Randomized Clinical Trial on Clinical Management of ASCUS and LSIL (ALTS)

Approximately 65 million Pap smears are performed each year in the United States. The vast
majority of results are negative (no abnormality identified) but about 5 percent to 8 percent
are reported as abnormal. Most low-grade changes regress spontaneously; only a minority of
such lesions would progress to a cancer precursor without treatment. However, there is no way
to determine morphologically which patients are at risk of progression. Therefore, both high-
and low-grade lesions were often managed with colposcopy and directed biopsy. It was
anticipated that determining alternative management strategies would yield important
potential benefits including fewer medical complications from over treatment, reduced patient
anxiety associated with referral for cytologic abnormalities, as well as cost savings.

Epidemiologic, virologic and molecular studies have clearly demonstrated that human
papillomavirus (HPV) is the central cause of cervical cancer. The motivation for the ALTS
trial was to use the information we have gained about the role of HPV to design better
treatment and prevention strategies to reduce the burden of cervical cancer and its
precursors.

ALTS consisted of three management strategies: (1) immediate colposcopy of all women; (2)
repeat cytology with colposcopy only if the results show a high grade lesion; and (3) HPV
testing and repeat cytology in combination, with referral to colposcopy if either the HPV
test is positive or the cytology shows a high grade lesion. Four Clinical Centers University
of Alabama, Birmingham AL; Magee-Womens Hospital, Pittsburgh PA; University of Oklahoma,
Oklahoma City OK; and University of Washington, Seattle WA - enrolled approximately 5,000
women with recent diagnosis of ASCUS or LSIL. Participants were followed at six month
intervals for a total of 2 years. The main results from ALTS showed that for women with ASCUS
cytology, HPV triage was at least as safe as universal immediate colposcopy in the detection
of high-grade lesion and would allow approximately half of women to return to routine follow
up without additional procedures (colposcopy). No efficient triage strategy was identified
for women with LSIL cytology.

The ALTS database and ALTS specimens continue to be a valuable research resource in studies
of cervical cancer precursors, screening tests, visual assessment of the cervix and
investigation of biomarkers.

- Inclusion Criteria:

- Diagnosis of atypical squamous cells of undetermined significance (ASCUS) or
low-grade squamous intraepithelial lesion (LSIL)

- 18 years or older

- Able to give informed consent with reasonable likelihood of follow-up

Exclusion Criteria:

- Previous Hysterectomy

- History of excisional or ablative treatment of cervix, such as laser treatment,
radiation therapy, cauterization (burning), freezing or surgery such as cone biopsy or
loop electrosurgical excision procedure (LEEP).

- Already known to be pregnant

- Already known to be human immunodeficiency virus (HIV) positive (HIV may negatively
affect the clinical history of human papillomavirus (HPV), making triage less
appropriate.