Activity, safety, and feasibility of cidofovir and imiquimod for treatment of vulval intraepithelial neoplasia (RT3VIN): a multicentre, open-label, randomised, phase 2 trial
Activity, safety, and feasibility of cidofovir and imiquimod for treatment of vulval intraepithelial neoplasia (RT3VIN): a multicentre, open-label, randomised, phase 2 trial
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DOI：
10.1016/s1470-2045(14)70456-5
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发表时间：
2014-11-01
期刊：
影响因子：
51.1
通讯作者：
Griffiths, Gareth
中科院分区：
文献类型：
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作者：
Tristram, Amanda;Hurt, Christopher N.;Griffiths, Gareth
背景外阴上皮内瘤变是一种影响外阴的皮肤疾病，如果不治疗，可癌变。目前，外阴上皮内瘤变患者的标准治疗方法是手术，但这种方法不能保证治愈，而且可能会毁容，造成身体和心理问题，特别是在育龄妇女中。我们的目的是评估的活性，安全性和可行性的两个局部治疗西多福韦和咪喹莫特作为一种替代手术的女性患者外阴上皮内neoplasia.Methods我们招募女性患者（年龄16岁或以上）从32个中心的开放标签，随机，2期试验。入选标准是活检证实的外阴上皮内瘤变3级，至少有一个病灶可以准确测量。我们将患者随机分配到局部治疗组，使用1%西多福韦（以10 g管中的凝胶形式提供，持续6周）或5%咪喹莫特（每次应用一个250 mg小袋），每周自我应用三次，最多持续24周。通过中央计算机系统分层最小化进行随机化（1：1），按医院、疾病病灶和表现阶段分层。主要终点是治疗结束后6周（治疗开始后最长30周）治疗后评估访视时组织学证实的完全缓解。主要终点的分析是通过意向治疗，次要终点是毒性反应（评估安全性）和治疗依从性（评估可行性）。我们在所有患者在6周时达到主要终点评估点后呈现结果;完全应答者的2年随访继续进行。该试验在当前对照试验中注册，ISRCTN 34420460。结果在2009年10月21日至2013年1月11日期间，180名参与者参加了这项研究; 89名患者随机分配西多福韦，91名患者分配咪喹莫特。在治疗后评估访视时，41例（46%; 90%CI 37.0-55.3）分配给西多福韦的患者和42例（46%; 37.2-55.3）分配给咪喹莫特的患者实现了完全缓解。治疗6周后，156例（87%）患者（每组78例）坚持治疗方案。西多福韦组的5名患者和咪喹莫特组的7名患者在第一个6周安全性评估之前退出或失访。在接受西多福韦治疗的84名患者中有31名（37%）报告了3级或更高级别的不良事件，在接受咪喹莫特治疗的84名患者中有39名（46%）报告了3级或更高级别的不良事件;最常见的3级和4级事件是外阴疼痛、瘙痒、疲劳和头痛。解释西多福韦和咪喹莫特有效，安全，并且对于治疗外阴上皮内瘤变是可行的，并且值得在3期环境中进一步研究。对于排除隐匿性浸润性疾病后的女性外阴上皮内瘤变患者，两种药物均为手术的有效替代方案。
Background Vulval intraepithelial neoplasia is a skin disorder affecting the vulva that, if left untreated, can become cancerous. Currently, the standard treatment for patients with vulval intraepithelial neoplasia is surgery, but this approach does not guarantee cure and can be disfiguring, causing physical and psychological problems, particularly in women of reproductive age. We aimed to assess the activity, safety, and feasibility of two topical treatments-cidofovir and imiquimod-as an alternative to surgery in female patients with vulval intraepithelial neoplasia.Methods We recruited female patients (age 16 years or older) from 32 centres to an open-label, randomised, phase 2 trial. Eligibility criteria were biopsy-proven vulval intraepithelial neoplasia grade 3 and at least one lesion that could be measured accurately. We randomly allocated patients to topical treatment with either 1% cidofovir (supplied as a gel in a 10 g tube, to last 6 weeks) or 5% imiquimod (one 250 mg sachet for every application), to be self-applied three times a week for a maximum of 24 weeks. Randomisation (1:1) was done by stratified minimisation via a central computerised system, with stratifi cation by hospital, disease focality, and presentation stage. The primary endpoint was a histologically confirmed complete response at the post-treatment assessment visit 6 weeks after the end of treatment (a maximum of 30 weeks after treatment started). Analysis of the primary endpoint was by intention to treat. Secondary outcomes were toxic effects (to assess safety) and adherence to treatment (to assess feasibility). We present results after all patients had reached the primary endpoint assessment point at 6 weeks; 2-year follow-up of complete responders continues. This trial is registered with Current Controlled Trials, ISRCTN 34420460.Findings Between Oct 21, 2009, and Jan 11, 2013, 180 participants were enrolled to the study; 89 patients were randomly allocated cidofovir and 91 were assigned imiquimod. At the post-treatment assessment visit, a complete response had been achieved by 41 (46%; 90% CI 37.0-55.3) patients allocated cidofovir and by 42 (46%; 37.2-55.3) patients assigned imiquimod. After 6 weeks of treatment, 156 (87%) patients (78 in each group) had adhered to the treatment regimen. Five patients in the cidofovir group and seven in the imiquimod group either withdrew or were lost to follow-up before the first 6-week safety assessment. Adverse events of grade 3 or higher were reported in 31 (37%) of 84 patients allocated cidofovir and 39 (46%) of 84 patients assigned imiquimod; the most frequent grade 3 and 4 events were pain in the vulva, pruritus, fatigue, and headache.Interpretation Cidofovir and imiquimod were active, safe, and feasible for treatment of vulval intraepithelial neoplasia and warrant further investigation in a phase 3 setting. Both drugs are effective alternatives to surgery for female patients with vulval intraepithelial neoplasia after exclusion of occult invasive disease.