Journal of the National Cancer Institute Advance Access originally published online on March 24, 2009
JNCI Journal of the National Cancer Institute 2009 101(7):439-440; doi:10.1093/jnci/djp044
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Published by Oxford University Press 2009.
EDITORIALS |
Primary and Secondary Prevention of Cervical Cancer—Opportunities and Challenges
Affiliations of authors: National Center for HIV, Viral Hepatitis, STD and TB Prevention (LEM), National Center for Zoonotic, Vector-Borne, and Enteric Diseases (ERU), and National Center for Chronic Disease Prevention and Health Promotion (MS), Centers for Disease Control and Prevention, Atlanta, GA
Correspondence to: Lauri E. Markowitz, MD, 1600 Clifton Rd, Division of STD Prevention, Centers for Disease Control and Prevention, MS E05, Atlanta, GA 30333 (e-mail: lem2{at}cdc.gov).
Two prophylactic human papillomavirus (HPV) vaccines have been shown to be highly effective in phase III trials (1,2) and are now recommended for use in many countries worldwide (3,4). As a result, primary prevention of cervical cancers that are attributable to HPV types 16 and 18 is now possible. Although this prospect has been enthusiastically embraced, it brings new challenges. These challenges will differ depending on a country's health care infrastructure, cultural issues, and political will, as well as on the status of cervical cancer control in that country. In countries like the United States that have an existing strategy of cervical cancer control via screening, one challenge is that primary prevention must be integrated into that strategy (5). Another challenge is the need to develop cost-effective strategies to monitor the impact of these expensive vaccines.
The study by Wheeler et al. (6) in this issue of the Journal includes information related to both of these challenges. The authors used a case–control study design with a statewide population-based sampling strategy. Specifically, they used the New Mexico Tumor Registry to identify cases and tested the archived tissues from available invasive cervical cancer cases (1980–1999) and in situ cervical cancers from two tertiary centers (1985–1999). Their control group was drawn from the routine cervical cancer screening population at the same two centers that served as the source of the in situ cases (1996–2000). The authors reasoned that the screening population would give a more accurate representation of the HPV type distribution in the at-risk population than would age-matched control subjects. The authors provide important details on tissue block retrieval and selection that give only a hint of the logistical problems that must be solved to attempt such a comprehensive analysis. What did we learn from this study to date (because the authors clearly have more information and analyses pending)?
As has been found in multiple studies worldwide (7), HPV16 was detected in most cancers overall (53%) followed by HPV18 (13%). The authors also found that the proportion of cervical cancers due to HPV16 and HPV18 was higher among younger women. They present HPV type– and species–specific risk assessments for in situ and invasive cancer as a whole and stratified by histology using HPV16-positive women as the reference group. This approach emphasizes the uniquely high risk conferred by HPV16.
The authors spend much of their discussion using these data, as well as information from a number of other studies, to argue that the age for initiation of cervical cancer screening can be shifted to older ages in HPV-vaccinated populations. There has been much discussion about the need to reevaluate cervical cancer screening after introduction of HPV vaccination programs, and the cost-effectiveness of various screening strategies has been investigated (8). Even without considering the data presented by Wheeler et al., it has been clear that problems with the low performance of cytology will be exacerbated after introduction of an HPV vaccine, and some have advocated for HPV testing to be used as a primary screening test while reserving cytology for triage of HPV-positive cases (5,9). Others have proposed initiating screening at older ages and using different screening intervals (8,10). It must be noted that screening recommendations have been debated even without considering HPV vaccine issues. Guidelines from national organizations already promote the initiation of screening at age 21 years or 3 years after the onset of vaginal sex and recommend lengthening of the screening intervals (11); however, most providers still screen women annually starting at age 18 years or below (12). Clearly, more education and policy interventions are required to translate evolving guidelines into best public health practice.
While the screening debate continues, it is important to consider the status of HPV vaccine implementation in the United States. The quadrivalent HPV vaccine was introduced in 2006 and is currently provided mainly by primary care providers rather than by school-based vaccination efforts that have achieved rapid high coverage in some countries (3). The National Immunization Teen Survey conducted in 2007 found that 25% of females aged 13–18 years had received at least one dose of HPV vaccine (13). Vaccine coverage will likely increase in the United States, but it may be years before a highly vaccinated cohort reaches cervical cancer screening age. Lower vaccine coverage among some age cohorts or subgroups may complicate cervical cancer screening if recommendations for screening are based on vaccination history.
Wheeler et al. (6) also provide important data to consider regarding monitoring the impact of HPV vaccination and the complex interaction between ongoing screening and the introduction of the vaccine. An unexpected finding was the decrease in the percentage of in situ and invasive cancers due to HPV16 over time. (This finding was based on modeled data; the unmodeled data might have allowed a more complete understanding of this observation.) If this decrease had been observed during a time of vaccine implementation, the apparent change could have been attributed to vaccination. This study was conducted before vaccine introduction, and the authors posit that the change was due to increases in Pap testing that might allow HPV16-associated lesions to be preferentially detected and treated before they could progress to a cervical cancer, because HPV16 has been reported to cause more obvious cytology changes than other HPV types (14). Although the differences in sample availability over the timeframe or other factors could have influenced the observed typing results, these data highlight the difficulties that may be encountered in evaluating vaccine impact and potential HPV type replacement (ie, the emergence of disease due to HPV types not included in the vaccine). A true population-based approach that uses denominators rather than proportions to determine HPV type–specific cancer and precancer incidence will be required because the proportion of disease due to non-vaccine HPV types will likely increase.
In the United States, the impact of the HPV vaccination program will eventually be able to be monitored through cancer registries that cover 100% of the population (15). However, because an impact on cervical cancer may not be detected for 20 years or more (16), monitoring more proximal measures, such as cervical intraepithelial neoplasia, may allow an earlier evaluation. As shown by Wheeler et al. (6), the mean age at diagnosis of in situ cancers was at least 15 years younger than that of invasive cancer. There are multiple challenges to monitoring these outcomes in the United States. Data regarding cervical precancers are not collected in most cancer registries, there are no Pap registries, cervical cancer screening recommendations may change, and vaccine registries are state-based and currently target mainly children younger than 6 years (17). Special monitoring projects and studies are underway to evaluate a variety of HPV-related outcomes (http://www.cdc.gov/std/Hpv/monitoring-rpt.htm); however, challenges remain to link data from immunizations, cervical cancer screening, and outcomes that will allow comprehensive monitoring and evaluation. The state-based initiative undertaken by Wheeler et al. (6) represents a potentially useful model. Data from all monitoring projects will need to be examined to determine the most efficient approaches to inform national monitoring needs.
This article raises many issues that we (and the authors) did not fully discuss, such as the biological significance of infection with multiple HPV types, the impact of DNA extraction and viral typing methods, the underrepresentation of HPV18 in precancerous lesions, and limitations of hierarchical risk stratification. Readers need to thoughtfully delve into the extensive data compiled and ponder some of the questions raised by the data presented by Wheeler et al. Over the next few years, a second HPV vaccine (2) may be licensed for use in the United States, and data will be available on quadrivalent HPV vaccine efficacy in men and in women older than 26 years. New tests for HPV detection may also become available. Continued work is needed to determine the best methods for monitoring vaccine impact and optimal strategies for both primary and secondary prevention of cervical cancer.
NOTES
The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
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J Natl Cancer Inst 2009 101: 437.
J Natl Cancer Inst 2009 101: 437.
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