer (%)

Cronje´ 2001 w3x Cronje´ 2003 w4x Michelow 1999 w37x Fonn 2002 w38x Denny 2000 w16x Wright 2000 w17x

1.0 4.7 2.4 1.8 2.2 3.0

0.3 1.0 0.9 0.5 0.1 0.3

generally not available in developing countries. In contrast to the low sensitivity, the Pap smear’s specificity is high (over 94%) w3,4,8–10x. The cytological prevalence of disease according to Pap smear from South African studies are listed in Table 2. Comparing this to the documented histological prevalences w3,4x of 8% for CIN 2 and 3, and 0.8% for infiltrating cancer, the sensitivity for cytology was only approximately 30%. The sensitivity of 50% documented by Fahey, McCrory, and Nanda w8–10x were determined under more ideal circumstances. Therefore, in developing countries, a sensitivity for the Pap smear of less than 50% can be expected, and is probably approximately 30%. In addition to its low sensitivity, the Pap smear has other disadvantages, making it not the ideal screening method for developing countries. These disadvantages include the following: ● the need for repetitive smears (due to the low sensitivity); ● the recall of patients for their results; ● the need for a laboratory and colposcopy with the associated human expertise; and ● the cost of a cytological screening program. In developing countries, at least one-third of the patients are lost to follow-up w2–4x and the necessary human expertise is lacking (most countries do not even possess cytological laboratory facilities). More importantly, however, is a lack of the required funding.

acetic acid test, speculoscopy and human papillomavirus (HPV) identification. Colposcopy is unrecognized as a screening method. 4.1. Cervicography Cervicography involves photography of the cervix after the application of diluted acetic acid with a special camera, known as a Cerviscope䉸 (National Testing Laboratories Worldwide, St. Louis, MO) w11x. The slides are evaluated by a certified evaluator. In our experience, its sensitivity is 50% and specificity 88% w3x. It seems to be more sensitive for low-grade lesions compared to high-grade lesions. Its main disadvantages include: advanced technology (camera, film, and development of color slides), cost, and the necessary recall of patients. 4.2. Acetic acid test (AAT) The AAT, also known as direct visual inspection (DVI) or direct inspection using acetic acid (DIA), is a simple, inexpensive test where the cervix is examined with the naked eye following the application of diluted acetic acid w12x. The presence of a visible acetowhite area signifies a positive result. Its sensitivity varies between 70 and 80%, but its specificity is low, approximately 50–70% w3,11,13x. Important advantages of the AAT include its simplicity, extremely low cost and the provision of an immediate result. Its main disadvantage is the high degree of over diagnosis.

4. Alternative screening methods 4.3. Speculoscopy In view of the Pap smear’s disadvantages, alternative screening methods have been considered. Recognized alternatives include cervicography, the

This is a variant of the AAT where a special light source is used when the cervix is examined

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w14x. This light, a chemiluminescent light, is supposed to increase the specificity. In our experience, however, its sensitivity and specificity are similar to that of the AAT w4x. Therefore, it does not offer any advantages above the AAT while it is marginally more expensive. 4.4. HPV DNA identification Since 80% or more of patients with cervical neoplasia are infected with high-risk HPV, particularly types 16, 18, 31 and 33, the prospect gained momentum of identifying these high-risk HPV DNA strains as markers for cervical neoplasia w15x. This is aided by more user-friendly devices, some of which may even provide immediate results w16x. Self-collecting samples taken by the women themselves have been implemented with success w17x. The sensitivity of HPV DNA testing, probably between 60 and 70%, has not been adequately determined, but seems to be higher than that of the Pap smear w15,18x. The specificity is also high, probably between 80 and 95% w15,18x. As this method is still rather expensive and in the developmental phase, it is not commonly available in developing countries. 4.5. Colposcopy Colposcopy, performed by an experienced colposcopist, has a sensitivity and specificity in excess of 90% w19x. Theoretically, this would make the ideal screening method for a developing country. Although a colposcope is expensive, its running cost is low and an immediate result is obtained. The main disadvantage is the need for a highly trained and experienced person to perform the examinations, a rare commodity in developing countries. Colposcopy as a screening method has also not been evaluated in sufficient detail. Of all these alternate screening methods, HPV identification seems to be the most promising, with colposcopy an untested alternative. 5. Combination of methods Since no single screening method with a sufficient sensitivity and specificity has been recog-

nized, combinations of tests have been investigated. Any combination of tests improves the sensitivity significantly w3,4,16x. The disadvantages of this approach, include the possible decrease in specificity w20x and the increase in the direct cost of screening. A combination of tests can be applied in one stage (e.g. cytology and cervicography or HPV DNA testing) or in sequential stages (e.g. the AAT followed by HPV DNA testing only if the AAT was positive) w3,4,16x. An example would be to screen patients initially with the AAT. Those that tested positive, would be tested immediately thereafter for HPV DNA. In this way the cost of HPV DNA testing is decreased. Although this approach of combining tests is very promising, insufficient research has been done to identify the ideal combination. 6. Screening programs The current internationally accepted screening programs are based on a perceived sensitivity of 80% w21x. In the USA, three annual smears are recommended after the first sexual intercourse. This is followed by triennial smears in low risk women and annual smears in high risk women w22x. Between the ages of 20 and 50 years, this means anything between 12 and 31 smears, which is not feasible in developing countries. As a result the World Health Organization (WHO) reviewed this problem and suggested one smear per woman between the ages 35 and 40 years w23x. It has been estimated that this policy will reduce infiltrating cancer by 65%. However, the perceived sensitivity of cytology was without doubt higher than 50%. With a true sensitivity of 50% or less a reduction of maximally 50% can be expected. In real clinical practice, however, this figure will even be lower. The South African government has adopted a policy of three smears per woman at the ages of 30, 40, and 50 years, respectively. It has been suggested that this policy may reduce the incidence of cancer by 87% w21x. These long intervals, however, will limit this perceived reduction w24x. During each 10-year interval, infiltrating cancer may develop in patients where a CIN lesion was not detected by the preceding smear. Therefore, by

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expanding the interval between smears to 10 years, the control of cancer will be reduced, probably to a level of less than 50%.

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of these methods will be utilized on a large scale in the foreseeable future in developing countries. 9. The AIDS problem

7. Coverage The coverage of the eligible women for screening is most important. Unless the screening program reaches 70–80% of these women, the decrease in the prevalence of infiltrating cancer will be insignificant w25x. In developing countries, with limited communication and other forms of infrastructure, coverage of 70% or more will be extremely difficult to achieve. A screening program conducted through primary health care where eligible women attending clinics are screened, is unlikely to succeed. The proportion of women attending clinics will be less than the desired target of coverage, probably approximately 60%. Furthermore, in our experience primary care nurses are reluctant to perform Pap smears on women without gynecological complaints. A dedicated screening program, performed by a dedicated team, is the way developing countries should follow when embarking on cervical screening. 8. Treatment methods Several treatment methods for cancer precursors have been used. These include cold knife cone biopsy, laser vaporization, large loop excision of the transformation zone (LLETZ) (also known as loop excision by electrosurgical procedure, LEEP) and cryotherapy w26x. All these methods require pre-treatment colposcopy (with the necessary human expertise) and except for cryotherapy, they are all expensive to apply. Cryotherapy, although the least expensive and easiest to apply, still needs a continuous supply of N2O. Although highly effective, the success of these methods in treating cervical cancer precursors is dependent on human expertise, both at pre-treatment colposcopic evaluation and the treatment itself. The less expertise, the higher the failure rate. In developing countries, a high degree of human expertise is often lacking as well as a shortage in available funds for treatment. These two factors make it unlikely that any

AIDS is a disease occurring predominantly in developing countries. HIV infection is associated with an increased incidence of HPV infection, CIN and cervical cancer w27–29x. The recurrence rate of CIN after treatment varies from 20 to 60% depending on the degree of immuno-suppression w29,30x. Subsequently, the cost-effectiveness of screening for cervical neoplasia in HIV infected women has been questioned w29,31x. The prevalence of HIV infection in a target population should be a major consideration when a population based screening program is considered. If the target population consists of women 30–50 years of age with a prevalence of HIV infection of 40%, the situation will be as follows: for every 100 women screened once, 50% of the high-grade lesions will be missed due to cytology’s limited sensitivity. Of the remaining 50 patients, 20 will be HIV positive. Given a prevalence of 6% for CIN 2 and 3 in uninfected women and 10% in infected women, two women in the uninfected group and two in the infected group will be diagnosed with high-grade CIN. At least one of these four will be lost to follow-up, leaving three for treatment. Of these, one treatment may fail due to HIV infection, leaving two patients with cure and an estimated six uncured. If all the patients were HIV negative, two would have been cured and four not. The HIV infection, therefore, caused two additional patients to be left uncured, an increase of approximately one-third. 10. Cost of screening Little research has been done on the affordability of screening in developing countries. In 1983, Aucamp from the South African Department of Health, examined the problem w32x. At that time, an ideal screening program was valued at R33 million per year, while the government allocated only R400 000 (US$ 1.00sR8.00) for cervical cancer in the preceding year. Presently, at R50 per patient, it will cost R40 million to screen each

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woman aged 30–50 years once only in the Free State province of South Africa. No further evidence is needed to realize that a population based screening program in South Africa (and in almost every other developing country) is unaffordable. More recent and detailed analyses also did not provide practical solutions w33x. 11. Treatment of infiltrating cancer Should women be left to develop cancer, which is then detected and treated, preferably at an early stage? This idea was evaluated in India without success w34x. Many developing countries do not have the facilities to treat cervical cancer. Although South Africa has an adequate number of facilities for irradiation, the results in the public sector are not encouraging. In the Free State province, during 1995–2000, of the 1171 cervical cancer patients, 45% were irradiated radically and 55% palliatively. After 6 years, 38% of the radically irradiated group and only 6% of the palliative group were still alive (unpublished data). However, 50% and 76% of the patients in the two respective groups were lost to follow-up. Therefore, to concentrate only on treating infiltrating cancer, is not viable. 12. Vaccination Much research has recently gone into the possible vaccination against HPV infection w35x. Vaccination can be aimed at either preventing disease or stimulating immunity in individuals already infected with HPV. In the first report on vaccination against HPV type 16, a vaccine efficacy of 100% was achieved w36x. This highly encouraging result is of great importance to developing countries. Once a vaccine is available, its success in developing countries will be determined by the cost and whether it will be a single or repetitive intervention. 13. Discussion The main elements of a mass screening program are information and education of the population, coverage, the screening process itself, and treat-

ment of the screening-positive patients. In developing countries, the first mentioned element is quite possible. Coverage, however, is difficult in view of poor infrastructures. The screening process is a major problem due to its cost, the necessary human expertise and the absence of an ideal screening method for developing countries. Furthermore, a simple but highly effective and inexpensive treatment method also does not exist. Cryotherapy is currently the best option, but it should be accompanied by expert colposcopy to limit the failures. This modality is unfortunately not available in developing countries. It is therefore clear that a true population based mass screening program in a developing country, particularly in Africa, is unlikely to succeed. A completely new strategy is needed and it seems as if immunization against oncogenic HPV strains holds promise for the future. 14. Conclusions In South Africa the necessary infrastructure for mass screening exists. The main problem is a lack of funds. In most other developing countries there is both a lack of funds and infrastructure. Governments generally consider other health problems more urgent, e.g. malnutrition, infant diarrhea, tuberculosis, AIDS, etc. However, cervical cancer is not an insignificant problem and governments have to be sensitized to a larger degree. Once money is allocated to treating cervical cancer, the question arises as to the most cost-effective implementation. More research is necessary into screening methods in developing countries, an area where developed and developing countries should collaborate to a larger extent. If screening is to be accomplished, it should start on a small scale. Careful documentation of the results should be obtained to evaluate the success. The Pap smear does not seem to be the best screening method for developing countries. HPV identification, alone or in combination with other tests, holds promise. In future, immunization against the HPV may be the most viable option.

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