Emerging technologies and cervical cancer.

Human papillomavirus (HPV) has been demonstrated to be anecessary cause of invasive cervical cancer across epidemio-logic and virologic studies worldwide (1). However, the biologicmechanisms for malignant transformation by HPV were wellestablished long before the epidemiologic studies showed anyconsistency among investigators or across study designs. Oncesensitive biologic assays became available for the detection ofHPV, correlational, case–control, and cohort studies demon-strated high relative risks, high attributable fractions, appropriatetime sequence, differential risk among higher viral load andhigher risk viral types, and consistency among investigators (2). Now, with the relationship of HPV to cervical cancer estab-lished, attention has turned to how to use this information todecrease the morbidity of and mortality from cervical cancer.Cervical cancer is the third most common cancer in womenworldwide. Parkin et al. (3) estimated that 371200 cases ofcervical cancer were diagnosed worldwide in 1990, 80% of themin developing countries. In 1999, there were an estimated 12800cases of invasive cervical cancer and 4800 deaths from thiscancer in the United States (4). The natural history of cervicalcancer is well understood; lesions progress from dysplasia tocarcinoma in situ to cancer. The cervix can be sampled cyto-logically by use of the Pap smear. Although never subjected toa randomized clinical trial, the Pap smear has decreased mor-tality in all countries in which cervical cancer screening pro-grams have been established.Meanwhile, the natural history of HPV infections in relation-ship to the natural history of cervical cancer is less well under-stood. A study by de Villiers et al. (5) has demonstrated thatsexually active women become infected and the prevalence ofinfection peaks between 18 and 25 years of age. Infection preva-lence falls off as patients reach age 30 years, the age at which theincidence of high-grade lesions and invasive cancers begins torise. The immunobiology of HPV is difficult to study given theepitheliotropic nature of the virus and the complicated functionof the immune system. Both the antibody and cell-mediatedimmune system respond to HPV infection. In fact, until recently,studies on the exact relationship between viral antibody responseto HPV and disease were producing very inconsistent results.The cell-mediated system also appears to be important in thecontrol of HPV as it is in the control of the human immunode-ficiency virus (HIV). Many studies [reviewed in (6)] are ad-dressing its role in anticipation of vaccine development. TheHPV prevalence data and the relationship of HPV infection toage suggest that patients who remain infected may be those mostat risk for the development of high-grade lesions, but the sero-logic and cell-mediated immunobiologic data to support thisconcept are still lacking.In the developing world, the resources for detecting and treat-ing cervical cancer are limited. The goals of cancer eradicationprograms include finding better screening methods, reaching un-screened populations, and developing treatment programs forcancers that are detected. In developed countries with estab-lished screening and treatment programs, the challenge of cer-vical cancer presents itself differently. In such countries, manyof the incident cases have not been screened at regular intervals.On the other end of the spectrum, 50 million Pap smears areperformed annually in the United States. Of these smears, anestimated 2.5 million reveal low-grade lesions and atypiaswhose natural history in more than 80% of cases includes re-gression. More than 6 billion dollars is spent annually in theUnited States on their evaluation and management (7). Thus, thechallenge in developed countries is finding ways to reach thefew women who are unscreened and identifying those lesionsmost likely to be or to become invasive cancer and using re-sources wisely to manage them.The present article by the ALTS Group in this issue of theJournal (8) is the first of a series of articles reporting long-awaited findings from the Atypical Squamous Cells of Undeter-mined Significance/Low-Grade Squamous Intraepithelial Le-sions (ASCUS/LSIL, or ALTS) Trial. Eligible patients includedwomen 16 years old and older who had had a cervical Pap smearshowing ASCUS or LSIL within 2 months priot to trial entry,had no history of cervical or other genital cancers, had no knownHIV infection, were not pregnant, were able to give writteninformed consent, and were likely to commit to follow-up.All patients were to undergo a repeat Pap smear, undergo acervigram, and have cervical specimens collected for HPV test-ing.The study was originally designed to recruit 3600 womenwith ASCUS and 3600 women with LSIL from a representativesample of U.S. women into a randomized, multicenter clinicaltrial with three arms: an immediate-colposcopy arm, an HPV-testing arm, and a conservative-management arm wherein pa-tients were followed with cytology. The end point for the samplesize calculation—screening efficacy at 3 years—was based onthe number of high-grade squamous intraepithelial lesions (i.e.,“management failures”) expected on the HPV-testing and con-servative-management arms. A two-tailed significance level of.05 was assumed, and a 0.1% failure rate on the immediate-colposcopy arms and 1%, 2%, and 3% failure rates on the con-servative-management or HPV-testing arms would have yieldedpowers of . 84, . 98, and . 999, respectively. The trial was to in-clude 3 years of follow-up and as many ethnic groups as pos-sible. Many safeguards were built into the original trial design,including central review committees for Pathology Quality Con-trol, HPV Testing Quality Control, and Colposcopy QualityControl. In addition, several committees were created to provideoversight: a Steering Committee, an Ethics and Data MonitoringCommittee, and a Coordinating Unit that would oversee all as-pects of the trial at the four participating clinical centers. While