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Bone Diseases

Patients with bone metastasis causing pain.

HIFU is the use of focused ultrasound energy to penetrate through soft tissue and causes localized high temperatures (55°C to 70°C) for a few seconds within the target producing well defined regions of protein and nerve denaturation, irreversible cell damage, and coagulative necrosis.

High Intensity Focused Ultrasound

Hervé Trillaud, Professor

This study is to confirm the safety and technical of MRI guided High Intensity Focused Ultrasound (HIFU) for Palliation for Pain of Skeletal Metastases.

MRI guided high intensity focused ultrasound uses ultrasound to heat and thermally ablate tissue. The MRI system identifies the ultrasound path and monitors heat rise in the tissue. The goal of the study is to show treatment safety and effectiveness. MR-guided HIFU will be performed in patients who pass inclusion/exclusion criteria.

Bone is the third most common site of metastases spread after the liver and the lungs, with a great incidence in breast, prostate, lung, kidney and thyroid cancers. For example, 90% of patients dying from breast cancer and most of patients with advanced prostate cancer suffer from bone metastases, which are frequently responsible of chronic pain and lead to an increase in morbidity and mortality with pathological fractures, compression syndrome and hypercalcemia..Moreover, the increasing longevity of patients with cancer resulting from the improvement of the effectiveness of the treatments leads to a higher incidence and prevalence of metastating bone lesions.

Palliative treatment with management of pain and improvement of quality of life remains the first goal of therapy. Current treatments options include systemic drug therapy (chemotherapy, hormonal therapy, analgesics and bi-phosphonates), local invasive treatment (surgery), local mini-invasive treatment with interventional radiological techniques (cimentoplasty, cryotherapy and radiofrequency ablation) and radiation therapy.

External-beam radiation therapy remains the current standard of care for patients with bone metastases in first intention. However, up to 20-30 % of patients treated do not experience pain relief and recurrence of pain appear in 27 % after treatment. Moreover radiation treatment is limited due to accumulation of dose. Since few years, cryotherapy and percutaneous radiofrequency ablation have shown good results in management of pain with bone metastases, however these techniques are still invasive.

In MRI-guided High Intensity Focused Ultrasound (HIFU), the ultrasound generated by the transducer is focused into a small focal tissue volume at specific target locations. During treatment, the beam of focused ultrasound energy penetrates through soft tissue and causes localized temperatures elevation up 55-70°C for a few seconds within the target producing well defined regions of irreversible protein denaturation, cell damage, and coagulative necrosis. A single exposure of focused ultrasound energy is called a "sonication." Multiple sonications are necessary to ablate the targeted tissue. Tight focusing is designed to limit the ablation to the targeted location.

Applying HIFU energy to a patient's lesion requires treatment planning, targeting of the ultrasound (US) beam to desired locations and monitoring of the energy delivery. In some applications this can be performed using diagnostic ultrasound imaging in combination with the HIFU. While diagnostic US provides some anatomical details and helps with procedure planning and treatment targeting, it does not provide 3D planning, means of measuring the temperature increase generated by HIFU, or metrics for quantifying the energy/dose delivered to the treatment zone. Currently, only MR imaging can provide a validated non-invasive temperature measurement and thermal dose quantification in the treated tissue. Furthermore, these real-time MR temperature measurements can be used to control the HIFU system to deliver optimal temperatures to the target locations. The Philips MR-guided focused ultrasound system will provide real-time tissue temperature mapping in multiple planes and control of the temperature delivering dose to the target location. Recent advances in MR temperature mapping make it possible to achieve temperature accuracy of 1°C in stationary soft tissues.

Pilot Study for Palliation of Pain in Bone Metastases by MR-HIFU

Pilot Study for the Treatment of Bone Metastases by High Intensity Focused Ultrasound Guided by MRI to Perform Pain Palliation

Technical efficacy of HIFU for treatment of bone metastasis as assessed by a change in the medication and pain scores

Safety of HIFU for treatment of the bone metastasis as determined by adverse event reporting

Safety of HIFU for treatment of the bone metastasis as determined by formation of intended lesions.

Philips Healthcare

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

High intensity focused ultrasound energy, delivered under the guidance of the MR images (MgFUS) allows for a predefined amount of energy to be delivered in the desired target (Metastasis). Bone readily absorbs focused ultrasound energy resulting in a thermo-related neurolysis of the periostium with consequent pain palliation. The amount of energy delivered can be modulated with the objective to penetrate cortical space and obtain necrosis of the metastasis thus preventing local recurrence.

Focused ultrasound energy is accumulated into the target tissue (skeletal metastasis) thanks to the real time guidance of the MR images.

MRgFUS

Alessandro Napoli, MD, PhD

Magnetic Resonance guided Focused Ultrasound (MRgFUS) has demonstrated to be effective for pain control through thermally-induced cell death and periosteal denervation caused by cortical heating relative to acoustic energy absorption. There is also evidence that a high intensity focused ultrasound beam can penetrate through the cortical bone to the medullary space, producing thermal necrosis of cancer tissue. However, little is known about the potential effects of MRgFUS as first line therapeutic modality for pain palliation in skeletal metastases.

Our hypothesis sought to assess the clinical performance of MRgFUS primary treatment of painful bone metastases and determine the potential of this technique for local tumor control.

Unlike previous studies, in which patients were enrolled for MRgFUS treatment because of the failure of other therapies, our study will be conducted in patients not previously treated with EBRT to the targeted lesion.

This is an important new feature, especially given the advantages of MRgFUS, such as lack of ionizing radiation, the ability to conduct treatment on an outpatient basis and the possibility to repeat the treatment as necessary.

Primary Pain Palliation in Bone Metastases Treated With Magnetic Resonance-guided Focused Ultrasound

Primary Pain Palliation and Local Tumor Control in Bone Metastases Treated With Magnetic Resonance-guided Focused Ultrasound

Patients will be monitored for major or minor adverse events

necrosis of the actual lesion will be analyzed according to area on non-perfused volume at the end of the procedure

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Pilot Study for Palliation of Pain in Bone Metastases by MR-HIFU	NCT01117246	Secondary Malig...	High Intensity ...	18 Years - 80 Years	Philips Healthcare
Thermal Testing in Bone Pain (TiBoP)	NCT02887833	Cancer Induced ... Secondary Malig... Toxicity Due to... Pain	Clinical biomar...	18 Years - 100 Years	University of Edinburgh
Primary Pain Palliation in Bone Metastases Treated With Magnetic Resonance-guided Focused Ultrasound	NCT01693770	Secondary Malig...	MRgFUS	18 Years - 90 Years	University of Roma La Sapienza
Primary Pain Palliation in Bone Metastases Treated With Magnetic Resonance-guided Focused Ultrasound	NCT01693770	Secondary Malig...	MRgFUS	18 Years - 90 Years	University of Roma La Sapienza
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 secondary malignant neoplasm of bone