Surgery is a common treatment for vulvar intraepithelial neoplasia (VIN) 2/3, the precursor to human papillomavirus (HPV) squamous cancers. However, there can be adverse side effects, including discomfort and scarring, and variable risks of recurrence.
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“If you get clear margins during surgery, the recurrence risk is about 8% for the first couple years,” says Chad Michener, MD, Vice Chair of Cleveland Clinic’s Obstetrics & Gynecology Institute and holder of the Neil and Barbara Lazar Endowed Chair in Gynecologic Oncology Research and Education. “If there are positive margins, the risk goes up to about 25%.”
Michener and colleagues recently conducted a phase 1 clinical study to evaluate the safety, tolerability and efficacy of topical artesunate ointment as an alternative treatment for biopsy-confirmed HPV-associated VIN 2/3. The results, published online in October 2023 in a Gynecologic Oncology journal article, indicate that the medical therapy is tolerable with manageable side effects.
Previous studies noted in the journal article point to high recurrence rates (30% to 46%) over time following partial vulvectomy. The recurrence rate for ablation therapy, which is commonly used to treat patients with multiple lesions, is approximately 25%, says Dr. Michener.
In addition, some patients require subsequent treatment. Side effects of repeated excisions and ablative therapies include pain, swelling, scarring, disfigurement, dyspareunia and vulvovaginal dysfunction.
Other trials have examined the use of imiquimod – a topical cream typically prescribed for genital warts – to treat VIN.
“The results were fairly good, but there were a lot of systemic side effects – low-grade fever, malaise, fatigue, diarrhea,” says Dr. Michener. “So, many people stopped using the therapy.” Dr. Michener and his peers collaborated with Frantz Medical Group to trial artesunate, a malaria therapy, for VIN.
Fifteen patients were enrolled in a prospective dose-escalation trial testing either one, two or three treatment cycles. The first group received five-day dosing for one cycle. The next two groups received five-day dosing with a week between subsequent doses.
Participants underwent a clinical assessment before each cycle, including a medical examination and review of completed adverse-event diary cards.
“We found that artesunate is tolerable and safe,” says Dr. Michener. “No patients stopped the therapy due to systemic side effects. A small number of patients missed a dose or a couple of doses due to local side effects, but overall, everybody was able to complete all the cycles they were allotted.” In addition, the researchers saw evidence of lesion regression with topical artesunate therapy. Complete responders underwent biopsy of the treated site at 28 weeks, while partial responders had surgical resection or biopsy and ablation.
The team is about to begin a phase 2 trial to examine treatment response. It will include an expanded cohort randomized to four cycles of topical artesunate therapy or a placebo group.
One of the advantages of a topical medication for VIN would be democratization of treatment.
“Not everybody has access to surgeries and ablative therapies,” says Dr. Michener. “It would be ground-breaking to be able to treat vulvar intraepithelial neoplasia topically with medications that are stable at room temperature and easily transported.”
Uses for topical artesunate could expand beyond the vulva.
“You could potentially consider treating anything HPV-centric with artesunate because it is a well-tolerated drug that has been given rectally, orally and intravenously for malaria,” says Dr. Michener. “The ultimate goal is to expand treatments for patients with lower genital tract disease who otherwise might not have easy access.”