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Will have community based assessment before and after radiotherapy to assess feasibility of using a clinical biomarker (thermal sensory testing) to predict treatment response

Thermal sensitivity testing: The area of CIBP and a corresponding unaffected (control) area will be assessed using warm and cool thermal rollers (Rolltemp, Somedic, Sweden). The control area will either be the contralateral side, or an area proximal to the affected site.

Clinical biomarker (thermal sensory testing)

Lesley Colvin, PhDFRCA FRCP

Marie Fallon, MD FRCP

If cancer spreads to bones it can be very painful, especially when trying to move around. One of the best treatments is radiotherapy, which has to be given in a cancer centre. Even with this treatment, only about half of people will get good pain relief, and that can take up to 6 weeks to work fully. If we know who is unlikely to benefit , then we can explore other forms of pain relief sooner, without having to go through radiotherapy unnecessarily.

We have found that there may be a very simple way to identify patients likely to get good pain relief, using a test of changes in temperature sensation over the painful bone. This study will explore whether this simple bedside test can be used in a community setting to identify which patients suffering from cancer induced bone pain will get good pain relief from radiotherapy.

Bone is the third most common site of metastatic disease, after liver and lung, with \~75 per cent of these patients suffering from related pain. Cancer-induced bone pain (CIBP) remains one of the major clinical challenges in palliative care, with a number of possible reasons for this. Bone pain can have a significant impact on physical, psychological and social functioning (and so overall quality of life). The mechanisms of CIBP are complex and may have unique characteristics that are different from neuropathic and inflammatory pain - this has clear implications for managing CIBP effectively. Current gold standard treatment for CIBP is palliative radiotherapy (XRT). Radiotherapy is the current standard treatment for CIBP, although only 55% of patients will achieve adequate analgesia from palliative radiotherapy, and this can take up to 6 weeks to work. There has been considerable interest in how clinical signs and symptoms in pain translate into underlying mechanisms, and how this may be used to direct treatment more effectively. The clinical assessment of somatosensory processing used for neuropathic pain can be extensive, and burdensome for frail patients.

The investigators have developed a modified assessment for use in patients with cancer, that can be used in a hospital setting. The investigators clinical pilot work used detailed phenotyping of CIBP, to try and better understand underlying mechanisms and detect changes in somatosensory processing. The investigators found that changes in temperature sensitivity may predict pain relief from XRT. Following on from this the investigators propose to develop a simple bedside tool, suitable for use in the community, which will potentially identify patients most likely to benefit from radiotherapy.

Development of this tool requires adequate validation and evaluation so that it can be used as an aid to deciding which patients are more likely to benefit from radiotherapy. In those patients unlikely to benefit, early identification would allow use of other symptom control strategies in the community, minimising the burden of unnecessary hospital attendance, and avoiding the acute pain flare that can occur with XRT.

The investigators hypothesis is that alterations in thermal sensitivity will reflect important changes in underlying pain neurobiology that will make that patient more, or less, likely to get effective analgesia from XRT. Assessment of CIBP There have been recommendations suggested for the use of pain measurement tools and methods in clinical practice to try and include the wider aspects of the pain experience (www.immpact.org). In patients with cancer, it is important to minimise any burden from assessment. We have therefore use a very a simple approach to try and capture the important elements of CIBP and its impact. This consists of a number of validated self report questionnaires (see below), plus a measurement of skin sensitivity to warm and cool (40°C, 25°C), as identified from our previous work as potential predictors of treatment response to XRT.

Self report measures include: the Brief Pain Inventory (BPI); The Short-Form McGill Pain Questionnaire (SF-MPQ-2); the Hospital Anxiety \& Depression Scale (HADS); the Distress Thermometer; the EORTC health-related quality of life questionnaire for bone metastases.

Patients with CIBP will be assessed prior to XRT, then at 2, 6 and 12 weeks after XRT.

Thermal Testing in Bone Pain (TiBoP)

An Exploratory Study to Develop and Evaluate a Simple Bedside Tool for Community Use to Identify Who is Most Likely to Benefit From Palliative Radiotherapy for Cancer Induced Bone Pain: Thermal Testing in Bone Pain (TiBoP)

A positive outcome is defined as: at least 30% reduction in BPI pain at 6 weeks AND no increase in opioid medication use within 6 weeks AND no toxicity from XRT at 2 weeks.

NHS Lothian

University of Edinburgh

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Combination of focused ultrasound and external beam radiotherapy

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.

combined radiotherapy and MR-HIFU

Helena M Verkooijen, MD, PhD

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.

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.

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).

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

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

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.

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.

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 \[Cleeland 1994\].

Toxicity/safety of the combined treatment will be assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Thermal Testing in Bone Pain (TiBoP)	NCT02887833	Cancer Induced ... Secondary Malig... Toxicity Due to... Pain	Clinical biomar...	18 Years - 100 Years	University of Edinburgh
Feasibility of Combined Focused Ultrasound and Radiotherapy Treatment in Patients With Painful Bone Metastasis	NCT04310410	Bone Metastases Bone Neoplasm Bone Lesion Bone Cancer Pain Cancer Induced ... Radiation Toxic... Quality of Life Tumor Neoplasm Metast...	combined radiot...	18 Years -	UMC Utrecht
Thermal Testing in Bone Pain (TiBoP)	NCT02887833	Cancer Induced ... Secondary Malig... Toxicity Due to... Pain	Clinical biomar...	18 Years - 100 Years	University of Edinburgh

Spots Global Cancer Trial Database for cancer induced bone pain