Abstract
Worldwide, approximately 500,000 new cases of cervical cancer (∼1 case per minute) are diagnosed and 275,000 related-deaths occur annually, making it the second or third most common female cancer and cancer-related cause of mortality. Cervical cancer has an especially profound societal impact because a substantial fraction of cervical cancer occurs in women in their 30's and 40's while they are still raising or supporting families. Cervical cancer is an even more vexing problem in developing countries and regions, where more than 80% of all cervical cancer occurs and is often the most common cancer in women.
Screening with cervical cytology (Pap tests) has led to drastic reductions in cervical cancer incidence in developed countries; in the U.S., only about 11,000 cases will be diagnosed and less than 4,000 will die from cervical cancer this year. However, 60% of all cervical cancer that occurs in the U.S. (http://www.cdc.gov/cancer/cervical/) occur pockets of underserved, underscreened populations as part of a complex of diseases linked to poverty and/or racial disparities.
Unfortunately, cytology-based cervical cancer prevention programs may have “maxed out”. The unequal burden of cervical cancer in resource-limited populations and the success of cervical cytology in developed countries highlights its limitations, including poor sensitivity and reproducibility, difficulty in sustaining high-quality facilities and staffing, and the requirement for a repeated three-visit intervention cycle of cytology/colposcopy/treatment that is prone to losses-to-follow-up. These limitations contribute to a very impractical and costly program; the cost of the U.S. program was estimated to be $6 billion/annually in 1992. Although triennial cytology screening and careful management of abnormalities by colposcopy, biopsy, and treatment of histologically-confirmed precancers throughout most of a woman's lifetime can reduce cervical cancer incidence by up to 90%, it seems unlikely that rounds of cervical cytology screening as a preventive measure against cervical cancer will reach most of those women in the greatest need, especially since there are competing needs for the few public health dollars available.
In the last 20 years, unprecedented, rapid progress has been made in understanding the etiology of cervical cancer: cervical infections by approximately 15 cancer-associated (“carcinogenic”) human papillomavirus (HPV) genotypes cause virtually all cervical cancer and its immediate precursor lesions. HPV infection is the most common sexually transmitted infection although there can significant regional variation due to differences in cultural and sexual norms. HPV infections, even those by carcinogenic HPV genotypes, are typically transient with virtually all clearing within 1–2 years. Carcinogenic HPV infections that do not clear (i.e., persist) pose a significant risk to a woman for developing precancer, which if undetected, can invade. Thus, cancer develops rarely (on a per event basis) from an almost universal exposure to HPV. A new paradigm of cervical carcinogenesis replaces the model of stepwise progression from low-grade to high-grade morphological changes and can now be summarized based on 4 reliably measured stages: 1) HPV acquisition, 2) HPV persistence (vs. clearance), 3) progression of a persisting infection to precancer, and 4) invasion.
Based on the central role of persistent carcinogenic HPV infection in the development of cervical cancer, two promising technologies targeting HPV have been developed in the fight against cervical cancer: Vaccination for preventing HPV infection and carcinogenic HPV testing for cervical cancer screening. The development of prophylactic HPV vaccines is based on the self-assembly of recombinantly-expressed L1 protein into non-infectious capsids without genetic material. Two commercial HPV vaccines have been developed, both that target HPV16 and HPV18, which cause ∼70% of all cervical cancer. One also targets HPV6 and HPV11, which cause approximately 90% of genital warts. Two vaccines have shown 90% or greater efficacy for preventing persistent HPV16 and HPV18 infections and related cervical precancer in women who are not infected with these genotypes. However, these vaccines do not treat preexisting carcinogenic HPV infections, precancer, or cancer and therefore do not obviate the need for screening. The next generation of vaccines will target 6 carcinogenic HPV genotypes responsible for 90% of cervical cancers.
While HPV vaccination, if it becomes available to developing countries, will be an important tool in the prevention of cervical cancer, it will provide little or no benefit to several generations of women over the age of 18 who have already been exposed to HPV. To rely on HPV vaccination as the sole prevention strategy in these populations, even if it could be rapidly implemented globally (which is not possible), is to doom literally millions of underserved women to cervical cancer deaths over the next 30 years. Additional tools for cervical cancer prevention are required to impact this important cause morbidity and mortality. Carcinogenic HPV testing offers several advantages over cytology including: (1) greater sensitivity for the detection of prevalent and incipient precancer or cancer; (2) as a consequence of greater sensitivity, has higher negative predictive value i.e., testing negative for carcinogenic HPV DNA implies an extremely low risk of prevalent or incipient precancer and cancer and permits an extension of screening intervals; and (3) has greater reproducible and more consistent clinical performance. Recent randomized clinical trials have emphatically confirmed these findings. Carcinogenic HPV testing has now been approved in the United States as an adjunct to cytology for triage of equivocal cytology at all ages and for general screening in women ≥30 years old.
Given the robustness of both new technologies, an integrated, age-targeted approach of HPV vaccination in young, naïve women and carcinogenic HPV-based screening in older women could significantly impact cervical cancer rates worldwide. In underserved populations, these HPV technologies if employed wisely could make cervical cancer prevention programs more cost-efficient and reduce the need for treatment, which has a negative impact on reproductive outcomes. However, we will need to consider rational strategies to integrate vaccination and screening to ensure women's safety and avoid costly duplication of prevention efforts in the future. These technologies, if made accessible, could effectively replace a lifetime program of cytology with many fewer visits and at significant cost savings. Together, HPV vaccination and screening could reduce the population risk within a 10–20 year time period.
We stand at the threshold of a sea change in the worldwide approach to the prevention of cervical cancer but a number of challenges that must first be addressed to aid those who need it most. First, these technologies must be made affordable. The introduction of HPV vaccination will probably require the involvement of donors to make vaccines available and affordable. Like HPV vaccines, existing HPV tests are unaffordable and need to be done in specialized laboratories. A new HPV DNA test has been developed for low-resource regions that has the sensitivity and specificity that approaches the current commercially available tests but at a cost of under US$5. Validation studies are on-going. Other tests are likely in development. However, in scarcest-resource settings, neither HPV technologies may be afforded. In such settings, visual inspection with acetic acid for screening may be the only realistic screening method when the alternative is nothing. Second, strategies must be developed that reduce the number of clinical visits per interventional cycle are a must. As described for cytology-based programs, three-dose vaccination, as needed for the current HPV vaccines, is liable to result in lost follow-up and incomplete vaccination. Alternative vaccine schedules, such as two-dose vaccination (which also reduces the cost), must be proven effective. HPV testing used in one-day screen and treat programs could be highly effective. Third, innovative programs will be needed that provide population coverage. For example, mother-daughter programs in which mothers are screened and daughters are vaccinated might increase compliance. Bundled, low-cost interventions might further extend the health care provided for a fixed expenditure. Fourth, there must be a commitment to treatment of screen-positive women, and there must be the recognition and understanding that a screening intervention in an unscreened, high-risk population will uncover many cases of cancers and spike incident rates. Fifth, demonstration projects are needed to provide convincing data that these new technologies should replace the standard of care, cytology/colposcopy programs. Finally, these programs will require government buy-in and long-term commitment in order to reap population benefits.
Finally, given the worldwide diversity in cultural and sexual norms and the competing health care demands, it seems improbable that any one strategy for cervical cancer prevention will meet the needs of all populations i.e., “one size does not fit all”. Any intervention must be designed to meet the demands of the population it is intended to serve rather than demanding the population to use any specific intervention. Thus, interdisciplinary teams of scientists, doctors, and public health advocates will need to work in concert to implement and sustain population-specific interventions to reduce the burden of cervical cancer.
Second AACR International Conference on the Science of Cancer Health Disparities— Feb 3–6, 2009; Carefree, AZ