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The FUTURE of Cervix Cancer Prevention?
Abstract & Commentary
By Robert L. Coleman, MD, Professor & Director, Clinical Research, Department of Gynecologic Oncology, University of Texas, M.D. Anderson Cancer Center Department of Gynecologic Oncology, Houston, is Associate Editor for OB/GYN Clinical Alert.
Dr. Coleman reports no financial relationship to this field of study.
Synopsis: A phase 3 trial was conducted to evaluate the efficacy of a prophylactic quadrivalent vaccine in preventing anogenital diseases associated with human papillomavirus (HPV) types 6, 11, 16, and 18.
Source: Quadrivalent Vaccine against Human Papillomavirus to Prevent Anogenital Diseases. Garland S, on Behalf of the FUTURE I investigators. New Engl J Med. 2007;356:1928-1943.
Human Papilloma Virus (HPV) is recognized worldwide as the principal culprit in the development of cervix cancer and its precursor dysplastic lesions. Also increasingly recognized is its role in other anogenital disease such as vulvar, vaginal and perianal warts, dysplasia and cancer. The purpose of the Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) I study was to assess the efficacy of the quadrivalent HPV vaccine (Gardasil, Merck) against the development of anogenital disease. Two primary hypotheses were considered: first, that HPV vaccination will reduce the incidence of a composite endpoint of anogenital warts, vulvar (VIN) or vaginal (VAIN) intraepithelial neoplasia grades 1 to 3 or cancer associated with vaccine-type HPV (types 6, 11, 16, 18) and second, that HPV vaccination will reduce the incidence of cervical (CIN) intraepithelial neoplasia, grades 1 to 3, adenocarcinoma in-situ (AIS) or cancer associated with vaccine-type HPV. To evaluate these endpoints, 5455 women aged 16 to 24, without a prior history of HPV infection or associated pathology and no more than 4 lifetime sexual partners were randomized to the 3 planned injections of the quadrivalent vaccine or an aluminum-based placebo. Three analysis populations were considered: those that followed the protocol strictly and were sero-negative on day 1 for vaccine-specific HPV (per protocol population), those that had protocol violations but were sero-negative on day 1 for vaccine specific HPV (unrestricted population) and those who were not sero-negative at baseline or had prevalent disease (intent-to-treat [ITT] population). The table summarizes the study's findings against the 2 primary endpoints and the populations considered:
|Population||1 (anogenital)||2 (cervical)|
|ITT + prevalent disease
(not type specific)
Table provided by R. Coleman
Adverse affects were more common in the vaccine cohort with injection site pain, erythema, pruritus and swelling being reported most commonly (~87%). Systemic effects were less frequent (~13%) but were also more common in the vaccine cohort. The authors conclude the vaccine is extremely effective in preventing type-specific HPV disease in this cohort of women.
On June 8, 2006, these and data from the FUTURE II trial (also published with the current trial in the same issue of the New England Journal of Medicine) were presented as part of the FDA submission leading to regulatory approval of this vaccine. The current reports add another year of follow-up (now an average 3 years from the injection #1 time point) and continues to demonstrate the favorable findings presented at that pivotal registration meeting. Since that time, significant dialogue, largely spurred by political mandates and advocacy groups, have raised the topic of HPV vaccination to the level of "water-cooler" or dinner conversation. While this development, for the most part, is good, there are many challenges that await what few would argue is the ultimate endpoint of this intervention—the elimination of anogenital cancer due to HPV infection.
The current report and availability of vaccination should serve not necessarily as the means to an end but a demonstration of what may be an effective strategy to define the ends and to establish a road map to get there. Clearly, there is suboptimal protection against incident disease not specifically vaccinated against highlighting the importance of continued vaccine research. Indeed, a bivalent HPV-16/18 vaccine with a different adjuvant is near FDA-filing and multivalent and non-virus like particle (VLP) vaccines are under investigation. In addition, these observations highlight the danger in complacency of gynecologic screening, which is recommended even in vaccinated subjects. There are also continued concerns as to the duration of protection in type-specific HPV disease even though re-challenge with antigen at 5 years evokes a type-specific immune response similar to acute infection. Add to this concerns of cost, uni-gender vaccination practice, reduced utility in HPV-positive (prevalent) subjects, limited experience in pre-teens and older women, potential underestimation of side-effects (control group received aluminum-adjuvant placebo instead of saline), absence of long-term follow-up to evaluate late-effects, strategies for vaccine implementation in the US (as well as worldwide) and time to see an impact (likely 30 to 50 years) and one can appreciate we are at the start of this race. However, we are moving and there is hope we can overcome these challenges with continued research.