奥地利格拉茨医科大学Gerda Trutnovsky团队比较了外阴鳞状上皮内病变外用咪喹莫特与手术治疗的效果。这一研究成果发表在2022年4月25日出版的《柳叶刀》杂志上。

外阴高级别鳞状上皮内病变（vHSIL）的最佳治疗颇具挑战性。手术是标准治疗方法，但有一半患者出现复发。咪喹莫特药物治疗是一种有效的替代方法，但这两种方法尚未在随机试验中进行比较。该研究旨在比较初次咪喹莫特与手术治疗vHSIL妇女的临床疗效、组织学反应、人乳头瘤病毒（HPV）清除率、接受度和性心理疾病发病率。

奥地利妇科肿瘤组在奥地利六家医院进行了一项多中心、随机、3期、非劣效性临床试验，招募18-90岁、经组织学证实为vHSIL、有可见的单灶或多灶病变的女性患者。主要排除标准是临床怀疑有外阴癌或严重外阴炎症性皮肤病病史，以及在过去3个月内曾积极治疗过vHSIL。排除已知免疫缺陷、怀孕或哺乳期的妇女。

将患者按区块随机（1:1）分配到咪喹莫特组或手术组，并按单灶或多灶疾病分层。咪喹莫特以缓慢递增的剂量方案自我给药，每周最多三次，为期4-6个月。手术包括切除或消融术。对患者进行外阴镜检查、外阴活检、HPV检测，并对患者在基线检查时、6个月后和12个月后报告的结果进行评估。主要终点是局部咪喹莫特治疗或一次手术干预后6个月的完全临床缓解（CCR）。初步分析按方案进行，非劣效性范围为20%。

2013年6月7日至2020年1月8日，研究组共随机分配了110例vHSIL患者，其中78%为单灶vHSIL，22%为多灶vHSIL。107名患者（咪喹莫特组54名，手术组53名）对治疗临床缓解进行了评估，98名患者（咪喹莫特组46名，手术组52名）按照方案完成了研究。

咪喹莫特组46名患者中有37名（80%）出现CCR，而手术组52名患者中有41名（79%），表明新治疗方案的效果并不差。5名患者在一期或二期手术中发现了侵袭性疾病，但在按方案给药咪喹莫特的患者中未发现。两组之间在HPV清除率、不良事件和治疗满意度方面没有显著差异。

研究结果表明，咪喹莫特是一种安全、有效、被广泛接受的vHSIL女性手术替代方案，可作为一线治疗。

附：英文原文

Title: Topical imiquimod versus surgery for vulvar intraepithelial neoplasia: a multicentre, randomised, phase 3, non-inferiority trial

Author: Gerda Trutnovsky, Olaf Reich, Elmar A Joura, Magdalena Holter, Alexandra Ciresa-Knig, Andreas Widschwendter, Christian Schauer, Gerhard Bogner, Ziga Jan, Angelika Boandl, Martin S Kalteis, Sigrid Regauer, Karl Tamussino

Issue&Volume: 2022-04-25

Abstract:

Background

The optimal management of vulvar high-grade squamous intraepithelial lesions (vHSILs) 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 trial. 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 vHSIL.

Methods

This study was a multicentre, randomised, phase 3, non-inferiority clinical trial done by the Austrian Gynaecological Oncology group at six hospitals in Austria. We recruited female 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 dermatosis of the vulva, and any active treatment for vHSIL within the previous 3 months. Women with known immunodeficiency, who were pregnant, or who were lactating were excluded. Patients were randomly assigned (1:1) 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 three times per week for a period of 4–6 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%. This trial is registered at ClinicalTrials.gov, NCT01861535.

Findings

110 patients with vHSIL (78% with unifocal vHSIL and 22% with multifocal vHSIL) were randomly assigned between June 7, 2013, and Jan 8, 2020. Clinical response to treatment could be assessed in 107 patients (54 in the imiquimod group and 53 in the surgery group), and 98 patients (46 in the imiquimod group and 52 in the surgery group) completed the study per protocol. 37 (80%) of 46 patients using imiquimod had CCR, compared with 41 (79%) of 52 patients after one surgical intervention, showing non-inferiority of the new treatment (difference in proportion –0·016, 95% CI –0·15 to –0·18; p=0·0056). Invasive disease was found in five 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 study groups.

Interpretation

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

DOI: 10.1016/S0140-6736(22)00469-X

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)00469-X/fulltext