{"paper_id":"84251c9f-70ec-48c4-ae20-dd8b8cd97ef0","body_text":"A Prospective Pilot Study of the Safety and\nEffectiveness of Uterine Artery Embolization for the\nTreatment of Endometriosis: The UAE-E Study\nJim Koukounaras 1,2 Warren Clements 1,2,3 W. Catarina Ang 4,5 Adil Zia 1 Matthew Lukies 1,6\nHeather K. Moriarty 7 Helen Kavnoudias 1,2\n1 Department of Radiology, Alfred Health, Melbourne, Victoria, Australia\n2 Department of Surgery, Monash University, Melbourne, Victoria, Australia\n3 National Trauma Research Institute, Melbourne, Victoria, Australia\n4 Department of Obstetrics and Gynaecology, Royal Women ’s\nHospital, Melbourne, Victoria, Australia\n5 Faculty of Medicine, Dentistry, and Health Sciences, University of\nMelbourne, Melbourne, Victoria, Australia\n6 Department of Diagnostic and Interventional Imaging, KK Women ’s\nand Children ’s Hospital, Singapore, Singapore\n7 Department of Radiology, Cork University Hospital, Cork, Ireland\nJ Clin Interv Radiol ISVIR 2023;7:179 –182.\nAddress for correspondence Warren Clements, MBBS, MHA,\nBBiomedScHons, FRANZCR, EBIR-ES, FCIRSE, Department of\nRadiology, Alfred Health, 55 Commercial Road, Melbourne, VIC 3004,\nAustralia (e-mail: w.clements@alfred.org.au).\nKeywords\n► adenomyosis\n► endometriosis\n► pain\n► chronic\n► embolization\nAbstract Purpose Uterine artery embolization (UAE) evidence is increasing in the setting of\nadenomyosis, which shares pathological simila rities to endometriosis. Endometriosis is\ncharacterized by the presence of endometrium-like tissue outside of the uterus, and the\nretrograde menstruation hypothesis may account for disease development. In women\nwhere fertility is no longer desired, hysterectomy can be offered to improve pain-\nrelated symptoms. The authors hypothesize that this cohort of patients may similarly\nrespond to UAE. The aim of this pilot study is to assess the safety and effectiveness of\nUAE in the management of endometriosis-related symptoms.\nMethods Six-patient prospective single-arm pilot study in female, premenopausal\npatients over 40 years with symptoms of endometriosis. Institutional review board\napproval was obtained.\nInclusion criteria include completed family, premenopausal, pelvic endometriosis as\nconfirmed by laparoscopy within the last 5 years, and symptoms of endometriosis\nimpacting quality of life as evidenced by the British Society of Gynaecological\nEndoscopy pelvic pain and Short Form-36 questionnaires.\nResults The primary endpoint will be safety, as assessed by the composite number of\nprocedural and postprocedural complicati ons during procedure, predischarge, and at\n6 weeks, 3 months, 6 months, and 12 months. Secondary endpoints will include\ntechnical success, clinical success, and durability.\nDiscussion This study will be a novel application of UAE in the setting of endometriosis\nand has the potential to improve patient quality of life. This pilot study will assess safety\nand allow the investigators to design a prospective randomized controlled study.\narticle published online\nMay 10, 2023\nDOI https://doi.org/\n10.1055/s-0043-1768942.\nISSN 2457-0214.\n© 2023. Indian Society of Vascular and Interventional Radiology. All\nrights reserved.\nThis is an open access article published by Thieme under the terms of the\nCreative Commons Attribution-NonDeri vative-NonCommercial-License,\npermitting copying and reproduction so long as the original work is given\nappropriate credit. Contents may not be used for commercial purposes, or\nadapted, remixed, transformed or built upon. (https://creativecommons.org/\nlicenses/by-nc-nd/4.0/)\nThieme Medical and Scienti fic Publishers Pvt. Ltd., A-12, 2nd Floor,\nSector 2, Noida-201301 UP , India\nTHIEME\nOriginal Article 179\nArticle published online: 2023-05-10\n\nIntroduction\nUterine artery embolization (UAE) is a cost-effective treatment\nfor symptomatic uterine leiomyomata,1,2 and there is increas-\ning evidence of its ef ficacy in the setting of adenomyosis. 3\nAdenomyosis and endometriosis share many pathological\nsimilarities. Endometriosis is an estrogen-driven disease char-\nacterized by the presence of endometrium-like tissue outside\nof the uterus.\n4 It affects between 6 and 10% of premenopausal\nwomen and accounts for an estimated 34,200 hospital admis-\nsions annually in Australia.5 It may cause a range of potential\nsymptoms including chronic pelvic pain, reduced fertility,\ndysmenorrhea, dyspareunia, and dyschezia, among many\nothers. These symptoms cause significant impact on a patient's\nquality of life.6\nWhile the exact mechanism of disease development is\nunknown, a postulated theory for the pathogenesis of endo-\nmetriosis is the retrograde menstruation hypothesis. This\nproposes retrograde expulsion of endometrial cells from the\nuterine cavity into the pelvis via the fallopian tubes.\n6 Existing\ntreatments for endometriosis depend on the severity of\ndisease but are centered predominantly on medical manage-\nment strategies. 6 Surgery to ablate or excise ectopic endo-\nmetrial tissue is effective, but disease and symptoms can\nrecur.4,6\nIn women where fertility is no longer desired, hyster-\nectomy either with or without oophorectomy may be\noffered, theorized to reduce the supply of retrograde\nmenstruation. 4,7,8 In their recently published study, Sand-\nström et al assessed the use of hysterectomy to treat pain\nsymptoms in females with endometriosis in Sweden using\na population-based registry. Over 5 years, 137 women\nwere treated. The authors showed a signi ficant reduction\nin pain particularly those with severe symptoms, including\nfor those without concomitant oophorectomy, and they\nconcluded that hysterectomy is valuable in women with\nendometriosis and severe pain.\n4 However, a review of\ncomplications after hysterectomy for benign disease by\nVarol et al showed an overall mortality rate of 1.5% in their\ncohort. 9 Hysterectomy when combined with oophorecto-\nmy has also recently been shown to be associated with\nincreased risk of stroke and cardiovascular disease. 10 In\naddition, studies have also shown that hysterectomy in the\nsetting of endometriosis is higher risk than in a non-\nendometriosis cohort.\n11\nGiven the bene fits associated with hysterectomy in\npatients with endometriosis, but the complications associ-\nated with hysterectomy in this cohort, an alternative treat-\nment such as embolization may be desirable. The authors\ntheorize that women with endometriosis may similarly\nrespond to UAE by reducing the supply of retrograde men-\nstruation after embolization.\nThe aim of this pilot study is to assess the safety and\neffectiveness of UAE in the management of endometriosis-\nrelated symptoms, and the hypothesis is that UAE will be safe\nand effective. This study will provide preliminary data and\nwill be used to determine if a larger feasibility and random-\nized controlled study will be undertaken.\nStudy Design\nReporting Standard\nThe reporting of this study protocol is according to the 2013\nStandard Protocol Items: Recommendations for Interven-\ntional Trials (SPIRIT) guidelines.\n12\nResearch Design\nThis is a prospective single-arm pilot study in female, pre-\nmenopausal patients over 40 years with symptoms of\nendometriosis.\nEthics Committee Approval\nThe study has been approved by the Alfred Hospital Human\nResearch and Ethics Committee, number 226/22 and was\nprospectively registered on the World Health Organization-\napproved clinical trials registry (Australian New Zealand\nClinical Trials Registry, number ACTRN12622001301752),\napproval date 07/10/2022.\nParticipant Recruitment and Consent\nPotential patients will be recruited in a community outpa-\ntient setting, by a consultant gynecologist with specialist\ninterest in management of endometriosis-related chronic\npelvic symptoms. Patients will consult with the study inter-\nventional radiologists in a tertiary academic hospital, will be\nprovided with patient information and consent form, and\ninformed consent obtained before the procedure.\nBaseline Assessment\nAfter consultation with both gynecologist and interventional\nradiologist and providing consent, patients will receive base-\nline blood testing (full blood examination, creatinine, and\ncoagulation profile), and will complete the British Society of\nGynaecological Endoscopy (BSGE) pelvic pain questionnaire\nand 36-Item Short Form Health Survey (SF-36) Quality of Life\nquestionnaire. The timeline of events is shown in\n►Table 1 .\nInclusion Criteria\n Completed family —no desire for future pregnancy.\n Premenopausal, de fined as the presence of menstrual\nbleeding in the previous 3 months and no change in\ntypical menstrual regularity in the past year.\n Pelvic endometriosis as con firmed by laparoscopy within\nthe last 5 years.\n Symptoms of endometriosis impacting quality of life as\nevidenced by the BSGE pelvic pain questionnaire and\nincluding at least one of the following:\n/C14Period-related pain (dysmenorrhea) affecting daily ac -\ntivities and quality of life.\n/C14Deep pain during or after sexual intercourse\n(dyspareunia).\n/C14Period-related or cyclical gastrointestinal symptoms, in\nparticular, painful bowel movements (dyschezia).\n/C14Period-related or cyclical urinary symptoms, in partic -\nular, blood in the urine or pain passing urine.\nJournal of Clinical Interventional R adiology ISVIR Vol. 7 No. 3/2023 © 2023. Indian Society of Vascular and Interventional Radiology. All rights res erved.\nUAE for Endometriosis Koukounaras et al.180\n\n\n Signed study participant information and consent form.\n Eastern Cooperative Oncology Group 0 to 1.\nExclusion Criteria\n Desire for future pregnancies or fertility treatment.\n Perimenopausal, de fined as changes in typical menstrual\nregularity in the past year or amenorrhea for the previous\n3m o n t h s .\n Postmenopausal, de fined as > 12 months of amenorrhea.\n Previous hysterectomy, bilateral oophorectomy, or UAE.\n Other comorbidities that are likely to be causing chronic\nabdominal or pelvic pain.\n Iodine contrast allergy.\n Active pelvic infection or in flammatory disease.\n Severe renal insuf ficiency.\n Gynecological malignancy.\nProcedure\nProcedures will be performed by study investigators who are\nsubspecialty trained interventional radiologists and holders\nof the European Board of Interventional Radiology with a\ncombined 24 years ’ experience.\nProcedures will be performed under intravenous con-\nscious sedation using titrated boluses of midazolam and\nfentanyl. Patients will receive premedication according to\nan existing internal treatment protocol including adminis-\ntration of the following preprocedure medications:\nondansetron 8 mg intravenously, droperidol 0.625 mg intra-\nvenously, metronidazole 500 mg intravenously, cephazolin\n1 g intravenously, paracetamol 1 g intravenously, parecoxib\n40 mg intravenously, and morphine 5 mg intravenously. All\nprocedures will be performed via transfemoral route using\n5-French sheath access. Diagnostic angiography will be\nperformed from the iliac artery on each side to assess\npreintervention uterine vascularity, and uterine arteries\nwill be selected with a microcatheter in all patients to reduce\nnontarget embolization and vasospasm (2.7 Fr 135 cm Pro-\ngreat, Terumo, Japan). Embolization will be performed using\naspherical polyvinyl alcohol (PVA) particles of size 355 to 500\nμm (Contour PVA, Boston Scienti fic, United States).\n13 The\nembolization endpoint will be reduced forward flow. An\narterial closure device will be used on all patients. Patients\nwill be admitted to the hospital for overnight monitoring and\nmanagement of any potential post-embolization syndrome.\nStatistics\nSix patients will be recruited for this pilot study. Data will be\ncollected including demographics, procedure-related data,\nadverse events, and BSGE/SF-36 questionnaire data (base-\nline, 6 weeks, 6 months, 12 months). More details are\navailable in\n►Table 1 .\nOutcome Measures\nPrimary Endpoint\n Safety, as assessed by the composite number of procedural\nand postprocedural complications during procedure, pre-\ndischarge, and at 6 weeks, 3 months, 6 months, and\n12 months.\nSecondary Endpoints\n Technical success of UAE as de fined by a signi ficant\nreduction in forward flow of both uterine arteries on\nangiography at the discretion of the proceduralist.\n Clinical success at 6 and 12 months as de fined by an\nimprovement in the BSGE pelvic pain questionnaire and\nSF-36 Quality of Life questionnaire.\n Durability of symptom relief at 12 months.\nAdverse Events\nThese will be collected according to the 2017 Cardiovascular\nand Interventional Radiological Society of Europe classi fica-\ntion system. 14 Potential complications from this procedure\nmay include:\n Access site complications including bleeding, hematoma,\npseudoaneurysm, occlusion, embolus, or super ficial skin\ninfection.\n Severe post-embolization syndrome.\n Uterine necrosis.\nTable 1 Timeline of patient assessment, procedure, and follow-up\nPreprocedure\n–30 to 7 d\nProcedure Discharge Postprocedure\n6w k 3m o 6m o 1 2m o\nInterventional radiologist consultation XX X X\nGynecologist consultation XX X\nLaparoscopic con firmation of endometriosis a X\nPelvic pain questionnaires b XX X X\nPreprocedure blood testing X\nProcedure X\nAssessment for adverse events XX X X X X\naLaparoscopy within 5 years con firming endometriosis.\nbBritish Society of Gynaecological Endoscopy pelvic pain questionnaire and SF-36 Quality of Life questionnaire.\nJournal of Clinical Interventional R adiology ISVIR Vol. 7 No. 3/2023 © 2023. Indian Society of Vascular and Interventional Radiology. All rights res erved.\nUAE for Endometriosis Koukounaras et al. 181\n\n\n Uterine or pelvic infection.\n Nontarget embolization.\n Procedure-related hysterectomy.\n Allergy to contrast agent.\nDiscussion\nAlthough UAE is an established procedure in the setting of\nleiomyomata and gaining further interest in the setting of\nadenomyosis,\n1,2 this study will be a novel application of this\nprocedure. The basis of the causative effect with UAE builds\nupon existing evidence for pain improvement in women\ntreated with hysterectomy,\n4,7,8 and the retrograde menstru-\nation hypothesis. 6\nAs such, the authors hypothesize that UAE will reduce\nretrograde menstruation by reduction of menstruation sup-\nply and thus has the potential to improve symptoms of\nendometriosis. There is a risk of confounding from any\nconcomitant adenomyosis in this cohort given the available\nevidence to support symptom improvement for emboliza-\ntion in patients with adenomyosis alone, and the overlap of\ndisease in this group.\n3 While patients with adenomyosis\nwould not be excluded, the presence will be recorded to\nallow for appropriate post hoc assessment.\nHowever, despite the hypothesized mechanism presented,\nthere may also be no benefit to this patient group. As such, the\nprimary endpoint in this pilot study is safety. Given the\nchallenges associated with providing appropriate statistical\nmeasurement of pain-related symptom improvement, a large\nand direct comparative study with a control group is needed to\nassess short- and long-term efficacy and will form the basis of a\nfuture direction after this pilot study is performed.\nEthical Approval\nEthical approval is not required for publication of this study\nprotocol, however, approval was obtained for the described\nstudy by The Alfred Human Research and Ethics Committee.\nInformed Consent\nInformed consent is not required for publication of this\nstudy protocol, however, informed written consent will\nbe obtained for individual participants in the study.\nConsent for Publication\nConsent is not required for publication of this study\nprotocol, however, written consent will be obtained for\nindividual participants in the study including consent for\npublication.\nClinical Registration\nWHO approved clinical trials registry: Australian New\nZealand Clinical Trials Register, approval number\nACTRN12622001301752, approval date 07/10/2022.\nFunding\nNone.\nConflict of Interest\nNone declared.\nReferences\n1 de Bruijn AM, Ankum WM, Reekers JA, et al. Uterine artery\nembolization vs hysterectomy in the treatment of symptomatic\nuterine fibroids: 10-year outcomes from the randomized EMMY\ntrial. Am J Obstet Gynecol 2016;215(06):745.e1 –745.e12\n2 Clements W, Moriarty HK, Koukounaras J, Joseph T, Phan T, Goh\nGS. The cost to perform uterine fibroid embolisation in the\nAustralian public hospital system. J Med Imaging Radiat Oncol\n2020;64(01):18–22\n3 Ma J, Brown B, Liang E. Long-term durability of uterine artery\nembolisation for treatment of symptomatic adenomyosis. Aust N\nZ J Obstet Gynaecol 2021;61(02):290 –296\n4 Sandström A, Bixo M, Johansson M, Bäckström T, Turkmen S.\nEffect of hysterectomy on pain in women with endometriosis:\na population-based registry study. BJOG 2020;127(13):\n1628–1635\n5 Ruff M, Abbott J. Royal Australian and New Zealand College of\nObstetricians and Gynaecologists. Endometriosis clinical practice\nguideline [internet]. Accessed December 29, 2022 at: https://ranz-\ncog.edu.au/resources/endometriosis-clinical-practice-guideline/\n6 Vercellini P, Viganò P, Somigliana E, Fedele L. Endometriosis:\npathogenesis and treatment. Nat Rev Endocrinol 2014;10(05):\n261–275\n7 Chalermchockchareonkit A, Tekasakul P, Chaisilwattana P, Sirimai\nK, Wahab N. Laparoscopic hysterectomy versus abdominal hys-\nterectomy for severe pelvic endometriosis. Int J Gynaecol Obstet\n2012;116(02):109–111\n8 MacDonald SR, Klock SC, Milad MP. Long-term outcome of non-\nconservative surgery (hysterectomy) for endometriosis-associat-\ned pain in women <30 years old. Am J Obstet Gynecol 1999;180(6\nPt 1):1360 –1363\n9 Varol N, Healey M, Tang P, Sheehan P, Maher P, Hill D. Ten-year\nreview of hysterectomy morbidity and mortality: can we\nchange direction? Aust N Z J Obstet Gynaecol 2001;41(03):\n295–302\n10 Poorthuis MHF, Yao P, Chen Y, et al; China Kadoorie Biobank\nCollaborative Group. Risks of stroke and heart disease following\nhysterectomy and oophorectomy in Chinese premenopausal\nwomen. Stroke 2022;53(10):3064 –3071\n11 Kiran A, Hilton P, Cromwell DA. The risk of ureteric injury\nassociated with hysterectomy: a 10-year retrospective cohort\nstudy. BJOG 2016;123(07):1184 –1191\n12 Chan AW, Tetzlaff JM, Altman DG, et al. SPIRIT 2013 statement:\ndefining standard protocol items for clinical trials. Ann Intern\nMed 2013;158(03):200 –207\n13 Liang E, Brown B, Rachinsky M. Clinical ef ficacy of uterine\nartery embolization using PVA form particles to treat\nsymptomatic adenomyosis. J Vasc Interv Radiol 2016;27(03):\nS202\n14 Filippiadis DK, Binkert C, Pellerin O, Hoffmann RT, Krajina A,\nPereira PL. CIRSE quality assurance document and standards for\nclassification of complications: the CIRSE classi fication system.\nCardiovasc Intervent Radiol 2017;40(08):1141 –1146\nJournal of Clinical Interventional R adiology ISVIR Vol. 7 No. 3/2023 © 2023. Indian Society of Vascular and Interventional Radiology. All rights res erved.\nUAE for Endometriosis Koukounaras et al.182","source_license":"CC0","license_restricted":false}