According to findings from a multicentre, randomised, phase III, non-inferiority study imiquimod is a safe, effective, and well accepted alternative to surgery for women with vulvar high-grade squamous intraepithelial lesions and can be considered as first-line treatment. The findings from the Austrian Gynaecological Oncology group study were published on 25 April 2022 in The Lancet.

The authors wrote in the study background that the optimal management of vulvar high-grade squamous intraepithelial lesions is challenging. Surgery is the standard treatment, but recurrences are observed in half of patients. Medical treatment with imiquimod is an effective alternative, but the two modalities have not been compared in a randomised study.

The aim of this study was to compare the clinical effectiveness, histological response, human papillomavirus (HPV) clearance, acceptance, and psychosexual morbidity of primary imiquimod treatment versus surgical treatment in women with vulvar high-grade squamous intraepithelial lesions.

This study was done by the Austrian Gynaecological Oncology group at 6 hospitals in Austria. The study team recruited female patients aged from 18 to 90 years with histologically confirmed vulvar high-grade squamous intraepithelial lesions with visible unifocal or multifocal lesions.

Main exclusion criteria were clinical suspicion of invasion, a history of vulvar cancer or severe inflammatory dermatosis of the vulva, and any active treatment for vulvar high-grade squamous intraepithelial lesions within the previous 3 months. Women with known immunodeficiency, who were pregnant, or who were lactating were also excluded.

Patients were randomly assigned in 1:1 ratio by block randomisation to imiquimod or surgery, and stratified by unifocal or multifocal disease. Treatment with imiquimod was self-administered in a slowly escalating dosage scheme up to 3 times per week for a period of 4 to 6 months.

Surgery consisted of excision or ablation. Patients were assessed with vulvoscopy, vulvar biopsy, HPV tests, and patient-reported outcomes at baseline and after 6 months and 12 months.

The primary endpoint was complete clinical response (CCR) at 6 months after local imiquimod treatment or one surgical intervention. Primary analysis was per protocol with a non-inferiority margin of 20%.

A total, 110 patients with vulvar high-grade squamous intraepithelial lesions, of whom 78% with unifocal disease and 22% with multifocal disease, were randomly assigned between 7 June 2013 and 8 January 2020. Clinical response to treatment could be assessed in 107 patients, of whom in 54 in the imiquimod arm and in 53 in the surgery arm. In total, 98 patients completed the study per protocol, of whom 46 in the imiquimod arm and 52 in the surgery arm.

In particular, 37 of 46 patients (80%) using imiquimod achieved CCR, compared with 41 of 52 patients (79%) after one surgical intervention, showing non-inferiority of the new treatment with difference in proportion –0.016 (95% confidence interval –0.15 to –0.18; p = 0.0056).

Invasive disease was found in 5 patients at primary or secondary surgery, but not in patients with per-protocol imiquimod treatment.

There was no significant difference in HPV clearance, adverse events, and treatment satisfaction between the study arms.

The study was funded by the Austrian Science Fund and Austrian Gynaecological Oncology group.


Trutnovsky G, Reich O, Joura EA, et al. Topical imiquimod versus surgery for vulvar intraepithelial neoplasia: a multicentre, randomised, phase 3, non-inferiority trial. The Lancet; Published online 25 April 2022. DOI: