Cytologic screening has significantly reduced the rates of cervicalcancer in many developed countries. However, cervical cancerremains a leading form of cancer among women living in low-resourceregions of the world (see map) and often kills women at youngages, when they are still raising families. In these same regions,programs to prevent cervical cancer are unavailable or underfundedbecause they compete with many other priorities.
Data are from the International Association of Cancer Registries, GLOBOCAN 2002.
The current standard of cervical-cancer prevention requiresthree clinical visits: one for screening, one for a colposcopicallyguided (i.e., magnified) biopsy for women with abnormal screeningresults, and one for treatment of precancerous conditions. Singlecytologic screenings are insensitive and do not provide sustainedreassurance with regard to the risk of cancer. Program effectivenessis achieved by repeated iterations of the three-visit cycle,but such repeated testing is usually unachievable in resource-limitedregions. Fortunately, as discussed by Goldie et al. in thisissue of the Journal (pages 2158–2168), new practicaloptions for cervical-cancer prevention are becoming available.
Promising new prevention strategies are based on our improvedknowledge of the pathogenesis of cervical cancer. Persistentcervical infection with 1 of approximately 15 types of humanpapillomavirus (HPV) causes virtually all cases of cervicalcancer1 as well as the preceding changes, which are evidenton cytologic, histologic, and visual examination. Because thereis a single, root cause of cervical cancer, we can envisionboth primary prevention through vaccination against HPV in youngwomen and secondary preventive screening directly for carcinogenicHPV in older women (see diagram).
The Natural History of HPV Infection and Cervical Cancer.
The peak prevalence of transient infections with carcinogenic types of HPV (blue line) occurs among women during their teens and 20s, after the initiation of sexual activity. The peak prevalence of cervical precancerous conditions occurs approximately 10 years later (green line) and the peak prevalence of invasive cancers at 40 to 50 years of age (red line). (The peaks of the curves are not drawn to scale.) The conventional model of cervical-cancer prevention is based on repeated rounds of cytologic examination, including Papanicolaou smears, and colposcopy (small blue arrows). Alternative strategies include HPV vaccination of adolescents (large beige arrow), one or two rounds of HPV screening at the peak ages of treatable precancerous conditions and early cancer (large reddish-brown arrows), or both.
HPV DNA testing is more sensitive and the results more easilyreproducible than cytologic screening and colposcopy for thedetection of existent and incipient cervical precancerous conditionsand cancer. As a corollary of the high sensitivity of HPV testing,a negative test for carcinogenic HPV types provides a degreeand duration of reassurance not achievable by any other diagnosticmethod. By understanding the natural history of the carcinogenicHPV types in relation to stages of development of cervical cancer,we can now adjust screening to meet resources. We can targetthe optimal age at which screening should be performed and determinethe most cost-effective testing intervals, screening tests (e.g.,the number of HPV types that range from strongly to weakly carcinogenicthat should be included in an assay), and thresholds for testpositivity (very low viral loads only minimally elevate therisk of precancerous conditions and cancer).
As appropriately modeled by Goldie et al., in low-resource regions,screening should be focused on reaching women at the time ofthe peak risk of treatable precancerous conditions due to persistentinfection and before the average age at which incurable invasivecancers occur (see diagram). In the several settings the authorsanalyzed, they found that screening women once, at 35 yearsof age, or twice, at 35 and 40 years, with current HPV DNA teststargeting 13 carcinogenic types at conventional thresholds ofviral detection can achieve more cost-effective reductions incancer than can conventional cytologic methods because of thegreater accuracy of HPV DNA tests. Conversely, it is not necessaryto detect transient HPV infection or the associated mild pathologicalor visible epithelial abnormalities in young women, among whomacute and resolving HPV infections are extremely common in thedecade after the initiation of sexual activity. In fact on thebasis of what we now know, cervical-cancer screening programsin resource-poor settings should purposely be separated fromclinical services that primarily serve young women.
Each round of prevention must be compressed into the fewestnumber of visits to reduce costs and loss to follow-up. In termsof screening, three-visit strategies or even two-visit strategies(in which women with abnormal screening results are called backand treated without a confirmatory colposcopic biopsy) are notoptimal choices in low-resource settings. HPV DNA tests arenow being developed into rapid, robust, easy-to-use formats.When these HPV tests are available, one-visit "screen-and-treat"strategies will be very appealing. Women who have negative HPVtests can be viewed as having a low risk and can be discharged.Women with positive HPV results can undergo further assessmentthrough visualization of the cervix to determine the appropriatemanagement strategy; most women in this setting can be treatedwith cryotherapy, which is widely available and easy to performon site. Only women with severe or extensive precancerous conditionsor obvious cancer that is untreatable by cryotherapy will requirereferral to a hospital for expert gynecologic management.
To complete the screen-and-treat strategies, we urgently needto validate a treatment that is inexpensive, safe, reliablyeffective, and similar in performance to cryotherapy with nitrousoxide, which is not widely available. Cryotherapy with carbondioxide is inexpensive and ubiquitous but is not dependablein terms of performance. Improving an inexpensive kind of cryotherapyor finding an alternative for use in low-resource settings isa critical missing link that will translate improved screeninginto improved prevention.
Promising vaccines designed to prevent infection with HPV types16 and 18 have been shown to have very high efficacy againstnew, persistent infections with these major carcinogenic types(which account for 70 percent of cancer risk).2,3 Because thesevaccines are not designed to treat infection once it occurs,young women would need to be vaccinated to achieve maximal effect.Vaccine evaluations are still under way. The follow-up datafrom these trials will establish the relative roles of HPV vaccinationin young women and of screening in older women. As is true forthe requirements for screening, HPV vaccines will need to beadapted for low-resource settings (i.e., they will have to below-cost and single-dose immunizations). Ultimately, programsto prevent cervical cancer may integrate these complementaryapproaches — vaccination in young women and screeningin older women — if they are proved to be cost-effective.
Inevitably, the estimates used by Goldie et al. will be challengedby groups concerned about the conclusions or assumptions regardingcosts, prevalence, test performance, and other details of thebase-case and sensitivity analyses. For example, the analysisby Goldie and colleagues suggests that visual inspection ofthe cervix with acetic acid might be an effective alternativeto other types of screening. However, the degree of accuracyachievable with visual assessment performed alone can be quitevariable, which shows that the best prevention strategies shouldbe determined regionally on the basis of local competencies,costs, needs, and perhaps most important, acceptability.
The important conclusion is that within a few years, we expectto have multiple tools not only to improve cervical-cancer screening,but also to restrict the spread of its viral cause. Becauseit is feasible to prevent cervical cancer and to avert the sufferingit causes so many women and their families, cervical cancerdeserves to be a high priority among global efforts to preventcancer.
Source Information
Dr. Schiffman is a senior investigator and Dr. Castle an investigator at the Hormonal and Reproductive Epidemiology Branch, Division of Cancer Epidemiology and Prevention, National Cancer Institute, National Institutes of Health, Bethesda, Md.
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