Bone Cancer, Bone Lesion, Bone Metastases, Bone Neoplasm, Cancer Induced Bone Pain, Neoplasm Metastasis, Pain, Quality of Life, Tumor
Conditions
Keywords
Bone Metastases, Cancer Induced Bone Pain, Pain palliation, Raiotherapy, Radiation oncology, Noninvasive, MR-HIFU, MRgFUS, HIFU, Focused Ultrasound
Brief summary
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. The FURTHER study consists of a multicenter, three-armed randomized controlled trial (FURTHER RCT) and a patient registry arm (FURTHER Registry), which will be performed in six hospitals in four European countries.
Detailed description
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. Objective: The FURTHER study aims to evaluate the effectiveness and cost-effectiveness of MR-HIFU (alone or in combination with EBRT), as a palliative treatment option to relieve CIBP. Study design: The FURTHER study consists of a prospective, multicenter, three-armed randomized controlled trial (FURTHER RCT) and a patient registry arm (FURTHER Registry), performed in six hospitals in four European countries, all of which are partners in the FURTHER consortium. The UMC Utrecht is coordinating center. Within the FURTHER RCT, a total of 216 patients with painful bone metastases will be included. These patients will be randomized in a 1:1:1 ratio to receive EBRT only, MR-HIFU only, or EBRT followed by MR-HIFU. In the Netherlands, we expect to enroll a minimum of 70 patients, and a maximum of 120 patients in three Dutch study sites. Within the FURTHER Registry, data of around 60-90 patients will be captured. Study population: The study will be performed in male and female adult (≥ 18 years) cancer patients capable of giving informed consent having painful non-spinal 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. In the FURTHER RCT, the intervention will be compared to standard treatment EBRT. Main study endpoints: Primary outcome of the study will be pain response at 14 days after the first day of 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.
Interventions
RADIATIONExternal beam radiotherapy
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.
PROCEDUREMR-HIFU
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.
Sponsors
UMC Utrecht
Turku University Hospital
Universitätsklinikum Köln
University of Roma La Sapienza
Istituto Ortopedico Rizzoli
University of Bologna
Isala
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention 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. In addition, data of around 60-90 patients will be captured within the FURTHER Registry arm.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patient capable of giving informed consent * Age ≥ 18 years * Painful metastatic bone lesion (NRS \> 2) * Patient-localised pain with a distinct pathological substrate on recent CT/MRI * Target lesion location is sufficiently accessible for MR-HIFU to expect clinical response, as judged by the (intervention) radiologist * Participant has a reasonable performance score (KPS ≥ 50% or Zubrod/ECOG/WHO \< 3) * Life expectancy ≥ 3 months
Exclusion criteria
* Participant is not able to fit in the MR gantry * Need for surgery of targeted location due to (impending) pathological fracture * Unavoidable critical structures or dense tissues in target area * Contra-indications for MRI or sedation/anesthesia * Clinically relevant medical history or physical findings that could interfere with the patient's safety as judged by the treating physician * Participant enrolled in another clinical interventional study related to bone metastases treatment or pain relief treatment All patients meeting the FURTHER in- and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pain response - 14 days after completion of treatment | 14 days | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pain response - 14 days after inclusion | 14 days | 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. |
| Patient reported pain scores - patient pain diary | 21 days | 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. |
| Patient reported pain scores - BPI | on baseline, at 1, 2, 4 and 6 weeks, and at 3 and 6 months | 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. |
| Physician reported toxicity - CTCAE 5.0 | at 3 days, at 1, 2, 4 and 6 weeks, and at 3 and 6 months | 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 |
| Patient reported quality of life - EORTC BM22 | on baseline, at 1, 2, 4 and 6 weeks, and at 3 and 6 months | 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. |
| Patient reported quality of life - EORTC C15-PAL | on baseline, at 1, 2, 4 and 6 weeks, and at 3 and 6 months | 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. |
| Patient reported quality of life - EQ-5D-5L | on baseline, at 1, 2, 4 and 6 weeks, and at 3 and 6 months | 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. |
| Patient reported quality of life - PGIC | at 1, 2, 4 and 6 weeks, and at 3 and 6 months | 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. |
| Patient reported quality of life - HADS | on baseline, at 1, 2, 4 and 6 weeks, and at 3 and 6 months | 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. |
| Local tumour control | 3 and 6 months | Assessed using CT and/or MRI imaging at patient discretion at three and/or six months after completion of treatment. |
| Cost-effectiveness of the treatment | 6 months | A hypothetical diagnosis related group (DRG) will be calculated from the perspective of the statutory health insurance (SHI). |
Countries
Finland, Germany, Italy, Netherlands
Outcome results
None listed