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

Michelle van der Linden, Kim Meeuwis, Colette van Hees, Eleonora van Dorst, Johan Bulten, Tjalling Bosse, Joanna IntHout, Dorry Boll, Brigitte Slangen, Manon van Seters, Marc van Beurden, Mariëtte van Poelgeest, Joanne de Hullu, Michelle van der Linden, Kim Meeuwis, Colette van Hees, Eleonora van Dorst, Johan Bulten, Tjalling Bosse, Joanna IntHout, Dorry Boll, Brigitte Slangen, Manon van Seters, Marc van Beurden, Mariëtte van Poelgeest, Joanne de Hullu

Abstract

Background: Vulvar 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.

Objective: This 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.

Methods: Topical 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.

Results: First results are expected in the summer of 2018.

Trial registration: ClinicalTrials.gov NCT02385188; https://ichgcp.net/clinical-trials-registry/NCT02385188 (Archived by WebCite at http://www.webcitation.org/6sXygHuhP).

Keywords: Paget disease; extramammary Paget disease; imiquimod; vulvar Paget disease.

Conflict of interest statement

Conflicts of Interest: KM provides consulting services for Eucerin Beiersdorf NV, the Netherlands.

©Michelle van der Linden, Kim Meeuwis, Colette van Hees, Eleonora van Dorst, Johan Bulten, Tjalling Bosse, Joanna IntHout, Dorry Boll, Brigitte Slangen, Manon van Seters, Marc van Beurden, Mariëtte van Poelgeest, Joanne de Hullu. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 06.09.2017.

References

    1. Paget J. On disease of the mammary areola preceding cancer of the mammary gland. St Bartholemew Hosp Res Lond. 1874;10:87–89.
    1. Dubreuilh W. Paget's disease of the vulva. Br J Dermatol. 1901;13(11):407–413.
    1. Crocker H. Paget's disease affecting the scrotum and penis. T Pathological Soc. 1889;40:187.
    1. Finan MA, Barre G. Bartholin's gland carcinoma, malignant melanoma and other rare tumours of the vulva. Best Pract Res Clin Obstet Gynaecol. 2003 Aug;17(4):609–633.
    1. Kneale BL, Fortune DW. Pathology of the vulva. Curr Opin Obstet Gynecol. 1991 Aug;3(4):548–552.
    1. Belousova IE, Kazakov DV, Michal M, Suster S. Vulvar toker cells: the long-awaited missing link: a proposal for an origin-based histogenetic classification of extramammary paget disease. Am J Dermatopathol. 2006 Feb;28(1):84–86. doi: 10.1097/01.dad.0000194052.65695.f1.
    1. Willman JH, Golitz LE, Fitzpatrick JE. Vulvar clear cells of Toker: precursors of extramammary Paget's disease. Am J Dermatopathol. 2005 Jun;27(3):185–188.
    1. Kazakov DV, Spagnolo DV, Kacerovska D, Michal M. Lesions of anogenital mammary-like glands: an update. Adv Anat Pathol. 2011 Jan;18(1):1–28. doi: 10.1097/PAP.0b013e318202eba5.
    1. Siesling S, Elferink MA, van Dijck JA, Pierie JP, Blokx WA. Epidemiology and treatment of extramammary Paget disease in the Netherlands. Eur J Surg Oncol. 2007 Oct;33(8):951–955. doi: 10.1016/j.ejso.2006.11.028.
    1. Wilkinson E, Brown H. Vulvar Paget disease of urothelial origin: a report of three cases and a proposed classification of vulvar Paget disease. Hum Pathol. 2002 May;33(5):549–554.
    1. Mendivil AA, Abaid L, Epstein HD, Rettenmaier MA, Brown JV, Micha JP, Wabe MA, Goldstein BH. Paget's disease of the vulva: a clinicopathologic institutional review. Int J Clin Oncol. 2012 Dec;17(6):569–574. doi: 10.1007/s10147-011-0325-0.
    1. Delport ES. Extramammary Paget's disease of the vulva: an annotated review of the current literature. Australas J Dermatol. 2013 Feb;54(1):9–21. doi: 10.1111/j.1440-0960.2012.00898.x.
    1. Baehrendtz H, Einhorn N, Pettersson F, Silfverswärd C. Paget's disease of the vulva: the Radiumhemmet series 1975-1990. Int J Gynecol Cancer. 1994 Jan;4(1):1–6.
    1. Gunn RA, Gallager HS. Vulvar Paget's disease: a topographic study. Cancer. 1980 Aug 01;46(3):590–594.
    1. van der Zwan JM, Siesling S, Blokx WA, Pierie JPE, Capocaccia R. Invasive extramammary Paget's disease and the risk for secondary tumours in Europe. Eur J Surg Oncol. 2012 Mar;38(3):214–221. doi: 10.1016/j.ejso.2011.12.008.
    1. Mohs FE, Blanchard L. Microscopically controlled surgery for extramammary Paget's disease. Arch Dermatol. 1979 Jun;115(6):706–708.
    1. Bae JM, Choi YY, Kim H, Oh BH, Ro MR, Nam K, Chung KY. Mohs micrographic surgery for extramammary Paget disease: a pooled analysis of individual patient data. J Am Acad Dermatol. 2013;68(4):632–637.
    1. Fanning J, Lambert L, Hale TM, Morris PC, Schuerch C. Paget's disease of the vulva: prevalence of associated vulvar adenocarcinoma, invasive Paget?s disease, and recurrence after surgical excision. Am J Obstet Gynecol. 1999;180(1):24–27.
    1. Funaro D, Krasny M, Lam C, Desy D, Sauthier P, Bouffard D. Extramammary Paget disease: epidemiology and association to cancer in a Quebec-based population. J Low Genit Tract Dis. 2013 Apr;17(2):167–174. doi: 10.1097/LGT.0b013e31825f4b4f.
    1. Chan J, Li GK, Chung JH, Chow VL. Extramammary Paget's disease: 20 years of experience in Chinese population. Int J Surg Oncol. 2012:416418. doi: 10.1155/2012/416418.
    1. Black D, Tornos C, Soslow RA, Awtrey CS, Barakat RR, Chi DS. The outcomes of patients with positive margins after excision for intraepithelial Paget's disease of the vulva. Gynecol Oncol. 2007 Mar;104(3):547–550. doi: 10.1016/j.ygyno.2006.09.017.
    1. Shaco-Levy R, Bean SM, Vollmer RT, Papalas JA, Bentley RC, Selim MA, Robboy SJ. Paget disease of the vulva: a histologic study of 56 cases correlating pathologic features and disease course. Int J Gynecol Pathol. 2010 Jan;29(1):69–78. doi: 10.1097/PGP.0b013e3181b1cc5e.
    1. Al Yousef A, Boccara O, Moyal-Barracco M, Zimmermann U, Saiag P. Incomplete efficacy of 5-aminolevulinic acid (5 ALA) photodynamic therapy in the treatment of widespread extramammary Paget's disease. Photodermatol Photoimmunol Photomed. 2012 Feb;28(1):53–55. doi: 10.1111/j.1600-0781.2011.00635.x.
    1. Raspagliesi F, Fontanelli R, Rossi G, Ditto A, Solima E, Hanozet F, Kusamura S. Photodynamic therapy using a methyl ester of 5-aminolevulinic acid in recurrent Paget's disease of the vulva: a pilot study. Gynecol Oncol. 2006 Nov;103(2):581–586. doi: 10.1016/j.ygyno.2006.04.009.
    1. Karam A, Dorigo O. Treatment outcomes in a large cohort of patients with invasive Extramammary Paget's disease. Gynecol Oncol. 2012 May;125(2):346–351. doi: 10.1016/j.ygyno.2012.01.032.
    1. Son SH, Lee JS, Kim YS, Ryu MR, Chung SM, Namkoong SE, Han GT, Lee HJ, Yoon SC. The role of radiation therapy for the extramammary paget's disease of the vulva; experience of 3 cases. Cancer Res Treat. 2005;37(6):365–369.
    1. Hanawa F, Inozume T, Harada K, Kawamura T, Shibagaki N, Shimada S. A case of metastatic extramammary Paget's disease responding to trastuzumab plus paclitaxel combination therapy. Case Rep Dermatol. 2011 Sep;3(3):223–227. doi: 10.1159/000333002.
    1. Tauveron V, Body G, Machet L, Lenain H, Ouldamer L, Lorette G. Prolonged remission of Paget disease of the vulva after chemotherapy for breast carcinoma. Br J Dermatol. 2014 May;170(5):1199–1200. doi: 10.1111/bjd.12825.
    1. Ewing TL. Paget's disease of the vulva treated by combined surgery and laser. Gynecol Oncol. 1991 Nov;43(2):137–140.
    1. Valentine BH, Arena B, Green E. Laser ablation of recurrent Paget's disease of vulva and perineum. J Gynecol Surg. 1992;8(1):21–24. doi: 10.1089/gyn.1992.8.21.
    1. European Medicines Agency European Public Assessment Report (EPAR): Aldara. 2008. [2017-08-13]. .
    1. Terlou A, van Seters M, Kleinjan A, Heijmans-Antonissen C, Santegoets LA, Beckmann I, van Beurden M, Helmerhorst TJ, Blok LJ. Imiquimod-induced clearance of HPV is associated with normalization of immune cell counts in usual type vulvar intraepithelial neoplasia. Int J Cancer. 2010 Dec 15;127(12):2831–2840. doi: 10.1002/ijc.25302. doi: 10.1002/ijc.25302.
    1. van Seters M, van Beurden M, ten Kate FJ, Beckmann I, Ewing PC, Eijkemans MJ, Kagie MJ, Meijer CJ, Aaronson NK, Kleinjan A, Heijmans-Antonissen C, Zijlstra FJ, Burger MP, Helmerhorst TJ. Treatment of vulvar intraepithelial neoplasia with topical imiquimod. N Engl J Med. 2008 Apr 03;358(14):1465–1473. doi: 10.1056/NEJMoa072685.
    1. Cowan RA, Black DR, Hoang LN, Park KJ, Soslow RA, Backes FJ, Gardner GJ, Abu-Rustum NR, Leitao MM, Eisenhauer EL, Chi DS. A pilot study of topical imiquimod therapy for the treatment of recurrent extramammary Paget's disease. Gynecol Oncol. 2016 Jul;142(1):139–143. doi: 10.1016/j.ygyno.2016.04.028.
    1. Marchitelli C, Peremateu MS, Sluga MC, Berasategui MT, Lopez DG, Wernicke A, Velazco A, Gogorza S. Treatment of primary vulvar paget disease with 5% imiquimod cream. J Low Genit Tract Dis. 2014 Oct;18(4):347–350. doi: 10.1097/LGT.0000000000000053.
    1. Machida H, Moeini A, Roman Ld, Matsuo K. Effects of imiquimod on vulvar Paget's disease: a systematic review of literature. Gynecol Oncol. 2015 Oct;139(1):165–171. doi: 10.1016/j.ygyno.2015.07.097.
    1. EQ-5D. [2017-08-13]. Crosswalk index value calculator .
    1. Cardiff University Department of Dermatology. [2017-08-13]. DLQI Manual .

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe