Anal Cancer, High-grade Squamous Intraepithelial Lesion, HIV Infection, Human Papilloma Virus Infection
Conditions
Keywords
anal cancer, high-grade squamous intraepithelial lesion, anal HSIL, HIV, HIV/AIDS, human papillomavirus, HPV
Brief summary
The randomized phase of the trial compared 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. The ANCHOR Data Safety Monitoring Board (DSMB) determined that the primary study endpoint was completed, based on the data and statistical analysis presented to them on 07SEP2021. In the post-randomization phase of this trial, all enrolled participants are offered treatment for HSIL and/or follow-up, at the participant's choice.
Detailed description
PRIMARY OBJECTIVES: The primary objective of this study has been completed for efficacy. 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. SECONDARY OBJECTIVES: I. To determine the safety of infrared coagulation (IRC), electrocautery, imiquimod, laser and 5- fluorouracil treatments for anal HSIL. II. To assess the responsiveness (sensitivity to change) and clinical significance of the ANCHOR Health-Related Symptom Index (A-HRSI) subscales by comparing change scores within groups of participants as defined by participant responses to the participant global impression of change (PGIC) item. (completed FEB2020) TERTIARY OBJECTIVES: Collect clinical specimens and data to create a bank of well-annotated specimens that will enable correlative science: I. Identification of viral factors in HSIL progression to cancer; II. Identification of host factors in HSIL progression to cancer; III. Identify host and viral biomarkers of progression from HSIL to cancer; IV. Identify medical history and behavioral risk factors for HSIL progression to cancer. QUALITY OF LIFE OBJECTIVES (completed FEB2022) I. Primary QOL Objective: To compare arms in terms of changes in physical symptoms and impacts from T2 to T3, adjusting for T1. ANCILLARY (COVID SUPPLEMENT) SUBSTUDY OBJECTIVES: I. Determine the prevalence of SARS-CoV-2 detection in anal and oropharyngeal swabs among people living with HIV (PLWH) being screened for and enrolled in the ANCHOR study. II. Determine the relationship between prevalent anal SARS-CoV-2 positivity, anal HPV infection, and anal high-grade squamous intraepithelial lesions (HSIL). III. Determine the 6-month incidence of SARS-CoV-2 detection in anal and oropharyngeal swabs among participants in the active monitoring arm being assessed for the first time for treatment and individuals already enrolled in the COVID substudy under protocol version 15.0. IV. Determine the relationship between prevalent or incident SARS-CoV-2 detection and regression of anal HPV infection or HSIL among active monitoring arm participants already enrolled in the COVID substudy under protocol version 15.0, and those who continue the protocol and who choose not to be treated at visit 101. OUTLINE: The randomized strategy to study the efficacy of HSIL treatment to reduce the risk of progression to anal cancer, as compared to active monitoring, was discontinued for all participants. Patients are randomized to 1 of 2 treatment arms. (accrual closed SEP2021) ARM I: Patients are directed to receive either topical or ablative treatment at the discretion of the clinician. Patients receiving topical treatment apply topical imiquimod intra-anally, peri-anally or both thrice weekly for up to 16 weeks, or topical 5-fluorouracil twice daily for 5 days every 2 weeks for up to 16 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 HRA examinations and anal cytology every 6 months. Every 12 months, patients undergo biopsies of visible lesions. Participants on both arms are to be followed for up to 5 years after randomization of the last participant. Post-randomization phase: Individuals in the treatment arm may continue treatment, and participants in the active monitoring arm are offered treatment. If upon assessment participants continue to have HSIL but do not intend to get treatment, they will be monitored for the potential for disease progression to anal cancer.
Interventions
DRUGimiquimod
Applied topically
DRUGfluorouracil
Applied topically
Undergo infrared coagulation
DEVICEthermal ablation therapy
Undergo hyfrecation/electrocautery therapy
DEVICElaser therapy
Undergo laser therapy
OTHERclinical observation
Undergo active monitoring (High Resolution Anoscopy \[HRA\]) with biopsies
OTHERlaboratory biomarker analysis
Correlative studies
Sponsors
National Cancer Institute (NCI)
The Emmes Company, LLC
University of Arkansas
University of California, San Francisco
University of Arizona
AIDS Malignancy Consortium
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Intervention model description
All participants are evaluated with high resolution anoscopy and anal cytology every 6 months during study participation. Participants randomized to treatment undergo biopsy of anal HSIL at each 6-month visit, and receive topical or ablative therapies for incident anal HSIL lesions. Active monitoring participants undergo close observation, with biopsy of anal HSIL at annual visits. Participants undergo biopsy of lesions at any time cancer is suspected.
Eligibility
Sex/Gender
ALL
Age
35 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* HIV positive. Documentation of HIV-1 infection by means of any one of the following: 1) Documentation of HIV diagnosis in the medical record by a licensed health care provider; 2) Documentation of receipt of ART by a licensed health care provider (receipt of at least two agents is required); 3) HIV-1 RNA detection by a licensed HIV-1 RNA assay demonstrating \>1000 RNA copies/mL; or, 4) Any licensed HIV screening antibody and/or HIV antibody/antigen combination assay confirmed by a second licensed HIV assay such as a HIV-1 Western blot confirmation or HIV rapid multispot antibody differentiation assay. * 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, documentation that the participant is being followed for cervical cytology (if having a cervix) and/or HPV testing per current ASCCP guidelines, and visual examination of the vulva, vagina, and cervix to rule out cancer/suspicion for cancer 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 or more), 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 receiving topical treatment during this study. Men who could father a child must agree to use at least one form of birth control during or continued abstinence from heterosexual intercourse if receiving topical treatment during the study, and for 2 weeks after stopping topical 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
Exclusion criteria
* Inability to provide informed consent * Patients who are receiving any other immunomodulatory investigational agents (replacement doses of steroids for adrenal insufficiency or treatment with prednisone ≤5 mg/day is permitted) within the 4 weeks before randomization enrollment, other than investigational antiretroviral agents for HIV, or investigational or approved agents for Hepatitis C. * History of anal cancer, penile, vulvar, vaginal or cervical cancer, or signs of these cancers at baseline. * Treatment or removal of HSIL less than 6 months prior to randomization. * 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 * Participants who only have a single HSIL lesion that is likely to be removed entirely with the initial screening biopsy * 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 to a location without an ANCHOR study site during study participation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Anal Cancer Incidence | Time from randomization to diagnosis of anal cancer, assessed up to 5 years post randomization | Anal cancer incidence is calculated as the number of anal cancer cases detected per 100,000 person years |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Adverse Events for Each Treatment | Up to 5 years after randomization | Participants who had at least one adverse event (serious or non-serious) |
| Change in Physical Symptom Score From Baseline (2-7 Days Post Randomization) Until 4 Weeks Post Randomization | 4 weeks post randomization | The physical symptom score is made up of the sum of responses to whether or not the participant had any of the 9 physical symptoms: anal pain, pain other than anal pain, pain during bowel movements, constipation, bleeding from anus, itching in/around the anus, discharge (wetness) in anal area, burning sensations in the anal area, and urgency for bowel movements. Responses are 0- not at all, 1-a little bit, 2-somewhat, 3-quite a bit, 4-very much. Thus physical symptom score ranges from 0 to 36. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Behavioral Risk Factors for HSIL Progression to Cancer | Up to 5 years after randomization | For each risk factor of interest, Fisher's exact test or Pearson's chi-square test will be used to determine if there is an association. Factors associated with invasive anal cancer at the 0.10 significance level will be incorporated into a logistic regression model to determine if they are independently associated with invasive anal cancer. Cox regression analyses will also be used to evaluate the association between risk factors and time to diagnosis of invasive anal cancer. |
| Viral Factors in HSIL Progression to Cancer | Up to 5 years after randomization | Descriptive statistics will be used to describe the integration locus of HPV In the invasive cancers and whether they differ from those of the overlying HSIL. Descriptive statistics will also be used to determine if the loci differ in HSIL that have progressed and concurrent HSIL biopsies that did not progress. In each case only tissues that contain HPV 16 will be analyzed. |
| Quality of Life Assessment Measured by the A-HRSI (Validated Tool) | A-HRSI completion occurred at 3 time points: Pre-randomization (T1), within 2-7 days (T2) and at 4 weeks of treatment/randomization (T3). | A-HRSI physical symptoms and physical impacts subscale change scores (T3 minus T2) using an analysis of covariance adjusting for the covariate baseline (T1) subscale to test for differences between arms at a one-sided 0.025 significance level with approximately 90% power. |
| ANCHOR Study Health-Related Symptom Index (A-HRSI) Scale Responsiveness (Sensitivity to Change) | A-HRSI and self-reported Patient Global Impression of Change (PGIC) scale and ECOG Performance Status (ECOG PS) item were administered at time of enrollment (T1) up until time of trial randomization (T2), and 71-112 days post-randomization (T3). | Participants at follow-up timepoints were categorized into two sets of three groups based on PGIC and ECOG PS responses (worse, no change, better), with the primary responsiveness analysis using these three groups in a one-way analysis of variance (ANOVA). |
| Host Factors in HSIL Progression to Cancer | Up to 5 years after randomization | Linear models will be fitted for each gene. Moderated t-statistics, fold-change and the associated p values will be calculated for each gene. Since thousands of genes will be tested, false discovery rate (FDR)-adjusted values will be calculated using the Benjamini-Hochberg method. FDR values indicate the expected fraction of falsely declared differentially expressed (DE) genes among the total set of declared DE genes, i.e. FDR = 0.15 would indicate that 15% of the declared DE genes were expected to be false due to experimental noise instead of actual differential expression. |
| Host and Viral Biomarkers of Progression From HSIL to Cancer | Up to 5 years after randomization | Biomarkers that are correlated with progression from anal HSIL to anal cancer |
Countries
Puerto Rico, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
imiquimod: Applied topically
fluorouracil: Applied topically
infrared photocoagulation therapy: Undergo infrared coagulation
thermal ablation therapy: Undergo hyfrecation/electrocautery therapy
laser therapy: Undergo laser therapy
clinical observation: Undergo active monitoring (High Resolution Anoscopy \[HRA\]) with biopsies
laboratory biomarker analysis: Correlative studies | 2,227 |
| Arm II (Active Monitoring) (Closed Since SEP2021) 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.
clinical observation: Undergo active monitoring (High Resolution Anoscopy \[HRA\]) with biopsies
laboratory biomarker analysis: Correlative studies | 2,219 |
| Total | 4,446 |
Baseline characteristics
| Characteristic | Arm I (Treatment) | Arm II (Active Monitoring) (Closed Since SEP2021) | Total |
|---|---|---|---|
| Age, Continuous | 50.9 years STANDARD_DEVIATION 8.9 | 50.9 years STANDARD_DEVIATION 9 | 50.9 years STANDARD_DEVIATION 8.9 |
| CD4 count | 602 cells/mm^3 | 607 cells/mm^3 | 604 cells/mm^3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 594 Participants | 502 Participants | 1096 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1582 Participants | 1665 Participants | 3247 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 51 Participants | 52 Participants | 103 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 11 Participants | 14 Participants | 25 Participants |
| Race (NIH/OMB) Asian | 27 Participants | 26 Participants | 53 Participants |
| Race (NIH/OMB) Black or African American | 935 Participants | 939 Participants | 1874 Participants |
| Race (NIH/OMB) More than one race | 89 Participants | 98 Participants | 187 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 4 Participants | 8 Participants | 12 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 144 Participants | 118 Participants | 262 Participants |
| Race (NIH/OMB) White | 1017 Participants | 1016 Participants | 2033 Participants |
| Region of Enrollment Puerto Rico | 110 participants | 110 participants | 220 participants |
| Region of Enrollment United States | 2117 participants | 2109 participants | 4226 participants |
| Sex: Female, Male Female | 342 Participants | 354 Participants | 696 Participants |
| Sex: Female, Male Male | 1885 Participants | 1865 Participants | 3750 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 55 / 2,227 | 48 / 2,219 |
| other Total, other adverse events | 82 / 2,227 | 60 / 2,219 |
| serious Total, serious adverse events | 370 / 2,227 | 375 / 2,219 |
Outcome results
Primary
Anal Cancer Incidence
Anal cancer incidence is calculated as the number of anal cancer cases detected per 100,000 person years
Time frame: Time from randomization to diagnosis of anal cancer, assessed up to 5 years post randomization
Population: Participants who were randomized and received the assigned intervention
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Treatment) | Anal Cancer Incidence | 173 cases per 100,000 person years |
| Arm II (Active Monitoring) (Closed Since SEP2021) | Anal Cancer Incidence | 402 cases per 100,000 person years |
Secondary
Change in Physical Symptom Score From Baseline (2-7 Days Post Randomization) Until 4 Weeks Post Randomization
The physical symptom score is made up of the sum of responses to whether or not the participant had any of the 9 physical symptoms: anal pain, pain other than anal pain, pain during bowel movements, constipation, bleeding from anus, itching in/around the anus, discharge (wetness) in anal area, burning sensations in the anal area, and urgency for bowel movements. Responses are 0- not at all, 1-a little bit, 2-somewhat, 3-quite a bit, 4-very much. Thus physical symptom score ranges from 0 to 36.
Time frame: 4 weeks post randomization
Population: Participants who were randomized on the ANCHOR study and for whom physical symptom scores were obtained at baseline and 4 weeks post-randomization.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Treatment) | Change in Physical Symptom Score From Baseline (2-7 Days Post Randomization) Until 4 Weeks Post Randomization | -2.22 score on a scale | Standard Deviation 4.69 |
| Arm II (Active Monitoring) (Closed Since SEP2021) | Change in Physical Symptom Score From Baseline (2-7 Days Post Randomization) Until 4 Weeks Post Randomization | -0.08 score on a scale | Standard Deviation 3.31 |
Secondary
Incidence of Adverse Events for Each Treatment
Participants who had at least one adverse event (serious or non-serious)
Time frame: Up to 5 years after randomization
Population: Participants who received assigned intervention
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Treatment) | Incidence of Adverse Events for Each Treatment | 416 Participants |
| Arm II (Active Monitoring) (Closed Since SEP2021) | Incidence of Adverse Events for Each Treatment | 429 Participants |
Other Pre-specified
ANCHOR Study Health-Related Symptom Index (A-HRSI) Scale Responsiveness (Sensitivity to Change)
Participants at follow-up timepoints were categorized into two sets of three groups based on PGIC and ECOG PS responses (worse, no change, better), with the primary responsiveness analysis using these three groups in a one-way analysis of variance (ANOVA).
Time frame: A-HRSI and self-reported Patient Global Impression of Change (PGIC) scale and ECOG Performance Status (ECOG PS) item were administered at time of enrollment (T1) up until time of trial randomization (T2), and 71-112 days post-randomization (T3).
Other Pre-specified
Behavioral Risk Factors for HSIL Progression to Cancer
For each risk factor of interest, Fisher's exact test or Pearson's chi-square test will be used to determine if there is an association. Factors associated with invasive anal cancer at the 0.10 significance level will be incorporated into a logistic regression model to determine if they are independently associated with invasive anal cancer. Cox regression analyses will also be used to evaluate the association between risk factors and time to diagnosis of invasive anal cancer.
Time frame: Up to 5 years after randomization
Other Pre-specified
Host and Viral Biomarkers of Progression From HSIL to Cancer
Biomarkers that are correlated with progression from anal HSIL to anal cancer
Time frame: Up to 5 years after randomization
Other Pre-specified
Host Factors in HSIL Progression to Cancer
Linear models will be fitted for each gene. Moderated t-statistics, fold-change and the associated p values will be calculated for each gene. Since thousands of genes will be tested, false discovery rate (FDR)-adjusted values will be calculated using the Benjamini-Hochberg method. FDR values indicate the expected fraction of falsely declared differentially expressed (DE) genes among the total set of declared DE genes, i.e. FDR = 0.15 would indicate that 15% of the declared DE genes were expected to be false due to experimental noise instead of actual differential expression.
Time frame: Up to 5 years after randomization
Other Pre-specified
Quality of Life Assessment Measured by the A-HRSI (Validated Tool)
A-HRSI physical symptoms and physical impacts subscale change scores (T3 minus T2) using an analysis of covariance adjusting for the covariate baseline (T1) subscale to test for differences between arms at a one-sided 0.025 significance level with approximately 90% power.
Time frame: A-HRSI completion occurred at 3 time points: Pre-randomization (T1), within 2-7 days (T2) and at 4 weeks of treatment/randomization (T3).
Other Pre-specified
Viral Factors in HSIL Progression to Cancer
Descriptive statistics will be used to describe the integration locus of HPV In the invasive cancers and whether they differ from those of the overlying HSIL. Descriptive statistics will also be used to determine if the loci differ in HSIL that have progressed and concurrent HSIL biopsies that did not progress. In each case only tissues that contain HPV 16 will be analyzed.
Time frame: Up to 5 years after randomization