In a phase III study, the ANCHOR Investigators Group found that participants who had undergone treatment for anal high-grade squamous intraepithelial lesions had a rate of progression to anal cancer that was 57% lower than those who had undergone active monitoring. The study was not designed to compare the efficacy of different methods of treatment of high-grade squamous intraepithelial lesions. However, most participants were treated with electrocautery, primarily hyfrecation, an office-based procedure that is quick and generally has an acceptable adverse-event profile. The study data provide support for the use of screening and treatment for anal high-grade squamous intraepithelial lesions as the standard of care for persons living with human immunodeficiency virus (HIV) who are 35 years of age or older and may also be relevant for other groups at increased risk for anal cancer. The findings are published by Dr. Joel Palefsky of the University of California in San Francisco, CA, US and colleagues on 16 June 2022 in The New England Journal of Medicine.

Like cervical cancer, anal cancer is caused by human papillomavirus (HPV) infection and is preceded by a high-grade squamous intraepithelial lesion. The risk of anal cancer varies widely among different population groups, with the highest risk seen in persons living with HIV. Other high-risk groups include persons with immunosuppression for solid-organ transplantation and women with a history of vulvar or cervical high-grade squamous intraepithelial lesions or cancer. Additional risk factors include a history of receptive anal sexual intercourse, a history of genital warts, anal fissures or fistulas, and smoking.

The authors wrote in the study background that efforts to prevent anal cancer in at-risk groups have been modelled after programmes for the secondary prevention of cervical cancer. These efforts consist of anal high-grade squamous intraepithelial lesions screening with the use of cytologic analysis, identification of high-grade squamous intraepithelial lesions through high-resolution anoscopy in those who are screen-positive, and high-grade squamous intraepithelial lesions removal through ablation, surgical excision, or other treatments.

The prevention of anal cancer is desirable because anal cancer is associated with poor survival when detected at late stages, and treatment of cancers at all stages with standard chemoradiation therapy is associated with acute and chronic adverse effects. However, formal inclusion of anal cancer prevention programmes in standard-of-care guidelines has awaited direct evidence that treatment for anal high-grade squamous intraepithelial lesions reduces the risk of progression to anal cancer.

The purpose of the ANCHOR study was to determine whether treating anal high-grade squamous intraepithelial lesions is effective and safe in reducing progression to anal cancer among persons living with HIV as compared with active monitoring of high-grade squamous intraepithelial lesions. The ANCHOR Investigators Group conducted a phase III study at 25 sites in the USA. Persons living with HIV who were 35 years of age or older and who had biopsy-proven anal high-grade squamous intraepithelial lesions were randomly assigned, in a 1:1 ratio, to receive either high-grade squamous intraepithelial lesions treatment or active monitoring.

Treatment included office-based ablative procedures, ablation or excision under anaesthesia, 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 high-grade squamous intraepithelial lesions was completely resolved. All the participants underwent high-resolution anoscopy at least every 6 months; biopsy was also performed for suspected ongoing high-grade squamous intraepithelial lesions in the treatment group, annually in the active-monitoring group, or any time there was concern for cancer.

Of 4459 participants who underwent randomisation, 4446 (99.7%) were included in the analysis of the time to progression to anal cancer. With a median follow-up of 25.8 months, 9 cases were diagnosed in the treatment group (95% confidence interval [CI] 90 to 332) and 21 cases in the active-monitoring group (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).

A total of 7 serious adverse events that were considered by the investigators to be related to a study intervention were reported in the treatment group, and 1 such event was reported in the active-monitoring group. Additional considerations should include assessment of the effect on quality of life and other risk–benefit measures. 

The authors commented that the rate of progression to cancer among the participants in the active-monitoring group, at 402 per 100,000 person-years, was higher than expected on the basis of published estimates from cancer–HIV registry matches. This finding may in part reflect early anal cancer detection in this study, as in the absence of screening, anal cancer is usually diagnosed after the development of symptoms.

The authors also commented that the high rate of progression from high-grade squamous intraepithelial lesions to anal cancer among persons living with HIV in their study highlights the need for strong prevention efforts. HPV vaccination effectively prevents the initial acquisition of anal HPV and the development of anal high-grade squamous intraepithelial lesions in young persons living with HIV. However, secondary prevention programmes including treatment of anal high-grade squamous intraepithelial lesions are urgently needed for those already exposed to anal HPV.

Additional research is needed to improve screening algorithms to identify anal high-grade squamous intraepithelial lesions. High-resolution anoscopy is not a feasible screening tool given its cost and limited availability, and both anal cytologic analysis and anal HPV testing have limitations. Expansion of diagnostic and therapeutic training programmes in the use of high-resolution anoscopy is also needed.

The study was supported by the US National Cancer Institute. In-kind support was provided by Hologic (ThinPrep vials) and Bausch Health (fluorouracil cream).


Palefsky JM, Lee JY, Jay N, et al. Treatment of Anal High-Grade Squamous Intraepithelial Lesions to Prevent Anal Cancer. N Engl J Med 2022; 386:2273-2282.