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Note: Separate PDQ summaries on Cervical Cancer Screening and Cervical Cancer Treatment are also available.
Factors With Adequate Evidence of an Increased Risk of Cervical Cancer
Human papilloma virus (HPV)
Based on solid evidence from observational studies, HPV infection is associated with the development of cervical cancer.
Magnitude of Effect: HPV has been implicated as the primary etiologic infectious agent causing virtually all cases of cervical cancer.
Based on solid evidence, being immunosuppressed is associated with an increased risk of cervical cancer.
Based on solid evidence, high parity is associated with increased risk of cervical cancer in HPV-infected women.
Magnitude of Effect: Among HPV-infected women, those who have had seven or more full-term pregnancies have approximately four times the risk of squamous cell cancer compared with nulliparous women, and two to three times the risk of women who have had one or two full-term pregnancies.
Long term use of oral contraceptives
Based on solid evidence, long-term use of oral contraceptives is associated with increased risk of cervical cancer in HPV-infected women.
Magnitude of Effect: Among HPV-infected women, those who used oral contraceptives for 5 to 9 years have approximately three times the incidence of invasive cancer, and those who used them for 10 years or longer have approximately four times the risk.
Cigarette smoke exposure
Based on solid evidence, cigarette smoking, both active and passive, is associated with an increased risk of cervical cancer in HPV-infected women.
Magnitude of Effect: Among HPV-infected women, current and former smokers have approximately two to three times the incidence of high-grade cervical intraepithelial neoplasia or invasive cancer. Passive smoking is also associated with increased risk but to a lesser extent.
Diethylstilbestrol (DES) exposure
Based on solid evidence, DES exposure is associated with an increased risk of developing clear cell adenocarcinoma of the cervix.
Magnitude of Effect: About one in 1,000 women exposed to DES in utero will develop a clear cell adenocarcinoma of the cervix.
Factors With Adequate Evidence of a Decreased Risk of Cervical Cancer
Based on solid evidence, abstinence from sexual activity is associated with a near-total reduction in the risk of developing cervical cancer.
Magnitude of Effect: Sexual abstinence essentially precludes HPV transmission.
Interventions With Adequate Evidence of a Decreased Risk of Cervical Cancer
Based on solid evidence, vaccination against HPV type 16 (HPV-16)/HPV type 18 (HPV-18) is effective in preventing HPV infection in HPV-naive individuals, and is associated with a reduced incidence of cervical intraepithelial neoplasia 2 and 3. By extrapolation, these vaccines should also be associated with a reduced incidence of cervical cancer.
Magnitude of Effect: Vaccination against HPV-16 and HPV-18 reduces incident and persistent infections with efficacy of 91.6% (95% confidence interval [CI], 64.5–98.0) and 100% (95% CI, 45–100), respectively. Efficacy beyond 6 to 8 years is not known.
Based on solid evidence, harms of HPV vaccines include injection site reactions, dizziness and syncope, headache, and fever. Allergic reactions occur rarely.
Use of barrier protection during sexual intercourse
Based on solid evidence, the use of barrier methods (e.g., condoms) during sexual intercourse is associated with a decreased risk of cervical cancer.
Magnitude of Effect: Total use of barrier protection decreases cervical cancer incidence (relative risk, 0.4; 95% CI, 0.2–0.9 ).
Based on fair evidence, the use of barrier methods during sexual intercourse is associated with few serious harms. Barrier methods can break, potentially resulting in unintended pregnancy. Allergic reactions to the barrier material (e.g., natural latex) can occur.
Incidence and mortality
An estimated 12,900 new cervical cancers and 4,100 cervical cancer deaths will occur in the United States in 2015. Also, approximately 1,250,000 women will be diagnosed with precancers annually by cytology using the Papanicolaou (Pap) smear. A continuum of pathologic changes may be diagnosed, ranging from atypical squamous cells of undetermined significance to low-grade squamous intraepithelial lesions (LSIL) to high-grade squamous intraepithelial lesions (HSIL) to invasive cancer. The precancerous conditions LSIL and HSIL are also referred to as cervical intraepithelial neoplasia (CIN) 1, 2, and 3. Lesions can regress, persist, or progress to an invasive malignancy, with LSIL (CIN 1) more likely to regress spontaneously and HSIL (CIN 2/CIN 3) more likely to persist or progress. The average time for progression of CIN 3 to invasive cancer has been estimated to be 10 to 15 years.
Human papillomavirus (HPV)
Epidemiologic studies to evaluate risk factors for the development of squamous intraepithelial lesions (SIL) and cervical malignancy demonstrate conclusively a sexual mode of transmission of a carcinogen. It is now widely accepted that HPV is the primary etiologic infectious agent that causes virtually all cases of cervical cancer.[4,5] Other sexually transmitted factors, including herpes simplex virus 2 and Chlamydia trachomatis, may play a cocausative role. More than 80 distinct types of HPV have been identified, approximately 30 of which infect the human genital tract. HPV type 16 (HPV-16) and HPV type 18 (HPV-18) are most often associated with invasive disease. Characterization of carcinogenic risk associated with HPV types is an important step in the process of developing a combination HPV vaccine for the prevention of cervical neoplasia. In a population-based study of HPV infection and cervical neoplasia in Costa Rica, 80% of HSIL and invasive lesions were associated with HPV infection by one or more of 13 cancer-associated types. In this study, the risk of about one-half of HSIL and invasive cervical cancer was attributable to HPV-16. HPV-18 was associated with 15% of invasive disease but only 5% of HSIL, suggesting that HPV-18 may have a role in more aggressive cases of cervical malignancy.
Most cases of HPV infection are resolved by the host immune system. Immunosuppression leads to persistence of viral infection with a subsequent increased risk of cervical neoplasia. Women with immunosuppression due to human immunodeficiency virus (HIV) infection have been studied over the past three decades of the AIDS epidemic. In one North American study, a group of 13,690 HIV-infected women were studied for a median of 5 years. The rate of invasive cervical cancer in the HIV-infected women was 26 cases per 100,000 women, and this was approximately four times greater than an HIV-uninfected control group. HIV-infected women with the lowest CD4 lymphocyte counts were at the highest risk of invasive cancer. Women who are immunosuppressed due to organ transplantation are also at risk of invasive cervical cancer, and one meta-analysis found a twofold increased risk.
High parity has long been recognized as a risk factor for cervical cancer, but the relation of parity to HPV infection was uncertain. A meta-analysis of 25 epidemiologic studies, including 16,563 women with cervical cancer and 33,542 women without cervical cancer, showed that the number of full-term pregnancies was associated with increased risk, regardless of age at first pregnancy. This finding was also true if analyses were limited to patients with high-risk HPV infections (relative risk, 4.99; 95% confidence interval [CI], 3.49–7.13 for seven or more pregnancies versus no pregnancies; linear trend test X2 = 30.69; P < .001).
Long-term use of oral contraceptives has also been known to be associated with cervical cancer, but its relation to HPV infection was also uncertain. A pooled analysis of HPV-positive women from the studies described above was undertaken. Compared with women who have never used oral contraceptives, those who have used them for fewer than 5 years did not have an increased risk of cervical cancer (odds ratio [OR], 0.73; 95% CI, 0.52–1.03). The OR for women who used oral contraceptives for 5 to 9 years was 2.82 (95% CI, 1.46–5.42), and for 10 or more years, the OR was 4.03 (95% CI, 2.09–8.02). A meta-analysis of 24 epidemiological studies confirmed the increased risk associated with oral contraceptives, which is proportionate to the duration of use. Risk decreases after cessation and returns to normal risk levels in 10 years.
Cigarette smoking by women is associated with an increased risk of squamous cell carcinoma.[3,13,14] This risk increases with longer duration and intensity of smoking. The risk among smokers may be present with exposure to environmental tobacco smoke and may be as high as four times that of women who are nonsmokers who are not exposed to environmental smoking. Case-control studies of women infected with HPV have examined the effect of various types and levels of tobacco exposure and found similar results.[14,15]
DES is a synthetic form of estrogen that was prescribed to pregnant women in the United States between 1940 and 1971 to prevent miscarriage and premature labor. DES is associated with a substantially increased risk of developing clear cell adenocarcinoma of the vagina and cervix among the daughters of women who used the drug during pregnancy (standardized incidence ratio, 24.23; 95% CI, 8.89–52.74); the risk persists as these women age into their 40s. Despite the greatly elevated risk relative to the general population, this type of cancer is still rare; about one in 1,000 daughters exposed to DES will develop a clear cell adenocarcinoma.
DES exposure in utero is also associated with an increased risk of developing cervical dysplasia. An evaluation of three cohorts, including the Diethylstilbestrol Adenosis study, the Dieckmann study, and the Women's Health Study, with long-term follow-up of more than 4,500 women exposed in utero to DES, found that 6.9% of exposed women developed grade II or higher CIN compared with 3.4% of nonexposed women (hazard ratio, 2.28; 95% CI, 1.59–3.27).
Nearly all cases of cervical cancer are associated with HPV infection, which is transmitted during sexual activity. Therefore, cervical cancer is seen more frequently in women with sexual activity at an early age and with multiple partners. (Refer to the Human papillomavirus section of this summary for more information.)
Given the etiologic role of HPV in the pathogenesis of cervical neoplasia, vaccines to immunize against HPV infection offer a primary prevention strategy for cervical cancer. A quadrivalent (HPV-6, -11, -16, and -18) vaccine using a late protein L1 construct to induce antibody-mediated immunity was approved for use by the FDA in 2006; a bivalent (HPV-16, -18) vaccine was approved in 2009; and a vaccine targeting nine HPV types was approved in 2014.
Persistent infection with oncogenic types of HPV, such as HPV-16 and HPV-18, is associated with the development of cervical cancer. A vaccine to prevent HPV infection with oncogenic-type viruses has the potential to reduce the incidence of cervical cancer. A vaccine against HPV-16 using empty-viral capsids called virus-like particles (VLP) was developed and tested for efficacy in preventing persistent infection with HPV-16.
A multicenter, double-blind, placebo-controlled trial enrolled 2,391 women aged 16 to 23 years and randomly assigned them to receive either 40 µg of HPV-16 L1 VLP vaccine or placebo on day 1, at 2 months, and at 6 months. Papanicolaou (Pap) tests and genital samples for HPV-16 DNA were obtained on day 1, at 7 months, and every 6 months for 48 months. Colposcopy and cervical biopsies were obtained when clinically indicated at study exit. Serum HPV-16 antibody titers were obtained at study entry, at 7 months, and then every 6 months. A total of 1,505 women (755 receiving vaccine and 750 receiving placebo) completed all three vaccinations and had follow-up after month 7. After immunization, HPV titers peaked at month 7, declined through month 18, and then stabilized in months 30 through 48. There were no cases of CIN in the vaccine-treated women, but there were 12 cases in the placebo group (six CIN 2 and six CIN 3). HPV-16 infection that persisted for at least 4 months was seen in seven vaccine-treated women compared with 111 placebo-treated women.
An international, double-blind, placebo-controlled trial of a bivalent HPV-16/HPV-18 VLP vaccine was performed in 1,113 women aged 15 to 25 years with normal cervical cytology who were seronegative for HPV-16, HPV-18, and 12 other oncogenic HPV types at enrollment. Women received either vaccine or placebo at 0, 1, and 6 months and were assessed by cervical cytology and self-obtained cervicovaginal samples for at least 18 months. A masked treatment allocation follow-up study was performed for an additional 3 years, for a combined analysis of up to 6.4 years of follow-up. The 12-month persistent infection rate of HPV-16 or HPV-18 in an "according-to-protocol" cohort (i.e., women who received all three doses of vaccine or placebo on the correct schedule) was 0 of 401 women in the vaccine arm compared with 20 of 372 women in the placebo arm, with a vaccine efficacy of 100% (95% CI, 81.8–100). Diagnoses of CIN 2 or higher in a "total vaccinated" cohort (i.e., women who received at least one dose of vaccine or placebo) were 0 of 481 women in the vaccine arm compared with 9 of 470 women in the placebo arm, with a vaccine efficacy of 100% (95% CI, 51.3–100). Adverse events were similar in vaccinated and placebo-treated women. It is important to note that neither analysis was intention-to-treat (ITT), making it difficult to know what the true vaccine efficacy for either virological or cytohistological endpoints would be in the routine clinical setting. Furthermore, cytohistological outcomes were reported only as composite endpoints (CIN 2+), making it impossible to distinguish the vaccine's efficacy against invasive cervical cancer alone and potentially inflating the observed efficacy by including lesions with a relatively high probability (approximately 50% for CIN 2 ) of spontaneous regression.
A quadrivalent vaccine (HPV types-6, -11, -16, and -18) was evaluated in a multinational, double-blind, randomized controlled trial of 17,622 women aged 15 to 26 years (FUTURE I and II). Women received either the HPV vaccine or placebo at 0, 2, and 6 months; participants were assessed by clinical exam, Pap test, and HPV DNA testing for 4 or more years. Two analyses were reported. One group was considered to be HPV naive: negative to 14 HPV types. The second group was an ITT analysis, which approximates a sexually active population. The composite endpoint for cervical disease included the incidence of HPV-16/18-related, CIN 2, CIN 3, adenocarcinoma in situ, or invasive carcinoma. Outcomes were reported as follows:
This study also demonstrated decreased rates of abnormal Pap tests and subsequent diagnostic procedures. No cases of invasive cervical cancer were identified during the trial.
A 9-valent virus-like particle vaccine was studied in another international randomized trial, which including 14,215 women. This new vaccine 9vHPV includes the four HPV types in the quadrivalent vaccine, qHPV (6, 11, 16, 18) and also 5 more oncogenic types (31, 33, 45, 52, 58). Sexually active women aged 16 to 26 years with fewer than five lifetime sexual partners received three intramuscular injections (day 1, month 2 and month 6) of either the qHPV vaccine or the 9vHPV vaccine. Women were evaluated every 6 months up to 5 years. The rate of high-grade cervical, vulvar or vaginal disease was the same in both groups (14.0 per 1,000 person-years) because of pre-existing HPV infection, but the rate of disease related to HPV-31, -35, -45, -52 and -58 was lower in the 9vHPV vaccine group (0.1 vs. 1.6 per 1,000 person-years). Injection site reactions were more common in the 9vHPV group. Although not addressed in this study, the benefit of HPV vaccination is optimal in younger females before the onset of sexual activity.
On the basis of their mechanism of action, L1/2 HPV vaccines do not appear to impact pre-existing infections. The FUTURE II trial demonstrated a markedly lower vaccine efficacy rate in the total randomized study population, which included individuals positive for HPV at baseline, compared with the "per-protocol" population (44% for lesions associated with HPV-16 or -18 and 17% for lesions associated with any HPV type vs. 98%, see Table 1 above). Additionally, an intermediate analysis of a randomized controlled trial primarily evaluating the efficacy of the HPV-16/18 vaccine in preventing infection found no effect on viral clearance rates in women aged 18 to 25 years who were positive at the time of study enrollment.
The type-specific vaccines, if successful in preventing invasive cancer, will offer protection for only a subset of cases, the proportion of which will vary worldwide. Using data from a multicenter case-control study conducted in 25 countries, it was estimated that a vaccine containing the seven most common HPV types could prevent 87% of cervical cancers worldwide. A vaccine with the two most common strains, HPV-16 and HPV-18, would prevent 71% of cervical cancers worldwide.
A study of cervical HPV DNA among 202 Australian women aged 18 to 24 years who were sampled between 2005 and 2007 before implementation of a national quadrivalent prophylactic HPV vaccine program compared the results with a matched group of 1,058 women who were sampled in the postvaccination era (2010–2012). This study found an adjusted prevalence ratio among fully vaccinated women of 0.07 (95% CI, 0.04–0.14; P < .0001) for vaccine-related HPV types and a smaller but significant magnitude of protection of 0.65 (95% CI, 0.43–0.96; P < .03) among unvaccinated women, suggesting herd immunity (protection of unvaccinated individuals). These data strengthen previous results that suggest herd immunity in this population manifested as a reduction in genital warts among heterosexual men, a group that includes sexual partners of vaccinated women. Data also suggest cross-protection against carcinogenic types that are not directly targeted by the quadrivalent vaccine but are included in the new nonvalent HPV vaccine.
Use of barrier method during sexual intercourse
Barrier methods of contraception are associated with a reduced incidence of SIL presumptively secondary to protection from sexually transmitted disease.[29,30] The effectiveness of condom use for the prevention of HPV infections has been evaluated in a prospective study of women aged 18 to 22 years who were virgins. The number of vulvovaginal HPV infections was reduced with consistent condom use, and HPV infection rate was 37.8 infections per 100 patient-years among women whose partners used condoms 100% of the time in the 8 months before testing, compared with 89.3 infections per 100 patient-years among women whose partners used condoms less than 5% of the time (P trend = .005). No cervical SIL were detected among women reporting 100% condom use by their partner.
Description of Evidence
Added text about a study of cervical human papillomavirus (HPV) DNA among 202 Australian women aged 18 to 24 years who were sampled between 2005 and 2007 before implementation of a national quadrivalent prophylactic HPV vaccine program that compared the results with a matched group of 1,058 women who were sampled in the postvaccination era; this study found an adjusted prevalence ratio among fully vaccinated women of 0.07 for vaccine-related HPV and a smaller but significant magnitude of protection of 0.65 among unvaccinated women, suggesting herd immunity. Also added text to state that these data strengthen previous results that suggest herd immunity in this population manifested as a reduction in genital warts among heterosexual men, a group that includes sexual partners of vaccinated women (cited Tabrizi et al. as reference 27 and Donovan et al. as reference 28).
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This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about cervical cancer prevention. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
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Last Revised: 2015-07-14
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