Topical or Ablative Treatment in Preventing Anal Cancer in Patients With HIV and Anal High-Grade Squamous Intraepithelial Lesions
This randomized phase III trial compares topical or ablative treatment with active monitoring in preventing anal cancer in patients with human immunodeficiency virus (HIV) and high-grade squamous intraepithelial lesions (HSIL). Anal HSIL is tissue in the anal canal that has been damaged by infection with human papillomavirus (HPV) and is at risk for turning into anal cancer. It is not yet known if treating HSIL is more effective than active monitoring in preventing patients from developing anal cancer.
- Anal Cancer
- High-grade Squamous Intraepithelial Lesion
- HIV Infection
- Human Papilloma Virus Infection
- Eligible Ages
- Over 35 Years
- Eligible Genders
- Accepts Healthy Volunteers
- HIV-1 infection, as documented by any federally approved, licensed HIV test performed in conjunction with screening (or enzyme-linked immunosorbent assay [ELISA], test kit, and confirmed by western blot or other approved test); alternatively, this documentation may include a record that another physician has documented that the participant has HIV infection based on prior ELISA and western blot, or other approved diagnostic tests; an approved antibody test will be used to confirm diagnosis; if the physician is treating a patient with combination antiretroviral therapy (cART) with a history of HIV positivity based on an approved antibody test then repeat antibody confirmation is not necessary
- No history of treatment or removal of HSIL
- No history of anal cancer or signs of anal cancer at baseline, and no history of penile, vulvar, vaginal or cervical cancer
- Biopsy-proven HSIL at baseline
- At least one focus of HSIL must be identified that is not within a condyloma that may be treated after enrollment into the study
- For females, cervical cytology (if having a cervix) and gynecologic evaluation including vulvar examination within 12 months prior to enrollment
- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
- Life expectancy of greater than 5 years
- Absolute neutrophil count: >= 750/mm^3
- Platelets: >= 75,000/mm^3
- Hemoglobin >= 9.0 g/dL
- Women of childbearing potential must have a negative urine pregnancy test within 7 days of initiating study treatment if they have been randomized to the treatment arm; all women of childbearing potential must agree to use a reliable birth control method (oral contraceptive pills, intrauterine device, Nexplanon, DepoProvera, or permanent sterilization, etc., or another acceptable method as determined by the investigator) during the entire period of the trial (5 years), and must not intend to become pregnant during study participation and for 3 months after treatment is discontinued; all participants must be willing to comply with an acceptable birth control regimen as determined by the Investigator
- Men randomized to the treatment arm should not father a baby while in this study; men who could father a child should use at least two forms of birth control for 3 months after stopping all study treatment
- Ability to understand and the willingness to sign a written informed consent document
- Participant is willing to be randomized and able to comply with the protocol
- Clinician is comfortable with either following patient for up to 5 years without therapy or treating patient for up to 5 years
- Inability to provide informed consent
- Patients who are receiving any other immunomodulatory investigational agents within the 4 weeks before randomization enrollment, other than investigational antiretroviral agents for HIV
- History of anal cancer, penile, vulvar, vaginal or cervical cancer
- History of prior treatment or removal of anal HSIL
- Participant has symptoms related to HSIL and would benefit more from immediate treatment than from entry into the study and potential for randomization to active monitoring arm
- Current systemic chemotherapy or radiation therapy that potentially causes bone marrow suppression that would preclude safe treatment of HSIL
- History of HPV vaccination, or intention to receive an HPV vaccine during study participation
- Prior pelvic radiation therapy that would preclude radiation therapy if anal cancer develops
- Warts so extensive that they preclude the clinician from determining the extent and location of HSIL
- Participant plans to relocate away from the study site during study participation
- Phase 3
- Study Type
- Intervention Model
- Parallel Assignment
- Primary Purpose
- None (Open Label)
Arm I (treatment)
|Patients are directed to receive either topical or ablative treatment at the discretion of the clinician. Patients receiving topical treatment apply imiquimod intra-anally, peri-anally or both thrice weekly for up to 16 weeks, fluorouracil twice daily for 5 days every 2 weeks for up to 16 weeks, or trichloroacetic acid every 3 weeks up to 12 weeks. Patients receiving ablative treatment using infrared photocoagulation therapy, hyfrecation/electrocautery (thermal ablation therapy), or laser therapy. Patients may undergo excision under anesthesia if the clinician believes none of the other treatment approaches will be effective. The number and timing of such treatments will be at the discretion of the investigator. Patients with persistent HSIL should continue a protocol-approved treatment or a new protocol treatment should be considered. All participants will have samples collected for laboratory biomarker analysis.||
Arm II (active monitoring)
|Patients undergo active monitoring with examinations for clinical observation every 6 months. Every 12 months, patients undergo biopsies of visible lesions. Patients have cytology sampling performed at every visit. All participants will have samples collected for laboratory biomarker analysis.||
- AIDS Malignancy Consortium
I. To determine the effectiveness of treating anal HSIL to reduce the incidence of anal cancer in human immunodeficiency virus (HIV)-infected men and women.
I. Determine safety of infrared coagulation, electrocautery, imiquimod, 85% trichloroacetic acid and 5-fluorouracil (fluorouracil) treatments for anal HSIL.
II. Compare quality of life measures between arms.
I. Determine the human papilloma virus (HPV) type in cancer and compare to that of overlying HSIL and HSIL biopsies collected concurrently that did not progress to cancer.
II. Determine the strain variant of HPV 16 in participants who progressed to anal cancer and compare to participants with HSIL biopsies who did not progress to cancer.
III. Determine the HPV integration site in overlying anal cancer to that of HSIL overlying the cancer and HSIL biopsies collected concurrently that did not progress to cancer.
IV. Perform gene expression array analysis comparing expression in anal cancer with HSIL overlying the cancer; perform gene expression array analysis comparing expression in HSIL biopsies that progressed to cancer with non-progressing HSIL biopsies at other locations; perform similar analyses comparing expression in HSIL biopsies that progressed to cancer with the same lesion at earlier time points prior to progression.
V. Characterize genetic changes in anal cancers compared with HSIL overlying the cancer; characterize genetic changes in HSIL biopsies that progressed to cancer compared with non-progressing HSIL biopsies at other locations; characterize genetic changes HSIL biopsies that progressed to cancer with the same lesion at earlier time points prior to progression.
VI. Identify host and viral biomarkers of progression from HSIL to cancer. VII. Evaluate medical history and behavioral risk factors for HSIL progression to cancer.
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients are directed to receive either topical or ablative treatment at the discretion of the clinician. Patients receiving topical treatment apply imiquimod intra-anally, peri-anally or both thrice weekly for up to 16 weeks, fluorouracil twice daily for 5 days every 2 weeks for up to 16 weeks, or trichloroacetic acid every 3 weeks up to 12 weeks. Patients receiving ablative treatment using infrared coagulation, hyfrecation/electrocautery, or laser. Patients may undergo excision under anesthesia if the clinician believes none of the other treatment approaches will be effective. The number and timing of such treatments will be at the discretion of the investigator. Patients with persistent HSIL should continue a protocol-approved treatment or a new protocol treatment should be considered.
ARM II: Patients undergo active monitoring with examinations every 6 months. Every 12 months, patients undergo biopsies of visible lesions. Patients have cytology performed at every visit.
After completion of study treatment, patients are followed up every 6 months for up to 5 years.