Neoplasms

All Conditions

Skin and Connective Tissue Diseases

Leiomyoma

Myofibroma

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Neoplasms, Connective Tissue

Connective Tissue Diseases

HIFU is the use of focused ultrasound energy to penetrate through soft tissue and causes localized high temperatures (55°C to 70°C) for a few seconds within the target producing well defined regions of protein denaturation, irreversible cell damage, and coagulative necrosis

Philips MR guided HIFU system

Uterine fibroids (leiomyomas) are a common cause of heavy uterine bleeding and pain in reproductive aged women and are the most common cause of hysterectomy in the United States. Women are seeking new ways to treat symptomatic uterine fibroids that allow them to avoid surgery. This study is the first step in this quest. We will study the novel use of magnetic resonance imaging (MRI) in enhancing the safety of the FDA approved technique to treat fibroids called High Intensity Focused Ultrasound (HIFU). The term 'high intensity focused ultrasound' means using ultrasound to heat and to thermally destroy tissue, in this case, uterine fibroids. The MRI system will allow us to watch the ultrasound path during treatment and monitor the temperature increase in the fibroid tissue that comes during the procedure.

In this pilot study, women with symptomatic fibroids will undergo MRI guided HIFU and then have a hysterectomy. This will allow us to confirm studies done in animals which show that it is possible to destroy specific tissue without harming normal tissue surrounding the targeted area.

The purpose of this clinical study is to confirm the safety and treatment capabilities of the Philips MR guided HIFU system for ablation of uterine fibroids. This is a single arm pilot study of 10 women who will undergo hysterectomy after the HIFU procedure. This study design of hysterectomy after treatment has been requested by the FDA as part of IDE approval for this new device and mirrors what has been required for similar devices. Safety will be assessed by evaluating treatment accuracy, complications, and adverse events. Treatment capabilities will be assessed by evaluating the fibroid volume ablated and other factors related to the procedure feasibility and acceptance including procedure duration, time to return to normal activity, and pain scores at the time of the procedure.

Study population

The Philips MR-HIFU System is intended for ablation of uterine fibroid tissue in pre- or perimenopausal women with symptomatic uterine fibroids who desire a uterine-sparing procedure. Patients must have completed child bearing prior to enrolling in this study. Patients will be recruited by referral to gynecology and interventional radiology at the NIH Clinical Center. Candidates for enrollment will already have symptomatic uterine leiomyomas and be willing to undergo hysterectomy for treatment. It is estimated that of apparently eligible subjects, at least 30 women will have to be screened in person in order to identify 10 who will be eligible for this study. Other studies of fibroid treatments are currently ongoing at the NIH. Women who have been interested in, but have not been selected for enrollment in those studies and who appear to be eligible to this study will be contacted for potential enrollment.

Study design:

This study is a multi-center, single arm trial evaluating the safety and treatment capabilities of the Philips MR-guided HIFU system in the treatment of symptomatic uterine fibroid patients who are otherwise healthy women. All patients enrolled in the study will undergo hysterectomy within a window of 30 days following HIFU treatment. Patients who have symptomatic uterine fibroids, meet clinical indications for hysterectomy, are eligible according to the inclusion and exclusion criteria and provide informed consent will be enrolled in this study. This study design of treatment followed by hysterectomy has been requested by the FDA as part of IDE approval for this new device and mirrors what has been required for similar devices. It is anticipated that women will participate in the study for a 3 month period to include the screening, HIFU treatment, hysterectomy and post hysterectomy follow-up.

The methodology used for this HIFU device capitalizes on the thermal properties of volumetric ablation rather than point ablation used by other focused ultrasound systems. Thus it is anticipated that this device will have a shorter treatment time compared to other HIFU machines. This HIFU system, via real-time MR thermometry monitoring, has automated thermal feedback during the procedure which may enhance safety. This pilot study will not only assess the safety of this device but will enable us to delineate the treatment capabilities of this system for future use in patients who want uterine sparing non-surgical treatment for symptomatic fibroids.

Uterine fibroids (leiomyomas) are a common cause of heavy uterine bleeding and pain in reproductive aged women and are the most common cause of hysterectomy in the United States. Women are seeking new ways to treat symptomatic uterine fibroids that allow them to avoid surgery. This study is the first step in this quest. We will study the novel use of magnetic resonance imaging (MRI) in enhancing the safety of the FDA approved technique to treat fibroids called High Intensity Focused Ultrasound (HIFU). The term high intensity focused ultrasound means using ultrasound to heat and to thermally destroy tissue, in this case, uterine fibroids. The MRI system will allow us to watch the ultrasound path during treatment and monitor the temperature increase in the fibroid tissue that comes during the procedure.

In this pilot study, women with symptomatic fibroids will undergo MRI guided HIFU and then have a hysterectomy. This will allow us to confirm studies done in animals which show that it is possible to destroy specific tissue without harming normal tissue surrounding the targeted area.

The purpose of this clinical study is to confirm the safety and treatment capabilities of the Philips MR guided HIFU system for ablation of uterine fibroids. This is a single arm pilot study of 10 women who will undergo hysterectomy after the HIFU procedure. This study design of hysterectomy after treatment has been requested by the FDA as part of IDE approval for this new device and mirrors what has been required for similar devices. Safety will be assessed by evaluating treatment accuracy, complications, and adverse events. Treatment capabilities will be assessed by evaluating the fibroid volume ablated and other factors related to the procedure feasibility and acceptance including procedure duration, time to return to normal activity, and pain scores at the time of the procedure.

Study population

The Philips MR-HIFU System is intended for ablation of uterine fibroid tissue in pre- or perimenopausal women with symptomatic uterine fibroids who desire a uterine-sparing procedure. Patients must have completed child bearing prior to enrolling in this study. Patients will be recruited by referral to gynecology and interventional radiology at the NIH Clinical Center. Candidates for enrollment will already have symptomatic uterine leiomyomas and be willing to undergo hysterectomy for treatment. It is estimated that of apparently eligible subjects, at least 30 women will have to be screened in person in order to identify 10 who will be eligible for this study. Other studies of fibroid treatments are currently ongoing at the NIH. Women who have been interested in, but have not been selected for enrollment in those studies and who appear to be eligible to this study will be contacted for potential enrollment.

Study design:

This study is a multi-center, single arm trial evaluating the safety and treatment capabilities of the Philips MR-guided HIFU system in the treatment of symptomatic uterine fibroid patients who are otherwise healthy women. All patients enrolled in the study will undergo hysterectomy within a window of 30 days following HIFU treatment. Patients who have symptomatic uterine fibroids, meet clinical indications for hysterectomy, are eligible according to the inclusion and exclusion criteria and provide informed consent will be enrolled in this study. This study design of treatment followed by hysterectomy has been requested by the FDA as part of IDE approval for this new device and mirrors what has been required for similar devices. It is anticipated that women will participate in the study for a 3 month period to include the screening, HIFU treatment, hysterectomy and post hysterectomy follow-up.

The methodology used for this HIFU device capitalizes on the thermal properties of volumetric ablation rather than point ablation used by other focused ultrasound systems. Thus it is anticipated that this device will have a shorter treatment time compared to other HIFU machines. This HIFU system, via real-time MR thermometry monitoring, has automated thermal feedback during the procedure which may enhance safety. This pilot study will not only assess the safety of this device but will enable us to delineate the treatment capabilities of this system for future use in patients who want uterine sparing non-surgical treatment for symptomatic fibroids.

Primary Outcome parameters:

1. Verifying with MR imaging that the location of the HIFU lesion matches the expected location (binary)
2. Verifying with MR imaging that no unintended lesions are formed as a result of the treatment (binary)
3. Examining the uterine capsule and surrounding areas for unintended damage during hysterectomy (binary)
4. Evaluating any complications or adverse events that result from the MR-guided HIFU treatment (categorical)
5. Comparing the actual MR-measured ablated volumes to MR thermal dose predicted volumes (categorical)
6. Comparing the ablated volumes from histology to MR thermal dose predicated volume (categorical)
7. Ensuring on histopathologic examination of the uterus that the zones treated by MR-guided HIFU treatment are indeed necrosed (binary)

Secondary Outcome Parameters:

1. Pain and discomfort scores immediately before, during and after HIFU treatment:
2. Length of Hospital Stay (LOS)
3. Return to Activity

Pilot Study of MRI-Guided High Intensity Focused Ultrasound Ablation of Uterine Fibroids

The number of treatment-related Adverse Events (AE) reported during the study, divided by the total number of treated subjects. This corresponds to the mean number of treatment-related Adverse Events per subject. Relatedness of an AE to the treatment was judged case-by-case by the investigator.

Count the number of participants in which both of the following conditions are satisfied: the fibroid treated area as shown on MRI images during treatment is the same as displayed on fibroids from histology slices after hysterectomy, and no unintended lesions are visible in the uterus.

Length of time to return to normal activity measured in number of days from HIFU treatment. Assessed by patient interviews during follow-up.

Pain Scores obtained by patient self-assessment on a 0-10 scale, with 0 corresponding to no pain and 10 corresponding to maximum pain.

Patient's self-assessed discomfort level on a 4-point scale, with: 0 = no pain; 1 = mild; 2 = moderate; 3 = severe.

Philips Healthcare

Adverse events assessed by patient questionnaire.

Only unexpected adverse events were reported in the "Other" Adverse Event Field.

All adverse events were reported including those not related to treatment.

HIFU Treatment

Women indicated for total abdominal hysterectomy underwent a single Magnetic Resonance guided-High Intensity Focused Ultrasound (MR-HIFU) session for uterine fibroid ablation prior to surgery. Subjects were followed up until the date of hysterectomy, or for 30 days if hysterectomy was declined.

HIFU Treated

Age, Categorical

Age Continuous

Sex: Female, Male

United States

Region of Enrollment

Sarah Baxter

Safety was assessed per protocol; all 11 participants were evaluated for adverse events after HIFU treatment.

Treatment-related Adverse Events (AE) Per Subject Resulting From HIFU Treatment of the Uterine Fibroids

All participants who underwent hysterectomy following MR-HIFU treatment were included in this endpoint measure. Patients who refused hysterectomy were not included.

HIFU Treatment Equals Location Per Hysterectomy

Length of Time to Return to Normal Activities

Treatment Day: Baseline

Treatment Day: Recovery

Treatment Day: Discharge

24 hours after treatment

48 hours after treatment

72 hours after treatment

1 week after treatment

2 weeks after treatment

Subjects were included into analysis at a given time point if they had not received hysterectomy yet prior to that time point.

Analysed subject numbers were:

from baseline up to including 72 hours: 11 subjects (per protocol population); at 1 week: 6 subjects; at 2 weeks: 4 subjects;

Numerical Range Scale (NRS) of Pain Level

Discomfort Level

Overall Study

Behaviors and Mental Disorders

Rare Diseases

Sarcoma

Fibromatosis, Aggressive

Fibromatosis, Abdominal

Aggression

Fibroma

Neoplasms, Fibrous Tissue

Soft Tissue Sarcoma

Desmoid Tumor

Central Nervous System Depressants

All Drugs and Chemicals

Anesthetics

Anesthetics, Local

Anesthetics, General

All participants receive HIFU to their target tumour, hence this is a single arm study with 4 recruitment pathways.

The focused ultrasound exposure will be performed using the Haifu® Model-JC200 Focused Ultrasound Tumour Therapeutic System at the Churchill Hospital site, CE-approved for tumour therapy (or subsequent CE-approved device upgrades by Haifu®). The participant will be positioned over the therapeutic device and water bath used to transmit the focused ultrasound to the target tumour. No anaesthesia or any combination of local anaesthesia, nerve block, epidural, conscious sedation or general anaesthetic may be used, depending on anatomical location, size of tumour, preference of HIFU team, patient and anaesthetist and other patient factors.

In therapy mode, the tumour volume is treated with focused ultrasound to ablate the tumour tissues to high temperatures (in excess of 60ºC) using focused ultrasound targeted from outside the body.

Patients are typically discharged with 24 hours.

High Intensity Focused Ultrasound Ablation

Where appropriate, participants are also encouraged to undergo a pre-HIFU (and in the case of unresectable STS, post-HIFU) ultrasound biopsy of the target tumour and additional blood tests to inform the immunological aspects of the study. Having the biopsy does not mandate enrolment on the trial, and patients will be free to leave the trial at any stage. The pre-HIFU (and post-HIFU) biopsies are altruistically encouraged but not absolutely essential to enrolment on the trial.

Biopsies will be performed under ultrasound guidance by an experienced radiologist using local anaesthetic.

Tumour Biopsy and Venous Blood Tests

Paul C Lyon, FRCR, DPhil

Paul C Lyon, DPhil, FRCR

Madhurima Chetan, BMBS

Joanna Hester, PhD

Feng Wu, PhD

Catherine McCarthy, FRCR

Tom Cosker, FRCS

Srikanth Reddy, FRCS

David Cranston, FRCS

Keaton Jones, FRCS

Martin Gillies, FRCS, DPhil

Fergus V Gleeson, FRCR

Constantin C Coussios, DPhil

Megan Jones, BSc, MRes

Around 3,300 people are diagnosed with soft tissue sarcoma (STS) each year in the UK, and a significant proportion of STS diagnoses are in people aged under 30 years. STS can arise from various tissue types and is comprised of over 50 tumour types. Although STS is treated with a combination of surgery, radiotherapy and chemotherapy, the prognosis is relatively poor with a five-year survival rate of 54%. There is an unmet need for further treatment modalities in STS.

High intensity focused ultrasound (HIFU) is a non-invasive way of treating cancers with minimal side effects, low complication rate and quick recovery. Ultrasound waves are used to destroy tumour cells and improvements in technology and experience are enabling complete destruction of tumour. HIFU also releases tumour antigens, increasing the immune response against cancer. HIFU has received FDA approvals for several indications, including bone metastases and we are using a CE-approved HIFU device in Oxford (UKCA-approvals anticipated for 2023). There have been some publications from China showing promise in STS, however this technology needs further evaluation within the UK's healthcare setting.

This study will recruit patients with both resectable and unresectable STS, in addition to unresectable small symptomatic desmoid tumours. 12-16 patients, and a minimum of 10 patients with malignant STS, will be treated over a maximum recruitment period of three years. HIFU treatment will be carried out as a day case procedure, and patients will be expected to be discharged home the same day.

The study is designed to generate evidence regarding safety and feasibility of HIFU for ablation of STS and intra-abdominal desmoids. In addition, the study is anticipated to provide information about the efficacy of HIFU against these tumour types which can help in the design of later phase studies. Short-term outcomes include feasibility, safety and the completeness of destruction of the tumour. Long-term outcomes include one-year survival, local recurrence and quality of life metrics (including pain scores). The study will also look at immunological response following ablation of STS using both blood and tumour samples pre- and post-HIFU ablation.

Tissues that can be affected by soft tissue sarcomas include fat, muscle, blood vessels, nerves, deep skin tissues, tendons and ligaments. Sarcoma accounts for 1% of all cancer diagnoses; around 3,300 people are diagnosed with soft tissue sarcoma (STS) each year in the UK. The incidence of STS is unusual for cancer in that a relatively large proportion can occur in children and young adults, with 9% of cases in the under 30-year group and only 43% of cases in the 65 and over group. Whilst STS is rare, it remains a significant cause of morbidity and mortality. Prognosis is typically poor, with a five-year overall survival of approximately 54%.

The Oxford Bone and Soft Tissue Tumour Service at the Nuffield Orthopaedic Centre, Oxford, is a nationally approved tertiary referral centre for the treatment of soft tissue and primary bone sarcomas, receiving 400 new patient referrals annually. These patients are currently treated via a multidisciplinary approach involving expert radiologists, surgeons, clinical oncologists and histopathologists.

At our centre, patients with smaller (\<5cm) STS proceed directly to surgical resection; this provides a low-risk opportunity to evaluate safety, feasibility and efficacy of novel pre-operative non-ionising ablative technologies, such as High Intensity Focused Ultrasound (HIFU). Patients with larger (\>5cm) resectable STS currently receive neoadjuvant radiotherapy within six weeks of surgery, in line with national guidelines (Dangoor, 2016). Upon recurrence within the radiotherapy field (in-field recurrence), radiotherapy has high morbidity, including complications such as poor wound healing and infection (Tsagozis, 2018), and is not indicated prior to further surgical resection. Thus, in resectable cases of in-field recurrence, there is further opportunity to evaluate non-invasive HIFU, anticipated to both reduce tumour size and tumour vascularity, facilitating subsequent surgical resection. Furthermore, recurrent STS or metastatic STS not suitable for surgery have limited treatment options, and if not suitable for further chemo- or radio-therapy, HIFU may provide an alternative treatment option before palliation.

HIFU is a versatile treatment modality capable of destruction of tumours by focusing ultrasound waves from outside the body, usually through the medium of water, to cause ablation at a precise anatomical location.

It has demonstrated an impressive safety profile by virtue of being both non-invasive and lacking radiation, leading to FDA approvals for several indications including pain relief in bone metastases (Scipione, 2018) and uterine fibroids. Previous studies using an ultrasound-guided therapeutic device in China have demonstrated that HIFU is a successful treatment modality for soft tissue sarcoma (Yu, 2019), but this treatment has currently not been widely investigated within the UK's health care setting.

The University of Oxford and the Oxford University Hospitals NHS Trust have extensive clinical HIFU experience. The first extracorporeal HIFU device in Europe was used for a study performed at the Churchill Hospital between 2002 and 2004 (Illing, 2005). The study used an ultrasound-guided HIFU system (Model-JC Tumour Therapy System, HAIFU Technology Company Ltd, Chongqing, China) to treat 30 patients with tumour deposits in the kidney or liver and demonstrated both safety and efficacy. This was followed by a non-randomised Phase II clinical trial of HIFU ablation of liver tumours (Leslie, 2008), which compared radiological response against histological findings and again demonstrated safety and feasibility for non-invasive treatment of solid tumour deposits. These studies have led to CE-marking of the JC and JC-200 treatment devices for non-invasive treatment of solid tumours such as liver cancer, kidney tumours, breast cancer, bone tumours, pancreatic tumours and uterine fibroids, based on previous clinical trials at our unit (Lyon, 2019), the latter indication recently receiving NICE approval for US-guided HIFU ablation.

Safety and efficacy of HIFU has already been demonstrated for sacral chordoma in our institution (Gillies, 2016). Due to the highly targeted capabilities of HIFU, whilst leaving superficial skin and pre-focal tissues unharmed, the ablative technology may have a role in treating local recurrence following previous neoadjuvant radiotherapy. For example, following recurrence, HIFU may be able to facilitate conversion from amputation for local control to limb salvage surgery.

Desmoid tumours are a relatively poorly understood subtype of STS which are benign and do not metastasise. However, this tumour subtype demonstrates characteristics of aggressive fibromatosis and comes with significant morbidity and mortality due to their locally invasive nature and, in the familial form, typical bowel involvement. Treatment options are limited and poorly evaluated; mortality is 34% in patients undergoing surgery for intra-abdominal desmoid and post-resection recurrence rates for abdominal wall and intra-abdominal desmoids are 41% and 71% respectively (Sturt, 2006). By virtue of not disrupting the tissue planes, promoting further fibromatosis, HIFU has previously been used on desmoid tumours in small case series outside the UK and have demonstrated encouraging outcomes for both extra- and intra-abdominal desmoid tumours (Shi, 2016), (Ghanouni, 2017).

HIFU is an attractive treatment modality for these indications due to its excellent safety profile, versatility in treating a range of tumour locations (Shim, 2016), its capability to treat multiple smaller tumours in a single session and, furthermore, being repeatable due to the lack of ionising radiation. Oxford has over two-decades of world-class expertise in clinical HIFU with published experiences in translational research of many benign and malignant solid tumour subtypes (Iling, 2005), (Lyon, 2019), (Gilies, 2016), (Leslie, 2012), (Lyon, 2018), (Wu, 2004), (Kennedy, 2004). As the Chinese JC200 device used in Oxford uses diagnostic ultrasound through a water bath to target tumours, rather than an integrated MRI tunnel, treatment of tumours at a variety of anatomical locations becomes both more practical and financially economical.

The clinical HIFU service is complimented by an extensive pre-clinical therapeutic ultrasound research facility at the Institute of Biomedical Engineering, University of Oxford. This laboratory has provided expertise in treatment planning for a previous HIFU clinical trial using patient specific models which employ CT data (Gray, 2019). The multidisciplinary team of co-investigators and other researchers in Oxford have world-class expertise in academic and musculoskeletal radiology, sarcoma surgery, sarcoma radiotherapy and oncology, clinical histopathology and immunology.

Thus, in Oxford there is a unique opportunity to explore the utility of preoperative HIFU in the ablation of infield recurrent STS, smaller STS and desmoid tumours as a pilot study. The primary outcome measure of the study will be safety and feasibility. Radiological response will be explored as a secondary endpoints of efficacy using cross sectional (MRI) and functional imaging (18F-FDG PET), incorporating both size, perfusion and metabolic activity. In addition, novel MRI sequences (DWI including whole body MRI, CEST) may also be explored with the academic radiology department, which pose minimal addition risk to the patient (Chetan, 2019), (Schmidt, 2009).

Crucially, post-resection histology will permit histopathological correlation, mitigating against the possibility of falsely reassuring radiological evaluations (false positive complete ablations). Tertiary endpoints will explore immune response, which HIFU has been demonstrated to mediate (Wu 2004), (Wu, 2016), both through circulating blood markers and immunohistochemistry. This is of importance, as whilst this study may demonstrate safe and effective ablation of targeted STS tumours, there may be micro-metastases or known metastases elsewhere which may limit the overall survival. Thus, thorough understanding of the immune mechanisms at play during HIFU ablation may inform future complimentary systemic treatments. Whilst one other centre has recently published early HIFU experience in STS \[6\], we believe our proposed study will be the first to elucidate immune mechanisms in HIFU-ablation of STS, and the first trial of HIFU for STS in Europe.

Pain scores and quality of life metrics will also be captured both pre- and post-HIFU and this qualitative data can be used to demonstrate that the HIFU procedure was acceptable to the patient.

No randomisation. Four recruitment cohorts, patients with:

1. Soft tissue sarcoma 1-5cm for resection
2. Soft tissue sarcoma \>1cm with infield recurrence for resection
3. Soft tissue sarcoma unsuitable for resection or further chemo- or radiotherapy
4. Small (1-8 cm) symptomatic intra-abdominal desmoid tumour unsuitable for surgery

HIFU Ablation of Soft Tissue Sarcoma

A Pilot Study in High Intensity Focused Ultrasound Ablation of Soft Tissue Sarcoma and Small Symptomatic Intra-abdominal Desmoid Tumours

To measure the immunological effects of HIFU treatment of STS by immunohistochemistry (IHC) using tumour samples post-HIFU relative to baseline

To measure the immunological effects of HIFU treatment of STS by immune blood markers using venous blood samples post-HIFU relative to baseline

One-year local recurrence endpoint assessed using available imaging (CT, MRI, PET-CT)

One-year survival endpoint assessed using available clinical information

Adverse events and serious adverse events deemed due to HIFU recorded using Clavien-Dindo grading

Number of resectable STS participants converted to unresectable by HIFU

Number of limb salvageable STS participants converted to amputation by HIFU

Number of patients with intra-abdominal desmoid tumour requiring surgery due to complication

Near pathological complete response (≥95% necrosis) in ≥25% of resectable STS participants post-HIFU

Non-perfused volume ratio (NPVR) ≥75% on MRI in ≥25% of all STS participants having MRI post-HIFU

RECIST partial response in the target tumour alone in ≥25% of unresectable STS participants having MRI post-HIFU

PERCIST partial metabolic response in the target tumour alone in ≥25% of all STS participants having PET-CT post-HIFU

Non-perfused volume ratio (NPVR) ≥50% on MRI in ≥25% of desmoid participants having MRI post-HIFU

RECIST partial response in the target tumour alone in ≥25% of desmoid participants having MRI post-HIFU

Number of desmoid tumour and unresectable STS participants with change in Pain Score assessed by Brief Pain Inventory

Number of desmoid tumour and unresectable STS participants with change in Quality of Life score assessed by EORTC QLQ-C30 v3 post-HIFU relative to baseline. In particular Qs 1-28 are on a scale of 1..4 with 1 being best and 4 being worse quality of life.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Pilot Study of MRI-Guided High Intensity Focused Ultrasound Ablation of Uterine Fibroids	NCT00837161	Uterine Fibroid... Uterine Leiomyo...	Philips MR guid...	18 Years - 59 Years	Philips Healthcare
HIFU Ablation of Soft Tissue Sarcoma	NCT05111964	Soft Tissue Sar... Desmoid; Abdomi...	High Intensity ... Tumour Biopsy a...	18 Years -	Oxford University Hospitals NHS Trust

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