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Focused Ultrasound and RadioTHERapy for Noninvasive Palliative Pain Treatment in Patients with Bone Metastasis

Periodic Reporting for period 3 - FURTHER (Focused Ultrasound and RadioTHERapy for Noninvasive Palliative Pain Treatment in Patients with Bone Metastasis)

Reporting period: 2022-01-01 to 2022-12-31

Sixty-five percent of patients with advanced cancer develop bone metastases, with pain as a common and devastating consequence. Metastatic bone pain strongly interferes with quality of life and daily functioning of patients and their families. It affects mobility, productivity and independence, creating an extra burden for informal carers. Current standard local treatment of metastatic bone disease consists of external beam radiotherapy, which is effective in only 65% of patients.
The FURTHER project sets out to demonstrate that Magnetic Resonance Guided High Intensity Focused Ultrasound (MR-HIFU), is an effective and cost-effective alternative or additional standard treatment option for patients with painful bone metastases, providing faster and long lasting pain relief. FURTHER also addresses scientific and socio-economic barriers that currently limit widespread adoption of MR-HIFU in order to raise awareness, and acceptance of MR-HIFU and promote its uptake into medical guidelines for palliative treatment of cancer induced bone pain.
In order to reach this main aim, the FURTHER consortium sets out to:
• Generate Level I evidence to demonstrate that short-term pain relief is superior in treatment regimens with MR-HIFU (alone or in combination with External Beam Radiation Therapy) as compared to standard-of-care treatment with External Beam Radiation Therapy (EBRT). A multicentre randomized controlled trial is designed to compare outcomes of EBRT, MR-HIFU in combination with EBRT, and MR-HIFU alone, for palliation in patients that present with painful bone metastases. Primary outcome of the trial will be pain at 14 days after randomization (WP1, 2, 3).
• Develop a prediction model that can be used to identify patients who are likely to benefit from MR- HIFU or radiotherapy in order to contribute to the (cost-) effective use of the treatment (WP2,3).
• Investigate the added value of integrating MR-HIFU into a comprehensive pain management pathway that does not only focus on the pathophysiological component of pain but also takes into account psychophysical aspects of pain. A pilot study will be performed, in which standard EBRT and MR-HIFU treatment is compared to EBRT or MR-HIFU treatment incorporated in a comprehensive pain management pathway. By doing so, we can determine whether MR-HIFU should be presented to the patient as a single modality treatment or as part of a comprehensive pain management pathway (WP3, 4).
• Determine the cost-effectiveness of pain palliation using approaches based on MR-HIFU and EBRT. In both clinical studies, we will collect Patient Reported Outcomes as well as qualitative and quantitative data on the impact of treatment on the social context of the patient, such as partners and care-giving relatives. Combined with cost data, of the MR-HIFU treatment, but also of the comprehensive pain management strategy, this will allow us to study the relation between cost and changes in quality of life compared to reference treatment using EBRT (WP 2, 3, 4).
• Identify strategies for the adoption of MR-HIFU into standard care, mapping and analysing socio- economic factors that influence uptake and access to MR-HIFU treatment (WP3, 5).
• Raise awareness and acceptance of MR-HIFU as a treatment option for pain palliation amongst patients, care professionals and informal carers (WP6).
The research initiative involves two Randomized Controlled Trials (RCTs), namely the Further trial and Pathway trial. During the first period, ethical approval for Randomized Controlled Trial 1 (RCT1) was obtained in the Netherlands and Italy. In the second period, the RCT1 protocol was approved in Germany and Finland. However, due to unforeseen circumstances, the UK partner's participation was terminated, leading to a halt in ethical approval in the UK amid the ongoing pandemic. To address this, a mitigation strategy was adopted under the leadership of the University of Bologna. An amendment was submitted and approved, introducing a registry for patients with painful bone metastases treated with High-Intensity Focused Ultrasound (HIFU) who are not part of RCT1.

Ethical approval for the registry has been secured in the Netherlands, Finland, and Bologna. Meanwhile, the FURTHER trial has made progress, with preliminary data generated, a database created, and all necessary trial and patient questionnaires developed and translated. A technical expert visited partner institutions to optimize the MR-HIFU workflow, addressing local logistics and approaches.

Trial monitors conducted initiation visits, either physically or virtually, at all clinical partner institutions. The impact of COVID-19 on clinical trial treatments led to a substantial delay in inclusions, with 23 patients enrolled by December 31, 2022. The accrual rate was lower than initially expected, prompting a detailed analysis of the eligibility of the radiotherapy-referred patient population for MR-HIFU.

Preparations for cost-effectiveness studies were completed, including a literature review, identification of observer groups, and parameter identification for cost-effectiveness analyses. Costing models for MR-HIFU and radiotherapy treatments were constructed, resulting in a publication on MR-HIFU costs from a hospital perspective in the German context.

A pan-European survey was conducted to identify barriers to the deployment of anesthetic services for MR-HIFU treatment. This involved clinical and patient stakeholders and informed the development of an integrated pain pathway following an evidence synthesis exercise.

Another European survey, using a Group Concept Mapping approach, identified barriers to the adoption of MR-HIFU treatment for painful bone metastases. Over 40 participants were involved in the brainstorming and sorting phases of the process.

The project achieved communication milestones with the launch of a project website and finalization of a communication plan. Several abstracts, presentations, and manuscripts have been published, covering Pre-FURTHER trial results, trial design, and the health economic aspects of HIFU.

Consortium meetings were held in the Netherlands and Italy, with a virtual meeting added under COVID-19 restrictions. Following the pandemic, an in-person consortium meeting was held in Italy in October 2022, signaling a return to face-to-face collaboration.
The research initiative comprises two Randomized Controlled Trials (RCTs): Further trial and Pathway trial. Ethical approval for Randomized Controlled Trial 1 (RCT1) was secured in the Netherlands and Italy during the first period, followed by approval in Germany and Finland in the second period. Unforeseen circumstances led to the termination of the UK partner's participation, pausing ethical approval in the UK. A mitigation strategy, led by the University of Bologna, introduced a registry for non-RCT1 patients with painful bone metastases treated with High-Intensity Focused Ultrasound (HIFU). Ethical approval for the registry was obtained in the Netherlands, Finland, and Bologna. Progress includes FURTHER trial advancements, optimization of MR-HIFU workflow, initiation visits, a pan-European survey on anesthetic services, a survey on MR-HIFU adoption barriers, and communication milestones. Consortium meetings, including a virtual session due to COVID-19, resumed in-person collaboration in Italy in October 2022.
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