Comparing Efficacy of Microwave vs Embolization Treatment for Adenomyosis

Study Overview
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Brief Summary
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Single blinded randomized controlled study of symptom improvement after uterine artery embolization (UAE) versus ultrasound guided percutaneous/transvaginal microwave ablation, evaluated by validated questionnaires. Adenomyosis is a benign condition causing pain and bleeding disorders in many women. Hysterectomy has historically been the golden standard for treatment as well as (postoperatively) diagnosis of the disease. In accordance with refined diagnostic tools such as ultrasound and/or MRI, minimally invasive treatments for adenomyosis are being explored. We plan to compare two minimally invasive techniques: embolization of the uterine artery (a commonly used procedure) and microwave ablation of adenomyotic tissue (previously only in clinical use in China).

Detailed Description
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Single blinded randomized controlled study of symptom improvement after uterine artery embolization (UAE) versus ultrasound guided percutaneous/transvaginal microwave ablation, evaluated by validated questionnaires. Background Adenomyosis is a benign gynecological condition, where endometrial glands and stroma invades the myometrial walls of the uterus. The disease is thought to be estrogen-dependent, but the etiology, as well as the prevalence, is currently unknown. Known risk-factors are previous uterine surgery and parity, although the disease has been found also in nulligravida with no previous uterine trauma. Adenomyosis can cause severe dysmenorrhea, menorrhagia, chronic pelvic pain and infertility. Historically diagnosis has been made post hysterectomy by pathologists, however with transvaginal ultrasound (TVUS) as well as MRI the condition is now possible to identify with non-invasive methods. Hysterectomy has previously been seen as the golden standard treatment for adenomyosis, but may cause long-term side effects such as genitovaginal prolapse. It also carries a substantial risk of short term complications such as infections and organ damage. Symptomatic treatment such as the levonogestrel intrauterine system (LNG-IUS) can be effective, however there is a risk of expulsion and irregular bleedings. In recent years, increasing attention has been paid to the study of minimally invasive or non-invasive therapies with uterine preservation such as uterine arterial embolization (UAE), radiofrequency (RF), microwave treatment and high intensity focused ultrasound (HIFU). A randomized controlled study is ongoing, comparing UAE and hysterectomy. RF ablation often requires the aid of a laparoscopic procedure, which is invasive. HIFU is currently only described in small cohorts and case-reports. Ultrasound or computer tomography guided percutaneous microwave thermal ablation is minimally invasive, has low time requirements, is easy to perform, and has been broadly used for the treatment of solid tumours in organs other than the uterus with favourable effects. Microwave ablation of adenomyosis has been performed in China. The effect and acceptability has been high. The research team in this study has been to China to study the treatment. We have visited the clinic and studied the procedure as well as talked to patients pre- and post operatively . The equipment at Danderyd Hospital has the same output effects as the equipment in China. Danderyd Hospital has approved the method for use in uterine myomas. However, no randomized comparative study of other minimally invasive methods has been performed. This study aims to compare the effectiveness, feasibility and acceptability of percutaneous CT- or ultrasound guided microwave ablation and uterine artery embolization for the treatment of adenomyosis in a randomized single blind study. Recruitment and Randomization Women fulfilling inclusion criteria and without exclusion criteria will be identified at the outpatient clinic of Danderyd Hospital. Advertisement may be placed in local newspapers or on social media (Facebook and Instagram) and relevant webpages or in gynecological clinics. Women will be randomized after having been informed orally and in written and after having signed informed consent and after fulfilling inclusion and exclusion criteria after MRI-examination. Randomization will be in random permuted blocks of 6 at a ratio of 1:1. The randomization will be according to a computer generated randomization sequence. After patients have signed informed consent and fulfill inclusion without exclusion criteria after the initial magnetic resonance imaging they will be allocated to an intervention by consecutive opening of sealed opaque envelopes containing the randomization code. Blinding Patients and investigators will not be blinded. The MRI will be performed and evaluated by a blinded radiologist. Method Pre randomization evaluation After having signed informed consent but before randomization patients will undergo MRI of the uterus. Patients with endometriosis or a clinically significant presence of uterine fibroids (myomas>3cm) will be excluded. All women included in the study after MRI examination will fill in a PBAC evaluation during the menses preceding treatment. Women will fill a VNRS for maximal pain during 1 month prior to treatment. In addition a full blood panel will be evaluated. As for uterine artery embolization no pathologist report will be performed before any treatment. Microwave ablation Microwave ablation will be performed percutaneously or vaginally using a Covidien Emprint microwave ablation system with a 30-80 Watts effect in 14-16 gauge needle with a ceramic tip using computer tomography with fusion technique or ultrasound for adenomyosis imaging and needle guidance. After identification of the needle path with CT or peroperative ultrasound a small skin incision using a scalpel will made for the needle entry in the case of percutaneous treatment. No incision will be made if treatment is given vaginally. When needed to optimize the needle path in order not to damage adjacent organs, artificial ascites (approx 500mL Ringer-acetate) will be created using a thin syringe through the abdominal wall. The ablation zone of a 70W needle is estimated to be 4x3x3 cm after 300s or 5x4x4 cm after 600s. Patients will be given intravenous anesthesia with spontaneous breathing or general anesthesia during treatment to minimize movement during ablation. Uterine artery embolization Embolization will be performed in conscious women with an epidural catheter or patient controlled analgesia for pain relief. A catheter will be inserted in the femoral artery to access the uterine artery during x-ray monitoring and during administration of contrast to visualize the adenomyotic tissue and its supporting arterial supply. When the supporting arterial branch has been identified polyvinyl alcohol particles are released into the bloodstream. These particles cause a thrombosis in the vessel. Evaluation post treatment Women will estimate VNRS maximum postoperative pain day of surgery and the following 7 days. In addition, they will note how many days passed before all pain subsided, use of pain medication will be noted and period until resuming normal daily activities. The period of hospitalization will be noted. Menstrual blood loss (PBAC) will be noted the first menstruation, menstruation number 3 and 5 post treatment. PBAC is a validated instrument for menstrual blood loss quantification. UFS-QOL is a validated instrument for women with uterine fibroids, but is commonly used also in trials regarding adenomyosis, and will be evaluated 6 months post treatment. Follow-up visits will be after 1-2 menstruation at approximately 2 months and at 6 months post-treatment. At follow up visit 2 months (+/-2 weeks) and 6 months (+/-2 weeks) post treatment acceptability will be assessed as overall satisfaction of treatment on a scale from 1-7 and if the woman would recommend the treatment to a friend. At the follow up visit at 6 months hemoglobin, cancer antigen 125 (CA-125), Anti-Müllerian Hormone (AMH), and prolactine (PRL) will be measured. AMH estimates the effect of the treatment on the ovarian reserve. CA-125 and PRL have been used to evaluate pathophysiological changes in adenomyosis. These will be compared to levels taken on the day of the operative procedure. A uterine biopsy will also be performed. A new MRI scan will be performed 6 months post treatment (+/-21 days). Women will then be asked to participate in a long-term follow up (>12 months) with evaluation of recurrence of symptoms, with clinical controls (gynecological exams and TVUS) and using PBAC and UFS-QOL yearly until retraction of consent. Clinical significance Adenomyosis is a benign condition but have a significant impact on the lives of women, and the condition is not well studied. Reports have suggested adenomyosis in approximately 40% of patients undergoing hysterectomy. Women with adenomyosis are much more likely to report on symptoms as dysmenhorrea, heavy menstrual bleeding, infertility and chronic pelvic pain. As hysterectomy is a highly invasive procedure with costs for women in terms of absence from work and short and long term complications, finding new minimally invasive and uterine-sparing treatments would be beneficial for affected women.

Official Title
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Single Blinded Randomized Controlled Study of Symptom Improvement After Uterine Artery Embolization (UAE) Versus Ultrasound Guided Percutaneous/Transvaginal Microwave Ablation, Evaluated by Validated Questionnaires

Conditions
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Adenomyosis

Intervention / Treatment
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* Procedure: Microwave treatment via needle antenna
* Procedure: Embolization of uterine artery or branches thereof (routine treatment where polyvinyl alcohol particles are released into the predefined bloodstream)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy women aged 30-55 with symptomatic adenomyosis Premenopausal Adenomyosis diagnosted by TVUS and MRI Willing to comply with protocol Exclusion Criteria: Current or future childwish Body Mass Index >35 Treatment with anticoagulant/bleeding disorder Visible myomas >3cm or visible endometriosis on UL/MRI Contraindication for UAE or general anesthesia

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Microwave treatment<br>Percutaneous or vaginal application of microwave antenna with microwave treatment for adenomyosis | Procedure: Microwave treatment via needle antenna<br>* Microwave treatment via needle antenna, (Emprint Covidien microwave ablation system) either percutaneous or vaginally administrated<br>|
| Active Comparator: Control<br>Uterine artery embolization; percutaneous application of a catheter into the femoral artery or branches thereof | Procedure: Embolization of uterine artery or branches thereof (routine treatment where polyvinyl alcohol particles are released into the predefined bloodstream)<br>* Embolization via percutaneous catheter<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1. Symptom improvement 6 months post treatment (+/-21 days) compared to pre treatment, evaluated by UFS-QOL - The score on Symptom Severity Scale | Symptom improvement evaluated by the validated questionnaire UFS-QOL, which is subdivided into Symptom Severity Scale (0-100, where higher number represent worsened symptoms) and HRQL items (concern, activities, energy/mood, control, self-consciousness and sexual function, range 0-100 where higher numbers represent better Quality of Life) | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction of adenomyosis by imaging | Reduction of uterus volume/adenomyosis affected areas, measured as lesional size (in mm or cm) measured by Transvaginal ultrasound and/or MRI | 6 months | 
| Hospitalization | How long time (in days) the patient needed postoperative care in the ward, identified by the patients Medical chart | Up to 8 weeks post treatment | 
| Sick leave | How many Days until the patient resumed normal working hours | Up to 8 weeks post treatment | 
| Pain medication | How much and what type of pain medication the patient needed post operatively | Up to 8 weeks post treatment | 
| Acceptability | Patients description wether they would recommend the treatment to a friend, measured by a 7-point Likert scale (1-7, where higher number represents a greater acceptability) | 2 months and 6 months post treatment | 
| Symptom improvement 6 months post treatment (+/-21 days) compared to pre treatment, evaluated by PBAC (pictorial blood loss assessment chart) | Symptom improvement in regard to menstrual blood loss, PBAC ranges from 0->4000 and cut-off for the diagnose of Heavy Menstrual Bleeding is normally PBAC>100 | 6 months | 
| Symptom improvement 6 months post treatment (+/-21 days) compared to pre treatment, evaluated by | Symptom improvement in regard to menstrual pain, evaluated by VNRS (0-10, recorded each day of the menstrual period, where 0 is no pain and 10 worst possible pain) | 6 months | 
| 1. Symptom improvement 6 months post treatment (+/-21 days) compared to pre treatment, evaluated by UFS-QOL - The Health related quality of life score | Symptom improvement evaluated by the validated questionnaire UFS-QOL, which is subdivided into Symptom Severity Scale (0-100, where higher number represent worsened symptoms) and HRQL items (concern, activities, energy/mood, control, self-consciousness and sexual function, range 0-100 where higher numbers represent better Quality of Life) | 6 months |