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Treatment group Magentic Resonance guided High Intensity Focused Ultrasound will be employed on uterine fibroids

Targeted vessel ablation of type 3 uterine fibroids with magnetic resonance guided high intensity focused ultrasound

Magnetic Resonance guided High Intensity Focused Ultrasound

Maurice van den Bosch, Prof Dr

So-called type 1 and 2 uterine fibroids are well treatable with Magnetic Resonance guided High Intensity Focused Ultrasound (MR-HIFU). The other type, type 3 fibroids, however, are known for their high perfusion and poor treatment outcome after MR-HIFU. This study proposes a new strategy to treat type 3 fibroids with MR-HIFU. Very precise, small, high-power sonications (heating points) will be used to occlude (part of) the feeding vessels of the fibroid. This deminishes the negative effect of the high perfusion and is hypothesized to transform a type 3 fibroid into a type 2 or possibly even a type 1 fibroid. Consequently, the bulk volume of the fibroid can be treated using the standard approach.

Rationale: Uterine fibroids or leiomyomas are common benign tumors that arise from smooth muscle cells of the uterus with a prevalence ranging from 20% to 40% in reproductive aged women. Invasive treatments, such as hysterectomy and myomectomy, represent the golden standard with respect to therapy. Alternatively, uterine artery embolization is offered as a less invasive option. However, to date the only non-invasive technique is high intensity focused ultrasound (HIFU) ablation. HIFU ablation uses focused ultrasound waves to non-invasively heat and thermally ablate tissue. Combined with magnetic resonance guidance (MR-HIFU) this allows an entirely non-invasive intervention with anatomical 3D images for the planning of the treatment volume, and real-time temperature monitoring for therapeutic guidance.

A limitation of MR-HIFU is that currently not all types of uterine fibroids are treatable. With respect to MR-HIFU treatment, uterine fibroids are classified in three classes based on the signal intensity of T2-weighted MR images. While MR-HIFU has been shown to result in a reliable positive therapeutic outcome in type 1 and type 2 fibroids, the therapeutic success in type 3 fibroids has so far been limited. The current clinical consensus is that the high perfusion in type 3 fibroids, which causes the heat deposited by the HIFU to be rapidly evacuated from the treatment site, results in insufficient temperatures to induce necrosis in the fibroids. Therefore, a new treatment strategy is proposed to effectively treat type 3 fibroids with MR-HIFU.

Objective: To investigate whether it is possible to manipulate perfusion in type 3 fibroids with MR-HIFU.

Study design: Single-center, single arm, non-randomized trial. Ten patients will be treated.

Study population: Adult women with a type 3 uterine fibroid who fulfill the in- and exclusion criteria.

Intervention: During the MR-HIFU treatment, the local vascular feeding network will be selectively targeted first with high power sonications with the intention to reduce or interrupt the perfusion of the entire fibroid volume. Subsequently, the remaining fibroid volume will be ablated, similar to the treatment approach of type 1/2 fibroids.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The fibroid type and the eligibility for MR-HIFU treatment will be determined on a clinically obtained MRI scan. The results of the scan and information about this study are provided to the patient during a phone call. If the patient is interested, the study information is sent by mail. The patient receives a second phone call to ask if she wishes to participate. If so, an appointment at the hospital is arranged to give details on the study, answer questions, and show the clinical MR scan. If the patient still wants to participate, informed consent (IC) is signed. The HIFU treatment will be scheduled in consultation with the patient.

Patients will be sedated during the HIFU intervention, as it is also the case during the standard HIFU treatment of type 1/2 fibroids. Compared to the standard HIFU treatment, the initial selective ablation of the vascular feeding network with high power sonications will be added. The subsequent therapy for the remainder of the fibroid will follow the standard therapeutic HIFU treatment of type 1/2 fibroids.

One week after the treatment the patient will receive a phone call to ask about adverse events. Three months after the treatment a follow-up MR scan, including a DCE scan, will be performed. In addition, the patient will be asked about any adverse events that might have occurred during a phone call.

Potential adverse effects include skin burns due to heating of the cutaneous and sub-cutaneous abdominal fat and risk of abdominal pain due to the occlusion of the vascular network. To mitigate the risk of skin burns, a cooling cushion is integrated in the HIFU table top and will protect the skin and part of the abdominal fat from overheating.

If women with a type 3 fibroid do not want to participate in this study, they are not eligible for MR-HIFU treatment and are referred by their gynecologist to a more invasive treatment option like uterine artery embolization or hysterectomy.

Targeted Vessel Ablation of Type 3 Uterine Fibroids With Magnetic Resonance Guided High Intensity Focused Ultrasound

The main endpoint of this feasibility study is the manipulation of perfusion in the type 3 uterine fibroid. The perfusion will be assessed by comparing the results of dynamic contrast-enhanced MRI (DCE-MRI) before and after treatment and after three months, i.e. the time to peak values. Data will be analyzed using Philips IntelliSpace Portal.

The main endpoint of this feasibility study is the manipulation of perfusion in the type 3 uterine fibroid and the possibly related adverse events. The perfusion will be assessed by comparing the results of dynamic contrast-enhanced MRI (DCE-MRI) before and after treatment and after three months, i.e. regional blood volumes (area under the curve). Data will be analyzed using Philips IntelliSpace Portal.

The adverse events will be reported in the case report form (CRF) based on the assessments one week and three months post treatment.

UMC Utrecht

Prof. Dr.

Antineoplastic Agents

Reproductive Control Agents

All Drugs and Chemicals

Leuprolide

Antineoplastic Agents, Hormonal

Women with a maximum fibroid dimension less than 8 cm and a total uterine volume less than 900 cc.

Intervention: Treatment of fibroids with Magnetic Resonance Guided High Intensity Focused Ultrasound.

Women with a maximum fibroid dimension greater than 8 cm or a total uterine volume greater than 900 cc.

Intervention A: Pre-treated with 11.25mg leuprolide acetate for depot suspension for 3 months to reduce size of fibroids.

Intervention B: Treatment with Magnetic Resonance Guided High Intensity Focused Ultrasound if fibroids decrease to treatable size of less than 8cm and uterine volume less than 900cc.

Direct treatment of uterine fibroids with MR-HIFU

Magnetic Resonance Guided High Intensity Focused Ultrasound

Treatment of uterine fibroids with leuprolide acetate prior to MR-HIFU

leuprolide acetate for depot suspension

Naana A Jumah, MD DPhil FRCSC

The purpose of this study is to demonstrate the effectiveness of MR-HIFU for the treatment of uterine fibroids in Northwestern Ontario, which is a rural and remote setting.

Uterine fibroids are benign smooth muscle tumours of the muscular wall of the uterus that affect 40 per cent of women. While the majority of fibroids are asymptomatic, fibroids may cause menorrhagia, bulk symptoms (i.e. ureteric obstruction, urinary frequency and urgency, bowel dysfunction), pain and in certain instances infertility.

Magnetic resonance image-guided high-intensity focused ultrasound (MR-HIFU) treatment of fibroids is an established method for symptom alleviation with over 3000 women receiving treatment worldwide. MR-HIFU is a non-invasive, non-surgical procedure that uses ultrasound energy to thermally ablate the fibroid leading to a reduction in bleeding and in the size of uterine fibroids over time. MR-HIFU it is not currently being used for the treatment of symptomatic fibroids in Canada.

The Thunder Bay Regional Research Institute has one of the first clinically available MR-HIFU equipment in Canada. In order to bring this technology into clinical practice, a knowledge translation study is needed to demonstrate that MR-HIFU can treat symptomatic uterine fibroids as successfully in Northwestern Ontario compared to urban centres where all of the clinical trials have been conducted. The ability to screen and follow up women treated with MR-HIFU with ultrasound rather than MRI would allow participants to receive follow up in regional centres in Northwestern Ontario and it would be more cost effective from a health system perspective. In addition, more research is needed to broaden the scope of treatment to include fibroids greater than 8 cm such that more women could benefit from this non-surgical fibroid management option.

Treatment of Uterine Fibroids With Magnetic Resonance Guided High Intensity Focused Ultrasound

Questionnaire to assess if participants are selecting to use alternative treatments for relief of symptoms of uterine fibroids.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Targeted Vessel Ablation of Type 3 Uterine Fibroids With Magnetic Resonance Guided High Intensity Focused Ultrasound	NCT02633254	Uterine Fibroid	Magnetic Resona...	18 Years - 100 Years	UMC Utrecht
Treatment of Uterine Fibroids With Magnetic Resonance Guided High Intensity Focused Ultrasound	NCT02736435	Uterine Leiomyo...	Magnetic Resona... leuprolide acet...	18 Years - 50 Years	Thunder Bay Regional Health Research Institute
Targeted Vessel Ablation of Type 3 Uterine Fibroids With Magnetic Resonance Guided High Intensity Focused Ultrasound	NCT02633254	Uterine Fibroid	Magnetic Resona...	18 Years - 100 Years	UMC Utrecht
Treatment of Uterine Fibroids With Magnetic Resonance Guided High Intensity Focused Ultrasound	NCT02736435	Uterine Leiomyo...	Magnetic Resona... leuprolide acet...	18 Years - 50 Years	Thunder Bay Regional Health Research Institute

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