Clinical trial NCT05111964: HIFU Ablation of Soft Tissue Sarcoma
Official title: A Pilot Study in High Intensity Focused Ultrasound Ablation of Soft Tissue Sarcoma and Small Symptomatic Intra-abdominal Desmoid Tumours
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Soft Tissue Sarcoma
Desmoid; Abdominal
Keywords: HIFU
Focused Ultrasound
Immunology
Lead sponsor: Oxford University Hospitals NHS Trust
Sponsor class: OTHER
Collaborators: name: Surgical Intervention Trials Unit, Oxford, UK
name: NIHR Direct Delivery Team
name: Oxford Radiology Research Unit, Churchill Hospital, Oxford, UK
First posted: 2021-11-08
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: 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
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

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The participant is eligible for the study if they are:

Willing and able to give informed consent for participation in the study.

Aged 18 years or above.

Diagnosed with histologically-confirmed and HIFU-targetable soft tissue sarcoma of several subtypes, including but not necessarily limited to:

* Malignant fibrous histiocytoma
* Undifferentiated (pleomorphic) sarcoma
* Fibrosarcoma and fibromyxoid sarcoma (fibroblastic sarcomas)
* Leiomyosarcoma
* Liposarcoma
* Malignant peripheral nerve sheath tumour
* Retroperitoneal sarcoma
* Rhabdomyosarcoma
* Synovial sarcoma
* Sacral chordoma (following amendment)
* Desmoid tumours (intra-abdominal, including extra-peritoneal tumours which involve the abdominal wall)

Have at least one of the following:

* Untreated or recurrent primary resectable STS tumour 1-5cm diameter, targetable by HIFU
* Infield recurrent primary resectable STS tumour of \>1cm diameter, targetable by HIFU
* Primary or metastatic STS unsuitable for resection or further chemo- or radiotherapy, targetable by HIFU
* Small (1-8cm) symptomatic intra-abdominal desmoid tumour, targetable by HIFU, which is unsuitable for surgery (or patient has previously refused surgery)

Have life expectancy of over 12 months and a World Health Organisation (WHO) performance status of less than or equal to 1.

Be able to attend Churchill Hospital and Nuffield Orthopaedic Center, Oxford, potentially for multiple visits, and thus be based in the UK.

Willing to allow his or her GP and Consultant to be notified of participation in the study.

Able and willing to give written informed consent, indicating that they are aware of the investigational nature of this study and potential risks, and able to comply with the protocol for the duration of the study, including scheduled follow-up visits and examinations.

Exclusion Criteria:

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The participant may not enter the study if ANY of the following apply:

Diagnosed with histologically confirmed Osteosarcoma or Chordoma

Diagnosed with histologically confirmed soft tissue sarcoma of the following subtypes:

* GIST
* Chondrosarcoma
* Kaposi's sarcoma
* Ewings sarcoma
* Giant cell tumour
* Angiosarcoma

Active medical or psychological illness that would render the patient unsuitable for the interventions required for the study (exclusion at the discretion of the investigator).

Pregnancy.

Ulceration / skin breakdown / erythema overlying the target tumour site due to tumour invasion (exclusion at the discretion of the investigator).

Significant radiation skin damage overlying the target tumour site (exclusion at the discretion of the investigator).

Impractical anatomical locations for HIFU targeting (using JC200 treatment device) (exclusion at the discretion of the investigator):

* Retroperitoneum
* Skull
* Neck
* Axilla
* Foot

Unfavourable imaging features on previously acquired cross-sectional imaging, including:

* Tumour within 1cm of the skin surface
* Interposition (or close proximity) of a gas-containing structure between tumour and skin such as fixed (retroperitoneal) bowel or lung
* Interposition of a continuous ossified bone between tumour and skin, such as coverage by pelvis or scapula
* Tumour margin close (\<1.5cm) or encasing major neurovascular bundles (such as the sciatic nerve)
* Tumour margin close (\<1.5 cm) to critical visceral structures (e.g. bladder or bowel)

Recent radiotherapy (under 6 months) to the target tumour site.

Recent surgery (under 6 weeks) to the target tumour site.

Have any known allergic reactions to intravenous imaging agents to be used in this study (exclusion at the discretion of the investigator).

Have contraindication(s) or intolerance to MRI (exclusion at the discretion of the investigator).

Current involvement in phase 1 studies.

Soft tissue sarcoma participants: Use of chemotherapy or of an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the intervention.

Desmoid participants: hormonal medication including the contraceptive pill or tamoxifen, or being treated with imatinib.

Primary outcomes:
measure: Safety: Adverse events and serious adverse events deemed due to HIFU
timeFrame: Adverse events endpoint assessed for up to 30 days post-HIFU (or up to point of surgery if sooner)
measure: Safety: Number of resectable STS participants converted to unresectable by HIFU
timeFrame: Adverse events endpoint assessed for up to 30 days post-HIFU (or up to point of surgery if sooner)
measure: Safety: Number of limb salvageable STS participants converted to amputation by HIFU
timeFrame: Adverse events endpoint assessed for up to 30 days post-HIFU (or up to point of surgery if sooner)
measure: Safety: Number of patients with intra-abdominal desmoid tumour requiring surgery due to complication
timeFrame: Adverse events endpoint assessed for up to 30 days post-HIFU (or up to point of surgery if sooner)
Secondary outcomes:
measure: Efficacy: Number of resectable STS participants with near pathological complete response
timeFrame: Pathological response assessed within 2 months of surgery or post-HIFU biopsy
measure: Efficacy: Number of STS participants with non-perfused Volume Ratio (NPVR) Radiological Response
timeFrame: NPVR endpoints assessed using pre-HIFU MRI vs. post-HIFU MRI at: 2-4 weeks (resectable or unresectable), 3-months (±1 month) (unresectable only) and 1-year (±1 month) (unresectable only)
measure: Efficacy: Number of STS participants with RECIST Partial Radiological Response
timeFrame: RECIST endpoints assessed using pre-HIFU MRI vs. post-HIFU MRI at: 2-4 weeks (resectable or unresectable), 3-months (±1 month) (unresectable only) and 1-year (±1 month) (unresectable only)
measure: Efficacy: Number of STS participants with PERCIST Partial Metabolic Response
timeFrame: PERCIST endpoints assessed using pre-HIFU MRI vs. post-HIFU PET-CT at: 2-4 weeks (resectable or unresectable), 3-months (±1 month) (unresectable only) and 1-year (±1 month) (unresectable only)
measure: Efficacy: Number of Desmoid tumour participants with Non-perfused Volume Ratio (NPVR) Radiological Response
timeFrame: NPVR radiological endpoint assessed using pre- and 2-4 weeks post-HIFU MRI
measure: Efficacy: Number of Desmoid tumour participants with RECIST Partial Radiological Response
timeFrame: RECIST radiological endpoint assessed using 1-year post-HIFU MRI
measure: Efficacy: Number of desmoid tumour and unresectable STS participants with change in Pain Score assessed by Brief Pain Inventory post-HIFU relative to baseline
timeFrame: Pain score and quality of life endpoints assessed at baseline, 2-4 weeks and 3, 6 and 12 months post-HIFU (±1 month)
measure: Efficacy: Number of desmoid tumour and unresectable STS participants with change in Quality of Life score assessed by EORTC QLQ-C30
timeFrame: Pain score and quality of life endpoints assessed at baseline, 2-4 weeks and 3, 6 and 12 months post-HIFU (±1 month)
Other outcomes:
measure: Exploratory: Systemic immune effects of HIFU for STS
timeFrame: Tissue samples from baseline (biopsy) and post-surgery stored and analysed with IHC within 6 months. Immune bloods taken at baseline and 2-4 weeks, 3 months, 6 months and 12 months post-HIFU
measure: Exploratory: Local immune effects of HIFU for STS
timeFrame: Tissue samples from baseline (biopsy) and post-surgery stored and analysed with IHC within 6 months. Immune bloods taken at baseline and 2-4 weeks, 3 months, 6 months and 12 months post-HIFU
measure: Exploratory: Number of STS participants with local recurrence within one-year
timeFrame: Within 13 months of HIFU
measure: Exploratory: Number of STS participants with survival for over one-year
timeFrame: Within 12 months of HIFU
Locations:
city: Oxford
country: United Kingdom
facility: Churchill Hospital
state: Oxfordshire
Study officials:
affiliation: Oxford University Hospitals NHS Trust
name: Paul C Lyon, FRCR, DPhil
role: PRINCIPAL_INVESTIGATOR
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