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McCrory DC, Matchar DB, Bastian L, et al. Evaluation of Cervical Cytology. Rockville (MD): Agency for Health Care Policy and Research (US); 1999 Feb. (Evidence Reports/Technology Assessments, No. 5.)
This publication is provided for historical reference only and the information may be out of date.
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
Incidence and Prevalence
The majority of cases of invasive cervical cancer occur in women who have either never had a Pap smear or have not had a smear in the previous 5 years (Shingleton, Patrick, Johnston et al., 1995). Lack of screening may explain many of the differences in cervical cancer rates among ethnic groups (Miller, Kolonel, Bernstein et al., 1998); for example, overall mortality from cervical cancer in black women is higher than in white women; stage-specific survival is identical, but black women present with more advanced disease (Ries, Kosary, Hankey et al., 1997).
Although all sexually active women are at risk for cervical cancer, the disease is more common in women of low socioeconomic status and in those who smoke, have a history of multiple sex partners, or have early onset of sexual intercourse.
Certain types of HPV have a strong epidemiological association with cervical cancer. Types 16 and 18 are two of several oncogenic strains of the more than 70 types of HPV. Both incidence and prevalence of HPV are greatest in women under the age of 25 (Koutsky, 1997). Ho, Bierman, Beardsley et al. (1998) have recently reported a cumulative 3-year incidence of 43 percent, or an average annual incidence of 14 percent, in a cohort of college women. Prevalence of HPV DNA in women with normal cervical cytology decreases with age in a variety of populations (Bauer, Hildesheim, Schiffman et al., 1993; Coker, Jenkins, Busnardo et al., 1993; ; Figueroa, Ward, Luthi et al., 1995; Hildesheim, Gravitt, Schiffman et al., 1993; Wheeler, Parmenter, Hunt et al., 1993). A second peak is seen after age 40 in some studies (Figueroa, Ward, Luthi et al., 1995); whether this is due to reinfection, or a cohort effect secondary to differences in age at onset of sexual activity, is unclear. Data on postmenopausal women are rare. Reported prevalence in peri- and postmenopausal women ranges from 1 percent (Ferenczy, Gelfand, Franco et al., 1997) to 38.1 percent (Smith, Johnson, Figuerres et al., 1997), a difference that may be attributable to differences in populations, cohort effects, or viral assay techniques. An international study found prevalence in women between 50 and 59 ranging from 4.1 percent in Spain to 13.6 percent in Brazil (Munoz, Kato, Bosch et al., 1996). Prevalence in a German cohort of women over 55 was 3.2 percent (De Villiers, Wagner, Schneider et al., 1992).
The natural history of HPV infection is complex, with clearance and persistence of viral DNA, along with progression to squamous intraepithelial lesion (SIL), varying depending on the viral type, patient characteristics such as age, and study design and assay methods (Herrero, 1996; Kiviat, 1996; Koutsky, 1997; Mitchell, Tortolero-Luna, Wright et al., 1996 ; Schiffman, Bauer, Hoover et al., 1993).
Disease Biology
Although a small percentage of cervical cancers do not have detectable HPV DNA, even with sensitive assays, there is consensus that HPV infection is the causative agent for the vast majority of cervical cancers (Herrero, 1996; Kiviat, 1996; Koutsky, 1997; Schiffman, Bauer, Hoover et al., 1993). Certain HPV types are clearly more likely to progress to cancer than others, and identification of these types in cervical cells may have a role in determining optimal diagnostic and treatment strategies for patients with abnormal Pap smears (Cox, Lorincz, Schiffman et al., 1995).
Natural History
Invasive cervical cancer usually is preceded by a long, premalignant phase during which it is readily treatable (Cannistra and Niloff, 1996; Wright and Richart, 1992; Wright, Kurman, and Ferenczy,1994). Even if this premalignant phase progresses to invasive cancer, early-stage disease is highly curable: 5-year survival rates for early-stage disease are above 90 percent, but if the disease has spread outside of the pelvis (Stage IV), cure rates are only 10-15 percent.
Epidemiological data suggest that a substantial proportion of patients with low-grade squamous intraepithelial lesions (LSIL) will have regression if the lesion are not treated, a finding that supports a "watchful waiting" strategy involving retesting.
Burden of Illness
Despite the success of Pap smear screening, women continue to develop cervical cancer. Treatment of early-stage disease is effective, but both of the alternatives, radical hysterectomy or radiation therapy, can have significant short- and long-term morbidity (Cannistra and Niloff, 1996; Landoni, Maneo, Columbo et al., 1997). Mortality from late-stage disease remains high.
Patient Population and Settings
Target Populations
The primary target population for this evidence report is women of average cervical cancer risk in the United States who are candidates for Pap smear screening. For the purposes of our analysis, candidates for Pap smear screening include women between the age of onset of sexual activity and the age of 85.
Although a large proportion of cervical cancer occurs in women with very limited or no screening, we did not examine programs or policies designed to improve screening compliance. Some previous studies have focused on special populations such as elderly women (Fahs, Mandelblatt, Schechter et al., 1992; U.S. Congress Office of Technology Assessment, 1990) and elderly women who have not previously been screened (Mandelblatt and Fahs, 1988).
Practice Settings
The principal practice setting considered will be the primary care practice in the United States (general internal medicine, family practice, adolescent medicine, and obstetrics/gynecology) and government and nongovernment family planning clinics (e.g., Planned Parenthood, public health clinics).
- Introduction - Evaluation of Cervical CytologyIntroduction - Evaluation of Cervical Cytology
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