Journal of the National Cancer Institute Advance Access originally published online on February 26, 2008
JNCI Journal of the National Cancer Institute 2008 100(5):290-291; doi:10.1093/jnci/djn038
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© The Author 2008. Published by Oxford University Press.
EDITORIALS |
Screening for Cervical Cancer in the Era of the HPV Vaccine—The Urgent Need for Both New Screening Guidelines and New Biomarkers
Affiliation of authors: Departments of Pathology (NBK, QF) and Epidemiology (SEH), University of Washington, Seattle, WA
Correspondence to: Nancy B. Kiviat, MD, Harborview Medical Center, 325 9th Ave, Rm 2E-H87, Seattle, WA 98104 (e-mail: nbk{at}u.washington.edu).
Over the past 25 years, not only have "high-risk" human papillomaviruses (HPVs) been identified as the causal agents of cervical cancer, but also accurate clinical assays have been developed for their detection. Most important, prophylactic vaccines to prevent infection with those high-risk HPVs most commonly found in cervical cancers have recently become available. Unfortunately, however, cervical cancer screening will need to continue for the foreseeable future because prophylactic vaccines cover only a subset of those HPV types that cause cancer and, further, women already infected with high-risk types of HPV will not benefit from these vaccines. Although current approaches to cervical cancer control have been highly successful (at least in the developed world) up to the present, how to most efficiently carry out cervical cancer screening in the era of HPV vaccination is unclear. Identifying the most cost-effective approach to cervical cancer screening in the era of the HPV vaccine is complicated, both because any screening program proposed must be appropriate for both the unvaccinated and the vaccinated populations and because little is known about the long-term impact of HPV vaccination programs. In addition, cytology and detection of high-risk types of HPV DNA are currently the only screening assays available.
The challenge of developing screening guidelines is addressed in this issue of the Journal by Goldhaber-Fiebert et al. (1), who assess the health and economic outcomes of various screening strategies initiated at different ages and carried out at different intervals using cytology and HPV DNA testing, HPV vaccination, and vaccination combined with screening. Using empirically calibrated microsimulation modeling, they conclude that the addition of preadolescent vaccination to current screening approaches will provide an additional 36% reduction in cancer risk. Further, for both vaccinated and unvaccinated women, age-based screening protocols that include HPV DNA testing, used for triage of atypical squamous cells of undetermined significance in younger women and for primary screening in older women, offer improved effectiveness as compared with current screening recommendations.
Importantly, through sensitivity analyses, the authors attempt to assess the way in which some of the uncertainties surrounding the addition of HPV vaccination to cervical cancer screening might affect cervical cancer screening. Specific analyses are included to explore how HPV vaccination at different ages, changes in screening behavior among women receiving vaccine, and disparities in HPV DNA testing might impact the success of screening programs. The results of such analyses demonstrate that it will be important both to target preadolescent females for vaccination, especially those who may be at a future disadvantage for regular screening, and to continue screening even in vaccinated women. The authors point out how the failure to institute widespread vaccination of preadolescents (<25% coverage) and the failure to send a clear message concerning the importance of continued screening (>30% reduction in screening) among both vaccinated and unvaccinated women might actually negatively impact cervical cancer control.
The models developed by Goldhaber-Fiebert et al. (1) and by others (2–4) have all been based on the use of currently available screening assays, cytology and HPV DNA testing. However, the shortcomings of such assays are well documented (5–9). Cytology lacks sensitivity, and HPV testing—especially in younger women—lacks specificity for identification of high-grade lesions and has a poor positive predictive value. As noted by Goldhaber-Fiebert et al. (1), if the sensitivity of cytology falls below 70%, screening that is primarily HPV based may be more appropriate than cytology-based screening; moreover, among vaccinated women, the positive predictive value of an abnormal cytology can be expected to decrease (10). Similarly, although not addressed in the model presented here, as an increasing proportion of the population is vaccinated against an increasing number of high-risk types of HPV, detection of high-risk types of HPV DNA will become less useful as a screening or triage assay because the absolute number of true positive tests—and hence the positive predictive value of current HPV detection assays—would decrease substantially. Thus, other screening assays will need to be developed. To achieve the necessary specificity, such assays are likely to be based on detection of changes associated with oncogenesis, rather than on detection of HPV infection (such as detection of various HPV gene products) or changes induced by the presence of HPV (such as changes in various molecules associated with cell cycle control). Such assays would also help indicate which of the high-grade lesions detected in very young women actually carry a substantial risk of progression.
In summary, the analyses presented by Goldhaber-Fiebert et al. (1) will undoubtedly support the urgently needed development of screening recommendations for the immediate future. However, development of novel biomarkers that are more appropriate for screening in the era of the HPV vaccine is necessary for development of truly cost-effective screening approaches.
REFERENCES
1. Goldhaber-Fiebert JD, Stout NK, Salomon JA, Kuntz KM, Goldie SJ. Cost-effectiveness of cervical cancer screening with human papillomavirus DNA testing and HPV-16,18 vaccination. J Natl Cancer Inst (2008) 100(5):308–320.
2. Kulasingam SL, Myers ER. Potential health and economic impact of adding a human papillomavirus vaccine to screening programs. JAMA (2003) 290(6):781–789.
3. Elbasha EH, Dasbach EJ, Insinga RP. Model for assessing human papillomavirus vaccination strategies. Emerg Infect Dis (2007) 13(1):28–41.[ISI][Medline]
4. Brisson M, Van de Velde N, De Wals P, Boily MC. The potential cost-effectiveness of prophylactic human papillomavirus vaccines in Canada. Vaccine (2007) 25(29):5399–5408.[CrossRef][ISI][Medline]
5. Franco EL. Chapter 13: primary screening of cervical cancer with human papillomavirus tests. J Natl Cancer Inst Monogr (2003) 31:89–96.
6. Sherman ME, Lorincz AT, Scott DR, et al. Baseline cytology, human papillomavirus testing, and risk for cervical neoplasia: a 10-year cohort analysis. J Natl Cancer Inst (2003) 95(1):46–52.
7. Cuzick J, Mayrand MH, Ronco G, Snijders P, Wardle J. Chapter 10: new dimensions in cervical cancer screening. Vaccine (2006) 24(suppl_3):S90–S97.[ISI][Medline]
8. Arbyn M, Sasieni P, Meijer CJ, Clavel C, Koliopoulos G, Dillner J. Chapter 9: clinical applications of HPV testing: a summary of meta-analyses. Vaccine (2006) 24(suppl 3):S78–S89.[CrossRef][Medline]
9. Mayrand MH, Duarte-Franco E, Rodrigues I, et al. Human papillomavirus DNA versus Papanicolaou screening tests for cervical cancer. N Engl J Med (2007) 357(16):1579–1588.
10. Schiffman M. Integration of human papillomavirus vaccination, cytology, and human papillomavirus testing. Cancer (2007) 111(3):145–153.[CrossRef][ISI][Medline]
Related Article in JNCI
CiteULike 
Connotea 
Del.icio.us What's this?
J Natl Cancer Inst 2008 100: 287.
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||