- Email: [email protected]
Overview of Cervical Cancer in the Developing World
S205
Overview of Cervical Cancer in the Developing World R SANKARANARAYANAN Head, Screening Group, World Health Organization – International Agency for Research on Cancer, Lyon 69008, France
INTRODUCTION The most recent global estimates for cancer burden indicate that there were 10.9 million new cancer cases (excluding non-melanoma skin cancers) in both sexes in the world around the year 2002: 5.8 million cases in men and 5.1 million in women 1 . There were 6.7 million cancer deaths, 3.8 million in men and 2.9 million in women. Cervical cancer accounted for 493 000 newly diagnosed cases, 1.4 million prevalent cases and 273 000 deaths world-wide in the year 2002. Of these, more than 80% occurred in the low- and medium-resource countries in South and South East Asia, sub-Saharan Africa, and South and Central America (Table 1) 1 . In fact, one third of cervical cancer burden in the world is experienced in South Asia. These statistics indicate that cervical cancer Table 1 Cancers of the uterine cervix. Incident cases, deaths and 5-year prevalence in 18 world regions in 2002 Cervix cancer
World
Cases
Deaths
5-year prevalence 1 409 200
492 800
273 200
More developed countries
83 400
39 500
309 900
Less developed countries
409 400
233 700
1 099 300
Eastern Africa
33 900
27 100
57 200
Middle Africa
8200
6600
13 900
Northern Africa
8100
6500
14 000
Southern Africa
7600
4400
13 100
20 900
16 700
35 700
6300
3100
18 400
Central America
17 100
8100
49 300
South America
48 300
21 400
139 200
Northern America
14 600
5700
58 200
Eastern Asia
61 100
31 300
191 900
South-Eastern Asia
42 500
22 500
132 500
South Central Asia
157 700
86 700
446 100
4400
2100
13 700
30 800
17 100
107 700
Northern Europe
5600
2800
21 100
Southern Europe
10 600
4100
40 900
Western Europe
12 700
5600
49 200
2000
800
6500
Western Africa Caribbean
Western Asia Eastern Europe
Oceania
continues to be a major public health problem in many developing countries. It is quite likely that the burden of disease in sub-Saharan Africa is underestimated given the inadequacy of diagnostic and treatment services and cancer information systems. It is well established that cervical cancer is caused by persistent infection with one or more of approximately 15 oncogenic types of human papillomaviruses (HPV) 2 . Persistent HPV infection promotes cellular changes that result in the occurrence of precancerous lesions and invasive cancer. Lack of effective screening programmes and the high prevalence of oncogenic HPV infection (>10% in women aged 30 years or over) are responsible for the high burden of cervical cancer in many developing countries 3−5 .
INCIDENCE AND MORTALITY PATTERNS There is an eight-fold variation in the incidence rates of cervical cancer world-wide and age-standardized incidence rates above 25 per 100 000 women are observed in many developing countries in sub-Saharan Africa, Central and South America, South Asia and South-East Asia as opposed to rates lower than 10 per 100 000 in most developed countries 1,6 . Rates lower than 7/100 000 women are observed in the middle eastern countries 6 . Estimated age-adjusted cervical cancer mortality rates exceed 10 per 100 000 women in most developing countries, with rates exceeding 25 per 100 000 in East African countries as opposed to less than 5 per 100 000 women in most developed countries. The high mortality is due to advanced clinical stage at presentation and to the fact that a significant proportion of patients do not avail or complete prescribed courses of treatment, due to deficiencies in treatment availability, accessibility and affordability in many developing countries 3 .
SURVIVAL FROM CERVICAL CANCER A large variation in survival from cervical cancer is observed even among developing countries due to the variations in clinical stages of presentation and the availability and accessibility to diagnostic and treatment services according to the level of development of cancer
Correspondence to: Dr R. Sankaranarayanan. Head, Screening Group, International Agency for Research on Cancer, 150 Cours Albert Thomas, 69372 Lyon CEDEX 08, France. Tel: +33-472738599; fax: +33-472738518. E-mail: [email protected]
S206
R SANKARANARAYANAN
related health services in different countries. For black patients in Uganda, Zimbabwe and the Gambia, 5-year survival rates lower than 25% are reported, while they are in the range of 30−50% in Cuba, India, and Philippines; 50−60% in Costa Rica, Thailand, Turkey and in mainland China; and more than 65% in Hong Kong, Singapore and South Korea 7−10 . The survival experience in more developed and accessible health services in East Asian countries such as Singapore and Korea is similar to those observed in the US and Europe.
the extent of reduction in cervical cancer incidence and mortality following screening. Cervical screening tests such as cytology, visual and HPV tests are capable of identifying women having CIN as well as early, preclinical invasive cancer. The critical components of successful cervical screening are high coverage of target women with accurate, quality-assured screening tests and of screen-positive women with diagnostic investigations, of women with confirmed cervical neoplasia with treatment and follow-up care. Cytology screening
VACCINATION The fact that cervical cancer is caused by persistent HPV infection provides enormous potential for cancer prevention through vaccination. More than 99% of cervical cancers contain one or more of the oncogenic HPV genotypes that cause cervical cancer, although approximately 50−60% of these cancers contain HPV16, and another 10−20% harbour HPV-18; and the currently evaluated vaccines target preventing infection by these two HPV types. Recent results from on-going randomized trials indicate that HPV vaccines have an excellent safety profile, are highly immunogenic, and have conferred a high degree of protection against HPV16/18 infection and associated precancerous cervical lesions in fully vaccinated women 11−13 . Some evidence of cross protection against related oncogenic types is also emerging 13 . It is likely that HPV vaccines may soon be licensed and will be available for clinical use in the near future. However, there are several unresolved issues such as the most critical target groups to vaccinate, integration into existing vaccine platforms in countries, acceptance of a vaccine designed to prevent a sexually transmitted infection, parental comfort with vaccination of their pre-adolescent/early adolescent daughters, duration of immune response, the need for booster doses, the extent of cross-protection against other HPV types. Another unresolved issue is vaccine costs and when the vaccine’s cost may be low enough for widespread implementation in the developing world, where 80% of cervical cancer occurs and when multivalent vaccines will be available.
SCREENING FOR CERVICAL CANCER The objective of cervical screening is to prevent invasive cervical cancer by detecting and treating women with high-grade cervical intraepithelial neoplasia (CIN 2 and 3 lesions) and the effectiveness of screening is evaluated by
Cytology screening has been largely responsible for the significant decline in the burden of cervical cancer in developed countries in the last 5 decades 1 . Organised screening with systematic call, recall, follow-up and surveillance systems have shown the greatest effect (e.g. Finland, Iceland), while using fewer resources than the less organised programmes (e.g. USA). Cervical cancer incidence has been reduced by as much as 80% where the cytology screening quality, coverage and follow-up of women are high. Cytology screening is yet to be effectively implemented in many developing countries or has failed to reduce cervical cancer burden to an appreciable extent in some developing countries in Latin America such as Costa Rica, Cuba, Brazil, Mexico, Chile, Peru, Colombia, etc., where it has been introduced regionally or nationally since the late 1960s and 1970s 3,14 . The main reasons for the lack of success in these countries were a combination of sub-optimal cytology testing, lack of quality assurance, poor coverage of women at risk, and inadequate follow-up of screen-positive women with diagnosis and treatment 3 . While poor quality cytology is a reflection of several challenges in providing quality-assured testing, the lack of coverage for diagnosis and treatment is related to the inadequate health care infrastructure, human resources and programme logistics. Cytology is a resource intensive technology and, unfortunately, it is not possible to commit sufficient financial and human resources to fulfil the optimal requirements for collection of cervical cells, slide preparation, staining, reading and reporting, as well as quality control measures, to ensure good quality cytology with optimal accuracy in low-resource countries. In most routine settings, cytology has been shown to have a wide range in sensitivity in detecting cervical neoplasia. The sensitivity to detect CIN 2 and 3 lesions ranged from 47% to 62% and the specificity from 60% to 95% in recent reviews 14−18 . There have been several cross-sectional
OVERVIEW OF CERVICAL CANCER IN THE DEVELOPING WORLD
studies in developing countries assessing the accuracy of cytology, in which the sensitivity varied from 44% to 78% and the specificity from 91% to 96% 18 . The apparent lack of impact of cervical cytology programmes and the difficulties in organizing such programmes in low- and medium-resource countries have prompted the search for and evaluation of alternative screening tests and paradigms that require one single, or two visits, to complete the screening and diagnosis/treatment processes 19 , as well as the reorganization of existing programmes and more effective utilization of resources in some countries such as Chile, Costa Rica and Brazil 3,20 . Reorganization of the programme in Chile has been associated with some decline in cervical cancer mortality in recent years 20 . Visual screening The fact that most precancerous and early cancerous lesions are visible to the naked eye after application of dilute acetic acid or Lugol’s iodine solution have prompted the evaluation of visual screening tests in comparison with conventional cytology in recent years. Visual inspection after application of 3−5% acetic acid (VIA), also known as direct visual inspection (DVI), as the acetic acid test (AAT), or cervicoscopy, is the most widely evaluated visual screening test. VIA involves naked eye inspection of the cervix, using a bright torch light or a halogen focus lamp, 1−2 minutes after the application of 3−5% acetic acid using a cotton swab or a spray. A positive test is characterized by well-defined acetowhite areas close to the squamocolumnar junction (SCJ) or the external os or by the entire cervix or a cervical growth turning acetowhite 21 . It is a simple, inexpensive test that can be easily learned, and yields real-time results allowing diagnostic investigations and treatment to be linked in the same session as screening. A range of personnel including doctors, nurses, midwives, and paramedical health workers can be rapidly trained in providing VIA in short training courses of 4−10 days 22 . A wide range of teaching materials is now available for training personnel in carrying out VIA competently 21,23 . It is possible for interested and motivated providers to self-learn the practice of VIA with the help of manuals and atlases. However, it is a subjective test that suffers from high false-positive rates and low to moderate specificity and reproducibility. Quality assurance procedures for VIA are yet to be standardized and assuring consistent high performance can be challenging under field conditions
S207
and requires constant monitoring and frequent re-training of test providers. The test characteristics of VIA have been evaluated in several cross-sectional studies in developing countries. In these studies, the sensitivity of VIA to detect CIN 2 and 3 lesions and invasive cervical cancer varied from 29% to 96% and the specificity varied from 49% to 98% 14,18 . The wide range in accuracy parameters of VIA in different studies underscore the subjective nature of the test. When conventional cytology was concurrently evaluated, the sensitivity of VIA was found to be higher than or similar to that of cytology, but had lower specificity than that of cytology 18 . It appears that VIA has an average sensitivity around 60% and specificity around 85% to detect high-grade CIN in experimental study settings. The immediate availability of test results following visual testing has opened up the option of ‘screen and treat’ or ‘single visit’ approach to ensure a high compliance to treatment of screen-positive women, in which the screenpositive women without clinical evidence of invasive cancer and satisfying the criteria for ablative therapy are immediately treated with cryotherapy, without confirmatory investigations such as colposcopy or histology. The safety, acceptability, and the feasibility of combining VIA and cryotherapy in a single-visit approach have been demonstrated in rural Thailand 24 and Guatemala 25 . This programme has been currently expanded to several Thai provinces. Recently, a randomized controlled trial in South Africa reported on the safety and efficacy of VIA screening or HPV testing followed by cryotherapy in reducing the prevalence of CIN 2 and 3 lesions as compared to a delayed evaluation (‘control’) group 26 . At 6 months from treatment, CIN 2 and advanced lesions was diagnosed in 0.8% of the women in the HPV testing group and 2.2% in the VIA group compared with 3.6% in the delayed evaluation group (P < 0.001 and P = 0.02 for the HPV and VIA groups, respectively). The respective cumulative prevalence rates at 12 months were 1.2% in the HPV testing group, 2.9% in the VIA group and 5.4% in the control group. Currently, the efficacy and effectiveness of VIA screening in reducing cervical cancer incidence and mortality are being addressed in randomized controlled trials in India and the final results from these studies, expected around 2007, will be very valuable for public health policy on VIA screening 27,28 . Visual inspection with Lugol’s iodine (VILI) involves naked eye examination of the cervix, to identify mustardyellow lesions in the transformation zone of the cervix,
S208
R SANKARANARAYANAN
after application of Lugol’s iodine. The VILI test 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 growth. The sensitivity of VILI varied between 44−92% and specificity between 50−90% in recent cross-sectional studies 14,18,29−31 . HPV testing The fact that cervical neoplasia are caused by persistent infection with one or more of the oncogenic types of HPV has led to the evaluation of HPV testing as a primary screening test for cervical neoplasia. HPV testing is the most objective and reproducible of all currently available cervical screening tests. The accuracy of HPV testing for the detection of cervical neoplasia has been evaluated in several cross-sectional studies. The sensitivity of HPV testing in detecting CIN 2 and 3 lesions varied from 66% to 100% and the specificity varied from 62% to 96% in these studies 14,18,32 . 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. In low-resource settings, where repeated testing of women at risk for cervical neoplasia may not be feasible, HPV testing may provide an objective method of identifying and investing the limited resources on women at risk for disease. However, it is currently more expensive (20−30 US$) than other screening tests and requires sophisticated laboratory infrastructure including testing equipment, storage facilities for samples and trained technicians. These requirements make HPV testing nonviable in developing countries. Further developments in terms of less expensive testing and less sophistication in infrastructure and equipment requirements are essential to make HPV testing feasible in low-resource settings. Efforts are now underway to develop affordable, rapid and accurate HPV testing methods for use in low- and medium-resource settings.
of 35, with a one- or two-visit screening strategy involving VIA reduced the lifetime risk of cancer by approximately 25−36%, and cost less than 500 dollars per year of life saved 33 . Relative cancer risk declined by an additional 40% 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. The study concluded that VIA in one or two clinical visits is one of the costeffective alternatives to conventional three-visit cytologybased screening programmes in low-resource settings.
PERSPECTIVES IN 3 COUNTRIES This 26th volume of the FIGO Annual Report on the Results of Treatment in Gynecological Cancer carries a perspective on cervical cancer in 3 countries in 3 different continents, where cervical cancer constitutes a major disease burden. Suarez & Prieto describe the evolution of the Chilean cervical screening programme and its reorganization in recent years resulting in a much higher coverage of target women, which has led to a significant decline in mortality in the last decade. Still cervical cancer continues to be a major burden in Chile where further improvements in the screening programme will lead to additional important declines in disease burden. Denny describes the South African situation, where the gap between the policy (to offer all asymptomatic women aged 30 years and above 3 cervical smears at 10-year intervals) and its actual implementation, in the backdrop of new developments such as HPV vaccines and the challenges in introducing vaccination as a strategy in the near future. Vallikad provides a situational analysis for India, the country with the largest disease burden in the world. While clinical early detection following awareness is emphasized as one control measure, the potential value of sensitizing a wider and larger pool of health care providers such as primary health workers, nurses, doctors and gynaecologists in delivering preventive services with the existing option of affordable screening tests and future option of vaccines should not be overlooked.
CONCLUSION Cost-effectiveness of screening in low-resource settings A recent study that assessed the cost-effectiveness of a variety of cervical-cancer screening strategies in India, Kenya, Peru, South Africa, and Thailand reported that screening women once in their lifetime, at the age
Although there have been exciting developments in vaccination and alternative methods of screening in the last few years, there are several barriers and challenges for the implementation of these approaches in developing countries in the near future. The costs of vaccines and creating or strengthening existing vaccine platforms
OVERVIEW OF CERVICAL CANCER IN THE DEVELOPING WORLD
for reaching out to adolescents will prove critical in a vaccination programme. On the other hand, implementation of screening as a public health programme would require considerable investments in health care infrastructure in many developing countries for testing, diagnosis, treatment and quality assurance as well as for trained human resources irrespective of whatever screening test is used. Scientific evidence for costeffectiveness and correct advocacy may help to catalyse the political will for finding and allocating sufficient resources and organising programmes that aim for a judicious combination of screening and vaccination in low- and medium-resource countries. The work carried out by the Alliance for Cervical Cancer Prevention supported by the Bill & Melinda Gates Foundation is instructive for cervical cancer prevention in lowand medium-resource countries 19 . Educating both the public and service providers is vital for diffusion of both the preventive approaches even in the absence of development of organised public health programmes in countries. It seems, in most countries, individual informed action by both the target women and service providers is likely to lead to varying levels of diffusion of vaccination and screening in public health and clinical practice, albeit in a disorganized manner. VIA and VILI are suitable early detection tests in this particular context in developing countries; however, rapid, validated and cheap HPV tests, when available, will be likely to be more accurate and effective.
REFERENCES [1] Ferlay J, Bray F, Pisani P, Parkin DM. Cancer Incidence, Mortality and Prevalence Worldwide. GLOBOCAN 2002. IARC Cancer Base 5(2.0), Lyon: IARC Press, 2004. [2] IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Vol. 90: Human Papillomavirus, in press. [3] Sankaranarayanan R, Budukh A, Rajkumar R. Effective screening programs for cervical cancer in low- and middleincome developing countries. Bull World Health Organization 2001;79:954−62. [4] IARC Handbooks on Cancer Prevention. Volume 10: Cervix Cancer Screening. IARC Press, Lyon 2004. [5] Clifford GM, Callus R, Herrero R, et al. Worldwide distribution of human papillomavirus types in cytologically normal women in the International Agency for Research on Cancer HPV prevalence surveys: a pooled analysis. Lancet 2005;366:991−8. [6] Parkin DM, Whelan SL, Ferlay J, et al. (Eds.). Cancer Incidence in Five Continents, Vol VIII. IARC Scientific Publications, 2002; 155, IARC Press, Lyon. [7] Chokunonga E, Ramanakumar A, Nyakabau AM, et al. Survival of cervix cancer patients in Harare, Zimbabwe, 1995–1997. Int J Cancer 2004;109:274−7.
S209
[8] Gondos A, Brenner H, Wabinga H, et al. Cancer survival in Kampala, Uganda. Br J Cancer 2005;92:1808−12. [9] Sankaranarayanan R, Black RJ, Parkin DM (Eds.). Cancer Survival in Developing Countries, IARC Scientific Publications. 1988, 15. Lyon: IARC Press. [10] Wang H, Chia KS, Du WB, et al. Population-based survival for cervical cancer in Singapore. Am J Obstet Gynecol 2003;188: 324−9. [11] Villa LL, Costa PL, Pesta CA, et al. Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: A randomised double-blind placebo-controlled multicentre phase II efficacy trial. Lancet Oncol 2005;6:271−8. [12] Mao C, Koutsky LA, Ault KA, et al. Efficacy of human papillomavirus-16 vaccine to prevent cervical intraepithelial neoplasia: A randomized controlled trial. Obstet Gynecol 2006;107:18−27. [13] Harper DM, Franco EL, Wheeler CM, et al. Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: Follow-up from a randomised control trial. Lancet 2006;367:1247−55. [14] IARC Handbooks on Cancer Prevention. Volume 10. Cervix Cancer Screening. IARC Press, Lyon 2004. [15] Fahey MT, Irwig L, Macaskill P. Meta-analysis of Pap test Accuracy. Am J Epidemiol 1995;141:680−89. [16] Mitchell MF, Schottenfeld D, Tortolera-Luna G, et al. Colposcopy for the diagnosis of squamous intraepithelial lesions: A metaanalysis. Obstet Gynecol 1998;91:626−31. [17] Nanda K, McCrory DC, Myers ER, et al. Accuracy of the Papanicolaou test in screening for and follow-up of cervical cytologic abnormalities: A systematic review. Ann Intern Med 2000;132:810−19. [18] Sankaranarayanan R, Gaffikin L, Jacob M, et al. A Critical Assessment of Screening Methods for Cervical Neoplasia. Int J Gynaecol Obstet, 2005;89(Suppl 2): S4−12. [19] Alliance for Cervical Cancer Prevention (ACCP). Planning and Implementing Cervical Cancer Prevention and Control Programs: A Manual for Managers. Seattle: ACCP, 2004. [20] Sepulveda C, Prado R. Effective cervical cytology screening programmes in middle-income countries: The Chilean experience. Cancer Detect Prev 2005;29:405−11. [21] Sankaranarayanan R, Wesley R. A practical manual on visual screening for cervical neoplasia. IARC Technical Publication, 2003, 41. IARC Press. [22] Blumenthal P, Lauterbach J, Sellors J, Sankaranarayanan R. Training for Cervical Cancer Prevention Programs in LowResource Settings: Focus on visual inspection with acetic acid and cryotherapy. Int J Gynaecol Obstet 2005;89(Suppl 2):S4−12. [23] Mcintosh N, Blumenthal PD, Blouse A (Ed.). Cervical Cancer Prevention Guidelines for Low-Resource Settings. JHPIEGO Technical Manual. JHPIEGO, 2001. [24] Royal Thai College of Obstetricians and Gynaecologists (RTCOG)/JHPIEGO Corporation Cervical Cancer Prevention Group. Safety, acceptability, and feasibility of a single-visit approach to cervical-cancer prevention in rural Thailand: A demonstration project. Lancet 2003;361:814–820. [25] Mathers LJ, Wigton TR, Leonhardt JG. Screening for cervical neoplasia in an unselected rural Guatemalan population using direct visual inspection after acetic acid application: A pilot study. J Low Genit Tract Dis 2005: 9: 232−5.
S210
R SANKARANARAYANAN
[26] Denny L, Kuhn L, De Souza M, et al.. Screen-and-treat approaches for cervical cancer prevention in low-resource settings: A randomized controlled trial. JAMA 2005;294:2173−81. [27] Sankaranarayanan R, Rajkumar R, Theresa R, et al. Initial results from a randomized trial of cervical visual screening in rural South India. Int J Cancer 2004;109:461−467. [28] Sankaranarayanan R, Nene BN, Dinshaw KA, et al., on behalf of the Osmanabad District Cervical Screening Study Group. A cluster randomised controlled trial of visual, cytology and HPV screening for cancer of the cervix in rural India. Int J Cancer 2005;116:617−623. [29] Sankaranarayanan R, Basu P, Wesley RS, et al., IARC Multicentre Study Group on Cervical Cancer Early Detection. Accuracy of visual screening for cervical neoplasia: Results from an IARC multicentre study in India and Africa. Int J Cancer 2004;110: 907−913.
[30] Sarian L, Derchain S, Naud P, et al. Evaluation of visual inspection with acetic acid (VIA), Lugol’s iodine (VILI), cervical cytology and HPV testing as cervical screening tools in Latin America. J Med Screen 2005;12:142−149. [31] Sangwa-Lugoma G, Mahmud S, Nasr SH, et al. Visual inspection as a cervical cancer screening method in a primary health care setting in Africa. Int J Cancer 2006 (Apr 7). [Epub ahead of print.] [32] Franco EL. Primary screening of cervical cancer with human papillomavirus tests. J Natl Cancer Inst Monogr 2003;31:89−96. [33] Goldie S, Gaffikin L, Goldhaber-Fiebert J, et al. Cost-effectiveness of cervical screening in five developing countries, N Engl J Med 2005;353:2158−68.
Overview of Cervical Cancer in the Developing World R SANKARANARAYANAN Head, Screening Group, World Health Organization – International Agency for Research on Cancer, Lyon 69008, France
INTRODUCTION The most recent global estimates for cancer burden indicate that there were 10.9 million new cancer cases (excluding non-melanoma skin cancers) in both sexes in the world around the year 2002: 5.8 million cases in men and 5.1 million in women 1 . There were 6.7 million cancer deaths, 3.8 million in men and 2.9 million in women. Cervical cancer accounted for 493 000 newly diagnosed cases, 1.4 million prevalent cases and 273 000 deaths world-wide in the year 2002. Of these, more than 80% occurred in the low- and medium-resource countries in South and South East Asia, sub-Saharan Africa, and South and Central America (Table 1) 1 . In fact, one third of cervical cancer burden in the world is experienced in South Asia. These statistics indicate that cervical cancer Table 1 Cancers of the uterine cervix. Incident cases, deaths and 5-year prevalence in 18 world regions in 2002 Cervix cancer
World
Cases
Deaths
5-year prevalence 1 409 200
492 800
273 200
More developed countries
83 400
39 500
309 900
Less developed countries
409 400
233 700
1 099 300
Eastern Africa
33 900
27 100
57 200
Middle Africa
8200
6600
13 900
Northern Africa
8100
6500
14 000
Southern Africa
7600
4400
13 100
20 900
16 700
35 700
6300
3100
18 400
Central America
17 100
8100
49 300
South America
48 300
21 400
139 200
Northern America
14 600
5700
58 200
Eastern Asia
61 100
31 300
191 900
South-Eastern Asia
42 500
22 500
132 500
South Central Asia
157 700
86 700
446 100
4400
2100
13 700
30 800
17 100
107 700
Northern Europe
5600
2800
21 100
Southern Europe
10 600
4100
40 900
Western Europe
12 700
5600
49 200
2000
800
6500
Western Africa Caribbean
Western Asia Eastern Europe
Oceania
continues to be a major public health problem in many developing countries. It is quite likely that the burden of disease in sub-Saharan Africa is underestimated given the inadequacy of diagnostic and treatment services and cancer information systems. It is well established that cervical cancer is caused by persistent infection with one or more of approximately 15 oncogenic types of human papillomaviruses (HPV) 2 . Persistent HPV infection promotes cellular changes that result in the occurrence of precancerous lesions and invasive cancer. Lack of effective screening programmes and the high prevalence of oncogenic HPV infection (>10% in women aged 30 years or over) are responsible for the high burden of cervical cancer in many developing countries 3−5 .
INCIDENCE AND MORTALITY PATTERNS There is an eight-fold variation in the incidence rates of cervical cancer world-wide and age-standardized incidence rates above 25 per 100 000 women are observed in many developing countries in sub-Saharan Africa, Central and South America, South Asia and South-East Asia as opposed to rates lower than 10 per 100 000 in most developed countries 1,6 . Rates lower than 7/100 000 women are observed in the middle eastern countries 6 . Estimated age-adjusted cervical cancer mortality rates exceed 10 per 100 000 women in most developing countries, with rates exceeding 25 per 100 000 in East African countries as opposed to less than 5 per 100 000 women in most developed countries. The high mortality is due to advanced clinical stage at presentation and to the fact that a significant proportion of patients do not avail or complete prescribed courses of treatment, due to deficiencies in treatment availability, accessibility and affordability in many developing countries 3 .
SURVIVAL FROM CERVICAL CANCER A large variation in survival from cervical cancer is observed even among developing countries due to the variations in clinical stages of presentation and the availability and accessibility to diagnostic and treatment services according to the level of development of cancer
Correspondence to: Dr R. Sankaranarayanan. Head, Screening Group, International Agency for Research on Cancer, 150 Cours Albert Thomas, 69372 Lyon CEDEX 08, France. Tel: +33-472738599; fax: +33-472738518. E-mail: [email protected]
S206
R SANKARANARAYANAN
related health services in different countries. For black patients in Uganda, Zimbabwe and the Gambia, 5-year survival rates lower than 25% are reported, while they are in the range of 30−50% in Cuba, India, and Philippines; 50−60% in Costa Rica, Thailand, Turkey and in mainland China; and more than 65% in Hong Kong, Singapore and South Korea 7−10 . The survival experience in more developed and accessible health services in East Asian countries such as Singapore and Korea is similar to those observed in the US and Europe.
the extent of reduction in cervical cancer incidence and mortality following screening. Cervical screening tests such as cytology, visual and HPV tests are capable of identifying women having CIN as well as early, preclinical invasive cancer. The critical components of successful cervical screening are high coverage of target women with accurate, quality-assured screening tests and of screen-positive women with diagnostic investigations, of women with confirmed cervical neoplasia with treatment and follow-up care. Cytology screening
VACCINATION The fact that cervical cancer is caused by persistent HPV infection provides enormous potential for cancer prevention through vaccination. More than 99% of cervical cancers contain one or more of the oncogenic HPV genotypes that cause cervical cancer, although approximately 50−60% of these cancers contain HPV16, and another 10−20% harbour HPV-18; and the currently evaluated vaccines target preventing infection by these two HPV types. Recent results from on-going randomized trials indicate that HPV vaccines have an excellent safety profile, are highly immunogenic, and have conferred a high degree of protection against HPV16/18 infection and associated precancerous cervical lesions in fully vaccinated women 11−13 . Some evidence of cross protection against related oncogenic types is also emerging 13 . It is likely that HPV vaccines may soon be licensed and will be available for clinical use in the near future. However, there are several unresolved issues such as the most critical target groups to vaccinate, integration into existing vaccine platforms in countries, acceptance of a vaccine designed to prevent a sexually transmitted infection, parental comfort with vaccination of their pre-adolescent/early adolescent daughters, duration of immune response, the need for booster doses, the extent of cross-protection against other HPV types. Another unresolved issue is vaccine costs and when the vaccine’s cost may be low enough for widespread implementation in the developing world, where 80% of cervical cancer occurs and when multivalent vaccines will be available.
SCREENING FOR CERVICAL CANCER The objective of cervical screening is to prevent invasive cervical cancer by detecting and treating women with high-grade cervical intraepithelial neoplasia (CIN 2 and 3 lesions) and the effectiveness of screening is evaluated by
Cytology screening has been largely responsible for the significant decline in the burden of cervical cancer in developed countries in the last 5 decades 1 . Organised screening with systematic call, recall, follow-up and surveillance systems have shown the greatest effect (e.g. Finland, Iceland), while using fewer resources than the less organised programmes (e.g. USA). Cervical cancer incidence has been reduced by as much as 80% where the cytology screening quality, coverage and follow-up of women are high. Cytology screening is yet to be effectively implemented in many developing countries or has failed to reduce cervical cancer burden to an appreciable extent in some developing countries in Latin America such as Costa Rica, Cuba, Brazil, Mexico, Chile, Peru, Colombia, etc., where it has been introduced regionally or nationally since the late 1960s and 1970s 3,14 . The main reasons for the lack of success in these countries were a combination of sub-optimal cytology testing, lack of quality assurance, poor coverage of women at risk, and inadequate follow-up of screen-positive women with diagnosis and treatment 3 . While poor quality cytology is a reflection of several challenges in providing quality-assured testing, the lack of coverage for diagnosis and treatment is related to the inadequate health care infrastructure, human resources and programme logistics. Cytology is a resource intensive technology and, unfortunately, it is not possible to commit sufficient financial and human resources to fulfil the optimal requirements for collection of cervical cells, slide preparation, staining, reading and reporting, as well as quality control measures, to ensure good quality cytology with optimal accuracy in low-resource countries. In most routine settings, cytology has been shown to have a wide range in sensitivity in detecting cervical neoplasia. The sensitivity to detect CIN 2 and 3 lesions ranged from 47% to 62% and the specificity from 60% to 95% in recent reviews 14−18 . There have been several cross-sectional
OVERVIEW OF CERVICAL CANCER IN THE DEVELOPING WORLD
studies in developing countries assessing the accuracy of cytology, in which the sensitivity varied from 44% to 78% and the specificity from 91% to 96% 18 . The apparent lack of impact of cervical cytology programmes and the difficulties in organizing such programmes in low- and medium-resource countries have prompted the search for and evaluation of alternative screening tests and paradigms that require one single, or two visits, to complete the screening and diagnosis/treatment processes 19 , as well as the reorganization of existing programmes and more effective utilization of resources in some countries such as Chile, Costa Rica and Brazil 3,20 . Reorganization of the programme in Chile has been associated with some decline in cervical cancer mortality in recent years 20 . Visual screening The fact that most precancerous and early cancerous lesions are visible to the naked eye after application of dilute acetic acid or Lugol’s iodine solution have prompted the evaluation of visual screening tests in comparison with conventional cytology in recent years. Visual inspection after application of 3−5% acetic acid (VIA), also known as direct visual inspection (DVI), as the acetic acid test (AAT), or cervicoscopy, is the most widely evaluated visual screening test. VIA involves naked eye inspection of the cervix, using a bright torch light or a halogen focus lamp, 1−2 minutes after the application of 3−5% acetic acid using a cotton swab or a spray. A positive test is characterized by well-defined acetowhite areas close to the squamocolumnar junction (SCJ) or the external os or by the entire cervix or a cervical growth turning acetowhite 21 . It is a simple, inexpensive test that can be easily learned, and yields real-time results allowing diagnostic investigations and treatment to be linked in the same session as screening. A range of personnel including doctors, nurses, midwives, and paramedical health workers can be rapidly trained in providing VIA in short training courses of 4−10 days 22 . A wide range of teaching materials is now available for training personnel in carrying out VIA competently 21,23 . It is possible for interested and motivated providers to self-learn the practice of VIA with the help of manuals and atlases. However, it is a subjective test that suffers from high false-positive rates and low to moderate specificity and reproducibility. Quality assurance procedures for VIA are yet to be standardized and assuring consistent high performance can be challenging under field conditions
S207
and requires constant monitoring and frequent re-training of test providers. The test characteristics of VIA have been evaluated in several cross-sectional studies in developing countries. In these studies, the sensitivity of VIA to detect CIN 2 and 3 lesions and invasive cervical cancer varied from 29% to 96% and the specificity varied from 49% to 98% 14,18 . The wide range in accuracy parameters of VIA in different studies underscore the subjective nature of the test. When conventional cytology was concurrently evaluated, the sensitivity of VIA was found to be higher than or similar to that of cytology, but had lower specificity than that of cytology 18 . It appears that VIA has an average sensitivity around 60% and specificity around 85% to detect high-grade CIN in experimental study settings. The immediate availability of test results following visual testing has opened up the option of ‘screen and treat’ or ‘single visit’ approach to ensure a high compliance to treatment of screen-positive women, in which the screenpositive women without clinical evidence of invasive cancer and satisfying the criteria for ablative therapy are immediately treated with cryotherapy, without confirmatory investigations such as colposcopy or histology. The safety, acceptability, and the feasibility of combining VIA and cryotherapy in a single-visit approach have been demonstrated in rural Thailand 24 and Guatemala 25 . This programme has been currently expanded to several Thai provinces. Recently, a randomized controlled trial in South Africa reported on the safety and efficacy of VIA screening or HPV testing followed by cryotherapy in reducing the prevalence of CIN 2 and 3 lesions as compared to a delayed evaluation (‘control’) group 26 . At 6 months from treatment, CIN 2 and advanced lesions was diagnosed in 0.8% of the women in the HPV testing group and 2.2% in the VIA group compared with 3.6% in the delayed evaluation group (P < 0.001 and P = 0.02 for the HPV and VIA groups, respectively). The respective cumulative prevalence rates at 12 months were 1.2% in the HPV testing group, 2.9% in the VIA group and 5.4% in the control group. Currently, the efficacy and effectiveness of VIA screening in reducing cervical cancer incidence and mortality are being addressed in randomized controlled trials in India and the final results from these studies, expected around 2007, will be very valuable for public health policy on VIA screening 27,28 . Visual inspection with Lugol’s iodine (VILI) involves naked eye examination of the cervix, to identify mustardyellow lesions in the transformation zone of the cervix,
S208
R SANKARANARAYANAN
after application of Lugol’s iodine. The VILI test 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 growth. The sensitivity of VILI varied between 44−92% and specificity between 50−90% in recent cross-sectional studies 14,18,29−31 . HPV testing The fact that cervical neoplasia are caused by persistent infection with one or more of the oncogenic types of HPV has led to the evaluation of HPV testing as a primary screening test for cervical neoplasia. HPV testing is the most objective and reproducible of all currently available cervical screening tests. The accuracy of HPV testing for the detection of cervical neoplasia has been evaluated in several cross-sectional studies. The sensitivity of HPV testing in detecting CIN 2 and 3 lesions varied from 66% to 100% and the specificity varied from 62% to 96% in these studies 14,18,32 . 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. In low-resource settings, where repeated testing of women at risk for cervical neoplasia may not be feasible, HPV testing may provide an objective method of identifying and investing the limited resources on women at risk for disease. However, it is currently more expensive (20−30 US$) than other screening tests and requires sophisticated laboratory infrastructure including testing equipment, storage facilities for samples and trained technicians. These requirements make HPV testing nonviable in developing countries. Further developments in terms of less expensive testing and less sophistication in infrastructure and equipment requirements are essential to make HPV testing feasible in low-resource settings. Efforts are now underway to develop affordable, rapid and accurate HPV testing methods for use in low- and medium-resource settings.
of 35, with a one- or two-visit screening strategy involving VIA reduced the lifetime risk of cancer by approximately 25−36%, and cost less than 500 dollars per year of life saved 33 . Relative cancer risk declined by an additional 40% 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. The study concluded that VIA in one or two clinical visits is one of the costeffective alternatives to conventional three-visit cytologybased screening programmes in low-resource settings.
PERSPECTIVES IN 3 COUNTRIES This 26th volume of the FIGO Annual Report on the Results of Treatment in Gynecological Cancer carries a perspective on cervical cancer in 3 countries in 3 different continents, where cervical cancer constitutes a major disease burden. Suarez & Prieto describe the evolution of the Chilean cervical screening programme and its reorganization in recent years resulting in a much higher coverage of target women, which has led to a significant decline in mortality in the last decade. Still cervical cancer continues to be a major burden in Chile where further improvements in the screening programme will lead to additional important declines in disease burden. Denny describes the South African situation, where the gap between the policy (to offer all asymptomatic women aged 30 years and above 3 cervical smears at 10-year intervals) and its actual implementation, in the backdrop of new developments such as HPV vaccines and the challenges in introducing vaccination as a strategy in the near future. Vallikad provides a situational analysis for India, the country with the largest disease burden in the world. While clinical early detection following awareness is emphasized as one control measure, the potential value of sensitizing a wider and larger pool of health care providers such as primary health workers, nurses, doctors and gynaecologists in delivering preventive services with the existing option of affordable screening tests and future option of vaccines should not be overlooked.
CONCLUSION Cost-effectiveness of screening in low-resource settings A recent study that assessed the cost-effectiveness of a variety of cervical-cancer screening strategies in India, Kenya, Peru, South Africa, and Thailand reported that screening women once in their lifetime, at the age
Although there have been exciting developments in vaccination and alternative methods of screening in the last few years, there are several barriers and challenges for the implementation of these approaches in developing countries in the near future. The costs of vaccines and creating or strengthening existing vaccine platforms
OVERVIEW OF CERVICAL CANCER IN THE DEVELOPING WORLD
for reaching out to adolescents will prove critical in a vaccination programme. On the other hand, implementation of screening as a public health programme would require considerable investments in health care infrastructure in many developing countries for testing, diagnosis, treatment and quality assurance as well as for trained human resources irrespective of whatever screening test is used. Scientific evidence for costeffectiveness and correct advocacy may help to catalyse the political will for finding and allocating sufficient resources and organising programmes that aim for a judicious combination of screening and vaccination in low- and medium-resource countries. The work carried out by the Alliance for Cervical Cancer Prevention supported by the Bill & Melinda Gates Foundation is instructive for cervical cancer prevention in lowand medium-resource countries 19 . Educating both the public and service providers is vital for diffusion of both the preventive approaches even in the absence of development of organised public health programmes in countries. It seems, in most countries, individual informed action by both the target women and service providers is likely to lead to varying levels of diffusion of vaccination and screening in public health and clinical practice, albeit in a disorganized manner. VIA and VILI are suitable early detection tests in this particular context in developing countries; however, rapid, validated and cheap HPV tests, when available, will be likely to be more accurate and effective.
REFERENCES [1] Ferlay J, Bray F, Pisani P, Parkin DM. Cancer Incidence, Mortality and Prevalence Worldwide. GLOBOCAN 2002. IARC Cancer Base 5(2.0), Lyon: IARC Press, 2004. [2] IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Vol. 90: Human Papillomavirus, in press. [3] Sankaranarayanan R, Budukh A, Rajkumar R. Effective screening programs for cervical cancer in low- and middleincome developing countries. Bull World Health Organization 2001;79:954−62. [4] IARC Handbooks on Cancer Prevention. Volume 10: Cervix Cancer Screening. IARC Press, Lyon 2004. [5] Clifford GM, Callus R, Herrero R, et al. Worldwide distribution of human papillomavirus types in cytologically normal women in the International Agency for Research on Cancer HPV prevalence surveys: a pooled analysis. Lancet 2005;366:991−8. [6] Parkin DM, Whelan SL, Ferlay J, et al. (Eds.). Cancer Incidence in Five Continents, Vol VIII. IARC Scientific Publications, 2002; 155, IARC Press, Lyon. [7] Chokunonga E, Ramanakumar A, Nyakabau AM, et al. Survival of cervix cancer patients in Harare, Zimbabwe, 1995–1997. Int J Cancer 2004;109:274−7.
S209
[8] Gondos A, Brenner H, Wabinga H, et al. Cancer survival in Kampala, Uganda. Br J Cancer 2005;92:1808−12. [9] Sankaranarayanan R, Black RJ, Parkin DM (Eds.). Cancer Survival in Developing Countries, IARC Scientific Publications. 1988, 15. Lyon: IARC Press. [10] Wang H, Chia KS, Du WB, et al. Population-based survival for cervical cancer in Singapore. Am J Obstet Gynecol 2003;188: 324−9. [11] Villa LL, Costa PL, Pesta CA, et al. Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: A randomised double-blind placebo-controlled multicentre phase II efficacy trial. Lancet Oncol 2005;6:271−8. [12] Mao C, Koutsky LA, Ault KA, et al. Efficacy of human papillomavirus-16 vaccine to prevent cervical intraepithelial neoplasia: A randomized controlled trial. Obstet Gynecol 2006;107:18−27. [13] Harper DM, Franco EL, Wheeler CM, et al. Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: Follow-up from a randomised control trial. Lancet 2006;367:1247−55. [14] IARC Handbooks on Cancer Prevention. Volume 10. Cervix Cancer Screening. IARC Press, Lyon 2004. [15] Fahey MT, Irwig L, Macaskill P. Meta-analysis of Pap test Accuracy. Am J Epidemiol 1995;141:680−89. [16] Mitchell MF, Schottenfeld D, Tortolera-Luna G, et al. Colposcopy for the diagnosis of squamous intraepithelial lesions: A metaanalysis. Obstet Gynecol 1998;91:626−31. [17] Nanda K, McCrory DC, Myers ER, et al. Accuracy of the Papanicolaou test in screening for and follow-up of cervical cytologic abnormalities: A systematic review. Ann Intern Med 2000;132:810−19. [18] Sankaranarayanan R, Gaffikin L, Jacob M, et al. A Critical Assessment of Screening Methods for Cervical Neoplasia. Int J Gynaecol Obstet, 2005;89(Suppl 2): S4−12. [19] Alliance for Cervical Cancer Prevention (ACCP). Planning and Implementing Cervical Cancer Prevention and Control Programs: A Manual for Managers. Seattle: ACCP, 2004. [20] Sepulveda C, Prado R. Effective cervical cytology screening programmes in middle-income countries: The Chilean experience. Cancer Detect Prev 2005;29:405−11. [21] Sankaranarayanan R, Wesley R. A practical manual on visual screening for cervical neoplasia. IARC Technical Publication, 2003, 41. IARC Press. [22] Blumenthal P, Lauterbach J, Sellors J, Sankaranarayanan R. Training for Cervical Cancer Prevention Programs in LowResource Settings: Focus on visual inspection with acetic acid and cryotherapy. Int J Gynaecol Obstet 2005;89(Suppl 2):S4−12. [23] Mcintosh N, Blumenthal PD, Blouse A (Ed.). Cervical Cancer Prevention Guidelines for Low-Resource Settings. JHPIEGO Technical Manual. JHPIEGO, 2001. [24] Royal Thai College of Obstetricians and Gynaecologists (RTCOG)/JHPIEGO Corporation Cervical Cancer Prevention Group. Safety, acceptability, and feasibility of a single-visit approach to cervical-cancer prevention in rural Thailand: A demonstration project. Lancet 2003;361:814–820. [25] Mathers LJ, Wigton TR, Leonhardt JG. Screening for cervical neoplasia in an unselected rural Guatemalan population using direct visual inspection after acetic acid application: A pilot study. J Low Genit Tract Dis 2005: 9: 232−5.
S210
R SANKARANARAYANAN
[26] Denny L, Kuhn L, De Souza M, et al.. Screen-and-treat approaches for cervical cancer prevention in low-resource settings: A randomized controlled trial. JAMA 2005;294:2173−81. [27] Sankaranarayanan R, Rajkumar R, Theresa R, et al. Initial results from a randomized trial of cervical visual screening in rural South India. Int J Cancer 2004;109:461−467. [28] Sankaranarayanan R, Nene BN, Dinshaw KA, et al., on behalf of the Osmanabad District Cervical Screening Study Group. A cluster randomised controlled trial of visual, cytology and HPV screening for cancer of the cervix in rural India. Int J Cancer 2005;116:617−623. [29] Sankaranarayanan R, Basu P, Wesley RS, et al., IARC Multicentre Study Group on Cervical Cancer Early Detection. Accuracy of visual screening for cervical neoplasia: Results from an IARC multicentre study in India and Africa. Int J Cancer 2004;110: 907−913.
[30] Sarian L, Derchain S, Naud P, et al. Evaluation of visual inspection with acetic acid (VIA), Lugol’s iodine (VILI), cervical cytology and HPV testing as cervical screening tools in Latin America. J Med Screen 2005;12:142−149. [31] Sangwa-Lugoma G, Mahmud S, Nasr SH, et al. Visual inspection as a cervical cancer screening method in a primary health care setting in Africa. Int J Cancer 2006 (Apr 7). [Epub ahead of print.] [32] Franco EL. Primary screening of cervical cancer with human papillomavirus tests. J Natl Cancer Inst Monogr 2003;31:89−96. [33] Goldie S, Gaffikin L, Goldhaber-Fiebert J, et al. Cost-effectiveness of cervical screening in five developing countries, N Engl J Med 2005;353:2158−68.