Background

Worldwide, carcinoma of the cervix is one of the most common malignancies in women. It is estimated that approximately 13,700 new cases of the disease will occur in the United States in 1998 (Landis, Murray, Bolden et al., 1998). A woman's lifetime risk of being diagnosed with cervical cancer in the United States is currently 0.83 percent, and the risk of dying from the disease is 0.27 percent (Ries, Miller, Hankey et al., 1997).

The incidence of cervical cancer and associated mortality have both decreased over 40 percent since 1973. The discrepancy between incidence and mortality risk, and the decrease in both over time, are largely attributable to the success of mass screening using the Papanicolaou (Pap) test to diagnose premalignant or early-stage disease (Cannistra and Niloff, 1996; Ries, Kosary, Hankey et al., 1998; Shingleton, Patrick, Johnston et al., 1995; U.S. Preventive Services Task Force, 1996). The decrease in invasive cervical cancer incidence and mortality since the introduction of the Pap smear has been so dramatic that it is one of the few interventions to receive an "A" recommendation from the U.S. Preventive Services Task Force even though there are no randomized trials demonstrating its effectiveness (U.S. Preventive Services Task Force, 1996).

Despite the indisputably dramatic impact of Pap screening, there is still uncertainty about the details of Pap smear performance, and much could be done to improve the performance of the test and followup of patients after screening. Controversy about the details of Pap smear performance is manifest in differing recommendations about the frequency of screening and the age (if any) at which screening may safely be stopped (American Academy of Pediatrics, 1988; American Cancer Society, 1993; American College of Obstetricians and Gynecologists, 1995; American College of Physicians, 1991; American Medical Association, 1994; Canadian Task Force on the Periodic Health Examination, 1994; Green, 1994).

A significant proportion of patients and providers fail to comply with even the least demanding recommendations for Pap screening frequency. Numerous barriers to screening have been identified that reduce access to Pap smears and other preventive services (Womeodu and Bailey, 1996). Organized screening programs implemented in other countries have shown higher compliance with recommended screening rates than ad hoc screening programs (Koopmanschap, van Oortmarssen, van Agt et al., 1990; van Ballegooijen, van den Akker-van Marle, Warmerdam et al., 1997).

Efforts have also been made to improve test performance by insuring appropriate followup of results. In the case of abnormal test results, efforts have been focused on improving patient compliance. In the case of normal results, models that vary the frequency of testing intervals have been used to determine the optimum timing of screening visits, although there is disagreement on the interpretation of the models and on the recommendations of authoritative bodies.

More recently, efforts to improve Pap smear performance have focused on reducing the number of false negative smears, that is, cases in which premalignant or malignant cells have failed to be diagnosed either because of sampling error (abnormal cells failed to be placed on the slide) or detection error (abnormal cells were misdiagnosed as normal). Measures adopted to improve laboratory performance on this point include manual rescreening of a portion of slides initially evaluated as negative, an approach mandated by Federal law (Clinical Laboratory Improvement Amendments [CLIA]). Recently, several technologies have been developed to optimize the Pap test by reducing sampling or detection error. These technologies are a major focus of this report.

Scope and Purpose

The purpose of the present report is threefold:

To determine the accuracy of cervical cytology using conventional Pap smears and newer technologies (thin-layer cytology, computerized rescreening, algorithm-based decisionmaking technology) for detecting cervical cancer and its precursors.

To estimate the direct medical costs associated with cervical cancer screening and evaluation, treatment and followup of cervical cytological abnormalities, and treatment and followup of cervical cancer.

To estimate the effects on total health care cost, morbidity, and mortality of regular cervical cytological screening using newer screening technologies (thin-layer cytology, computer rescreening, algorithm-based decisionmaking technology) compared with conventional Pap smear in women participating in a screening program.

On the first point, the report will review published studies comparing cervical cytological diagnosis with clinical diagnosis based on colposcopy or biopsy. The results of this review will form the basis for a meta-analysis.

On the second point, the report will identify and examine current claims data and other datasets to empirically estimate costs associated with cervical cytological screening.

On the third point, the report will review the literature on the effectiveness and cost-effectiveness of cervical cytology screening and use these data to develop a comprehensive cost-effectiveness model to examine the impact of the newer screening technologies. In the absence of definitive clinical trials on key questions of cervical cancer screening, policymakers have relied on decision-modeling studies to integrate epidemiological data on the natural history of cervical cancer precursors, data on the performance of diagnostic tests for early cervical cancer or cervical cancer precursors, and data on cost. These models estimate the efficacy of various screening programs, balance estimated efficacy against estimated cost, and lead to decisions about appropriate screening intervals and age cutoffs (Eddy, 1990; Fahs, Mandelblatt, Schechter et al., 1992; Mandelblatt and Fahs, 1988; Schechter, 1996; U.S. Congress Office of Technology Assessment, 1981, 1990).

New Technologies Assessed

Three new devices recently approved by the Food and Drug Administration (FDA) are considered in this report: ThinPrep^®, Papnet^®, and AutoPap^®. The three devices employ three different types of technology: thin-layer cytology (ThinPrep^®), and computerized rescreening utilizing neural-network technology (Papnet^®) or algorithmic classification (AutoPap^®).

Each of these technologies was developed to reduce the false negative rate associated with cervical cytological screening. The two major components to this false negative rate are false negatives related to sampling error and false negatives related to detection error. About two-thirds of false negatives are due to sampling error and the remaining one-third due to detection error. Each of the new technologies is directed at one these components of false negatives. Thin-layer cytology aims primarily to fix sampling error, whereas computerized rescreening targets detection error. This implies that neither technology will be able to reduce false negatives beyond a certain threshold.

Thin-layer cytology is a new technology for processing cytological samples. The sample is collected as in the conventional Pap test using a cervical broom or cervical spatula and endocervical brush, but rather than smearing the cytological sample directly onto a microscope slide, this new method suspends the sample cells in a fixative solution, disperses them, and then selectively collects cells on a filter. The cells are then transferred to a microscope slide for cytological interpretation. Because cytological samples are fixed immediately after collection, there are fewer artifacts in cellular morphology. Fewer cells on the slide are obscured, both because the process reduces artifactual material such as blood and mucous and because cells are deposited on the slide in a monolayer. Clinical studies of the ThinPrep^® 2000 (Cytyc Corporation, Boxborough, MA) have shown that the sensitivity is improved compared with conventional Pap smears; however, few data are available on the specificity of this technology compared with conventional Pap smears. The improvement in sensitivity appears to be greater in populations with a low prevalence of cytological abnormalities.

Papnet^® is a newly approved device that uses neural-network computerized rescreening of Pap smears initially read as negative by a cytotechnologist. The system works by using automated imaging of Pap smear slides and computerized interpretation of images. The Papnet^® system (Neuromedical Systems, Inc.) identifies cells or clusters of cells that require review and displays up to 128 images of the slide likely to contain abnormalities. These images must be reviewed by a cytotechnologist who can decide whether to review the slide using light microscopy.

AutoPap^® 300 QC system (Neopath, Inc.), which uses algorithm-based decisionmaking technology, identifies slides exceeding a certain threshold for the likelihood of abnormal cells. The laboratory can select different thresholds, corresponding to 10, 15, and 20 percent review rates. In contrast to random rescreening, the population of slides selected by the AutoPap^® 300 QC system is enriched with abnormalities and should contain 70-80 percent of the slides containing abnormalities missed by manual screening.

A variety of other technologies or clinical strategies have been proposed to improve Pap testing, including various devices for collecting a cytological sample from the cervix. Still other technologies have been proposed to augment or replace cervical cytological screening; for example, colposcopic photographs for review by experts (cervicography) and DNA testing for specific human papillomavirus (HPV). These technologies are not considered in the present report.

Cervical Cancer

Patient Population and Settings