Treatment of Anal High-Grade Squamous Intraepithelial Lesions to Prevent Anal Cancer

Abstract

Background: The incidence of anal cancer is substantially higher among persons living with the human immunodeficiency virus (HIV) than in the general population. Similar to cervical cancer, anal cancer is preceded by high-grade squamous intraepithelial lesions (HSILs). Treatment for cervical HSIL reduces progression to cervical cancer; however, data from prospective studies of treatment for anal HSIL to prevent anal cancer are lacking.

Methods: We conducted a phase 3 trial at 25 U.S. sites. Persons living with HIV who were 35 years of age or older and who had biopsy-proven anal HSIL were randomly assigned, in a 1:1 ratio, to receive either HSIL treatment or active monitoring without treatment. Treatment included office-based ablative procedures, ablation or excision under anesthesia, or the administration of topical fluorouracil or imiquimod. The primary outcome was progression to anal cancer in a time-to-event analysis. Participants in the treatment group were treated until HSIL was completely resolved. All the participants underwent high-resolution anoscopy at least every 6 months; biopsy was also performed for suspected ongoing HSIL in the treatment group, annually in the active-monitoring group, or any time there was concern for cancer.

Results: Of 4459 participants who underwent randomization, 4446 (99.7%) were included in the analysis of the time to progression to cancer. With a median follow-up of 25.8 months, 9 cases were diagnosed in the treatment group (173 per 100,000 person-years; 95% confidence interval [CI], 90 to 332) and 21 cases in the active-monitoring group (402 per 100,000 person-years; 95% CI, 262 to 616). The rate of progression to anal cancer was lower in the treatment group than in the active-monitoring group by 57% (95% CI, 6 to 80; P = 0.03 by log-rank test).

Conclusions: Among participants with biopsy-proven anal HSIL, the risk of anal cancer was significantly lower with treatment for anal HSIL than with active monitoring. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT02135419.).

Figure 1.. Screening, Randomization, and Follow-Up.

Of the six participants in the treatment group who discontinued the intervention for “other reason,” two received a diagnosis of anal cancer but were ineligible for analysis and were discontinued from the trial because they were determined to have had anal cancer before randomization, three relocated to a nontrial site, and one received immunomodulatory agents after a kidney transplantation. Of the two participants in the active-monitoring group who discontinued the intervention for “other reason,” both relocated to a nontrial site. A total of 25 of 2219 participants (1.1%) in the active-monitoring group were considered to be nonadherent because they had received treatment for anal high-grade squamous intraepithelial lesions at some time after randomization.

Figure 2.. Kaplan–Meier Curve of the Time to Progression to Anal Cancer.

The inset shows the data on an expanded y axis. The shaded areas represent 95% confidence intervals.