Introduction

Cervical cancer, a largely preventable disease, is one of the most common cancers found in women living in low- and middle-income countries (LMICs). A striking reduction in the incidence of and mortality from cervical cancer occurred in the past century in those countries that were able to establish successful national screening programs. These programs relied on cytology-based Papanicolaou smears to identify cervical cancer precursors that can be removed before progressing to invasive cancer. Prevention of up to 91 percent of all invasive cervical cancers has been achieved in countries able to implement widespread cytology-based screening.

However, these programs are expensive and require robust and well-funded health care systems. Few LMICs have initiated or sustained cytology-based cervical cancer prevention programs, and these countries experience very high incidence and mortality rates. The unequal burden of cervical cancer is an example of the impact of unequal access to health care. Fortunately, alternative strategies to prevent cervical cancer have been investigated and extensively evaluated in these settings. The recent introduction of two commercially available vaccines against human papillomavirus (HPV) has offered the possibility of primary prevention of cervical cancer. This chapter focuses on these innovations.

Burden of Cervical Cancer¹

Global Burden of Disease

Cervical cancer, caused by HPV, is the third leading malignancy among women in the world, after breast cancer and colorectal cancer, with an estimated 527,624 new cases and 265,653 deaths in 2012 (Ferlay and others 2013). Incidence and mortality rates have been declining in most areas of the world in the past 30 years, at a worldwide rate of about 1.6 percent per year (Forouzanfar and others 2011). This decline is a result of increased access to health services, reductions in some risk factors (such as fertility rates), improvements in treatment, and successful cytology-based screening programs. However, more than 80 percent of cases and 88 percent of deaths occur in LMICs. Cervical cancer is still the leading cancer in women in many LMICs; some areas report recent increases in rates, including several economies in Europe and Central Asia (Arbyn and others 2011).

A striking characteristic of cervical cancer is its variation by country, with a generally strong inverse correlation between the level of development and the incidence and mortality. Survival once the disease has developed is also much better in richer than in poorer countries. Figure 4.1 shows trends of incidence and mortality in selected countries.

Figure 4.1

Trends of Age-Standardized Rates of Cervical Cancer Incidence and Mortality in Selected Countries.

Regional Burden of Disease

Despite the declining global rates, the number of new cases and deaths has increased constantly by about 0.5 percent per year because of population aging. With no new intervention, the increase will continue, particularly in LMICs where the life expectancy of women is improving. For example, in Latin America and the Caribbean, the estimated number of new cases is likely to increase by 75 percent between 2002 and 2025 if the incidence rates remain at 2002 levels, because of population growth and aging alone (Parkin and others 2008).

The disease is strongly influenced by cultural and religious practices that govern sexual behavior and transmission of HPV. Sub-Saharan Africa has the highest estimated rates of cervical cancer; in Guinea, Malawi, and Zambia, the age-standardized incidence rate is over 50 per 100,000 (Arbyn and others 2011). In contrast, in countries in the Middle East and North Africa, such as Algeria, the Arab Republic of Egypt, Libya, Sudan, and Tunisia, where sexual behaviors are more conservative, the recorded incidence rates are below 10 per 100,000 women. In high-income countries (HICs), rates are even lower, at about 5 per 100,000 women.

In Latin America and the Caribbean, Guyana, Honduras, Jamaica, and Nicaragua have rates around 40 per 100,000. In Asia, the highest rates are in Bangladesh, Cambodia, India, and Nepal.

Map 4.1 shows the incidence of cervical cancer by country in 2012; figure 4.2 shows the contrast between the rates of incidence and mortality between national income groupings.

Map 4.1

Age-Standardized Cervical Cancer Incidence Rates, 2012.

Figure 4.2

Age-Standardized Cervical Cancer Incidence and Mortality Rates per 100,000 Women, by World Bank Income Group.

Even within HICs, the highest incidence and mortality rates are among the poorest or most marginalized women. For example, in the United States, where the average rates are low and cervical cancer has consistently declined in recent decades, strong disparities still exist by race and socioeconomic status (Singh 2012), reflecting the variability in accessibility of services. The other notable characteristic of cervical cancer is that it affects relatively young women who often have many children and are frequently sole providers. The median age at death for women with cervical cancer is 54 years; the burden of disease among women under age 40 years is high compared with other cancers, because of the large numbers of women in these age groups in LMICs and the fact that cervical cancer rates begin to rise at younger ages than other cancers.

Because cervical cancer affects relatively young women, it ranks highest among cancers according to a disability-adjusted life years (DALYs) metric. In a recent study, DALYs caused by cervical cancer ranged from 84 per 100,000 women in areas with a very high Human Development Index (HDI)² to 595 per 100,000 in areas with a low HDI (Soerjomataram and others 2012). Breast cancer DALYs ranged from a high of 566 age-adjusted DALYs per 100,000 in populations with a very high HDI to 387 in those with a low HDI.

Natural History of Cervical Cancer

The natural history has been studied extensively, and persistent infection of the cervix with certain high-risk types of HPV has been well established as a necessary cause of cervical cancer (Walboomers and others 1999). HPV is a very common sexually transmitted infection, usually acquired soon after initiation of sexual activity. Most HPV infections clear spontaneously within one to two years; those that persist, particularly high-risk types of HPV (including HPV 16 and 18), may progress to cervical cancer precursors, and ultimately to invasive cervical cancer. High-risk types of HPV are identified in nearly all cancers of the cervix, and the relative risk of cervical cancer associated with persistent, ongoing infection with high-risk types of HPV is higher than the risk of lung cancer associated with smoking. HPV 16 and 18 are responsible for about 70 percent of cases worldwide (http://www.iarc.fr). There is little geographic variation in the predominant HPV types associated with cervical cancer.

A study that evaluated HPV infection in 10,575 histologically confirmed cases of invasive cancer from 38 countries in Asia, Europe, Latin America and the Caribbean, North America, Oceania, and Sub-Saharan Africa over a 60-year period found that 85 percent (n = 8,977) of the cases were positive for HPV DNA (de Sanjose and others 2010). HPV types 16, 18, and 45 were the three most common types in each histologic form of cervical cancer (squamous cell, adenocarcinoma, and adenosquamous carcinoma), accounting for 61 percent, 10 percent, and 6 percent, respectively.

Good evidence suggests that HPV infection precedes the development of cervical cancer by decades and that persistent infection with HPV is necessary for the development and progression of precancerous lesions of the cervix, either to higher grades of precancerous disease or to cancer. Cervical cancer progresses slowly from a preinvasive state to invasive cervical cancer, a process that can take 10–30 years (Wright and Kurman 1994).

However, HPV infections are very common, particularly among young women (Herrero and others 2005), where the majority of infections are likely to regress spontaneously as a result of activation of the immune system.

Secondary Prevention of Cervical Cancer Through Screening

Historically, cervical cancer screening, also known as secondary prevention of cervical cancer, was based on examining cells collected from the surface of the cervix by Pap smear (cytology), followed by colposcopy for women with abnormal smears and histological assessment, followed by surgical treatment for histologically proven cancer precursors. This approach resulted in dramatic reductions in cervical cancer incidence and mortality in health systems that were robust enough to support relatively complex screening programs effectively. However, very few LMICs have been able to initiate or sustain cytology-based screening programs because of lack of adequate resources or health care or laboratory infrastructure.

For screening and treatment of precancerous lesions, several new tools have been developed that are better suited to low-resource settings. Depending mainly on the target age group and frequency of screening, these tools may be effective in reducing cervical cancer rates. The new interventions include the following:

• Screening with visual inspection with acetic acid (VIA)
• Screening with HPV DNA testing
• Treatment with ablative techniques (cryotherapy and cold coagulation)
• Treatment using excisional techniques, called loop electrocautery excision procedure (LEEP), also known as large loop excision of the transformational zone (LLETZ), and cone biopsy.

Alternative Approaches to Cytology for Cervical Cancer Screening

Visual Inspection with Acetic Acid

VIA involves applying a 3–5 percent acetic acid solution to the cervix and then examining it with the naked eye using a bright light source. No expensive equipment or supplies are needed, and screening takes less than five minutes. A well-defined aceto-white area close to the transformation zone indicates a positive test.

VIA is inexpensive and simple and can be carried out by primary care staff. Most important, VIA provides an immediate result that can be used to decide on treatment, usually with cryotherapy, which requires training but no surgery or anesthetic.

It is difficult to recommend VIA unconditionally, however, because its sensitivity and specificity are lower than those of other screening methods (table 4.1). VIA sensitivity and specificity are variable, because they are highly dependent on the training and skill of the staff carrying out the examinations. The accuracy of the test decreases with the increasing age of the women screened. In cross-sectional studies, the sensitivity and specificity of VIA compared favorably with cytology in detecting high-grade cervical cancer precursor lesions and cervical cancer. Sensitivity has varied from 49 to 96 percent, and specificity has varied from 49 to 98 percent (Denny, Quinn, and Sankaranarayanan 2006). However, many of these studies suffer from verification bias, where the true status of disease in test-negative women is unknown. Sauvaget and others (2011) performed a meta-analysis of 26 studies of VIA with confirmatory testing, using high-grade squamous intraepithelial lesions (HSIL) as the disease threshold. Sauvaget and others (2011) report a sensitivity of 80 percent specificity (range 79–82 percent) and 92 percent specificity (range 91–92 percent) for VIA, with a positive predictive value of 10 percent. They conclude that in very low-resource settings where the infrastructure for laboratory-based testing is not available, VIA is a reasonable alternative to cytology. However, in more recent randomized studies, VIA has performed less well.

Table 4.1

Performance and Characteristics of Screening Methods.

Despite its limitations, the possibility of immediate diagnosis and treatment makes VIA the only possible alternative in many low-resource settings. One potential use of VIA that would have a significant impact is following an HPV test, for HPV-positive women only, to make treatment decisions. The utility of VIA in this context is promising but yet to be proven.

Case Study of Upscaling VIA

From 2005 through 2009, the World Health Organization (WHO) sponsored a VIA demonstration project in six Sub-Saharan African countries: Madagascar, Malawi, Nigeria, Tanzania, Uganda, and Zambia (WHO 2012). In all, 19,579 women were screened with VIA. Of these, 1,980 were VIA-positive (11.5 percent); cancer was suspected in 326 (1.7 percent). Of the VIA-positive women, 1,737 were eligible for cryotherapy (87.7 percent); of these, 1,058 (60.9 percent) were treated, 601 (34.6 percent) were lost to follow-up, and 78 women were not treated. Of the women treated, 243 (39.1 percent) were treated during the same visit as the screening.

No information was available for 230 of the 326 women in whom cancer was suspected (70.5 percent); of the 96 women investigated, cancer was confirmed in 79, but no staging information was recorded; 77 of the women were treated, mostly with radiation.

This is an interesting study of “real world” VIA screening, with all of the difficulties of any screening program, even with a test as simple as VIA. These difficulties range from achieving adequate coverage; to losing to follow-up the large number of women needing treatment (only 60 percent of eligible women were treated); to treating women on the same day as screening (“screen and treat”), which occurred for less than 40 percent of the women. The failure to refer over 70 percent of women with suspicious lesions for further evaluation—possibly because cervical biopsy is not a free service in any of these countries and most women could not afford to pay—is disturbing. The greatest utility of VIA in countries that cannot afford any alternative is to establish the necessary infrastructure to provide health care services to older women. Once VIA becomes successfully implemented, it should be relatively easy to introduce more sensitive methods of screening into the system. In many LMICs, establishing a sustainable and appropriate infrastructure is most likely the priority.

HPV Testing

Highly sensitive and reproducible laboratory techniques to detect oncogenic HPV and cervical cancer have been developed and are being used or considered in place of cervical cytology for primary screening, in addition to other potential uses (Cuzick and others 2008). The cervix is sampled with a brush, which is inserted into the endocervix and then removed and placed in a tube containing special transport media. The U.S. Food and Drug Administration has approved five of the many tests available for routine laboratory service:

• Hybrid Capture 2 detects 13 oncogenic types of HPV (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68).
• Cervista HPV HR detects 14 HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68).
• Cervista HPV 16/18 detects only HPV 16 and 18.
• Aptima (transcription–mediated amplification test) detects RNA from 14 HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68).
• Cobas 4800 (real-time polymerase chain reaction [PCR]–based test) detects 14 HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68).

Other tests that use PCR technology are being used in many clinical studies.

HPV testing is an excellent alternative to cytology for cervical cancer screening (Arbyn and others 2012). In meta-analyses of cross-sectional studies, the sensitivity of the Hybrid Capture 2 (HC2) DNA test, the most commonly used test, was 90 percent to detect CIN2+ and 95 percent to detect CIN3+, with more heterogeneity in studies from LMICs. Compared with cytology, the sensitivity of HC2 is 23–46 percent higher on average, and the specificity is 3–8 percent lower (note we are using the terminology as reported by the authors, hence the switch between cervical intraepithelial neoplasia (CIN) and squamous intraepithelial lesion (SIL) terminology).

Another advantage of HPV testing is the possibility of linking screening to treatment without colposcopy or prior histological sampling, particularly once either simplified or point-of-care HPV tests are developed. A randomized screening trial to evaluate safety investigated the acceptability and efficacy of screening women and treating those with positive tests without colposcopy and histological sampling (Denny and others 2010). A total of 6,555 previously unscreened women, ages 35–65 years, were tested for high-risk types of HPV using HC2 (Qiagen, Gaithersburg, MD, United States) and VIA, performed by nurses in primary care settings. This study found that the HPV screen-and-treat arm was associated with a 3.7-fold reduction in the cumulative detection of CIN2 or greater by 36 months; VIA was associated with a 1.5-fold reduction. For every 100 women screened, the HPV and screen-and-treat strategy averted 4.1 cases of CIN2 and greater compared with VIA-and-treat strategies, which averted 1.8 cases.

A further advantage of HPV testing is that specimens can be obtained by self-collection, with almost complete preservation of the sensitivity and specificity of the screening method. Self-collection, which can be done at home, is accepted by women and could significantly increase participation in screening, particularly by women who are reluctant to undergo a gynecological examination or who live in remote areas.

Another landmark study was a cluster randomized trial of villages and centers where 131,746 women ages 30–59 years were recruited and randomly assigned to one of four groups: HPV testing; cytologic testing; VIA; or the standard of care, which involved no organized or opportunistic screening (Sankaranarayanan and others 2009). The incidence rate of cervical cancer stage 2 or higher and death rates from cervical cancer were significantly higher in the cytologic, VIA, and control groups compared with the HPV testing group. Further, the age-standardized incidence rate (ASIR) of invasive cancer among women who had negative test results on cytological or VIA testing was more than four times the rate among HPV-negative women.

The high negative predictive value of HPV testing (nearly 100 percent) allows the extension of the screening interval, with consequent savings that can offset the possibly higher cost of the test compared with cytology. Screening with HPV testing under age 30 is not recommended, as HPV infection in this group of women is common, and most infections are likely to be transient with a low likelihood of developing into cancer. Screening younger women will add to the costs of the program and may result in significant overtreatment that may be associated with reproductive morbidity, in addition to significant emotional and social problems.

The HPV test is already in use for primary screening in several countries, although in the United States, primary HPV testing has been recommended only in combination with cytology in primary screening or for triage of cytologic abnormalities. A recent study including more than 300,000 women in the United States concluded that HPV testing without cytology might be sufficiently sensitive for primary screening (Katki and others 2011).

Triage of Positive HPV Tests

Even among women over age 30 years, most HPV infections regress; only a minority of women develop persistent infection with high-risk types of HPV that progresses to cervical cancer precursors and cervical cancer. HPV testing identifies women at risk, but not those HPV-positive women who are most likely to have or to develop in the near future significant disease requiring treatment. The challenge is to triage these women by further testing with visual methods, cytology, molecular biomarkers, or a combination of techniques.

Among the visual methods, colposcopy with subsequent biopsy and treatment of visible lesions is the usual procedure in cytology-based programs. However, this method requires highly specialized training and relatively costly equipment. More importantly, the colposcopic impression, colposcopically guided biopsy, and histologic diagnosis are poorly reproducible and have important limitations to the point of reducing the potential of highly sensitive screening tests. The current practice of selecting the most worrisome lesion for biopsy misses up to one-third of prevalent small HSIL lesions. The collection of multiple biopsies from aceto-white lesions can increase the sensitivity of colposcopy (Pretorius and others 2011).

Cytology of HPV-positive women is under strong consideration as a triage method in screening programs, given the high specificity of cytology and ample expertise and infrastructure existing in some areas. This method has the advantage of being highly specific, but it suffers from limited sensitivity. Sensitivity of cytology is influenced by many factors and is complex, but used as a triage test for women already identified as high risk, cytology may suffice. The reduction in the number of cytology tests required and the restriction to HPV-positive women may improve the quality of cytology by reducing the workload and the number of negative slides.

Using DNA biomarkers, limiting further follow-up to women infected with HPV 16 and 18, which are responsible for about 70 percent of cervical cancer and precursors, can reduce the number of women referred to colposcopy while maintaining adequate sensitivity (Castle and others 2011). Overexpression of certain oncoproteins is a marker for increased risk of progression to cervical cancer and may be a better predictor of cancer risk than HPV DNA testing alone, although this is yet to be confirmed (Dockter and others 2009). One biomarker under intensive study is p16^ink4a, which is overexpressed in cancerous and precancerous cervical cells. In a meta-analysis of studies using several detection methods, the proportion of smears overexpressing p16^ink4a increases with the severity of cytological abnormalities (12 percent of normals and 89 percent of HSIL) and histological abnormalities (2 percent of normals and 82 percent of CIN3) (Sahasrabuddhe, Luhn, and Wentzensen 2011). A rapid test for the E6 oncoproteins of HPV types 16, 18, and 45 is undergoing clinical trials (Schweizer and others 2010).

Primary Prevention of Cervical Cancer: HPV Vaccines

Vaccines that prevent infection with certain types of HPV are a major breakthrough in preventing cervical cancer. Monovalent (against HPV 16), bivalent (against HPV 16 and 18; Cervarix, GlaxoSmithKline Biologicals, Rixensart, Belgium), and quadrivalent (against HPV 6, 11, 16, and 18; Gardasil, Merck and Co., Inc., West Point, Pennsylvania) vaccines have been tested in randomized placebo-controlled trials and shown to be safe, immunogenic, and highly efficacious at preventing HPV infection for up to eight years after vaccination. The bivalent and quadrivalent vaccines are delivered by intramuscular injection at zero, one, and six months, with the first dose between the ages of 9 and 13 years.

Treatment of Cervical Cancer

As a result of screening, particularly at long intervals, some more advanced cancers will be detected, and some women will come for treatment because of symptoms, commonly abnormal vaginal bleeding (postcoital, irregular, or postmenopausal), offensive vaginal discharge, pelvic pain, dysuria, or symptoms of local or advanced metastatic disease.

As for all cancers, treatment of cervical cancer is determined by the stage of the disease at presentation. Cervical cancer is staged clinically, for example, through a pelvirectal examination combined with some basic tests as part of the metastatic work-up. Most institutions rely on the International Federation of Gynecology and Obstetrics (FIGO) 2009 staging.

Treatment options for most stage 1 cancers favor surgery alone and usually are curative. For women with later stage 1, stage 2, and early stage 3 cancers, primary treatment is chemotherapy and radiotherapy, with curative intent but lower success rates than for earlier stages. For stage 4 disease, treatment is usually palliative and may involve chemotherapy, radiotherapy, and surgery, although few women in LMICs are likely to have access to these services.

Cost-Effectiveness Analysis

Conclusions

Cervical cancer remains one of the most common cancers among women living in LMICs, yet it is a preventable and treatable cancer. Resource-constrained countries have been unable to initiate or sustain cytology-based cervical cancer screening programs because of weak health care infrastructure and prohibitive cost. There are two new avenues for cervical cancer prevention:

• Primary prevention through prophylactic vaccination against the most common HPV types causally associated with cervical cancer.
• Use of alternative screening tests and strategies for cervical cancer prevention, namely, HPV DNA testing and VIA. Both tests have their advantages and disadvantages, but the development of a highly reproducible, reliable, and accurate point-of-care HPV DNA test (or an alternative test yet to be developed but fulfilling these criteria) will enable women to be screened and treated in one visit and without the need for colposcopy and laboratory infrastructure. HPV DNA testing has shown very promising results; however, issues of specificity, overtreatment, and effective triage still need to be resolved.

Screening and vaccinating either separately or together are shown to be highly cost-effective public health interventions.

Notes

The World Bank classifies countries according to four income groupings. Income is measured using gross national income per capita, in U.S. dollars, converted from local currency using the World Bank Atlas method. Classifications as of July 2014 are as follows:

• Low-income countries = US$1,045 or less in 2013
• Middle-income countries are subdivided:
• Lower-middle-income = US$1,046–US$4,125
• Upper-middle-income = US$4,126–US$12,745
• High-income countries = US$12,746 or more

1

The map and figures in this chapter are based on incidence and mortality estimates for ages 0–69 years, consistent with reporting in all DCP3 volumes. Cancer statistics are estimates for 2012 and have been provided by the International Agency for Research on Cancer from its GLOBOCAN 2012 database. Observed population-based cancer incidence rates were derived from Cancer Incidence in Five Continents, 10th edition, and for trends over time from CI5plus (http://ci5​.iarc.fr/CI5plus/Default.aspx). The discussion of burden (including risk factors), however, includes all ages unless otherwise noted. Interventions also apply to all age groups, except where age ranges or cutoffs are specified.

2

HDI is a composite of three dimensions of human development: a long and healthy life (life expectancy at birth), access to knowledge (adult literacy and enrollment at different educational levels), and standard of living (gross domestic product adjusted for purchasing power parity).

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