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 or progression. Therefore, both high- and low-grade lesions were often managed with colposcopy and directed biopsy.

Epidemiologic, virologic and molecular studies have clearly demonstrated that human papillomavirus (HPV) is the central cause of cervical cancer. The motivation for the Atypical squamous cells of undetermined significance (ASCUS)- Low grade squamous intraepithelial lesion (LSIL) Triage Study (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 Alabama (AL); Magee-Womens Hospital, Pittsburgh Pennsylvania (PA); University of Oklahoma, Oklahoma City OK; and University of Washington, Seattle Washington (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 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.

Study Overview

• Status: Completed
• Conditions: Cervical Intraepithelial Neoplasia
• Intervention / Treatment: Device: Thinprep; Device: Hybrid capture 2; Procedure: Colposcopy

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 5060
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73019
      • University of Oklahoma
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Magee Womens Hospital
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: SCREENING
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Cytology; Referred to colposcopy if cytology is high grade	Device: Thinprep; Pap test
EXPERIMENTAL: Human Papillomavirus (HPV); Referred to colposcopy if cytology is high grade or HPV +	Device: Hybrid capture 2; Human Papillomavirus (HPV) Deoxyribonucleic Acid (DNA) Test
EXPERIMENTAL: Colposcopy; All refer to colposcopy	Procedure: Colposcopy; Procedure performed by a healthcare practitioner to examine the cervix, vagina, and vulva.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Cervical Intraepithelial Neoplasia III (CIN III)	A cervical exam, pap test, human papilloma virus (HPV) deoxyribonucleic acid (DNA) test, and/or colposcopy was performed to detect whether or not a participant had CINIII. CINIII is defined as moderate or severe dysplasia or abnormal cells located on the cervix that can lead to cancer.	up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Cumulative Detection of Clinical Center Histologically Confirmed Cervical Intraepithelial Neoplasia 2 (CIN2) and Above (High Grade Lesion) Over the 2 Years of the Trial.	Cumulative detection of CIN2 and above was assessed by pathologists who reviewed specimens from cervical pelvic exams (i.e. thin prep pap test, Human papillomavirus (HPV) Deoxyribonucleic acid (DNA) test, and/or colposcopy). Pathologists graded the specimens from CIN2 (moderate grade lesion) to CIN3 (high grade lesion).	up to 2 years

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)

Publications and helpful links

General Publications

• Boshart M, Gissmann L, Ikenberg H, Kleinheinz A, Scheurlen W, zur Hausen H. A new type of papillomavirus DNA, its presence in genital cancer biopsies and in cell lines derived from cervical cancer. EMBO J. 1984 May;3(5):1151-7. doi: 10.1002/j.1460-2075.1984.tb01944.x.
• Cox JT, Lorincz AT, Schiffman MH, Sherman ME, Cullen A, Kurman RJ. Human papillomavirus testing by hybrid capture appears to be useful in triaging women with a cytologic diagnosis of atypical squamous cells of undetermined significance. Am J Obstet Gynecol. 1995 Mar;172(3):946-54. doi: 10.1016/0002-9378(95)90026-8.
• Dyson N, Howley PM, Munger K, Harlow E. The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science. 1989 Feb 17;243(4893):934-7. doi: 10.1126/science.2537532.

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 20, 2008
• Primary Completion (ACTUAL): February 5, 2009
• Study Completion (ACTUAL): February 5, 2009

Study Registration Dates

• First Submitted: May 25, 2010
• First Submitted That Met QC Criteria: May 25, 2010
• First Posted (ESTIMATE): May 26, 2010

Study Record Updates

• Last Update Posted (ACTUAL): November 20, 2018
• Last Update Submitted That Met QC Criteria: October 22, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Keywords: Triage; Cervix; HPV; CIN; ASCUS/LSIL; Pap Smear; HPV Test
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Carcinoma in Situ; Cervical Intraepithelial Neoplasia
• Other Study ID Numbers: 999908076; 08-C-N076

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The only data sharing is in cervical images which are included as a part of a larger IRB approved release to collaborators completing a data sharing agreement that prohibits re-sharing of data images. The images are shared with limited test results, metadata, and age. The images are saved in encrypted files and shared under individual password protection. Images will only be shared with bonafide researchers who are verified and complete a pilot.
• IPD Sharing Time Frame: Now and indefinitely.
• IPD Sharing Access Criteria: The images are saved in encrypted files and shared under individual password protection. Images will only be shared with bonafide researchers who are verified and complete a pilot.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes