Feasibility of Combined Focused Ultrasound and Radiotherapy Treatment in Patients With Painful Bone Metastasis

Study Overview
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Brief Summary
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The PRE-FURTHER study aims to evaluate the feasibility of the combined treatment with radiotherapy and focussed ultrasound for pain palliation in patients with painful bone metastases, and to optimize the combined treatment logistics. Six to ten patients will be included according to in- and exclusion criteria.

Detailed Description
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Rationale: Metastatic bone pain strongly interferes with quality of life and daily functioning of patients with advanced cancer. Pain palliation may be improved by including magnetic resonance image guided high intensity focused ultrasound (MR-HIFU) in addition to External Beam Radiotherapy (EBRT). For this purpose, feasibility and optimal logistics of the combined treatment need to be evaluated. Objective: The PRE-FURTHER project aims to evaluate the feasibility of the combined EBRT and MR-HIFU treatment for relief of metastatic bone pain, and to optimize the combined treatment logistics. Study design: The PRE-FURTHER study is a prospective case series, stage I and IIA study according to the Innovation, Development, Evaluation, Assessment and Long term evaluation (IDEAL) recommendations. 6-10 patients will receive MR-HIFU treatment following standard EBRT. Endpoints: The main outcome of this study is the feasibility of the procedure, in terms of planability as well as patient-tolerability of the combined treatment within a short time frame (3 hours - 4 days interval). In addition, pain relief and safety of the combined procedure will be monitored.

Official Title
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Feasibility of Combined Focused Ultrasound and Radiotherapy Treatment in Patients With Painful Bone Metastasis - the PRE-FURTHER Study -

Conditions
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Bone Metastases, Bone Neoplasm, Bone Lesion, Bone Cancer, Pain, Cancer Induced Bone Pain, Radiation Toxicity, Quality of Life, Tumor, Neoplasm Metastasis

Intervention / Treatment
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* Combination Product: combined radiotherapy and MR-HIFU


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women with age ≥ 18 years Patient capable of giving informed consent and able to attend study visits Uncomplicated painful bone metastases Weight <140kg and able to fit in the MRI gantry Radiologic evidence of bone metastases from any solid tumor Pain is localized to the targeted area, or is likely to be referred pain arising from the targeted area Pain related to the target lesion is refractory to less invasive treatments for pain relief Multiple metastatic lesions, with one predominantly painful lesion (>=2 points higher pain score than other lesions). The lesion should be clearly distinguishable from other painful lesions. Device accessible tumors: extremities (excluding joints), pelvis, shoulders, posterior vertebral spine below L5, in selected cases ribs and sternum Target lesion maximum dimension ≤ 8cm Intended target volume visible by non-contrast MR imaging Distance between target and skin ≥ 1cm Numeric Rating Scale (NRS) score >= 4 or equivalent Life expectancy >3 months Exclusion Criteria: Planned treatment lesion is a primary bone tumor or due to lymphoma, multiple myeloma, or leukemia. Communication barrier present Patient enrolled in another clinical study related to bone metastases treatment or pain relief treatment Unable to tolerate required stationary position during treatment despite adequate pain medication Need for surgery Pregnant woman Pain related to target lesion is predominantly due to fracture or impending fracture Pain related to target lesion is due to involvement of a neighboring major nerve by the metastatic tumor (cord or nerve compression) Target < 3cm from bladder / bowel / nerve along the beam path and < 1cm in the plane orthogonal to the beam Target in contact with hollow viscera Target located in skull, joints, ribs (when HIFU beam overlapping with lung), spine (excluding sacrum which is allowed) or in most cases sternum Internal or external fixation device along the proposed HIFU beam path or at the target MRI contraindicated (e.g. paramagnetic implants, pacemaker, claustrophobia) MRI contrast agent contraindicated (e.g. previous anaphylaxis or Glomerular Filtration Rate < 20 ml/min/1.73m2) Sedation contraindicated Previous surgery or minimally invasive treatment at targeted site within the last three months Clinically relevant medical history or abnormal physical findings that could interfere with the safety of the participant as judged by the treating physician or investigator Karnofsky performance score (KPS) < 60% Oligometastatic disease planned for curative treatment Indication for stereotactic radiotherapy (e.g. patients with radioresistant histology such as renal cell, melanoma, sarcoma metastases) History of photodermatoses (of the skin overlying the target area) Need for remineralisation

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: Other
Intervention Model: Sequential Assignment
Interventional Model Description: Prospective case series (n = 6 - 10), stage I and IIA study according to the Innovation, Development, Evaluation, Assessment and Long term evaluation (IDEAL) recommendations. The study will be performed in male and female adult (≥ 18 years) cancer patients capable of giving informed consent and referred for EBRT of painful bone metastases (Numerical Rating Scale (NRS) ≥ 4).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combined Focused Ultrasound and Radiotherapy<br>Combination of focused ultrasound and external beam radiotherapy | Combination Product: combined radiotherapy and MR-HIFU<br>* Following standard EBRT (single or multiple fraction), patients will receive one MR-HIFU treatment with the Profound Sonalleve MR-HIFU device on the most painful of their bone metastases. This treatment will take place in a short time frame of 3 hours to maximum 4 days. Patients will be followed up until 4 weeks after treatment. During follow-up they will be phoned around day 3, 7, 14, 21 and 28 to retrieve pain scores, pain medication and (serious) adverse events. At day 3 the patient's experience with the combined treatment will also be inquired.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of combined treatment with EBRT and MR-HIFU - Patient tolerance: questionnaire | The main outcome of this study is the feasibility of the combined procedure in terms of patient tolerance and hospital logistics. Patient tolerance will be assessed using a Patient Reported Experience Measure questionnaire. | 4 weeks | 
| Feasibility of combined treatment with EBRT and MR-HIFU - hospital logistics | The main outcome of this study is the feasibility of the combined procedure in terms of patient tolerance and hospital logistics. Hospital logistics will be assessed by analysing comments of the treating physicians and research staff on the problems that occurred during treatment planning, and whether extra hospital visits that were needed. | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient reported pain scores. | Patient reported pain scores will be based on a Numeric Rating Scale (from 0 to 10 with 0 being no pain and 10 being the worst pain imaginable) from the Brief Pain Inventory (BPI) questionnaire [Cleeland 1994]. | at 3 days, and at 1, 2, 3 and 4 weeks | 
| (Serious) adverse events (CTCAE) | Toxicity/safety of the combined treatment will be assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 | at 3 days, and at 1, 2, 3 and 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bone metastases, Cancer Induced Bone Pain, Pain palliation, Radiotherapy, Radiation oncology, MR-HIFU, MRI-guided high intensity focused ultrasound, Focused ultrasound, HIFU