Although researchers are not yet ready to declare victory over cervical cancer, one crucial battle may have been won. In late November, pharmaceutical maker Merck & Company Inc. announced that, 2 years into a planned 4-year proof-of-principle study, the companys investigational vaccine against human papillomavirus type 16 (HPV16) is working exactly as designers had hoped: It eliminated the risk of infection with HPV16 in 100% of women who were not previously infected.
The investigation involved 2,392 American women ranging in age from 16 to 23 who were randomly assigned to receive the vaccine or a placebo. In the placebo group, 3.8% of women developed HPV16 infection annually.
"The Merck study is certainly big news," said Doug Lowy, M.D., chief of the National Cancer Institutes Laboratory of Cellular Oncology. "In the long term, the vaccine will change the landscape. Even without screening well have the prospect of preventing cervical cancer." Especially encouraging about the Merck study, Lowy added, is that the tested version has engendered no serious side effects, and those inoculated with an active version of the vaccine all mounted a strong immunologic response.
The trial owes its success to the development of papillomavirus-like particles in the early 1990s. Although the particles cannot replicatethey contain no DNA and therefore cannot spread infectionthey nevertheless mimic natural virion structure and so engender a potent immune response. In the Merck study, subjects were randomly assigned to receive either three doses of vaccine or placebo.
HPV infection is responsible for the majority of cervical cancers. Of the four-dozen-plus kinds of HPV viruses that infect the genital tract and mucosal surfaces, 15 can cause cellular abnormalities with the potential to progress to cancer, said Allan Hildesheim, Ph.D., senior investigator in NCIs Environmental Epidemiology Branch. HPV16 is responsible for causing half of all cervical cancers. Types 18, 31, 33, and 45 together account for an additional 20%, while the rest of the strains account for the remainder of cervical cancer cases.
Although there is no specific cure for an HPV infection, the virus sometimes can be controlled by interferon or podophyllinmedicine derived from the roots of the plant Podophyllum peltatumand the warts can be removed by cryosurgery, laser treatment, or conventional surgery.
"Modern medicine has a limited effect on the rate of cervical cancer because all our interventions are weak in comparison with the efficiency of the host immune system," wrote Christopher Crum, M.D., a pathologist at Brigham and Womens Hospital in Boston, in a November New England Journal of Medicine editorial that accompanied the publication of the Merck study outcomes. "Ninety percent of cervical papillomavirus infections resolve spontaneously, so that cervical cancer develops in only a minority of women, even in the absence of screening. Screening appears to benefit only a small fraction of women, although a much larger percentage endure the inconvenience of a Papanicolaou smear in order to avoid cervical cancer."
Hildesheim noted that most varieties of HPV simply disappear within a year of infection, eradicated by the bodys immune system, and that only a small minority of women infected with HPV will develop cancer. In an ideal world, a cervical cancer vaccine would be multivalent, both protecting women who are not yet infected against all known disease-causing strains and treating those who are already infected with the virus. Hildesheim said he believes that such a combination is at least a decade off, however.
"We dont have a therapeutic vaccine for any disease at this point," said Laura Koutsky, Ph.D., principal investigator of the report on the Merck HPV16 trials and professor of epidemiology at the University of Washington in Seattle. "Its a very difficult problem to address. Right now, once you get a disease you cant be vaccinated [to stop it]."
Currently, only prophylactic vaccines have progressed to large-scale human trials, including a phase III NCI effort slated to begin in 2003 in Costa Rica. That trial will target HPV16 and HPV18 strains and will include more than 10,000 women. NCI investigators will be working with their Costa Rican colleagues out of dedicated facilities established close to existing health clinics.
For its part, Merck is beginning phase III trials worldwide of a multivalent preventive vaccine that will include the HPV16, 18, 11, and 6 strains. Strains 11 and 6 are responsible for 90% of all genital warts. Should investigators be able to replicate their initial success with the HPV16 variety, those free of genital warts may be able to remain so indefinitely.
In the United States, Hildesheim said that confirmed duration of protection will be a key element in any potential Federal Drug Administration approval of a cervical cancer vaccine. So too will be safety and demonstrated effectiveness against pre-invasive cervical lesions. The drug industry has promised to aggressively address cost and ease-of-delivery issues, which critics contend remain stumbling blocks to global vaccine rollout.
In the meantime, despite the promising advance suggested by the Merck HPV16 investigation, women everywhere would be advised to follow a more conservative course when it comes to cervical cancer, said NCIs Lowy.
"Even though Im very enthusiastic about the long-term potential of [HPV vaccines], I dont think screenings should be eliminated," he said. "Improved screening in the short term has the potential for saving more lives, especially considering that vaccine hasnt yet been approved [by the FDA]. Good screening in the absence of a vaccine is better than a good vaccine with no screening."
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