Example of Cervical Cancer Screening

Incidence and Mortality

In 2004, an estimated 10,520 new cases of and 3,900 deaths from invasive cervical cancer were expected.20 In 2000, the age-adjusted incidence rate in nine Surveillance, Epidemiology, and End Results Program (SEER) registries was 8 per 100,000 women; the age-adjusted mortality rate was 3 per 100,000.21 From 1950 to 1970, the incidence and mortality rates of invasive cervical cancer fell impressively by more than 70%. From 1970 to 2000, the rates continued to decrease by more than 40%.22 This trend has been attributed largely to screening with the Papanicolaou (Pap) test.

Screening Tests

The Pap test, the standard screening test for cervical cancer, has never been studied in an RCT. A large body of consistent observational data, however, supports its effectiveness in reducing mortality from cervical cancer. Both incidence and mortality from cervical cancer have sharply decreased in a number of large populations following the introduction of well-run screening programs.23-26 Reductions in cervical cancer incidence and mortality were proportional to the intensity of screening.22,27

Case-control studies have found that the risk of developing invasive cervical cancer is 3 to 10 times greater in women who have not been screened.28-32 Risk also increases with longer duration following the last normal Pap test, or similarly, with decreasing frequency of screening.33,34 Screening every 2 to 3 years, however, has not been found to increase significantly the risk of finding invasive cervical cancer above the risk expected with annual screening.34,35

The precise sensitivity and specificity of Pap tests has been difficult to determine because of the methodological limitations of studies.36 Studies that compare the Pap test with repeat Pap testing have found that the sensitivity of any abnormality on a single test for detecting high-grade lesions is 55% to 80%.7,8 Because of the usual slow-growing nature of cervical cancer, the sensitivity of a program of regular Pap testing is likely higher.

Specificity of the Pap test is probably above 90%; it seldom categorizes a woman without any degree of cervical intraepithelial neoplasia (CIN) as having anything more than a mild cytologic abnormality. Specificity is lower, however, for women with mild, clinically unimportant degrees of dysplasia, who are often categorized as having cytologic abnormalities that require further testing and even treatment. Women with such cytologic findings as atypical squamous cells of undetermined significance (ASCUS) are often shown on further evaluation to have neither severe dysplasia nor invasive cancer. If these women are counted as false positives, then specificity will be calculated as lower.7

Newer techniques that employ liquid-based cytology (e.g., ThinPrep) have been developed to improve the sensitivity of screening. As with the Pap test, the optimal studies to determine the sensitivity and specificity of these technologies have not been done. Some less than optimal studies show that sensitivity is modestly higher for detecting any degree of CIN, with modestly lower specificity.37,38 One careful study, however, showed that conventional Pap testing was slightly more sensitive and specific than liquid-based cytology.39

The evidence is also mixed about whether liquid-based techniques improve rates of test adequacy.37,38 One advantage of liquid-based cytology is that human papillomavirus (HPV) testing can be done on the same preparation; one disadvantage is that liquid-based approaches are more expensive than conventional Pap testing. No study has examined whether liquid-based cytology actually reduces the number of women dying of cervical cancer compared with conventional Pap testing.

Rationale for Screening

Invasive squamous carcinoma of the cervix results from the progression of preinvasive precursor lesions called cervical intraepithelial neoplasia (CIN), or dysplasia. Not all these lesions progress to invasive cancer; many mild and moderate lesions regress. The rate at which invasive cancer develops from CIN is usually slow, measured in years and perhaps decades.40 This long natural history provides the opportunity for screening to effectively detect this process during the preinvasive phase, thus allowing early treatment and cure. Because many of these preinvasive lesions (especially low-grade lesions) would have never progressed to invasive cancer,41-43 screening also runs the risk of leading to treatment of women who do not need to be treated. This approach leads to harms of screening by overtreatment.

The leading etiologic factor in the development of prein-vasive and invasive cervical cancer is infection with specific types of HPV transmitted by sexual contact. Thus, women who are not sexually active rarely develop cervical cancer, whereas sexual activity at an early age with multiple sexual partners is a strong risk factor. About 95% of women with invasive cervical cancer have evidence of HPV infection.44-47 Many women with HPV infection, however, never develop cervical cancer; thus, this infection is necessary but not sufficient for the development of cancer.48

Harms of Screening

The major potential harm of screening for cervical cancer lies in the detection of many lesions [such as most cases of low-grade squamous intraepithelial lesions (LSIL)] that would never progress to cervical cancer. Women with abnormal LSIL or high-grade squamous intraepithelial lesions (HSIL) on Pap testing are usually referred for colposcopy and treated with cryotherapy or loop electrosurgical excision procedure (LEEP), which permanently alters the cervix and has unknown fertility and pregnancy consequences. As younger women have the highest incidence of acquisition of HPV and LSIL, they are disproportionately at risk of receiving intervention for a condition that often spontaneously resolves.

The cost of newer screening methods is also problematic. A cost-effectiveness analysis found little effect on life expectancy with the new technologies when used for annual screening.49 They may be more cost-effective when used on a less frequent (e.g., every 3 years) basis.

Balance of Benefits and Harms

Based on an analysis of screening records from nearly 350,000 women in Bristol, England, investigators projected that 1,000 women would need to be screened for cervical cancer for 35 years to prevent 1 death from the disease.50 For each death prevented, the authors estimated that more than 150 women have an abnormal result, more than 80 are referred for investigation, and more than 50 receive treatment.

Annually in the United States, 50 million women undergo screening; about 3.5 million (7%) will be referred for further evaluation. Of these, more than 2 million will be referred for further evaluation of atypical squamous cells of undetermined significance (ASCUS).51 Fewer than 11,000 cases of invasive cervical cancer were expected in 2004. Thus, Pap test screening results in a large number of colposcopies for benign conditions. Strategies to improve the specificity of the cervical cytopathology test are being evaluated by the ASCUS/LSIL Triage Study (ALTS).52 Improved specificity, even at the cost of sensitivity, will likely improve the balance between benefits and harms, given the large burden of false positives, abnormalities that do not represent risk for invasive cancer or death.

Improved cervical cancer screening practices may also favor a more positive benefit-to-harm balance. Such practices include not screening women who have had hysterectomies (with removal of the cervix) for benign disease. More than one-third of U.S. women have had hysterectomies by age 65, more than 90% of which are done for noncancer indications.53 These women rarely have important abnormalities on Pap testing.54,55 In addition, continued Pap test screening for women over age 65 who previously have had regular cervical cancer screening with normal test results provides little benefit. The risk of cervical cancer and yield of screening decline steadily through middle age.56 The majority of older women who are found to have invasive cervical cancer have not been screened recently, if at all.53 Thus, the focus of cervical cancer screening practices should be on finding and screening women at increased risk because of inadequate past screening rather than continuing to screen women at low risk.

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