Focused Ultrasound and RadioTHERapy for Noninvasive Palliative Pain Treatment in Patients With Bone Metastases

Study Overview
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Brief Summary
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The FURTHER study aims to evaluate the effectiveness and cost-effectiveness of MR-HIFU (alone or in combination with EBRT) compared to EBRT alone, the standard-of-care, as a palliative treatment option to relieve CIBP. This multicenter, three-armed randomized controlled trial will be performed in six hospitals in four European countries, and will include a total of 216 patients with painful bone metastases.

Detailed Description
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Rationale: Cancer induced bone pain (CIBP) as a result of bone metastases strongly interferes with quality of life and daily functioning of patients with advanced cancer. The current standard of care for patients with painful bone metastasis includes palliative external beam radiotherapy (EBRT). While EBRT is a well-established treatment option, it takes up to 4-6 weeks for EBRT to induce optimal pain relief, and 30-40% of patients do not respond to EBRT. Pain palliation may be improved by including magnetic resonance image guided high intensity focused ultrasound (MR-HIFU) as alternative or in addition to EBRT. Study design: The FURTHER study is a multicenter, three-armed randomized controlled trial, performed in six hospitals in four European countries, all of which are partners in the FURTHER consortium. The UMC Utrecht is coordinating center. A total of 216 patients with painful bone metastases will be randomized in a 1:1:1 ratio to receive EBRT only, MR-HIFU only, or EBRT followed by MR-HIFU. Study population: The study will be performed in male and female adult (≥ 18 years) cancer patients capable of giving informed consent, who were referred to the department of radiation oncology for treatment of painful bone metastases (pain score on Numerical Rating Scale (NRS) ≥ 4). Intervention: The intervention under study is MR-HIFU alone or in combination with EBRT. The intervention is aimed at rapid and persistent relief of CIBP. The intervention will be compared with standard treatment EBRT. Main study endpoints: Primary outcome of the trial will be pain response at 14 days after completion of the treatment. Secondary outcomes include pain response at 14 days after inclusion, and pain scores, toxicity, adverse events, quality of life and survival in the first 6 months after treatment, and cost-effectiveness of the treatments.

Official Title
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Focused Ultrasound and RadioTHERapy for Noninvasive Palliative Pain Treatment in Patients With Bone Metastases

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

Intervention / Treatment
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* Radiation: External beam radiotherapy
* Procedure: MR-HIFU


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient capable of giving informed consent Referral to radiotherapy department due to painful metastatic bone lesion (NRS ≥ 4) Pain from target lesion is distinguishable from other lesions Target lesion location is ccessible for MR-HIFU and EBRT Target lesion is visible on pre-treatment MR or CT imaging, with a maximum diameter of 8 cm Participant is able to fit in the MRI gantry Participant has a reasonable performance score (KPS ≥ 50% or Zubrod/ECOG/WHO < 3) Life expectancy ≥ 3 months Exclusion Criteria: Previous surgery on the target location Neurological symptoms due to nerve involvement of target lesion Need for surgery of targeted location due to (impending) pathological fracture Unavoidable critical structures or dense tissues in target area Curative intention of treatment plan Contra-indications for MRI or sedation/anesthesia Participant enrolled in another clinical interventional study related to bone metastases treatment or pain relief treatment Clinically relevant medical history or physical findings that could interfere with the patient's safety as judged by the treating physician

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A total of 216 patients with painful bone metastases will be randomized in a 1:1:1 ratio to receive EBRT only, MR-HIFU only, or EBRT followed by MR-HIFU.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: External Beam Radiotherapy<br>In the control arm, patients will undergo standard radiotherapy for painful bone metastases.The radiation schedule is at the discretion of the treating radiation oncologist. | Radiation: External beam radiotherapy<br>* The current standard of care for patients with uncomplicated painful bone metastases is palliative locoregional external beam radiotherapy, often in combination with systemic therapy and analgesics.<br>|
| Experimental: MR-HIFU<br>In the intervention arm, patients will be offered MR-HIFU treatment instead of standard radiotherapy. Treatment will be given following the international guidelines for MR-HIFU. | Procedure: MR-HIFU<br>* MR-HIFU is a non-invasive treatment modality that delivers acoustic energy to heat tissue to ablative temperatures of more than 60°C. The combination of focused ultrasound with magnetic resonance imaging (MRI) enables physicians to perform localized tumor tissue ablation, with real-time temperature monitoring using magnetic resonance (MR) thermometry.<br>* Other names: MR guided High Intensity Focused Ultrasound;|
| Experimental: Combination EBRT + MR-HIFU<br>In the combination arm, patients will undergo standard radiotherapy followed by MR-HIFU in a short timeframe. | Radiation: External beam radiotherapy<br>* The current standard of care for patients with uncomplicated painful bone metastases is palliative locoregional external beam radiotherapy, often in combination with systemic therapy and analgesics.<br>Procedure: MR-HIFU<br>* MR-HIFU is a non-invasive treatment modality that delivers acoustic energy to heat tissue to ablative temperatures of more than 60°C. The combination of focused ultrasound with magnetic resonance imaging (MRI) enables physicians to perform localized tumor tissue ablation, with real-time temperature monitoring using magnetic resonance (MR) thermometry.<br>* Other names: MR guided High Intensity Focused Ultrasound;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain response - 14 days after completion of treatment | Patient reported pain response will be based on a Numeric Rating Scale (from 0 to 10 with 0 being no pain and 10 being the worst pain imaginable) and the pain severity index calculated from the Brief Pain Inventory (BPI) questionnaire [Cleeland 1994]. In addition, analgesic and anti-neuropathic drug use is recorded, and all opioid analgesics are expressed as the oral equivalent daily morphine use (OMED). The primary endpoint of the RCT will follow the International Consensus on Palliative Radiotherapy Endpoints for Future Clinical Trials in Bone metastases (Chow 2012). Patients will be categorized as responders when a complete or partial pain response is achieved. All other patients will be categorized as non-responders. | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain response - 14 days after inclusion | Patient reported pain response will be based on a Numeric Rating Scale (from 0 to 10 with 0 being no pain and 10 being the worst pain imaginable) and the pain severity index calculated from the Brief Pain Inventory (BPI) questionnaire [Cleeland 1994]. In addition, analgesic and anti-neuropathic drug use is recorded, and all opioid analgesics are expressed as the oral equivalent daily morphine use (OMED). This endpoint will follow the International Consensus on Palliative Radiotherapy Endpoints for Future Clinical Trials in Bone metastases (Chow 2012). Patients will be categorized as responders when a complete or partial pain response is achieved. All other patients will be categorized as non-responders. | 14 days | 
| Patient reported pain scores - patient pain diary | 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). This will be assessed using a daily patient pain diary during the first 21 days after completion of treatment. | 21 days | 
| Patient reported pain scores - BPI | 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). This will be assessed using the Brief Pain Inventory (BPI) questionnaire at 7 time points during the total follow up of 6 months. | on baseline, at 1, 2, 4 and 6 weeks, and at 3 and 6 months | 
| Physician reported toxicity - CTCAE 5.0 | Assessed in seven telephone calls during the first six months following completion of treatment according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 | at 3 days, at 1, 2, 4 and 6 weeks, and at 3 and 6 months | 
| Patient reported quality of life - EORTC BM22 | During the follow up time of 6 months, patients will receive the EORTC BM22 quality of life questionnaire at baseline, one, two, four and six weeks, and three and six months following completion of treatment. | on baseline, at 1, 2, 4 and 6 weeks, and at 3 and 6 months | 
| Patient reported quality of life - EORTC C15-PAL | During the follow up time of 6 months, patients will receive the EORTC C15-PAL quality of life questionnaire at baseline, one, two, four and six weeks, and three and six months following completion of treatment. | on baseline, at 1, 2, 4 and 6 weeks, and at 3 and 6 months | 
| Patient reported quality of life - EQ-5D-5L | During the follow up time of 6 months, patients will receive the EQ-5D-5L quality of life questionnaire at baseline, one, two, four and six weeks, and three and six months following completion of treatment. | on baseline, at 1, 2, 4 and 6 weeks, and at 3 and 6 months | 
| Patient reported quality of life - PGIC | During the follow up time of 6 months, patients will receive the Patient Global Impression of Change scale (a 7 point likert scale about overall improvement after treatment) at one, two, four and six weeks, and three and six months following completion of treatment. | at 1, 2, 4 and 6 weeks, and at 3 and 6 months | 
| Patient reported quality of life - HADS | During the follow up time of 6 months, patients will receive the Hospital Anxiety and Depression Scale (HADS) questionnaire at one, two, four and six weeks, and three and six months following completion of treatment. Assessed among patients, patients' partners and caregivers by the Hospital Anxiety and Depression Scale (HADS) at baseline, two and four weeks, and three and six months fol-lowing completion of treatment. | on baseline, at 1, 2, 4 and 6 weeks, and at 3 and 6 months | 
| Local tumour control | Assessed using CT and/or MRI imaging at patient discretion at three and/or six months after completion of treatment. | 3 and 6 months | 
| Cost-effectiveness of the treatment | A hypothetical diagnosis related group (DRG) will be calculated from the perspective of the statutory health insurance (SHI). | 6 months | 

 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, Raiotherapy, Radiation oncology, Noninvasive, MR-HIFU, MRgFUS, HIFU, Focused Ultrasound