NEWS

Trial Quickly Changed Management of Cervical Abnormalities

Sarah L. Zielinski

This is part of an occasional series that recalls some of the stories reported 10 years ago in the News section of the Journal.

In less time than it takes some clinical trials to start, the ASCUS/LSIL Triage Study (ALTS) for cervical cancer was completed and had its results incorporated into clinical guidelines and practice.

ALTS was born out of a change in terminology. In 1989, the National Cancer Institute developed standard terminology to describe abnormal cervical results—a lexicon referred to as the Bethesda System—that grouped ambiguous cytological abnormalities under the name "atypical squamous cells of undetermined significance (ASCUS)." About 5% of Pap tests were labeled as ASCUS, but physicians had no way of knowing which of these mild cervical lesions could progress to cancer and which were benign. "There really was no efficient triage test," said Diane Solomon, M.D., senior investigator in the Division of Cancer Prevention at the National Cancer Institute and one of the lead investigators in ALTS.



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Diane Solomon

 
The NCI designed ALTS in 1995 to figure out the most appropriate follow-up for women who were diagnosed with ASCUS or its neighboring category, low-grade squamous intraepithelial lesions (LSILs), and how the new knowledge of human papillomavirus (HPV) could be used to manage these women. "It became clear that we should be able to use HPV testing to somehow rationalize what we were doing with ASCUS," said Mark Schiffman, M.D., a senior investigator at NCI and another lead investigator in ALTS.

More than 5,000 women diagnosed with ASCUS or LSIL were recruited into the trial at four centers and randomly assigned to one of three management strategies: immediate colposcopy, repeat cytology with colposcopy only if the results showed a high-grade lesion, or HPV testing plus a repeat cytology with referral to colposcopy only if the HPV test was positive or repeat cytology indicated a high-grade lesion. The participants were followed up at 6-month intervals for a total of 2 years, and the trial was complete by the end of 2000.

The investigators determined that for LSIL, HPV testing was not a useful triage method because most cases of LSIL are associated with high-risk types of HPV, so few women would be excluded from colposcopy. However, for ASCUS, HPV testing found nearly as many precancerous lesions and cancers as colposcopy in women ages 29 and older, and only about half of women with ASCUS who were tested for HPV had to undergo colposcopy.

In an unusual move, the ALTS investigators decided to give their data to a consensus conference sponsored by the American Society for Colposcopy and Cervical Pathology in 2001 before their data had been published. "It would have been more timely for us if the ASCCP conference had been held a year later," Schiffman said, but by releasing their data early, "we bypassed several years of process."

The ASCCP guidelines, which were published in 2002, were based mainly on the ALTS data, and clinical management of ASCUS has already changed. Now, "most ASCUS cases are triaged by HPV testing," Solomon said.

ASCCP will hold another consensus conference in September 2006 and will consider data from new studies in addition to late-breaking data from ALTS. The ALTS investigators plan to publish several articles within the next year.

One of the more surprising findings from ALTS was that colposcopy, considered the "gold standard" for cancer detection, is not nearly as good as had been thought. The exam misses about a quarter of precancerous lesions and has its own limitations. It cannot be considered a complete ascertainment of disease, Solomon said.

This has led to the question of what to do with women who are HPV positive but have negative colposcopies, particularly since most of these viral infections disappear on their own and few will ever develop into cancer.

"We've, in a way, solved the problem of ASCUS," Schiffman said. "We know what the different components are." However, researchers are still working to figure out what to do with the categories that have replaced ASCUS in the 2001 update of the Bethesda System and how to handle HPV infections, particularly in young women where they are common. "We're moving to a higher order of confusion," he said.



             
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