Clinical trial NCT03106675: MR Imaging- Guided High Intensity Focused Ultrasound (HIFU) Therapy of Bone Metastases
Official title: MR Imaging- Guided High Intensity Focused Ultrasound (HIFU) Therapy of Bone Metastases
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Bone Metastases
Bone Neoplasm
Bone Cancer
Bone Lesion
Keywords: HIFU
MR-HIFU
MRgFUs
MRI-intervention
Palliation
Lead sponsor: Turku University Hospital
Sponsor class: OTHER_GOV
First posted: 2017-04-10
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Potential participants are recruited by oncologist from oncology outpatient clinic. Pretreatment imaging with computer tomography and magnetic resonance imaging is performed to evaluate whether the patient is eligible for HIFU-treatment. Those eligible will continue to the treatment and unsuitable participants will continue in the study as a control group receiving radiation therapy.

Participants in these groups will have follow-up MRI:s, ct:s, laboratory exams and fill in VAS (visual analog scale) and health questionnaire SF-36 regularly. Also intake of pain medication will be followed.
Primary purpose: SUPPORTIVE_CARE

Brief summary: Bone metastasis give rise to major complications that lead to significant morbidity and impairment of life quality. The most common primary for bone metastasis is prostate, lung and breast carcinoma. These three have the highest cancer incidence in the USA with up to 85% prevalence of bone metastases at the time of death. Pain from these osseous lesions can be related to mechanical or chemical factors. Pressure effects on the periosteum or adjacent neural structures can cause local or radiating pain. Hemorrhage from local bone osteolysis by osteoclastic activity causes a local release of bradykinin, prostaglandins, histamine and substance P that can irritate the endosteal nerves as well as local nerves.

The life expectancy of patients with osseous metastatic disease is variable but can be substantially longer for patients with multiple myeloma, breast or prostate cancer. Therefore, finding an effective local therapy that can improve patient quality of life and can be done at a single outpatient sitting would be beneficial.

The current and emerging treatments for osseous metastases may be considered in several categories: radiotherapy, systemic chemotherapy (cytotoxic, hormonal and radionuclides), surgical stabilization and percutaneous tumor ablation. These treatments may be applied in isolation but also frequently in combination.

MRI Guided High Intensity Focused Ultrasound (HIFU) is a completely non-invasive technology for thermal ablation. HIFU is capable of concentrating ultrasonic pressure waves to a specified region without any physical penetration of the body. The converging ultrasonic pressure wave is converted to thermal energy at the specific depth, resulting in local heating at the focus. Temperature elevation is proportional to the proton resonance frequency shift, therefore MR imaging provides accurate technique for target definition and energy deposition control. MRI guided Focused Ultrasound therapy is being performed in treatment of uterine leiomyomas (fibroids). Recently the method has gained both AMAR authorization and FDA approval, and CE approval for that indication.

Clinical trials of HIFU in bone metastases have indicated that the method is safe and gives an effective reduction of patient pain. The short- and long-term effects on tumor volume and morphology do not seem to have been evaluated thus far.

The primary objective of this trial is to evaluate effectiveness of MRI guided HIFU in the treatment of metastatic bone tumors

Detailed description: Clinical Background

Bone metastasis give rise to major complications that lead to significant morbidity and impairment of life quality. The most common primary for bone metastasis is prostate, lung and breast carcinoma. These three have the highest cancer incidence in the USA with up to 85% prevalence of bone metastases at the time of death. Pain from these osseous lesions can be related to mechanical or chemical factors. Pressure effects on the periosteum or adjacent neural structures can cause local or radiating pain. Hemorrhage from local bone osteolysis by osteoclastic activity causes a local release of bradykinin, prostaglandins, histamine and substance P that can irritate the endosteal nerves as well as local nerves.

The life expectancy of patients with osseous metastatic disease is variable but can be substantially longer for patients with multiple myeloma, breast or prostate cancer. Therefore, finding an effective local therapy that can improve patient quality of life and can be done at a single outpatient sitting would be beneficial.

Current Treatment of Bone Metastases

The current and emerging treatments for osseous metastases may be considered in several categories: radiotherapy, systemic chemotherapy (cytotoxic, hormonal and radionuclides), surgical stabilization and percutaneous tumor ablation. These treatments may be applied in isolation but also frequently in combination.

External beam radiation therapy (EBRT) is one of the main treatments for osseous metastases. Radiation therapy creates its effect by destroying of the local tumor and inflammatory cells that are responsible for causing pain. Although the effect of radiotherapy to palliate pain and to control osseous metastatic disease is well established., there is significant relapse rate within patients who survived at least 12 weeks. Also the pain relief is often suboptimal leading to supplemental and persisting medication. Thus, the "net pain relief" less than the goal of pain relief for the total duration of life after treatment. Also, there is a limit on how much radiation can be given, this constitutes a problem in clinical oncology care.

Chemotherapy has a variable effect on bone metastases related to a number of neoplasm, drug and patient related factors. Newer systemic treatments with radionuclides and bisphosphanates have shown some success. More recently, the development of recombinant osteoprotegerin and an anti-parathyroid hormone-related protein monoclonal antibody represent promising new options for the treatment of patients with bone metastases. However, there are numbers of important factors to consider such as potential side effects of treatment and unanswered questions regarding the optimal use of systemic agents: when should treatment begin, how long must treatment be continued, and what are the optimal dose and schedule to achieve clinically meaningful anti-tumor effects?

Surgical therapy is essential in certain instances where mechanical strengthening is necessary such as an impending or occurred pathological fracture but it has little role in palliative therapy due to invasiveness and potential complications associated. Therefore, a more effective modality of local treatment for bone metastases could substantially improve quality of life.

More recently, percutaneous procedures for local tumor ablation such as radiofrequency ablation and cryotherapy have shown promise in the treatment of metastatic bone lesions.

MRI Guided High Intensity Focused Ultrasound (HIFU) is a completely non-invasive technology for thermal ablation. HIFU is capable of concentrating ultrasonic pressure waves to a specified region without any physical penetration of the body. The converging ultrasonic pressure wave is converted to thermal energy at the specific depth, resulting in local heating at the focus. Temperature elevation is proportional to the proton resonance frequency shift, therefore MR imaging provides accurate technique for target definition and energy deposition control. MRI guided Focused Ultrasound therapy is being performed in treatment of uterine leiomyomas (fibroids). Recently the method has gained both AMAR authorization and FDA approval, and CE approval for that indication.

Technical background: MR-guided intervention

Since the first report of MR-guided biopsy in 1986 there has been an increasing interest in MR-guided interventions. Technical barriers, such as the inaccessibility to the patient during imaging and the lack of MR-compatible instruments (needles, scissors, etc.) have largely been solved. Today the majority of MR-guided interventions are made in conventional closed-bore scanners alongside diagnostic imaging. Also, MRI guidance is a cost effective approach to perform these minimally invasive procedures and can in many cases replace the more invasive and in-patient based procedures.

New Possibilities: integration of MR imaging with therapy Until recently, control of destructive energy deposition has been an unresolved problem in tumor treatment. One of the greatest potentials of MRI is in monitoring the delivery of various destructive energies. Thermal monitoring is a particularly important application of interventional MRI. Thermal ablation techniques require not only good localization and targeting but also quantitative spatiotemporal control of energy deposition, which in turn requires monitoring of the thermal changes and the resulting tissue alterations.

Hyperthermia is based on slight temperature elevation (about 41° C), which requires relatively long homogenous thermal treatment of solid tumors. The main assumption of hyperthermia is that malignant cells have a higher sensitivity to thermal damage than normal ones. The temperature sensitivity of various MRI parameters (T1, diffusion, and chemical shift) can be exploited for detecting temperature changes within the critical temperature range. Compared with hyperthermia, thermal surgery uses temperatures above 55-60° C, but for a short period only.

Above 55-60 °C, proteins are denatured, and the resulting thermal coagulation causes irreversible tissue damage. Appropriate MRI sequences can demonstrate the normal margins surrounding thermal lesions, where the temperature elevation is still too low to cause cell necrosis, and, most importantly, can differentiate tissue phase transitions.

Since MRI enables monitoring, new possibilities have emerged for interstitial laser therapy, cryo- or RF-ablation and high-intensity focused ultra¬sound treatment of different tumors.

High-Intensity Focused Ultrasound (HIFU) The ability of the ultrasound imaging modality for guidance of minimally invasive procedures has been shown in various disorders but moreover, it has a significant potential to produce coagulation necrosis in exposed tissue by high-power focused sonication. By focusing high-power ultrasound beams at a distance from the source, total necrosis of tissues lying within the focal volume can be achieved without damage to the structures elsewhere in the path of the beam.

Since diagnostic ultrasound images are not sensitive enough to guide focused ultrasound thermal therapy, MRI has been used to guide this intervention. MRI thermometry based on temperature-dependent proton resonance frequency has been shown to accurately reflect thermal changes in tissue. Currently, two types of HIFU-methods are clinically used: point-by-point ablation and volumetric ablation, the latter considered more energy-efficient.

Clinical trials of HIFU in bone metastases have indicated that the method is safe and gives an effective reduction of patient pain. The short- and long-term effects on tumor volume and morphology do not seem to have been evaluated thus far.

Objectives of the study

MRI guided HIFU has been utilized to effect in treating metastatic and bening bone tumors. However detailed information upon treatment effect to pain, to the tumor volume and to the systemic immunological processes are lacking, and there are no prospective studies upon these issues. Furthermore, there is no randomized study comparing HIFU therapy to radiation therapy. There is no data upon HIFU therapy planning utilizing therapy planning software.

The primary objective of this trial is to evaluate effectiveness of MRI guided HIFU in the treatment of metastatic bone tumors:

* Safety: To further evaluate incidence and severity of adverse events associated with MRI-HIFU therapy using novel cooled technique.
* Effectiveness: To determine the effect of MRI-HIFU treatments of metastatic bone tumors. Efficacy will be determined by the level of pain relief (as measured by the Visual Analog Scale; VAS), decrease in analgesics/opiate and improved quality of life (as measured by SF36 questionnaire, in Finnish) from baseline up to 24-Weeks post HIFU treatment.

This study is designed as a prospective, two arm, nonrandomized study (Where one arm will consist of HIFU group and the other from RT group). Later on a wider randomized two arm study comparing outcomes between HIFU and RT could be executed. Furthermore, this study follows the "International Bone Metastases Consensus Working Party" on endpoint measurement for future clinical trials that was established in 2012 in conjunction with the American Society for Therapeutic Radiology and Oncology (ASTRO), the European Society for Therapeutic Radiology and Oncology (ESTRO), and the Canadian Association of Radiation Oncology (CARO)( Int J Radiat Oncol Biol Phys. 2012 Apr 1;82(5):1730-7. doi: 10.1016/j.ijrobp.2011.02.008. Epub 2011 Apr 12.)

Specific Objectives:

1. Pain relief. The change in the patient pain relief will be assessed with the Visual Analog Scale (VAS), whereas the treated patient quality of life will be assessed the quality of life questionnaire. These assessments will be performed at baseline, on treatment day, and at each follow up time point.
2. Additional data regarding dosage and frequency of analgesic consumption for the management of the metastatic bone tumor induced pain will also be collected.
3. Effect on systemic immunological processes, such as tumor markers and cytokines will be monitored via repeated blood samples.
4. Relative Safety will be evaluated using a common description of Significant Clinical Complications for patients treated in this study. This study will be performed on either the 1.5T or 3T MR scanners.
5. Temporal effect of HIFU to tissue as observed with longitudinal imaging.

The ultimate goal of this project is to establish a multidisciplinary mini-invasive environment using a 3 T MR imager with integrated high-intensity focused ultrasound.

Eventually, during the years to come, the goal is to develop and clinically validate the MR-guided HIFU-interventions and place the potential treatment option in a clinical perspective, i.e. with regard to cost, morbidity rate and outcome in following disorders

* metastatic bone disease
* cortical and intra-articular osteoid osteomas
* solitary aggressive (giant cell tumor) or malignant (plasmacytoma) lesions

Patient selection and pre -and postoperative imaging In this first phase, we include patients with intractable pain despite proper analgesics and radiotherapy treatment. These patients should not have more than three bone metastasis planned for treatment, and the source of pain should unambiguously localize to the metastasis that is considered to be sonicated. As this is a preliminary study, the anatomic location should be relatively easily accessible, i.e. the metastases should be located in the pelvic region, shoulders or in the extremities. Exclusion criteria include disease diffusely spread to bones, and the source of pain is not localized to the metastasis. Also, close proximity of a major nerve or artery is considered exclusion criteria. Other contraindications include ASA-class greater than II, when anesthesia during the procedure is required, allergy to MRI contrast medium or anesthetic agents.

MRI unit, HIFU-system and sonication. As a novel image guided therapy platform for a 3-T scanner (Ingenia, Philips Healthcare, Best, The Netherlands) we will utilize completely non-invasive MRI guided High Intensity Focused Ultrasound platform (Sonalleve, Philips Healthcare, Vantaa, Finland) to perform and study the treatment. The high intensity focused ultrasound (HIFU) tabletop harbors a 256- element phased array HIFU transducer (focal length of 140 mm, operating at 1.2 MHz). The system has different ellipsoidal treatment volumes with cross-sectional diameter from 2 to 12 mm.

The patient preparation includes preferably concise sedation e.g. with phentanyl and midazolam. However, the optimal pain relief is always individual, and is based on mutual agreement by the patient and the anesthesiologist specialized in pain relief.

After pre-sonication MR imaging, the targeted volume is defined by the radiologist, and the thermal effect is assessed by the vendor provided pulse-sequences (fast-field echo with echo planar imaging) that enable the proton resonance frequency shift (PRFS) MR thermometry method. The temperature should reach more than 55 degrees for each volume in order to achieve thermal coagulation that causes irreversible tissue damage.

Current status of the work The magnet and sonication instrumentation has been installed in early 2016, and currently the MRI is used for clinical examinations and for HIFU therapy of uterine myomas (fibroids).

Clinical significance MRI guided high-intensity focused ultrasound has the potential to become a cost-saving clinical application of MR as it integrates imaging with therapy. Lack of ionizing radiation, improved target visualization with reduced risk of injury, and have a direct impact on patient care, eventually leading to improved quality of life.

Institutional environment and resources South West Finland Imaging centre is the diagnostic hub of Turku University hospital with 60 academic radiologists and supporting staff. Department of Oncology has extensive experience in oncological research and related imaging. The team headed by Docent Roberto Blanco Sequeiros has access to the scanning facilities that will be used in the project. South West Finland Imaging centre will provide the software development tools and computers required for the project. In addition, Prof. Heikki Minn, director of department of oncology is the main collaborator and Co-PI in the research. This will facilitate adequate patient selection and monitoring of research subjects. Close collaboration will be performed with Karolinska institutet where similar project is underway with the leadership of Professor Seppo Koskinen.

Ethical Considerations Corresponding ethical approval for the proposed clinical studies has been obtained from the ethical committee at Turku University Hospital, Turku. Clinical studies will start only after organizational permit is gained. Relevant patient information will be anonymized and protected in separate electronical storage which will be protected with encryption and researcher specific login data.

Funding The project has initial funding from the EVO-funding. Additional funding has been applied from the Swedish ALF- 2017 funding (Anslag forskning, utveckling och utbildning)

Eligibility criteria: Inclusion criteria

* Bone metastasis
* Maximum three metastasis to be treated
* Pain that clearly locates to certain metastatic lesion
* Intolerable pain regardless of radiotherapy and adequate pain medication

Exclusion criteria from HIFU-treatment group

* ASA-group III or higher or anesthesia during procedure is required
* Metastasis not safely reachable with HIFU

Exclusion criteria from the study

- Diffusely spread metastasis on bone

Primary outcomes:
measure: Change in subjective pain relieve
timeFrame: 6 months
Secondary outcomes:
measure: Change in tumor morphology in imaging
timeFrame: 6 months
measure: Change in pain medication usage
timeFrame: 6 months
measure: Change in general subjective health
timeFrame: 6 months
measure: Change in cytokine-levels
timeFrame: 1 month
measure: Change in tumor-specific markers
timeFrame: 1 month
Other outcomes:
measure: Adverse effects
timeFrame: 6 months
Locations:
Study officials:
affiliation: TYKS/VSKK (Turku University Hospital / Proper Finlands Imaging center)
name: Gaber Komar, PhD, MD
role: STUDY_DIRECTOR
affiliation: TYKS Oncology (Turku University Hospital)
name: Mira Huhtala, MD, PhD student
role: PRINCIPAL_INVESTIGATOR
affiliation: TYKS Oncology
name: Heikki Minn, Professor, MD
role: STUDY_DIRECTOR
affiliation: TYKS/VSKK (Turku University Hospital / Proper Finlands Imaging center)
name: Teija O Sainio, MSc, PhD Student
role: PRINCIPAL_INVESTIGATOR
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