Descriptive epidemiology

Cervical cancer is the second most commonly diagnosed cancer in women. Worldwide, it is estimated that there are approximately half a million new cases of cervical cancer each year, accounting for approximately 12% of all female cancers (Garcia et al 2007). The cumulative incidence rate up to 74 years of age (assuming no prior death) ranges from 5% in parts of Latin America to approximately 0.5% in parts of the Middle East and Finland. In most European countries, it is under 2% (Curado et al 2007). Cervical cancer is also extremely common in sub-Saharan Africa, but African incidence data are unreliable, particularly for older women.

The incidence of cervical cancer in most countries has decreased significantly since the 1960s. In the UK, mortality from cervical cancer has been declining since 1950. The difference between mortality rates in 1950–1952 compared with 2005–2007 varies with age, from an extraordinary 85% reduction in women aged 55–64 years to a more moderate 15% reduction in women aged 25–34 years. Figure 34.1 shows the age-specific mortality rates for cervical cancer in the UK since 1971. It is seen that the greatest decreases have been in older women (aged ≥65 years), and that the increasing rates in younger women between 1970 and 1985 reversed in the 1990s.

Figure 34.1 Age-specific mortality rates for cervical cancer, UK 1971–2007.

The differing cervical cancer mortality and incidence trends by age can be examined by birth cohort analysis in addition to analysis by year of death. Plotting the rate of disease against age for women born in different 5-year periods yields a series of curves, approximately parallel, but with some higher than others. In other words, women born at one time might be at relatively high risk of cervical cancer in their 20s and 30s, and remain at relatively high risk through their 40s, 50s, 60s and 70s. The authors’ understanding of this effect is that there is an underlying characteristic of increasing rate of disease with age, but the level is determined by environmental exposure (to a sexually transmitted agent) in the late teens and 20s. So, for example, for women born at the end of the 19th century or around 1920, cervical cancer mortality was higher throughout their lives than for previous and subsequent birth cohorts. These two cohorts of women with increased risk would have become sexually active around the times of World War I and World War II.

The level of environmental exposure will be determined by social norms and will vary between ethnic groups and over time. Modelling shows that the idea that incidence and mortality rates can be modelled by age and cohort effects works well until the 1980s. However, more recent data require the addition of age-specific time trends corresponding to a beneficial effect of screening, particularly in younger women, to provide a satisfactory model (Sasieni and Adams 2000). From a public health perspective, it is important to note that women born in the 1960s are at three- to four-fold higher risk of cervical cancer compared with women born in the 1930s.

Risk factors

Evidence for an association between cervical cancer and sexual activity dates back to 1842, when Rigorni-Stern published data showing that whereas married women were more likely to die of cancer of the uterus (predominantly cervix) than breast cancer, nuns very rarely died of cancer of the uterus. Since then, the epidemiological evidence suggestive of a sexually transmitted agent causing cervical cancer has grown steadily. Traditional risk factors include the number of sexual partners and age at first sexual intercourse. The behaviour of men is also important, as shown by increasing risk in women with just one partner according to the number of partners of their husband (Buckley et al 1981). More recently, the sexually transmitted agent has been identified as certain types of HPV. The evidence that the relationship between HPV infection and cervical cancer is causal is overwhelming (Bosch et al 2002). Several large studies have been carried out to determine the prevalence of HPV in cervical cancer and precancerous lesions. Over 90% of cervical cancers have been found to include HPV DNA (Smith et al 2007), and when full adjustment for tissue adequacy and a range of polymerase chain reaction primers are used, the estimates rise to almost 100% (Walboomers et al 1999). Several studies have shown that HPV-negative women have an extremely low risk of CIN 3 or cancer (Bulkmans et al 2007, Cuzick et al 2008a, Dillner et al 2008). Furthermore, a recent study (Sankaranarayanan et al 2009) found no cancer deaths among 30,000 HPV-negative women in the subsequent 8-year period.

There are over 100 types of HPV, and only some of these infect the anogenital region. These can be split into low-risk types, which cause genital warts, and high-risk types, which can lead to cervical cancer. Types 16 and 18 are strongly associated with cervical cancer; other types including 31, 33, 35, 39, 45, 51, 52, 56, 58 and 66 are associated with a more moderate elevated risk. Table 34.2 details the prevalence of the most common high-risk types of HPV in women with normal cytology, precancerous cervical lesions and invasive cervical cancer in the UK and worldwide.

Table 34.2 High-risk human papilloma virus (HPV) prevalence in women with normal cytology, precancerous cervical lesions and invasive cervical cancer

It has been estimated that HPV is a very common sexually transmitted infection worldwide, with the majority of people being exposed to the virus by 30 years of age. Most infections with high-risk types are transitory and harmless. In a minority of women, the infection may become persistent and lead to high-grade cervical lesions with a potential for progression to cancer. Immune factors are certainly associated with persistence, but are poorly understood. Similarly, it is largely unknown why some women with persistent infection develop cervical cancer whereas others do not.

Other risk factors are less clear cut. Smoking is generally found to be associated with cervical cancer, but it is difficult to disentangle the confounding caused by the sociological link between smoking and increased number of sexual partners. Nevertheless, the body of evidence available suggests that smoking increases the risk of cervical cancer two- to three-fold by reducing the local immune response to HPV (Kapeu et al 2009). The association between oral contraceptive use and cervical cancer is also confounded by sexual behaviour; however, a large pooled analysis including 24 studies found that women who had used oral contraceptives for 5 years or more were at almost double the risk of cervical cancer compared with women who had never used oral contraceptives. This risk declines after the use of oral contraceptives is stopped; within 10 years, the risk is similar to non-users (Appleby et al 2007). High parity and young age at first full-term pregnancy have, independently, been found to increase the risk of invasive cervical carcinoma, and this association remains after adjusting for other reproductive factors. Women with seven or more pregnancies are at approximately 78% greater risk than women with one or two pregnancies. It is estimated that cervical cancer could be reduced by 30% in developing countries if parity and age at first intercourse were the same as in developed countries (International Collaboration of Epidemiological Studies of Cervical Cancer 2006). Previous exposure to sexually transmitted diseases, in particular Chlamydia trachomatis and herpes simplex virus type 2, also increases the risk of cervical cancer, even after adjusting for HPV infection (Bosch and de Sanjose 2007).

Immunosuppression certainly conveys an increased risk of cervical cancer, as shown in studies on renal transplant patients receiving immunosuppressive drugs (Birkeland et al 1995) and on women who are human immunodeficiency virus (HIV) positive (Grulich et al 2007). It seems likely that diet plays a role in the immune response to HPV, but studies on diet and cervical cancer have found little evidence for a strong effect of intake of fruit and vegetables on the risk of cervical cancer (IARC Handbooks of Cancer Prevention 2003). It has been shown recently that cervical neoplasia (including CIS) exhibits familial clustering and that the strength of association increases with increasing genetic relatedness (Magnusson et al 1999). Independently, several groups have found an association between certain human leukocyte antigen class II antigens and cervical neoplasia. However, much more remains to be done in understanding the factors that determine why some women infected with oncogenic HPVs develop cervical cancer but the vast majority do not.

Natural history

There are few data from studies that directly observe the natural history of cervical cancer development because it is generally felt to be unethical not to treat precancerous cervical disease. The situation is further complicated by the possibility that the process of taking a biopsy, required for definitive diagnosis of disease, may affect the natural history by stimulating regression. Therefore, most of what is known of the natural history of cervical precancer is derived from the follow-up of women with cytological abnormalities and the study of the incidence and prevalence of cervical lesions. There is one exception — cervical CIS in Auckland, New Zealand between 1965 and 1974. Women with CIS were not treated. A judicial inquiry in 1988 concluded that this practice was unethical, but allowed the histological and other material to be used for further research. Two studies have been published using this data (McIndoe et al 1984, McCredie et al 2008), with the most recent paper including over 25 years of follow-up (McCredie et al 2008). This study provides the most direct estimates available of the rate of progression from CIS to invasive cancer; the results show that approximately 30% of CIS progress to cancer within 30 years.

For the vast majority (estimated as well over 95%) (Walboomers et al 1999) of cervical cancers, the first step is exposure to one of the oncogenic HPVs. The time from infection to the development of invasive cancer is thought to be many years; typically between 10 and 40. Longitudinal studies on young women show that the majority of HPV infections are transient (Moscicki et al 2004) and that the virus is indeed sexually transmitted (Burk et al 1996). Persistence of infection has been shown to be associated with the development of cervical lesions (Ho et al 1995). It is generally believed that one of the key steps in the development of cancer is integration of the viral DNA in the host genome (Das et al 1992), although some carcinomas only have episomal viral DNA (Cullen et al 1991).

Cervical neoplasia appears to constitute a disease continuum ranging from CIN grades I to III, to microinvasive cancer and, finally, fully invasive cancer. More recent evidence shows that CIN I is frequently not associated with HPV infection and may not be part of the continuum. However, histology is not currently able to distinguish CIN I associated with oncogenic HPV infection from CIN I without HPV DNA. The histological report of HPV infection is based on morphological features, and is not particularly tightly correlated with the presence of oncogenic HPV DNA.

Follow-up studies of women with CIN have found that approximately 60% of CIN I regresses compared with approximately 33% of CIN III; 11% and 22% of CIN I and II, respectively, progressed to CIN III (Östör 1993). Modellers find that regression is more common in younger women, and that three-quarters of CIN in women under 35 years of age will regress (van Ballegooijen et al 1997). They estimate the mean duration of CIN to be 12 years, and that the time from HPV infection to CIN is between 1 and 10 years. Although the details of progression and regression are largely speculative, it is clear that, at most, approximately one-third of high-grade CIN will progress to cancer over approximately 15 years and that the majority of CIN I will regress.

CIN III rates rise rapidly before 30 years of age. Rates then decrease, rather more slowly, being at approximately half their peak by 40 years of age and just 10–20% of their peak by 50 years of age (Office for National Statistics 2006). The extent to which published CIN III rates reflect the prevalence of an untreated condition and the extent to which they mirror incidence is not completely clear.

Prevention and screening

Prevention of cervical cancer could be approached in several ways. Strategies aimed at promoting safe sex (use of condoms, particularly with an occasional partner), delaying the age of first sexual intercourse and reducing the number of women who smoke are only likely to have modest effects on cervical cancer rates. However, if successful, they would also have additional health benefits in terms of control of sexually transmitted diseases (including chlamydia with the resultant pelvic inflammatory disease), reduction in teenage pregnancies and reduction in heart disease and lung cancer, respectively.

The impact of vaccination on rates of cytological abnormalities, CIN III and invasive cancer will not be seen for at least 12–16 years after vaccination is rolled out. It is possible that, in 30 years time, prevention of cervical cancer may be achievable by vaccination of teenage girls (within a well-organized high-coverage programme) against a large subset of HPV oncogenic types. Until that time, the most likely route to reducing the morbidity associated with cervical cancer is through the detection and treatment of precancerous cervical lesions. Screening by cytological analysis of cervical smears has proven to be an effective means of reducing the incidence of cervical cancer in many industrialized countries. It satisfies most of the criteria that should be considered before introducing a public screening programme. Cervical screening programmes were set up with the intention of preventing cervical cancer. They also have the additional benefit of reducing mortality from cervical cancer by diagnosing occult invasive tumours at an early stage when they are more treatable. Cervical screening was offered to women well before its effectiveness had been demonstrated. By the time that people considered the possibility of evaluating cervical screening in a randomized controlled clinical trial, the indirect evidence of the benefits of such screening made a trial in which some women were deprived of screening unethical in a setting where screening is already routine. In the absence of randomized trials, researchers sought evidence from population trend studies and studies that looked at screening at the individual level rather than in populations. The individual-level studies have mainly been carried out as case–control studies, comparing the screening experience of women diagnosed with or dying from cervical cancer with that of healthy women. Ideally, case–control and population trend studies should be interpreted together. The fact that women with cervical cancer are less likely to have been screened than healthy women could be confounded, to some extent, by socioeconomic status and attitudes to healthy lifestyles. Women who do not attend for screening may be at greater risk than those who attend even if screening is useless, simply because they are more likely to smoke, to have a poor diet and to be exposed to oncogenic HPVs. Taken together, however, one sees a picture in which overall cancer rates are falling and women who have been screened are less likely to develop cancer than those who have not.

Estimates of the sensitivity of cytology are available from studies in which a large number of women with negative cytology have colposcopy. Ideally, colposcopy should be offered to all women, but this would be expensive and taking a biopsy from all women would be unethical. Many studies comparing two or more screening tests (such as cytology, HPV testing, direct visual inspection) offer colposcopy to all women who are positive on one or more of the screening tests. From such studies, the sensitivity of cytology for high-grade CIN is found to be between 50% and 75% (Nanda et al 2000, Cuzick et al 2006). However, most cases of missed CIN 3 would not become cancerous within 5 years. It is for this reason that screening is recommended, in most countries, to start around the age of 20 years and continue at regular intervals (of between 3 and 5 years) up to the age of 65 years.

There is now sufficient evidence that testing for HPV infections with a primary screening tool can reduce cervical cancer incidence and mortality rates (IARC Monographs 2007). Although HPV testing has high sensitivity (>90%), it is, on average, 6% less specific than cytology (Cuzick et al 2008b). This leads to a higher number of women being referred to colposcopy with no visible lesions. This is especially important in women under 30 years of age, in whom transient HPV infection and cervical lesions are most common. In many high-resource settings, HPV testing is being used in the triage of women over 30 years of age with borderline or mild smears. However, in low-resource settings where organized cytology is not feasible, introduction of HPV testing with subsequent ablative treatment for those women that are positive is an attractive alternative (Sankaranarayanan et al 2009). The introduction of HPV testing to the screening programme would allow the screening interval to be extended (Bulkmans et al 2007, Cuzick et al 2008b, Dillner et al 2008).

Human papilloma virus vaccines

Prophylactic HPV vaccines are L1 virus-like particles (VLPs) in which the surface L1 protein is made to aggregate into particles, mimicking the virus in antigenic respects but not containing the viral DNA. VLPs have been shown to induce a high titre of in-vitro neutralizing antibodies and to protect against experimental challenge with homologous virus in animal models. As VLPs do not contain any viral genes, they are non-infectious and non-oncogenic. To date, two vaccines are commercially available (Cervarix™ and Gardasil™); both are licensed to be applied in three doses within 6 months. Both preparations immunize against HPV 16 and 18, and Gardasil also immunizes against HPV 6 and 11. Results from a number of randomized controlled trials have been published to date. The phase III trials are designed to evaluate the endpoint of CIN 2/3 associated with the HPV types included in the vaccine (Harper et al 2006, Garland et al 2007, Paavonen et al 2007). The smaller phase II trials were powered primarily to evaluate protection from infection by the vaccine types (Villa et al 2005, Mao et al 2006).

There is no evidence that vaccination is effective against an HPV infection that is already present at the time of vaccination (i.e. vaccines do not induce HPV clearance or reduce progression) (Hildesheim et al 2007

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