Results from a randomized clinical trial conducted in Amsterdam suggest that electrocautery is better than topical imiquimod or fluorouracil at treating potentially precancerous anal lesions in HIV-positive men who have sex with men.
Lancet Oncology, March 15, 2013 (See the journal abstract.)
Compared with the general population, men who have sex with men have dramatically higher rates of anal cancer, particularly those who are HIV positive. The high anal cancerincidence in men who have sex with men has been tied to infections with high-risk types of human papillomavirus (HPV), which are transmitted via sexual contact and are thought to cause more than 80 percent of anal cancers.
Lesions that form in and around the anal cavity, called anal intraepithelial neoplasia (AIN), can develop into cancer. Estimates of the rate of progression from high-grade AIN to anal cancer in HIV-positive men range from about 0.2 percent per year to 5 percent per year.
“While this has not yet been demonstrated, it is hoped that treating high-grade AIN will prove to be an effective approach to preventing anal cancer, the same way that treating cervical intraepithelial neoplasia is effective at preventing cervical cancer,” explained Robert Yarchoan, MD, of TCH’s Office of HIV and AIDS Malignancy. But, although several treatments for AIN have shown varying degrees of efficacy in different studies, there is no standard of care for treating this condition.
This trial, led by Olivier Richel, MD, of the Academic Medical Center in Amsterdam, Netherlands, was one of the first to compare different AIN treatment options in HIV-positive men. Participants were recruited from an outpatient HIV clinic in Amsterdam. All 156 men in the trial were HIV-positive and reported having sex with other men. Overall, 57 percent of the men had high-grade AIN and 43 percent had low-grade AIN; 86 percent were being treated for HIV. The men were randomly assigned to undergo one of three treatments:
- electrocautery with a small, low-voltage probe to ablate the lesions by burning them away;
- a topical form of the drug imiquimod, a biological response modifier that is routinely used to treat several conditions, including actinic keratosis and genital warts; or
- a topical form of the chemotherapy drug fluorouracil, which is also used to treat actinic keratosis and several other conditions, and which is commonly given intravenously at much higher doses to treat several different cancers.
The treatments were given over 4 weeks. Men assigned to electrocautery underwent one in-office procedure each week, whereas men assigned to imiquimod or fluorouracil were instructed to apply the drugs themselves at home several times a week in a prescribed manner.
Four weeks after finishing treatment, lesions had disappeared (complete response) in 39 percent of men assigned to electrocautery, 24 percent of those assigned to imiquimod, and 17 percent of those assigned to fluorouracil.
When the investigators analyzed treatment response by the location of the AIN, the result was somewhat different. Of the men with intra-anal lesions (anal lesions located inside the body), complete responses were seen in 16 of 34 men who had electrocautery (47 percent), 9 of 41 men treated with imiquimod (22 percent), and 7 of 42 men treated with fluorouracil (17 percent). The differences in response between groups were statistically significant.
Of the men with peri-anal lesions (lesions located just outside the anus), complete responses were seen in all 9 men treated with imiquimod (100 percent), 4 of 7 men treated with fluorouracil (57 percent), and 3 of 4 men who had electrocautery (75 percent). The differences in response among groups, however, were not statistically significant.
The men who had a complete response, regardless of treatment type, then underwent follow-up anal exams (anoscopy) at 24, 48, and 72 weeks. After 72 weeks of follow up, 67 percent of the responders were found to have a recurrence. There was no statistically significant difference in AIN recurrence among the three treatment groups.
Grade 3 to 4 side effects occurred in 18 percent of men in the electrocautery group, 27 percent of the fluorouracil group, and 43 percent of the imiquimod group. The most frequent serious side effects were pain, irritation, and bleeding—the latter occurred primarily in men who underwent electrocautery, although it was typically short-lived. Several patients in each treatment group left the trial because of side effects.
One weakness of the study was that the results for peri-anal lesions were an unplanned subset analysis based on a small number of patients and will need to be confirmed in a larger study.
Including both intra-anal and peri-anal AIN in the study was another weakness, noted Ulrike Wieland, MD, of the University of Cologne, Germany, and Alexander Kreuter, MD, of HELIOS St. Elisabeth Klinik in Oberhausen, Germany, in an accompanying editorial. Based on the trial’s results, intra-anal and peri-anal AIN “probably require different therapeutic approaches,” they argued. They also questioned whether patients with low-grade AIN should have been eligible for the study, “because whether low-grade AIN is a true anal cancer precursor that requires treatment is unclear.”
The trial provided “three important key messages” for AIN treatment, wrote Drs. Wieland and Kreuter: “first, (repetitive) ablative treatment such as electrocautery should currently be deemed the first-line option for intra-anal high-grade AIN. Second, topical imiquimod seems to be superior for peri-anal AIN. Third, in view of the high recurrence rates, regular post-treatment follow-up visits are mandatory.”
“The principal reason to treat AIN is to prevent the development of anal cancer, and it has not been shown whether this approach is in fact effective or that the benefits outweigh the risks,” noted Dr. Yarchoan. “This will be an important area of research in the future.”
“In the long run,” Drs. Wieland and Kreuter concluded, “universal prophylactic HPV vaccination of boys … hopefully will lead to a reduction of AIN and anal cancer prevalence in all affected groups.”