UICC World Cancer Congress 2006

Objective: Methods: Results: Universal deployment of organized or opportunistic screening with Pap cytology in high and middle income countries has been the primary reason for the substantial reductions in cervical cancer morbidity and mortality during the last 50 years. However, in many low income countries Pap cytology screening is yet to be effectively implemented or has failed to reduce cervical cancer rates to an appreciable extent. Cervical cancer thus remains a critical public health problem that is second only to breast cancer in overall disease burden for women throughout the world. Global incidence estimates indicate that approximately 470,000 cervical cancer cases and around 230,000 deaths occur annually.

One of the greatest cancer research advances of the past decade has been the accrued evidence that human papillomavirus (HPV) infection is a necessary cause of cervical cancer. The 40+ mucosotropic genotypes of HPV are among the most common sexually transmitted infectious agents, with lifetime risks of around 80%. Although most infections are transient and resolve spontaneously, a small subset of women may develop persistent infections with oncogenic genotypes, such as HPVs 16 and 18. Such women experience substantially increased risks of cervical neoplasia later in life. This discovery has led to new research fronts on the prevention of cervical cancer: immunization against HPV and screening for cervical cancer precursors with HPV testing.

Prophylactic vaccines against HPVs 16 and 18 are currently at advanced stages of clinical testing in adolescent and young adult women. Made from viral capsid proteins, these vaccines induce strong protective antibody response. Recent research on the safety and efficacy of candidate prophylactic HPV vaccines have shown very promising results with nearly 100% efficacy in preventing the development of persistent infections and cervical precancerous lesions associated with HPV types 16 and 18, the two HPV types included as immunogens. Such studies have formed the basis for licensing of candidate vaccines by the major pharmaceutical companies in the next two years, Merck and GSK. Ongoing phase III studies are likely to corroborate the preliminary findings from the latter trials concerning the high vaccine efficacy against high grade preneoplastic cervical lesions. Mathematical models of the potential impact of HPV vaccines have also suggested a substantial public health benefit to be derived in most geographical areas.

Although the future seems bright on the HPV vaccine front policy makers are strongly cautioned to avoid scaling back cervical cancer screening. It will take many years before we can rationally develop cervical cancer screening strategies that will be cost-effective for the proper surveillance of women protected by HPV vaccination. Perhaps one of the most neglected aspects of the ongoing debate on the potential impact of prophylactic HPV vaccination is the need to examine existing screening practices to permit synergy between primary and secondary cervical cancer prevention efforts. Assuming that HPV vaccination will become an accepted approach for primary prevention of cervical cancer and other HPV-associated diseases it becomes essential to consider what to do with the prevailing secondary prevention strategy for this disease, i.e., screening with the Pap cytology test. Implementation of prophylactic HPV vaccination is likely to be a gradual process that will reflect specific health policy environments in different countries. In some jurisdictions, vaccination may be adopted as universal policy for all young women and covered by a centrally managed health care system. In other settings, the costs of vaccination may be shared between the public sector and individuals, based on categories of risk defined by immunization advisory committees serving ministries of health or other governmental bodies. It is also conceivable that some countries may not opt at all for covering the costs of vaccination and may leave the decision to health care providers and their patients. Finally, it is also likely that due to other pressing health care priorities some countries may not even contemplate the opportunity to adopt vaccination. The diversity in implementation scenarios is thus likely to be substantial. Nevertheless, they will likely reflect individual countries' perceptions regarding the cost-effectiveness of adding vaccination as a primary prevention measure. To be well informed, such decisions must imply that consideration was given to whether or not existing screening programs are to be modified for cost-effectiveness to be reached.

The two candidate vaccines, Merck's Gardasil and GSK's Cervarix, do not protect against all HPV types that cause cervical cancer. Although a small degree of cross-protection against other oncogenic HPVs is expected, there is also the potential for the distribution of HPV types in vaccinated populations to change gradually as a reflection of the vacated ecologic niches following the progressive elimination of HPVs 16 and 18. There is also the possibility that the type-specific immunity conferred by vaccination may wane over periods extending much beyond five years.

While much is yet to be learned about these and other vaccine-related issues, such as target ages and whether or not men should be vaccinated, it is sensible to consider that existing cervical cancer prevention strategies cannot be cost-effective following the incorporation of HPV vaccination without substantial changes to existing screening policies. Even health-care resource-rich countries will be hard pressed to absorb the high societal costs of vaccination without some form of streamlining or restructuring of their cervical cancer screening programs and management practices. Simply making cytology screening less frequent may not be a viable strategy in light of the potential problems that may plague Pap cytology performance in conditions of low lesion prevalence which will prevail after successive cohorts are vaccinated. HPV testing has the characteristics that would make it an ideal primary cervical cancer screening test in such conditions. Pap cytology should be reserved for triage settings, i.e., in assisting management of HPV positive cases because it is more likely to perform with sufficient accuracy when lesion prevalence is high, either artificially as in triage, or in unscreened populations. Another key advantage of using HPV testing as the primary screening tool is the opportunity to create HPV infection registries with the provision to link test results from the same women over time, thus allowing an efficient and low-cost strategy to monitor long-term protection among vaccinated women.