Topical imiquimod versus surgery for vulvar intraepithelial neoplasia: a phase 3 multicenter, randomized, noninferiority study



Optimal management of high-grade vulvar squamous intraepithelial lesions (vHSILs) is challenging. Surgery is the standard treatment, but recurrences are seen in half of patients. Drug treatment with imiquimod is an effective alternative, but the two modalities have not been compared in a randomized trial. The aim of this study was to compare the clinical efficacy, histological response, human papillomavirus (HPV) clearance, acceptability, and psychosexual morbidity of primary treatment with imiquimod versus surgical treatment in women with vHSIL.


This study was a phase 3, multi-centre, randomized, non-inferiority clinical study conducted by the Austrian Gynecological Oncology Group at six hospitals in Austria. We recruited patients aged 18-90 years with histologically confirmed vHSIL with visible unifocal or multifocal lesions. Main exclusion criteria were clinical suspicion of invasion, a history of vulvar cancer or severe inflammatory vulvar dermatosis, and any active treatment of vHSIL within the past 3 months. Women with known immunodeficiency who were pregnant or breastfeeding were excluded. Patients were randomized (1:1) by block randomization to imiquimod or surgery and stratified by unifocal or multifocal disease. Imiquimod treatment was self-administered in a slowly escalating dosing regimen up to three times per week for 4-6 months. The operation consisted of excision or ablation. Patients were evaluated with vulvoscopy, vulvar biopsy, HPV testing, and patient-reported outcomes at baseline, 6 months, and 12 months. The primary endpoint was complete clinical response (CCR) 6 months after topical imiquimod treatment or surgery. The primary analysis was per protocol with a non-inferiority margin of 20%. This study is registered at, NCT01861535.


110 patients with vHSIL (78% with unifocal vHSIL and 22% with multifocal vHSIL) were randomized between June 7, 2013 and January 8, 2020. Clinical response to treatment was maintained in 107 patients (54 in the imiquimod group and 53 in the surgical group) and 98 patients (46 in the imiquimod group and 52 in the surgical group) completed the study per protocol. Thirty-seven (80%) of 46 patients receiving imiquimod had CCR compared to 41 (79%) of 52 patients following surgery, demonstrating non-inferiority to the new treatment (difference of -0.016 ratio, 95% CI -0*15 to -0.18; p=0.0056). Invasive disease was identified in five patients at primary or secondary surgery but not in those on per-protocol imiquimod treatment. There was no significant difference in HPV clearance, adverse events, and treatment satisfaction between study groups.


Imiquimod is a safe, effective, and well-accepted alternative to surgery for women with vHSIL and can be considered as a first-line therapy.


FWF and Austrian Gynecological Oncology Group.


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