Cervical Cancer
On this page:
- Risk Factors
- Prevention
- Early Detection, Diagnosis, and Prognosis
- Treatment
- Cancer Control, Survivorship, and Outcomes Research
An estimated 12,200 cases of invasive cervical cancer are expected to be diagnosed in American women in 2003, with about 4,100 deaths from the disease. The overall incidence and mortality rates in the United States have declined by approximately 80 percent, since 1950. This dramatic decrease is largely due to screening programs using the Papanicolaou test (Pap smear), implemented in the last 50 years. Throughout the world, the incidence of cervical cancer is second only to breast cancer as the leading, invasive cancer among women, although in some developing nations, cervical cancer is more prevalent. The 471,000 new cases diagnosed annually worldwide are predominantly among the economically disadvantaged in both developing and industrialized nations.
Women in America have not benefitted equally from the overall cervical cancer mortality reductions noted above. African American women have more than twice the death rate compared with white women. Native Americans of the northern plains; Native Alaskans; and Vietnamese, Korean, and Hispanic women have higher than average cervical cancer mortality rates. Also of note, the incidence rate among Hispanic women declined by 4.3 percent per year between 1992 and 1999, though this rate remains higher than average. Many factors may interact to create and perpetuate discrepancies, including biology, sociocultural factors, economics, and provider issues.
NCI Center to Reduce Cancer Health Disparities (CRCHD) held a series of three meetings in 2001and 2002 on cervical cancer disparities in the United States. The first two meetings examined in detail the geographic patterns of cervical cancer mortality in the United States and explored social, cultural, and system barriers that could be contributing to the disparities in the United States. A working hypothesis was developed of cervical cancer as an index disease that highlights the complex health care issues facing women in the Deep South and Appalachia, regions which also have high rates of other life-threatening, chronic illnesses, as well as chronic living conditions of poverty. The third meeting in October 2002 brought together health care leaders from these regions to address what is known about cervical cancer rates, the health care available to medically underserved women who live there, and information, access, and cultural issues affecting that care. Using currently available research and medical information, participants are developing recommendations in the areas of Communication and Education, Advocacy and Partnerships, Outreach and Services, and Research. Regional and race-specific programs to study cervical cancer disparities are supported through the CRCHD's Special Populations Network.
The Report of the Gynecologic Cancers Progress Review Group in 2001 described research priorities and the resources needed to bridge gaps in understanding and overcoming barriers to progress. The PRG stressed the importance of developing an effective prophylactic and therapeutic human papillomavirus (HPV) vaccine, which could have the potential to nearly eradicate cervical cancer globally and also reduce the cost of screening. Additional recommendations specific to cervical cancer included developing better screening and prevention strategies, developing treatment approaches to reduce sexual dysfunction and improved fertility outcomes, and understanding the mechanisms and efficacy of combination therapies. High-impact priorities of the PRG applicable to all gynecologic cancers included a Virtual Shared Specimen Resource (VSSR) and research to understand and improve quality of life and reduce or eliminate disparities related to care.
Risk Factors
HPV. Studies have shown that approximately 90 percent of cervical cancers and cervical hyperplasias are associated with HPV, primarily types 16, 18, 31, and 45. HPV type 16 is found in 50 percent of cancers and their precursors, high grade squamous intraepithelial lesions and various degrees of association with the development of cervical neoplasias. A case control study of Costa Rican women less than 50 years old found that cervical inflammation may be associated with high grade lesions and may be an etiologic cofactor in women infected with oncogenic HPV, suggesting that HPV infection is a primary cause of cervical neoplasia and supporting the clinical applications of HPV DNA testing and primary prevention of cervical cancer by vaccination.
Cofactors. Women who have never had a Pap test or who have not had one for several years have a 3- to 10-fold increased risk of developing cervical cancer compared to women who have been tested. Women who first had sexual intercourse at an early age or who have had many sexual partners have a higher than average risk of developing cervical cancer due to the risk of infection with HPV. Oral contraceptive use was associated with HSIL/CA among women with fewer than three pregnancies. Another cofactor for cervical cancer, herpes simplex virus-2 (HSV-2) was identified following meta-analysis of seven case-controlled studies.
Investigators are looking at the interactions between immune system functioning, smoking, nutritional and hormonal factors, and the presence of other sexually transmitted diseases in a large study of cervical cancer cofactors. New diagnostic technologies are also being evaluated.
Tobacco. Studies show an increased amount of tobacco-specific cancer-causing agents in the cervical lining of smokers. Active cigarette smokers have been shown to have a two-fold greater risk of developing cervical cancer. The risk appears to be dose-dependent with women who smoked approximately 20 cigarettes per day associated with high-grade disease. Nonsmokers exposed to environmental tobacco smoke lasting for at least 3 hours per day have 3 times the risk over unexposed nonsmokers. Risk for HSIL or cancer in HPV-positive women increased with the number of live births and was almost three times greater among women who smoked more than six cigarettes a day. Current use of barrier contraceptives reduced the risk. Increased incidence of squamous carcinomas has been associated with smoking, with an inverse risk association for adenocarcinoma.
HIV. The Centers for Disease Control and Prevention (CDC) has designated invasive cervical cancer as an AIDS-defining cancer. 63 percent of HIV-infected women in a study of the Women's Interagency HIV Study (WIHS) were HPV antibody positive at last screen compared to 28 percent of HIV-uninfected women. An association has been found between low amounts of serum retinol and risk of cervical dysplasia in HIV-infected women but not in high-risk uninfected women. HIV-infected women were nearly twice as likely to have high-risk subtypes of HPV infection and had higher rates of high-grade squamous intraepithelial lesions. Anal HPV infection was more common than cervical HPV infection in both HIV-infected and -uninfected women. It is still unclear whether treatment by highly active antiviral therapy for HIV leads to real regression of HPV-associated ano-genital lesions.
Diethylstilbestrol. The drug diethylstilbestrol, given to pregnant women in the United States and Europe between 1938 and the early 1970s to prevent miscarriage or premature delivery, has been linked to the development of clear cell adenocarcinoma, a rare cancer of the vagina and cervix. A study of exposed daughters followed for diagnosis of high-grade disease showed a two to three-fold increase in risk, depending on timing of exposure. Results of the NCI DES Follow-up Study, which has been following over 15,000 exposed men and women since 1992, are anticipated in Spring of 2003.
NCI has partnered with the CDC since 1999 to build a national education campaign on the potential health effects of DES exposure. Information in various formats was developed and tested for a broad range of health care professionals and consumers with and without known DES exposure. The CDC will begin information dissemination in early 2003, including the DES website and will also convene five teleconferences on topics pertinent to known-exposed persons.
Prevention
HPV Vaccine. Several candidate vaccines have undergone preclinical evaluation, and a small number have been approved for clinical trials. One of these vaccines developed at NCI, HPV-16 L1 VLP (virus-like particle), was shown to be safe and effective at stimulating production of HPV antibodies in a Phase 1 trial. A larger scale, double-blind, placebo-controlled efficacy trial of this vaccine was conducted in nearly 2,400 women. All of the women treated with a full course of the vaccine were free of HPV-16 at the end of the trial, while in those treated with a placebo, 41 developed persistent HPV-16 infections, of which 9 progressed to HPV-16-related cervical intraepithelial neoplasia. NCI plans to do a large efficacy trial in Costa Rica involving 10,000 to 15,000 women. Two additional NCI-supported trials were conducted for another VLP vaccine, HPV-16 E7 VLP and a recombinant vaccinia virus containing HPV-16/18 E6 and E7 (TA-HPV). Phase 1 has been completed for HPV-16 E7 VLP, and Phases 1 and 2 are completed for HPV-16/18 E6 and E7.
Diet. Previous research has shown decreased risk of cervical cancer development with dietary intake of beta carotene and vitamin A. NCI is supporting continued research in this area.
Early Detection, Diagnosis, and Prognosis
Pap Test Screening. Data from the 1994 National Health Interview Survey show that about one fifth of women ages 18B64 had not had a Pap test in the preceding 3 years, and about half of women with newly diagnosed invasive cervical cancer had not had a Pap test in the past 5 years. The largest groups of unscreened populations include the uninsured; ethnic minorities, especially Hispanics; elderly African American women; and poor women, particularly those in rural areas; and older women, who do not see it as a risk. NCI has initiated an information dissemination project to improve screening in women over age 65, alerting them to their need for Pap smears. Collaborative research is also underway to find a more accessible and cost effective alternative to Pap tests.
Certain Asian and Hispanic/Latina and Southeast Asian women have greater risk than white women for cervical cancer, while mortality rates are highest among African American women. Low screening rates could account for these trends. Ongoing studies in the Applied Cancer Screening Research Branch, http://dccps.nci.nih.gov/acsrb/ , include novel methods to target the older population as well as ethnic and racial minorities for cervical cancer screening. An NCI-supported study among Chinese Americans in the Seattle area resulted in an increase in cervical cancer screening when culturally and linguistically appropriate educational materials were developed, distributed, and followed up with home visits.
The American Cancer Society (ACS) and the U.S. Preventive Services Task Force, in partnership with NCI, have recently published new guidelines for cervical cancer screening. The guidelines recommend cervical screens 3 years after sexual intercourse is initiated or by age 21, to be repeated every 3 years through age 65 - 70. Women should consult medical advice for screening initiation, frequency, and termination, especially if they are at an increased risk for cervical cancer.
The 2001 Bethesda System, developed by an NCI-sponsored workshop, is used by the majority of diagnostic laboratories in the United States. It serves as the basis for guidelines for communicating cervical cancer screening results to physicians, published by The American Society for Colposcopy and Cervical Pathology (ASCCP) in 2002.
HPV Testing. An NCI supported study in Costa Rica indicated that testing for HPV DNA can accurately identify many precancerous changes in the cervix and may be a useful screening tool for cervical cancer in some populations. The HPV test was more sensitive but less specific than conventional Pap testing.
The ASCUS/LSIL Triage Study (ALTS), sponsored by NCI, was designed to help physicians and women decide what to do about ASCUS and LSIL Pap test results. HPV testing followed by ASCUS results proved to be highly sensitive in detecting lesions needing immediate attention. However, HPV testing in women with LSIL is limited because of the high prevalence (82.9 percent) of HPV infection in these women. It was concluded that testing for HPV DNA in women with ASCUS is a more sensitive and specific detector for cervical intraepithelial neoplasia grade 3 (CIN3) or above, compared to a single additional cytologic test. These studies were the partial basis for the ACS/NCI guidelines published in 2002.
Studies of HPV and cervical cancer found that increased viral loads were positively associated with greater risk of an abnormal Pap test within 5 years. Other studies in HPV-positive women were assessed for viral clearance and cytologic regression by HPV DNA testing and thin-layer cytology for 2 years. HPV DNA detection persisted longer than related cytologic abnormalities. It appears that the natural history of HPV can be detected before and after cytologic abnormalities by a more sensitive HPV DNA method.
Treatment
Five large randomized clinical trials found that chemotherapy administered with radiation therapy decreased the risk of death from cervical cancer by 30 to 50 percent, supporting concomitant chemotherapy with radiotherapy for advanced disease. There are currently 29 new or ongoing treatment clinical trials, with most investigating the differences between types and combinations of chemotherapy drugs for the treatment of cervical cancer.
Cancer Control, Survivorship, and Outcomes Research
Psychological Issues. The Cognitive Behavioral Stress Management (CBSM) study is exploring the impact of group-based interventions for distress, quality of life, and cervical cellular atypia level. Another study is looking at behavioral and immunologic components that correlate to psychological distress and coping in women diagnosed with mild dysplasia of the cervix caused by HPV infection.
Sexuality Issues. Several studies are under way to track the sexual function and general quality of life for women receiving treatment for different stages of cervical cancer.
Treatment-Related Side Effects. Studies in progress are examining the efficacy of drugs to alleviate or prevent side effects of cervical cancer treatment, including treatment-induced anemia and quality of life changes.
