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Cidofovir, imiquimod effective alternatives to surgery for vulval intraepithelial neoplasia
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Topical cidofovir and imiquimod appeared safe and effective alternatives to surgery for women with grade 3 vulval intraepithelial neoplasia, according to results of a phase 2 trial.
Vulval intraepithelial neoplasia is a chronic pre-malignant disorder that affects the vulval skin. Left untreated, it may become cancerous. Age-standardized incidence is approximately one case per 100,000 women per year, but incidence has increased during recent years, according to background information provided by researchers.
Surgery is the standard treatment; however, it does not guarantee cure and also can cause disfigurement, physical complications and psychological problems.
Amanda Tristram, MD, of the department of obstetrics and gynecology at Cardiff University School of Medicine in the United Kingdom, and colleagues sought to assess the clinical activity, safety and feasibility of topical cidofovir (Vistide, Gilead Sciences) or imiquimod as an alternative to surgery.
The analysis included 180 women aged 16 years or older treated at one of 32 centers across the United Kingdom. All women had biopsy-proven grade 3 vulval intraepithelial neoplasia and at least one lesion that could be measured accurately.
The median age of patients was 47 years, and 82% reported a history of smoking. About half (46%) of patients had recurrent vulval intraepithelial neoplasia. Researchers detected high-risk HPV DNA in 91% of the 166 baseline biopsy specimens, and 89% were HPV-16.
Researchers randomly assigned 89 patients to topical treatment with 1% cidofovir, and they assigned the other 91 women to topical treatment with 5% imiquimod. Both treatments were self-applied three times weekly for a maximum of 24 weeks.
Histologically confirmed complete response at the post-treatment assessment 6 weeks after the conclusion of treatment served as the primary outcome. Secondary outcomes included adverse events and adherence to treatment.
At 6 weeks, treatment adherence was 87% in both study arms. Five patients (5.6%) assigned cidofovir and seven patients (7.6%) assigned imiquimod withdrew or were lost to follow-up at that time point, leaving 84 evaluable patients in each treatment arm.
At the post-treatment assessment, researchers observed complete responses in 46% of patients assigned cidofovir and 46% of patients assigned imiquimod.
Grade ≥3 adverse events occurred in 37% of patients assigned cidofovir and 46% of patients assigned imiquimod. The most frequent grade 3 and grade 4 adverse events were fatigue, headache, pain in the vulva and pruritus.
Follow-up of complete responders is still underway. Although data are not yet mature, preliminary results suggest the majority of complete responders treated with cidofovir (87%) and imiquimod (78%) maintained that response for 12 months.
“HPV vaccination is expected to prevent most cases of vulval intraepithelial neoplasia in the future; therefore, obtaining funding for future trials could be challenging,” Tristram and colleagues wrote. “In the meantime, a pragmatic approach will most likely have to be taken, whereby we explain to patients the potential benefits and risks of the available treatment options and take their priorities for treatment into account in this difficult management decision.”
Although no topical drug is approved for treatment of vulval intraepithelial neoplasia, these results support the use of imiquimod in women with vulval high-grade squamous intraepithelial lesions and also demonstrate the potential of cidofovir as a therapeutic option, Sven Mahner, MD, PhD, and Linn Wölber, MD, both of the department of gynecology and gynecologic oncology at University Medical Centre Hamburg-Eppendorf in Germany, wrote in an accompanying editorial.
“In the future, topical treatments could evolve to become the treatment of choice for people with high-grade squamous intraepithelial lesions, with cold-knife resection and laser vaporization reserved for patients not responding to initial treatment,” Mahner and Wölber wrote. “Until results of phase 3 studies comparing these different treatment modalities are available, the choice of treatment will mainly be based on the individual patient’s preference.”
For more information:
- Mahner S. Lancet Oncol. 2014;doi: 10.1016/S1470-2045(14)70491-7.
- Tristram A. Lancet Oncol. 2014;doi:10.1016/S1470-2045(14)70456-5.
Disclosure: The study was funded by Cancer Research UK. The researchers report educational grants from Pfizer for investigator-initiated clinical trials, as well as a consultant role with Pfizer.
Perspective
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Erin K. Crane, MD, MPH
With the introduction of universal HPV vaccination, an overall reduction in HPV-related cancers and dysplasia is anticipated. However, within recent years, there has been a disproportionate increase in HPV-related vulvar neoplasia in young patients in the United States. The psychosocial consequences of vulvar resection and physical disfigurement in reproductive-aged women can prove severe, with detrimental effects on self-image.Tristram and colleagues have provided us with confirmation that topical treatment of vulvar intraepithelial neoplasia is a safe and effective alternative to surgery in a carefully selected patient population. Pretreatment screening and work-up with subsequent follow-up is paramount, as a missed or progressive carcinoma can have devastating consequences, and necessitate a much more involved, extensive surgery than local resection.
Ten percent to 20% of patients with a high-grade vulvar lesion may harbor an underlying invasive carcinoma; therefore, an adequate representative biopsy is necessary prior to pursuing conservative management. Patients with a lesion that appears raised, ulcerated or irregular should undergo surgical excision. Additionally, as the authors allude, patients with non–HPV-related (or differentiated type) lesions have a higher propensity toward development of an invasive carcinoma, and it is uncertain whether topical immunomodulation is acceptable in this patient population. Finally, choosing reliable patients who will adhere to close follow-up is critical in identifying treatment failures.
Until phase 3 data comparing the surgical standard of care to topical treatment are available, the authors have delivered some strong evidence that in a select, carefully surveilled patient population, topical imiquimod or cidofovir can be substituted for surgical resection.
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