The Paget Trial: A Multicenter, Observational Cohort Intervention Study for the Clinical Efficacy, Safety, and Immunological Response of Topical 5% Imiquimod Cream for Vulvar Paget Disease

Abstract

BackgroundVulvar Paget disease is a rare skin disorder, which is most common in postmenopausal Caucasian women. They usually present with an erythematous plaque that may show fine or typical “cake icing” scaling or ulceration that may cause itching, pain, irritation, or a burning sensation. Although most cases are noninvasive, vulvar Paget disease may be invasive or associated with an underlying vulvar or distant adenocarcinoma. The histological evidence of so-called “Paget cells” with abundant pale cytoplasm in the epithelium confirms the diagnosis. The origin of these Paget cells is still unclear. Treatment of choice is wide local excision with negative margins. Obtaining clear surgical margins is challenging and may lead to extensive and mutilating surgery. Even then, recurrence rates are high, ranging from 15% to 70%, which emphasizes the need for new treatment options. A number of case reports, retrospective case series, and one observational study have shown promising results using the topical immune response modifier imiquimod.ObjectiveThis study aims to investigate the efficacy, safety, and immunological response in patients with noninvasive vulvar Paget disease using a standardized treatment schedule with 5% imiquimod cream.MethodsTopical 5% imiquimod cream might be an effective and safe treatment alternative for vulvar Paget disease. The Paget Trial is a multicenter observational cohort study including eight tertiary referral hospitals in the Netherlands. It is ethically approved by the Medical-Ethical Committee of Arnhem-Nijmegen and registered in the Central Committee on Research Involving Human Subjects (CCMO) Register by as NL51648.091.14. Twenty patients with (recurrent) noninvasive vulvar Paget disease will be treated with topical 5% imiquimod cream three times a week for 16 weeks. The primary efficacy outcome is the reduction in lesion size at 12 weeks after end of treatment. Secondary outcomes are safety, immunological response, and quality of life. Safety will be assessed by evaluation of adverse events and tolerability of treatment. To evaluate the immunological response, various immunological markers will be tested on biopsy specimens taken before, during, and after treatment. Quality of life will be assessed with three questionnaires taken before, during, and after treatment.ResultsFirst results are expected in the summer of 2018.Trial RegistrationClinicalTrials.gov NCT02385188; https://clinicaltrials.gov/ct2/show/NCT02385188 (Archived by WebCite at http://www.webcitation.org/6sXygHuhP).

The European Society of Gynaecological Oncology (ESGO), the International Society for the Study of Vulvovaginal Disease (ISSVD), the European College for the Study of Vulval Disease (ECSVD) and the European Federation for Colposcopy (EFC) Consensus Statements on Pre-invasive Vulvar Lesions

“…Complete response rates have been reported with a range from 22% to 90% of cases. 22,143,144 This allows a chance for the anatomical and functional conservation of vulvar structures. Treatment schedule varies among different studies (1-5 times a week, from a minimum of 3 weeks to an entire year).…”

“…A total treatment duration of 16 weeks seems to be commonly used. 22,143 Photodynamic therapy is not curative at all but can be used for symptom control. 145 Radiotherapy can be considered when there is lymph node positivity or positive surgical margin in situations with associated invasive disease where there are contraindications for surgery or inoperable situations.…”

The European Society of Gynaecological Oncology (ESGO), the International Society for the Study of Vulvovaginal Disease (ISSVD), the European College for the Study of Vulval Disease (ECSVD) and the European Federation for Colposcopy (EFC) consensus statements on pre-invasive vulvar lesions

“…Topical 5% imiquimod cream has also been shown to be a safe conservative treatment option for in situ vulvar Paget’s disease with minimal adverse effects. Complete response rates have been reported with a range from 22% to 90% of cases 22 140 141. This allows a chance for the anatomical and functional conservation of vulvar structures.…”

“…Treatment schedule varies among different studies (1–5 times a week, from a minimum of 3 weeks to an entire year). A total treatment duration of 16 weeks seems to be commonly used 22 140…”

Consensus Statements on Preinvasive Vulvar Lesions of the European Society of Gynecological Oncology, the International Society for the Study of Vulvovaginal Diseases, the European College for the Study of Vulvar Diseases, and the European Colposcopy Federation (Review)

“…Было доказано, что 5% крем имиквимод для локального применения является безопасным вариантом консервативного лечения болезни Педжета вульвы in situ с минимальными побочными эффектами. Сообщается о полном ответе в диапазоне от 22% до 90% случаев [9,46].…”