1. What is ALTS?
ALTS is a clinical trial designed to find the best way to manage the mild abnormalities that often show up on Pap tests. The study began enrolling patients in November 1996 and completed enrollment in December 1998. Analysis of the data is under way.
ALTS, which stands for the ASCUS/LSIL Triage Study, was organized and funded by the National Cancer Institute (NCI), the U.S. government's principal agency for cancer research. It was conducted at four major medical centers: the University of Alabama at Birmingham; the University of Oklahoma in Oklahoma City; Magee-Womens Hospital of the University of Pittsburgh Medical Center in Pittsburgh, Pa.; and the University of Washington in Seattle.
2. What are ASCUS and LSIL?
ASCUS and LSIL are acronyms for two mild abnormalities detected by Pap tests. ASCUS stands for atypical squamous cells of undetermined significance and LSIL for low-grade squamous intraepithelial lesion.
A diagnosis of ASCUS means that the nature of the abnormality is uncertain or equivocal. A diagnosis of LSIL means that there is a more definite, but still mild, abnormality.
3. Why did NCI initiate ALTS?
NCI initiated this trial to help resolve the controversy over what physicians and women should do about ASCUS and LSIL Pap test results. Most of these mild abnormalities will go away without treatment, but some may lead to a precancerous condition or cancer.
Many physicians in the United States now opt for aggressive management of ASCUS and LSIL, referring women to a colposcopic exam with biopsies of suspicious abnormalities. This approach carries a small risk of medical complications and is expensive. Other doctors opt for a more conservative, wait-and-see approach, recommending frequent, repeat Pap tests to see if the abnormalities go away without treatment.
The ALTS study looked at three different ways to manage ASCUS and LSIL: immediate colposcopy, conservative management, and HPV triage.
4. How was the study designed?
Women who enrolled in the study were divided into those with ASCUS and those with LSIL diagnoses. Patients in each category were then assigned randomly to one of three groups or study arms.
Immediate Colposcopy: Women in this arm were referred to colposcopy (examination with a magnifying instrument) to identify abnormal tissue for biopsy and, if necessary, treatment. This is the aggressive management option used commonly in the United States. Women in this arm, as in the others, also had a repeat Pap test every six months.
Conservative Management: Women in this arm were closely followed with repeat Pap tests (or, to use the more scientific term, cervical cytology) every six months. Patients had a colposcopy and a biopsy only if the repeat Pap test results suggested they had more severe abnormalities. This conservative approach is now common in Canada and in some European countries.
HPV Triage: Women in this arm were managed based on results of the Pap test plus a test for the human papillomavirus (HPV), which is the cause of most cervical cancers. If their Pap test showed more severe abnormalities or if their cervical cells contained DNA from certain HPV types associated with cancer, they had colposcopy. The HPV Triage arm tested the hypothesis that HPV testing is effective at determining which women with ASCUS need colposcopy.
5. What specifically do the researchers expect to learn from ALTS?
Researchers are comparing the three different groups to learn 1) how effective each management option is in early detection of the serious abnormalities that can progress to cancer; 2) how acceptable each option is to patients; and 3) how cost effective each option is. These are the trial's three main objectives, or "endpoints."
In addition, the investigators are analyzing the ALTS data to learn more about mild cervical abnormalities and their relationship to cancer. For instance, they hope to gain information about immune system factors that may help determine whether a mild abnormality goes away without treatment or progresses to a more severe abnormality.
6. What are the principal findings of ALTS?
Analysis of the ALTS data is ongoing. To date, the results show:
For women with an ASCUS diagnosis, the HPV test identified virtually all women with underlying abnormalities that need immediate attention.
To conduct this analysis, the researchers looked at results from women who received a colposcopy when they enrolled in the trial. They compared the HPV test results, the colposcopy results, and the results of the repeat Pap test at enrollment (the initial Pap test was done before the patient entered the trial). The data showed that:
- About 5 percent to 10 percent of women with ASCUS turned out, on colposcopy, to have precancer or (rarely) cancer.
- Of the women who had precancer or cancer on colposcopy, 96.3 percent also had a positive HPV test. Thus the test had a 96-percent sensitivity in triaging women with precancer or cancer to colposcopy. [Sensitivity: The percent of people with disease who have a positive test.]
- About 55 percent of women with ASCUS were HPV positive and thus would have been referred to colposcopy if the HPV test had been used for triage in all cases.
- About 10 percent to 20 percent of women with a positive HPV test had precancer or, rarely, cancer. In scientific terms, the test's positive predictive value was 10 percent to 20 percent. [Positive predictive value: For positive test results, the percent of cases in which disease is present.]
- About 99.5 percent of the women with a negative HPV test did not have precancer or cancer. The test's negative predictive value was 99.5 percent. [Negative predictive value: For negative test results, the percent of cases in which disease is absent. A high negative predictive value provides strong reassurance that disease is absent.]
- About 57 percent of women with ASCUS had the same or a more serious result on a repeat Pap test using a thin-layer slide preparation method, done when they enrolled in the study. If these ASCUS-or-worse Pap test results had been used as a basis for assigning women to colposcopy (a current method for managing ASCUS), about 85 percent of those with precancerous abnormalities would have been triaged to colposcopy. Thus, the sensitivity of the repeat, thin-layer Pap test, using ASCUS or a more serious abnormality as the basis for referral to colposcopy, was 85 percent.
Conclusion: HPV testing is highly sensitive in detecting the underlying abnormalities that need immediate attention.
Reference: D. Solomon, M. Schiffman, R. Tarone for the ALTS Group, Comparison of Three Management Strategies for Patients With Atypical Squamous Cells of Undetermined Significance: Baseline Results From a Randomized Trial, Journal of the National Cancer Institute, Vol. 93, No. 4,
Feb. 21, 2001.
- For women with an LSIL diagnosis, the HPV test is positive in a large majority of cases.
This analysis focused on the 642 women in ALTS with an initial LSIL diagnosis. The investigators looked at the HPV test results in this group and also at data that had been collected through questionnaires and interviews. They found that:
- The HPV test was positive for 82.9 percent of these patients. The high frequency of HPV, as measured by the HPV test, was confirmed by another sensitive test, known as polymerase chain reaction or PCR, in a subset of this group.
- Women 30 years of age and older were less likely to be HPV positive
- Women with three or more lifetime sex partners were more likely to be HPV positive than those with one or two partners.
Conclusion: The high prevalence of HPV infection in women with LSIL limits the usefulness of HPV testing in deciding how to manage these abnormalities.
Reference: The ASCUS/LSIL Study (ALTS) Group, Human Papillomavirus Testing for Triage of Women With Cytologic Evidence of Low-Grade Squamous Intraepithelial Lesions: Baseline Data From a Randomized Trial, Journal of the National Cancer Institute, Vol. 92, No. 5, March 1, 2000.