Cervical Cancer and Other HPV-Related Studies
Portland Kaiser Cohort Study of HPV and Cervical Neoplasia
The Portland Kaiser Permanente cohort study of human papillomavirus (HPV) infection and cervical neoplasia was established in 1989-1990 by enrolling almost 24,000 women obtaining routine Pap smear screening at any one of seven Portland Kaiser-Permanente screening clinics. The enrollment phase yielded a prevalent case-control comparison which demonstrated that HPV was the primary risk factor for cervical intraepithelial neoplasia explaining other traditional risk factors, an "atypia" study which showed HPV testing could be used to clarify borderline smears, and a study of determinants of HPV DNA in controls and several ancillary studies on the women with atypia. In the prospective years of the project, we have focused on 3 sub-cohorts: the incidence , recurrence, and progression cohorts. An incident case-control study based on the first five years of follow-up has been published. The full cohort based on up to 10 years of follow-up is underway. A variety of HPV DNA and serologic studies are underway. More information, Mark Schiffman
The Guanacaste Study of HPV Natural History
Guanacaste Province is an area in Costa Rica with a very high incidence rate of cervical cancer. This prospective cohort study of HPV infection and cervical neoplasia is based on the recruitment and ongoing 7-year follow-up of a random sample of approximately 10,000 women 18+ years of age, residing in Guanacaste. The study is the companion to the prospective study of HPV and cervical neoplasia in Portland, which is a very low-risk, well-screened, mainly white middle-class U.S. population. Enrollment in 1993-1994 included a personal interview, cervical cytologic smears, Cervicography, cervical swabs for HPV, and a blood specimen. Participation was about 93% and all women with any screening abnormality were referred for colposcopy and biopsy. The prevalent phase of the study permitted several studies of HPV infection, cytology, Cervicography, and the whole spectrum of cervical neoplasia. The epidemiologic risk factors for each stage of neoplasia were identified, controlling for the central role of type-specific HPV infection. Follow-up of the cohort at six month to yearly intervals depending on disease status is nearly complete, to examine the origins of high-grade cervical intraepithelial neoplasia. The study has joint natural history and molecular diagnostic goals. More information, Mark Schiffman
Vaccine Trial
The HPV Vaccine Trial in Costa Rica is a collaboration between investigators in Costa Rica and the National Cancer Institute. The trial is designed as a blinded, randomized, phase III clinical trial to evaluate the efficacy of a bivalent HPV-16/18 virus-like particle (VLP) vaccine. The vaccine used in the trial was developed by investigators at NCI and other research institutions and is manufactured by GlaxoSmithKline Biologicals. The trial was initiated on June 28, 2004 and enrollment was completed on December 22, 2005; there were 7466 women enrolled.
Trial staff will follow all enrolled women for a period of four years. Women who are eligible, consent, and are randomized into the trial receive three doses of the HPV-16/18 VLP or Havrix (Hepatitis A) vaccine over a period of six months. At entry and throughout follow-up, women are carefully monitored and receive state-of-the-art screening for cervical neoplasia.
This study was designed to evaluate vaccine efficacy, immunological correlates of long-term vaccine success and failure, and other factors of immunological and etiological interest. Active follow-up of participants and the extensive data and biological specimen collection components of the study will permit such evaluations. More information, Allan Hildesheim
ASCUS/LSIL Triage Study (ALTS)
This project is a study of the clinical management of low-grade cervical cytologic abnormalities. The major hypothesis to be tested is whether HPV testing can reliably triage the common cytologic diagnoses of ASCUS (Atypical squamous cells of undetermined significance) and LSIL (Low-grade squamous intra-epithelial lesions), which represent the bulk of cervical abnormalities seen on Pap smears. Currently, the most aggressive standard of care is immediate colposcopy and biopsy of all suspected lesions. This type of aggressive management is expensive with some associated morbidity, and probably represents over-treatment, since evidence indicates that most cases of ASCUS and LSIL eventually regress. This clinical trial of management alternatives consists of three arms: immediate colposcopic referral of all patients; triage using HPV testing as an adjunct to cytology; and conservative management with repeat Pap smears. All participants are being followed every 6 months for two years. Over 5,000 women were randomized during enrollment that ended in December, 1998. The baseline data showed that HPV DNA testing is a viable strategy for clarifying ASCUS cytology. However, HPV DNA prevalence in cases of LSIL proved too uniformly high to permit use of HPV DNA testing for triage. More information, Mark Schiffman
ALTS Immunology
The ALTS Immunology Study is a prospective study designed to identify biomarkers associated with a permissive versus protective immune response to low-grade cervical lesions. Approximately 900 women with low-grade cervical disease have been enrolled in this study and are being followed at 6 month intervals for two years. Cellular and humoral immunological responses at entry will be correlated with progression, persistence or regression of low-grade lesions during follow-up. Immunological parameters are also being measured over time in a subgroup of approximately 300 women in our study. Both systemic and local responses are being examined. More information, Allan Hildesheim
Cervical Adenocarcinoma Case-Control Study
A multi-center case-control study of cervical adenocarcinomas and other rare histological forms of cervical cancer was conducted to examine the role of viral and non-viral exogenous and endogenous factors associated with cervical adenocarcinomas and adenosquamous carcinomas. Incident and histologically confirmed cases of in situ and invasive cervical tumors of glandular histology were ascertained. Two control groups were also selected for study. The first comprised a sample of women with squamous cell cervical cancer and the second comprised population controls selected by a modified random digit dialing method. A total of 595 women agreed to participate in the study. Participants responded to a detailed risk factor questionnaire and had blood and cervical specimens collected for HPV testing and other bioassays of interest. More information, Allan Hildesheim
Study to Understand Cervical Cancer Early Endpoints and Determinants (SUCCEED)
The main objective of SUCCEED is to comprehensively assess biomarkers of risk for each progressive stage of cervical neoplasia (normal, HPV-infected, precancer, cancer) and thus develop a new set of biomarkers that can distinguish those at highest risk of cervical cancer from those with benign HPV infection. Over 1000 women will be recruited into the study. An initial cross-sectional component is planned and intended to identify potential biomarkers of interest. A subsequent two-year prospective component will be conducted to validate the most promising candidate biomarkers for the key intermediate outcomes of HPV clearance, persistence, and progression to precancer. More information, Sophia Wang
Genetic Supplementation Study (GSS)
Nested within The Guanacaste Study, GSS is a case control study intended to systematically evaluate the role of both viral variants and host immune response genes in cervical carcinogenesis. Biological specimens collected will allow detailed genotyping of the viral genome as well as genotyping of genetic polymorphisms in the human genome. A major focus of the study will be immune genes, particularly those known to interact with HPV; in addition, assessment of genes potentially modifying other HPV cofactors is planned. More information, Sophia Wang
Mississippi Delta Project
Mississippi Delta region is a region along the southern portion of the Mississippi River with one of the highest incidence rates of cervical cancer in the U.S. High incidence rates are due in part to poor access to, and limited resources for, Pap screening. The Mississippi Delta Project (MDP) is a community-based demonstration project to examine whether self-collection of cervicovaginal specimens in combination with HPV DNA testing in women aged 30 and older might be a viable and acceptable method of cervical cancer screening in this population. MDP is the first in series of demonstration projects in underserved U.S. regional and international populations to develop, evaluate, and implement alternative, cost-effective approaches to cervical cancer screening with the long-term goal of establishing self-sustaining, community-based, screening programs. More information, Philip Castle
