Feasibility of Combined Focused Ultrasound and Radiotherapy Treatment in Patients With Painful Bone Metastasis - the PRE-FURTHER Study -
Phase: PHASE1
Conditions: Bone Metastases, Bone Neoplasm, Bone Lesion, Bone Cancer, Pain, Cancer Induced Bone Pain, Radiation Toxicity, Quality of Life, Tumor, Neoplasm Metastasis
Sponsor: UMC Utrecht

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RESEARCH PROTOCOL 
February 2019 
 
 
Feasibility of combined Focused Ultrasound 
and Radiotherapy treatment in patients with 
painful bone metastasis  
- the PRE-FURTHER study - 
 
H.M. Verkooijen, MD, PhD1 
C.T.W. Moonen, PhD2 
L.W. Bartels, PhD3 
C. Bos, PhD3 
M.N.G.J.A. Braat, MD4 
E.J. Vonken, MD, PhD4 
N. Kasperts, MD5 
W.S.C. Eppinga, MD5 
J.J.C. Verhoeff, MD, PhD5 
H.H.B. Vaessen, PhD6 
C.J. Ferrer3 
M.F. Boomsma, MD, PhD7 
E. Phernambucq, MD, PhD8 
I.M. Nijholt, PhD7, previously1 
J.A.C van Osch9 
I.M. Verpalen, MD7 
H.R. Naber, MD10 
 
1 Trial Office Imaging Division, University Medical Center Utrecht, The Netherlands 
2 Research group Image Guided Molecular Interventions, University Medical Center Utrecht, The Netherlands 
3 Image Sciences Institute, University Medical Center Utrecht, The Netherlands 
4 Department of Radiology, University Medical Center Utrecht, The Netherlands 
5 Department of Radiation Oncology, University Medical Center Utrecht, The Netherlands 
6 Department of Anesthesiology, University Medical Center Utrecht, The Netherlands 
7 Department of Radiology, Isala hospital, Zwolle, The Netherlands 
8 Department of Radiation Oncology, Isala hospital, Zwolle, The Netherlands 
9 Department of Medical Physics, Isala hospital, Zwolle, The Netherlands 
10 Department of Anesthesiology, Isala hospital, Zwolle, The Netherlands 

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PROTOCOL TITLE 
Feasibility of combined Focused Ultrasound and 
Radiotherapy treatment in patients with painful bone 
metastasis 
Protocol ID 
NL68441.041.19 
Short title 
PRE-FURTHER 
Version 
2 
Date 
16-02-2019 
Project leader 
 
H.M. (Lenny) Verkooijen, MD PhD 
Professor Evaluation of Image-guided Interventions 
Imaging Division 
University Medical Center Utrecht  
Email: H.M.Verkooijen@umcutrecht.nl 
Tel: +31 88 75 595 75 
Principal investigators 
 
UMC Utrecht 
H.M. (Lenny) Verkooijen, MD PhD 
Professor Evaluation of Image-guided Interventions 
Imaging Division 
University Medical Center Utrecht  
Email: H.M.Verkooijen@umcutrecht.nl 
Tel: +31 88 75 595 75 
 
Isala 
M.F. Boomsma, MD PhD 
Radiologist 
Isala Zwolle 
Email: m.f.boomsma@isala.nl 
Tel: +31 38 424 7202 
Sponsor  
University Medical Center Utrecht 

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Subsidising party 
European Commission Horizon 2020 programme 
Independent expert 
M.P.W. Intven, MD, PhD Radiation oncologist 
University Medical Center Utrecht 
Email: M.Intven@umcutrecht.nl 

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PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Head of Department: 
Prof. dr. P.R. Luijten 
Medical-scientific division manager 
 
 
 
Project leader: 
H.M. Verkooijen, MD PhD 
Professor Evaluation of Image-guided Interventions 
  
 
 
 
 

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TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE ................................................................................ 10 
1.1 
Bone metastases ....................................................................................................... 10 
1.2. 
Current standard of care: external beam radiotherapy (EBRT) ................................ 10 
1.3. 
MR-HIFU treatment ................................................................................................... 11 
1.4 
The FURTHER study ................................................................................................. 12 
1.5 
Combining EBRT and MR-HIFU: the PRE-FURTHER study ................................... 12 
1.6 
IDEAL recommendations .......................................................................................... 14 
2. 
OBJECTIVES .................................................................................................................... 16 
2.1 
Primary objective ....................................................................................................... 16 
2.2 
Secondary objectives ................................................................................................ 16 
3. 
STUDY DESIGN ............................................................................................................... 17 
4. 
STUDY POPULATION...................................................................................................... 19 
4.1 
Population (base) ...................................................................................................... 19 
4.2 
Inclusion criteria ......................................................................................................... 19 
4.3 
Exclusion criteria........................................................................................................ 20 
4.4 
Sample size calculation ............................................................................................. 21 
5. 
TREATMENT OF SUBJECTS .......................................................................................... 22 
5.1 
Investigational product/treatment .............................................................................. 22 
5.2 
Use of co-intervention ................................................................................................ 22 
5.2.1 
EBRT .................................................................................................................. 22 
5.2.2 
Pain medication .................................................................................................. 22 
6. 
INVESTIGATIONAL PRODUCT ....................................................................................... 24 
6.1 
Name and description of investigational product ...................................................... 24 
6.2 
Summary of findings from non-clinical studies ......................................................... 25 
6.3 
Summary of findings from clinical studies ................................................................. 25 
6.4 
Summary of known and potential risks and benefits ................................................ 25 
7. 
METHODS ........................................................................................................................ 27 
7.1 
Study parameters/endpoints ..................................................................................... 27 
7.1.1 
Main study parameter/endpoint ......................................................................... 27 
7.1.2 
Secondary study parameters/endpoints ............................................................ 27 
7.1.3 
Other study parameters ..................................................................................... 27 
7.2 
Randomisation, blinding and treatment allocation .................................................... 27 
7.3 
Study procedures ...................................................................................................... 28 
7.4 
Withdrawal of individual subjects .............................................................................. 29 
7.4.1 
Specific criteria for withdrawal ........................................................................... 30 
7.5 
Replacement of individual subjects after withdrawal ................................................ 30 
7.6 
Follow-up of subjects withdrawn from treatment ...................................................... 30 
7.7 
Premature termination of the study ........................................................................... 30 
8. 
SAFETY REPORTING...................................................................................................... 31 
8.1 
Temporary halt for reasons of subject safety ............................................................ 31 
8.2 
Definitions in safety reporting .................................................................................... 31 

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8.2.1 
Investigational medical device ........................................................................... 31 
8.2.2 
Device deficiency (DD) ....................................................................................... 31 
8.2.3 
Adverse event (AE) ............................................................................................ 31 
8.2.4 
Adverse device effect (ADE) .............................................................................. 31 
8.2.5 
Serious adverse event (SAE) ............................................................................. 32 
8.2.6 
Serious adverse device effect (SADE) .............................................................. 32 
8.2.7 
Unanticipated serious adverse device effect (USADE) ..................................... 32 
8.3 
Safety reporting ......................................................................................................... 32 
8.3.1 
Recording of adverse events ............................................................................. 32 
8.3.2 
Reportable events .............................................................................................. 33 
8.3.3 
Report by whom ................................................................................................. 33 
8.3.4 
Report to whom .................................................................................................. 33 
8.3.5 
Reporting timelines............................................................................................. 33 
8.3.6 
Reporting standards ........................................................................................... 33 
8.4 
Causality assessment ................................................................................................ 33 
8.5 
Follow-up of adverse events ..................................................................................... 35 
8.6 
Data Safety Monitoring Board (DSMB) / Safety Committee ..................................... 35 
9. 
STATISTICAL ANALYSIS ................................................................................................ 36 
10. 
ETHICAL CONSIDERATIONS ..................................................................................... 37 
10.1 
Regulation statement ................................................................................................. 37 
10.2 
Recruitment and consent .......................................................................................... 37 
10.3 
Benefits and risks assessment, group relatedness .................................................. 38 
10.4 
Compensation for injury............................................................................................. 39 
10.5 
Incentives ................................................................................................................... 39 
11. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .......................... 40 
11.1 
Handling and storage of data and documents .......................................................... 40 
11.2 
Monitoring and Quality Assurance ............................................................................ 40 
11.3 
Amendments .............................................................................................................. 41 
11.4 
Annual progress report .............................................................................................. 41 
11.5 
Temporary halt and (prematurely) end of study report ............................................. 41 
11.6 
Public disclosure and publication policy .................................................................... 41 
12. 
STRUCTURED RISK ANALYSIS ................................................................................. 42 
12.1 
Potential issues of concern ....................................................................................... 42 
12.2 
Synthesis ................................................................................................................... 46 
13. 
REFERENCES .............................................................................................................. 47 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
ASADE 
Anticipated Serious Adverse Device Effect 
BPI 
Brief Pain Inventory 
CCMO 
Central Committee on Research Involving Human Subjects; in Dutch: Centrale 
Commissie Mensgebonden Onderzoek 
CRF 
Case Report Form 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DD 
Device Deficiency 
DNA 
Deoxyribonucleic Acid 
DSMB 
Data Safety Monitoring Board 
EBRT  
External beam radiotherapy 
EU 
European Union 
EM 
Equivalent Minutes 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation; in Dutch: Algemene Verordening 
Gegevensbescherming (AVG) 
Gy 
Gray 
H2020 
European Commission Horizon 2020 Programme 
IB 
Investigator’s Brochure 
IC 
Informed Consent 
IDEAL 
Innovation, Development, Evaluation, Assessment and Long term evaluation 
KPS 
Karnofsky Performance Score 
METC 
Medical research ethics committee (MREC); in Dutch: medisch-ethische 
toetsingscommissie (METC) 
MR 
Magnetic Resonance 
MR-HIFU  
Magnetic Resonance Image guided High Intensity Focused Ultrasound 
MRI 
Magnetic Resonance Imaging 
NRS 
Numeric Rating Scale 
PREM 
Patient Reported Experience Measure 
PRESENT Prospective Evaluation of Interventional Studies on Bone Metastases 
PRFS 
Proton Resonance Frequency Shift 
PSA 
Procedural Sedation and Analgesia 
QA 
Quality Assurance 

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RCT 
Randomized Controlled Trial 
RT 
Radiotherapy 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event  
Sponsor 
The sponsor is the party that commissions the organisation or performance of 
the research, for example a pharmaceutical 
company, academic hospital, scientific organisation or investigator. A party that 
provides funding for a study but does not commission it is not regarded as the 
sponsor, but referred to as a subsidising party 
UAVG 
Dutch Act on Implementation of the General Data Protection Regulation; in 
Dutch: Uitvoeringswet AVG 
UMC 
University Medical Center 
USADE 
Unanticipated Serious Adverse Device Effect 
WMO 
Medical Research Involving Human Subjects Act; in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 

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SUMMARY 
 
Rationale: Magnetic Resonance Image guided High-Intensity Focused Ultrasound (MR-
HIFU) is a non-invasive technique, which may induce rapid induction of pain relief in patients 
with painful bone metastases. In 2019, an international, H2020 funded randomized controlled 
trial (FURTHER) will be started comparing MR-HIFU with the current standard of care, 
external beam radiotherapy (EBRT), and the combination of both modalities in terms of rapid 
and long lasting pain relief. 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: Prospective case series (n = 6 - 10),  stage I and IIA study according to the 
Innovation, Development, Evaluation, Assessment and Long term evaluation (IDEAL) 
recommendations. 
Study population: 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). 
Intervention: 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. 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. 
Main study parameters/endpoints: The main outcome of this study is feasibility of the 
procedure, in terms of plannability 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.  
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness: In terms of benefits, patients participating in this study may experience 
a more rapid and longer lasting pain relief as a result of the MR-HIFU intervention. In terms 
of burden, patients in most cases will need to pay an extra visit to the hospital, undergo a 
rather lengthy additional intervention (MR-HIFU treatment), under conscious sedation. In 
addition, they are contacted regularly by phone. Serious adverse events due to the combined 
treatment are not to be expected. 
 
 

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1. 
INTRODUCTION AND RATIONALE 
 
1.1 Bone metastases 
Bone metastases are a common manifestation of advanced cancer. Due to rising cancer 
incidence rates and improved survival, the number of cancer patients living long enough to 
develop bone metastases is increasing rapidly. Depending on the location of the primary 
tumour approximately 30-80% of patients with advanced cancer develop bone metastases, 
with pain as a common and devastating consequence (Ripamonti, 2000, 2001; Portenoy, 
2011; Lipton, 2010; Coleman 2006; Suva 2011). Metastatic bone pain strongly interferes with 
quality of life and daily functioning of patients and their families (Mantyh, 2014, Paice and 
Ferrell, 2011). Intermittent episodes of extreme pain, either occurring spontaneously or by 
movement of the affected limb, are often referred to as “breakthrough” pain, as it breaks 
through the opiate pain palliation regime, and is refractory to pharmacologic pain treatment. 
Metastatic bone pain affects mobility, productivity and independence, placing an increasing 
burden on health-care and social care systems.  
 
1.2. Current standard of care: external beam radiotherapy (EBRT) 
The current standard of care for patients with uncomplicated painful bone metastases 
includes palliative locoregional treatment using external beam radiotherapy (EBRT) 
(Ripamonti, 2010; Chow, 2014; Huisman, 2015), often in combination with systemic therapy 
and analgesics. EBRT alleviates pain through induction of deoxyribonucleic acid (DNA) 
damage, leading to tumour shrinkage, and through inhibition of the release of chemical pain 
mediators. Multiple randomized controlled trials and several systematic reviews over the past 
30 years have demonstrated the efficacy of radiotherapy in palliating pain from 
uncomplicated bone metastases (Jones, 2014). Overall, approximately 25% of patients can 
expect to have complete pain relief whereas a total of 60-70% of patients can expect some 
response to radiotherapy. However, time to optimal symptom control, even after short 
courses of radiotherapy, is usually measured in weeks to months after radiation treatments 
are delivered, as clearly demonstrated in the case of pain relief from bone metastases. On 
average, it takes four weeks for EBRT to induce adequate pain relief. In the Dutch Bone 
Trial, including 1100 patients, only 71% of patients reported adequate pain response (van 
der Linden, 2004; Westhoff, 2015). In the large hospital based PRESENT (prospective 
evaluation of interventional studies on bone metastases; METC 13-261) cohort of unselected 
patients with bone metastases, 64% of patients experienced pain response following EBRT 
(van der Velden, 2018). Moreover, approximately 50% of responders experience recurrent 
pain. Radiotherapy retreatment of non-responders or those with recurrent bone pain is 
limited by cumulative doses of radiation delivered to sensitive structures surrounding the 

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bone metastases. In addition, re-irradiation is only effective in a small majority (58%) of 
patients (Huisman, 2012). 
In summary, there is a clear clinical need for a treatment that provides rapid pain relief with a 
lasting effect, at least to bridge the time it takes for EBRT to take effect. In addition, since 30-
40% percent of patients do not respond to EBRT, alternative treatment strategies could be of 
added value for the large group of patients that we are currently unable to treat effectively. 
 
1.3. MR-HIFU treatment  
Pain palliation may be substantially improved by including magnetic resonance image guided 
high intensity focused ultrasound (MR-HIFU) as alternative or in addition to EBRT. MR HIFU 
is a non-invasive outpatient treatment modality that delivers acoustic energy to heat lesions 
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 
(Jolesz, 2008). The biological mechanism of pain relief induced by MR-HIFU treatment has 
not been completely elucidated, although it is generally assumed that periosteal denervation 
induced by cortical heating plays a major role. The importance of this therapy is that it offers 
a low-risk, non-invasive, focal therapy, avoiding side-effects to surrounding normal tissue that 
occur with radiation therapy. In contrast to EBRT, it does not require computed tomography 
(CT) for treatment planning or therapy.  
Preliminary clinical studies on the use of MR-HIFU for palliation of painful bone metastases 
demonstrated excellent response rates and safety (Catane, 2007; Gianfelice, 2008; Napoli, 
2013; Huisman, 2014). Hurwitz et al (2014) reported results of a multicenter randomized 
placebo-controlled trial to evaluate safety and efficacy of MR-HIFU for treating bone 
metastases in patients with persistent or recurrent pain. This study demonstrated that MR-
HIFU is a safe and effective, non-invasive treatment for alleviating pain caused by bone 
metastases. Response to MR-HIFU was typically rapid, with about two-thirds of responses 
seen within days after treatment (Hurwitz, 2014). A recent single-centre matched-pair study 
showed that MR-HIFU provides a similar overall treatment response rate but faster pain relief 
compared with EBRT and thus has the potential to serve as the first-line treatment for painful 
bone metastasis in selected patients (Lee, 2017). University Medical Center Utrecht 
participated in a multicenter pilot study (METC 12-035) in which an early improvement in 
pain and quality of life in patients with painful bone lesions treated with MR-HIFU was 
shown (Harding, 2018). These studies were, however, performed in patients who were 
ineligible, or who failed or declined radiation. As such, there is a lack of evidence that 
supports the uptake of MR-HIFU as a standard (first-line) treatment option and alternative to 

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EBRT, even though these results show that MR-HIFU has the potential to provide added 
value in standard care. 
 
1.4 The FURTHER study 
Hitherto, no Phase III clinical trial has been conducted in which EBRT and MR-HIFU have 
been compared as a first-line treatment. Thus, strong evidence and context is lacking for 
wide-spread implementation of MR-HIFU into routine care. 
A consortium of partners from 5 European countries and the Focused Ultrasound Foundation 
recently joined forces to provide the evidence base to stimulate the uptake of MR-HIFU as 
a first line treatment option in clinical guidelines for the treatment of cancer induced bone 
pain. Reaching this ambitious goal will require a demonstration of the added value of 
MR-HIFU in standard care with comprehensive outcome testing that will convince a wide 
variety of stakeholders of the added value of including and reimbursing MR-HIFU as part 
of standard care and a feasible alternative for the golden standard EBRT treatment. 
The FURTHER consortium will undertake a three armed phase III multicenter randomized 
controlled trial (RCT) and a pain management pathway pilot. The multicenter RCT is 
designed to compare outcomes of EBRT, MR-HIFU alone and EBRT in combination with 
MR-HIFU, for palliation in patients that present with painful bone metastases. By 
combining the two modalities in one RCT arm the hypothesis can be tested whether the 
combined treatment has superiority over either modality alone with regard to overall pain 
response. 
 
1.5 Combining EBRT and MR-HIFU: the PRE-FURTHER study 
There are several hypotheses about the possible synergistic effect of EBRT and MR-
HIFU. By combining both modalities, a substantial proportion of patients with painful 
bone metastases are expected to experience early pain relief and improved response 
durability, while all of the tumour tissue receives radiation.  
Additionally, it is recognised that radiation and heat both induce tumour-specific immune 
responses (Wattenberg 2014; Udono 1993; Milani 2002; Hurwitz 2010).  
The putative main mechanism of pain relief by EBRT involves the inactivation of 
osteoclasts to change the microenvironment of bone resorption followed by sterilization 
of cancer cells to reduce tumor-induced compression (Hartsell, 2007). The direct 
mechanism of action of EBRT is damage to DNA of tissues, including both single strand 
and double strand DNA breaks, originating mostly from different oxygen radicals. The 
mechanism of action of MR-HIFU is coagulative necrosis and apoptosis of tissue due to 
heat leading to rapid and durable pain relief from immediate periosteal nerve ablation 

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and thermal necrosis of the targeted bone tumor followed by remineralization of the 
trabecular bone and bone healing a few months later. Since the mechanism of action of 
EBRT and MR-HIFU differ, MR-HIFU provides an alternative means to overcome 
radioresistance and is recommended for patients with bone metastasis for whom 
radiotherapy (RT) is considered to have failed (Hurwitz, 2014). 
 
Since the mechanism of action of EBRT and MR-HIFU differ, the two methods may be 
synergistic in first-line, or when applied nearly simultaneously. Heat-induced coagulative 
ablation is the main action of MR-HIFU, hence its pain palliation effect is expected to be 
rapid. However, heat distribution is often spatially heterogeneous in bone metastases 
because of the fact that absorption of ultrasound energy depends on many factors 
including the degree of bone lysis or formation, and incident ultrasound angle. Therefore, 
it might be that the, more long-term, systemic responses of EBRT of the tumor and its 
microenvironment, reduction of tumor-induced compression and inactivation of 
osteoclasts, can be augmented by local ablation of periosteal nerve ablation by MR-
HIFU.  
 
Some other effects should be mentioned:  
- Hyperthermia (temperatures 42-45°C) beyond the ablated area results in 
complementary radiosensitization (reduction of hypoxia; inhibition of DNA repair 
mechanisms) (van der Zee, 2000; Dababou, 2018) thereby increasing the risk of 
damage to surrounding tissue. 
- Coagulative ablation by MR-HIFU (temperatures around 60°C) also may lead to 
reduction/elimination of local perfusion leading to hypoxia of the treated area. This 
may render subsequent EBRT less efficient (less production of oxygen radicals).  
Because of the above arguments, our patients will first undergo the EBRT treatment 
followed by MR-HIFU with an interval of at least three hours.   
 
In the PRE-FURTHER study University Medical Center (UMC) Utrecht and Isala Zwolle will 
collaborate in determining the feasibility of the EBRT/MR-HIFU combination treatment. As 
part of the multicenter RCT design, both treatments should not be more than 4 days apart, 
but the aim is to minimize this time by optimizing hospital logistics. The benefits of the 
expected earlier pain relief when both modalities are combined, are substantial, 
considering the relatively short life expectancy of these patients.  
 

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Until now the combined EBRT and MR-HIFU treatment was only applied to patients with 
radiation refractory metastatic bone pain with an interval of at least several weeks 
between the two treatments. Hitherto, no information on feasibility is available when the two 
modalities are combined within a time frame of 4 days. 
 
We may have to decide that we will not include the combined treatment in the FURTHER 
RCT, when hospital logistics hampers us from providing the combined treatment within a 
defined time frame, when patients are not willing to undergo the combined treatment or when 
the combined treatment leads to serious adverse events which are the result of combining 
EBRT and MR-HIFU,  
 
1.6 IDEAL recommendations 
This pilot study will be set up according to the IDEAL recommendations (McCulloch 2009; 
Verkooijen 2017). These recommendations provide direction for reporting and evaluation of 
innovative surgical procedures which are being undertaken for the first time, and for adoption 
of new procedures in other centers and by other teams. IDEAL is an acronym for the five 
stages that complex interventions go through, namely Innovation, Development, Evaluation, 
Assessment and Long term evaluation.  
Stage 1 demonstrates feasibility and absence of unexpected detrimental effects. The initial 
patients are usually highly selected on an individual basis. Feasibility, duration and 
complication are reported for a small number of patients. These reports should contain clear 
anonymous details of the patient, their condition, the rationale and background for use of the 
procedure, exactly what was done, and adequate details of relevant outcomes.  
After Stage 1 has shown technical feasibility, without major unexpected toxicities or 
complications, the technique enters Stage 2a. 
Stage 2a aims to refine the technique and to optimize the work-flow. Outcomes of this stage 
are technical feasibility and safety. With practitioners maintaining confidence, the new 
approach becomes a practical alternative to the standard procedure. Reporting during this 
stage needs to include: selection criteria and proportion of eligible patients selected; a clear 
description of the procedure and each modification, with timing; and relevant outcomes, with 
recognized standard definitions of important categories, such as specific complications. 
Transition to stage 2b (Evaluation or Exploration) is justified by improvements in procedure 
times and the avoidance of adverse events, with major refinements of the method completed. 
This stage consists of a larger series of consecutive patients. Stage 3 (Assessment) aims to 
answer the essential question: Is the clinical efficacy of this intervention better than the 
standard treatment? Comparative studies, preferably with a randomized component, are 
favored. Stage 4 (Long term evaluation) starts when the effectiveness of new intervention 

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has been demonstrated and the intervention is implemented in daily clinical practice. This 
pilot study is a combination of stage 1 (Idea) and stage 2a (Development).  
 

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2. 
OBJECTIVES 
 
2.1 
Primary objective 
 To assess the feasibility of combining MR-HIFU and EBRT in a 4 day time window for the 
treatment of painful bone metastases from the perspective of  
1. the patient (patient tolerance) 
2. hospital logistics (standardisation of the procedure) 
 
2.2 
Secondary objectives  
 To assess the pain reducing capabilities of the combined treatment:  
Pain response:  
 rapidity of pain relief 
 duration of pain relief  
 pain medication used 
 To assess the safety profile of the combined treatment. 
 

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3. 
STUDY DESIGN 
 
This study will be a prospective development study (IDEAL stage 1 and 2a) (McCulloch, 
2009; Verkooijen, 2017) performed at the UMC Utrecht and Isala Zwolle. A group of 6-10 
patients with painful bone metastases will be studied to evaluate feasibility and logistics of 
the combined EBRT MR-HIFU treatment within a 3 hours - 4 day time window.  
 
Participating doctors will be informed about the study and will be asked to inform possible 
eligible patients about its existence. If the patient is considered to be eligible for MR-HIFU by 
the treating physicians and investigators and when the patient is willing to participate, the 
investigator or an authorized delegate will take over and inform the patient in more detail 
about the study, explaining the study design and procedures and collecting informed consent 
and baseline data. 
The inclusion preferably takes place shortly after the patient has been diagnosed and before 
treatment is started.  
 
Patients who fulfil all inclusion criteria, none of the exclusion criteria, and sign an informed 
consent will first receive the standard of care, single or multiple fraction EBRT, followed by 
MR-HIFU within a 3 hours - 4 day time window.   
 
The optimal logistic approach for administering both treatments will be assessed and 
protocolled. For this purpose, we will test several treatment schedules and make adjustments 
when needed. We will aim for the shortest time interval possible between the two treatments 
with a minimum interval of 3 hours and we set out to minimize additional hospital visits for 
participating patients. 
 
During a follow-up period of 4 weeks, patients will be contacted by phone to retrieve 
information about their level of pain and pain medication around 3 days and 1, 2, 3 and 4 
weeks after the MR-HIFU treatment.  
 
A general flowchart of the study is given in the figure on the next page for both single and 
multiple fraction EBRT. 

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4. 
STUDY POPULATION 
 
4.1 Population (base)  
The study population will consist of male and female adults (age ≥ 18 years) with painful 
bone metastases who have given informed consent. This is a group of (often elderly) 
patients, with a limited life expectancy, in whom maintenance of quality of life and pain 
control is of utmost importance.  
 
In the UMC Utrecht, the subjects will be recruited from the PRESENT cohort. In PRESENT, 
patients planned for radiation treatment of bone metastatic disease at the department of 
Radiation Oncology of the UMC Utrecht are included (around 400 per year).  
In Isala patients will be recruited from patients that visit the outpatient clinic of the department 
of Radiation Oncology. In Isala, approximately 600 patients present annually to the 
department of Radiation Oncology for the treatment of painful bone metastases. In about one 
third of these patients the metastases are located outside the spine or the cranium. 36% of 
these 200 patients (72 patients annually) were estimated to be eligible for MR-HIFU 
treatment on the basis of a random sample of 50 patients.  
 
4.2 Inclusion criteria 
In order to be eligible to participate in this study, a subject must meet all of the following 
criteria: 
 
Criteria 
How Measured 
Men and women with age ≥ 18 years 
Birth date 
Patient capable of giving informed consent and able 
to attend study visits 
Physician’s interview 
Uncomplicated painful bone metastases 
Physician’s examination / radiology 
Weight < 140kg and able to fit in the MRI gantry 
Physician’s examination / patient history 
Radiologic evidence of bone metastases from any 
solid tumor 
Radiology 
Pain is localized to the targeted area, or is likely to be 
referred pain arising from the targeted area  
Physician’s examination / patient history 
Pain related to the target lesion is refractory to less 
invasive treatments for pain relief 
Physician’s interview and examination 
Multiple metastatic lesions, with one predominantly 
painful lesion (>=2 points higher pain score than 
other lesions). The lesion should be clearly 
distinguishable from other painful lesions. 
Radiology / patient history 
Device accessible tumors: extremities (excluding 
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joints), pelvis, shoulders, posterior vertebral spine 
below L5, in selected cases ribs and sternum 
Target lesion maximum dimension ≤ 8cm 
Radiology 
Intended target volume visible by non-contrast MR 
imaging 
Radiology 
Distance between target and skin ≥ 1cm  
Radiology 
Numeric Rating Scale (NRS) score >= 4 or 
equivalent 
NRS 
Life expectancy >3 months 
Physician’s examination  
 
4.3 Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from participation 
in this study: 
 
Exclusion Criteria 
How Measured 
Planned treatment lesion is a primary bone tumor or 
due to lymphoma, multiple myeloma, or leukemia. 
Patient history 
Communication barrier present 
Physician’s interview / patient history 
Patient enrolled in another clinical study related to 
bone metastases treatment or pain relief treatment 
Physician’s interview / patient history 
Unable to tolerate required stationary position during 
treatment despite adequate pain medication 
Physician’s interview / examination / positioning 
test in MRI before treatment 
Need for surgery 
Radiology 
Pregnant woman 
Pregnancy test / patient history 
Pain related to target lesion is predominantly due to 
fracture or impending fracture 
Physician’s examination / radiology 
Pain related to target lesion is due to involvement of 
a neighboring major nerve by the metastatic tumor 
(cord or nerve compression) 
Physician’s examination / radiology 
Target < 3cm from bladder / bowel / nerve along the 
beam path and < 1cm in the plane orthogonal to the 
beam 
Radiology 
Target in contact with hollow viscera 
Radiology 
Target located in skull, joints, ribs (when HIFU beam 
overlapping with lung), spine (excluding sacrum 
which is allowed) or in most cases sternum 
Radiology 
Internal or external fixation device along the 
proposed HIFU beam path or at the target 
Physician’s examination / radiology 
MRI contraindicated (e.g. paramagnetic implants, 
pacemaker, claustrophobia) 
 
Patient history 
MRI contrast agent contraindicated (e.g. previous 
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Exclusion Criteria 
How Measured 
anaphylaxis or Glomerular Filtration Rate < 20 
ml/min/1.73m2) 
Sedation contraindicated 
Laboratory tests / patient history 
Previous surgery or minimally invasive treatment at 
targeted site within the last three months 
Patient history 
Clinically relevant medical history or abnormal 
physical findings that could interfere with the safety 
of the participant as judged by the treating physician 
or investigator 
Physician’s interview / patient history 
Karnofsky performance score (KPS) < 60% 
Physician’s interview 
Oligometastatic disease planned for curative 
treatment 
Physician’s interview / patient history 
Indication for stereotactic radiotherapy (e.g. patients 
with radioresistent histology such as renal cell, 
melanoma, sarcoma metastases) 
Physician’s examination / radiology 
History of photodermatoses (of the skin overlying the 
target area) 
Patient history / physician’s examination 
Need for remineralisation 
Physician‘s examination 
Previous radiation to same site 
Patient history 
 
4.4 
Sample size calculation 
The total number of patients included in this pilot study will be 6-10 patients. The main 
objective of the current study is to determine feasibility of combining EBRT and MR-HIFU 
within a 3 hour - 4 day time window. As this is a first-in-man study there is no data present to 
perform a formal sample size calculation. We will closely monitor unexpected side effects. 
Changes in the protocol will be made where appropriate. 
 
 
 

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5. 
TREATMENT OF SUBJECTS 
 
5.1 
Investigational product/treatment 
The intervention that will be studied is single or multiple fraction EBRT in combination with 
MR-HIFU within a 3 hour - 4 day time window. The combined treatment is aimed at rapid and 
persistent relief of metastatic bone pain. For more information on the Sonalleve MR-HIFU 
Bone metastases Therapy System we refer to the Investigator’s brochure.  
 
5.2 
Use of co-intervention 
5.2.1 
EBRT 
In a first step, patients will undergo EBRT according to the standard of care on a priority base 
within maximally 7 days after they visit the outpatient clinic of the Department of Radiation 
Oncology. Patients undergo a planning CT scan, as part of standard care, in treatment 
position. 
EBRT is provided as single fraction radiotherapy or multiple fraction radiotherapy. According 
to the American Society for Radiation Oncology (2012) evidence-based guidelines for the 
management of bone metastases, a single fraction of 8 Gray (Gy) has an equivalent pain 
relief quality indicator compared to longer courses of radiotherapy, including 5 or 6 
fractions of 4 Gy and 10 fractions of 3 Gy (Lutz et al, 2014). However, multiple fraction 
radiotherapy may have a larger contribution to local tumor control and is therefore often 
used in patients with a longer life expectancy. The above dose fractionation schemes are 
recommended as quality indicators of palliative radiotherapy by the American National 
Quality Measures for EBRT for bone metastases. Acute and late side effects of 
radiotherapy for bone metastases are generally similar with single fraction versus multi 
fraction regimens, with some studies showing decreased acute side effects in patients 
receiving single-fraction radiotherapy. Time to pain relief also appears similar, with an 
optimal time to measure pain relief of 2 months after the completion of palliative 
radiotherapy. 
5.2.2 
Pain medication 
Subjects should receive pain medication if and as required by their symptoms, both before 
and after the combined EBRT and MR-HIFU treatment. The amount of pain medication used 
is part of the secondary endpoints of the study, and should be recorded at baseline before 
treatment and during the follow-up after treatment.  
Pain medication used for treatment-related pain shall be noted in a separate Data Element in 
the CRF and in Concomitant Medication Forms. The fact that the medication was used for 

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treatment related pain is marked on the Concomitant Medication Forms, and the use of this 
medication will not be considered in the assessment of the pain response. 
 
 
Patients can continue to use chemotherapy, targeted therapies (e.g. angiogenesis inhibitors) 
or bisphosphonates if they are already using them. The treatment type and the date the 
treatment was started/stopped will be recorded. 
 
During the MR-HIFU treatment the patient will be under conscious sedation. This will enable 
adequate pain control and ensure a stable patient position during treatment. The sedatives 
used are at the preference of the anaesthesiologist/sedation specialist. 
 
 
 
 

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6. 
INVESTIGATIONAL PRODUCT  
 
6.1 Name and description of investigational product 
The Profound MR-HIFU Sonalleve System integrates a high intensity phased array 
focused ultrasound transducer with a magnetic resonance (MR) imaging system and 
electromechanical transducer positioning system to deliver spatially and temporally 
controlled ultrasound energy and thermal heat to tissues non-invasively. The MR system 
is used to provide images to plan the therapy, and to guide and monitor the thermal 
ablation with thermal imaging during the treatment.  
The MR-HIFU system consists of: 
 HIFU Therapy Console, where treatment planning, treatment control and post-
treatment operations are performed; 
 Generator Cabinet that houses the control electronics and the 256-channel ultrasound 
generator with individually programmable amplitude and phase; 
 Patient Tabletop that houses the electromechanical transducer positioning system, the 
phased array 256-channel ultrasound transducer immersed in a liquid bath, and 
integrated radiofrequency surface and wrap-around coils for MR imaging. 
 
Patient contact materials are described in the Investigator’s Brochure. The users are 
required to be trained for safety, system/treatment workflow and quality assurance (QA) 
procedures.  
 
The Profound Sonalleve MR-HIFU system used in Isala and UMC Utrecht is a CE-
marked device for pain palliation of bone metastases. They were manufactured by 
Philips Medical Systems Oy, Vantaa, Finland. The systems will be traceable by their 
serial number and the Device History Records maintained by the manufacturer. One 
Sonalleve MR-HIFU device is available at each study location.  
Traditionally, the Profound Sonalleve MR-HIFU device allows physicians to heat and 
ablate tissue under MR image guidance. Bone metastases cause bone destabilization 
(due to destruction) leading to stimulation of the mechanosensitive receptors in the 
periosteum (outer bone covering). HIFU treatment will aim at ablating the periosteum and 
thus reducing the localized bone pain. Ablation can be performed with volumetric 
techniques, which are designed to allow heating of larger zones or cells in one 
sonication. During a sonication, the transducer applies heat in a continuous manner to 
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are placed within a target treatment area to sonicate the targeted bone. Full treatment is 
performed by stepping through several treatment cells with cooling times between each 
sonication. Each HIFU ablation is performed with user selected ultrasound power set to 
achieve sufficient tissue heating to ablate the periosteal nerves, typically achieved in the 
temperature range 55-70°C. Heating of the surrounding tissue can be monitored by MR 
temperature mapping. The duration of the exposures linked with the cell size are fixed by 
the system. 
Three different ablation approaches will be used to ablate the periosteum, i.e., the near-
field approach, the direct approach and the soft-tissue approach. The main factors 
determining choice of ablation approach are the presence of cortical destruction, tissue 
in the far field and safety concerns. In patients with an intact cortex at metastasis level 
ablation of the metastasis is not possible. In that case the periost is ablated by heating 
the cortex. In patients with a (partly) destructed cortex it is unclear which part of the 
periost is still intact. The tumor itself and the overlying periost will be ablated. All three 
approaches aim for pain reduction.    
The Profound Sonalleve MR-HIFU system displays real-time temperature data overlaid 
on anatomical MR images, accumulated thermal dose information, and the ultrasound 
therapy parameters such as transmitted output power, frequency, and timing. 
Additionally, the operator can select specific thermal areas to obtain temperature 
readouts. The temperature display is updated every 3 seconds with new information.   
 
For more details about the system, please refer to the Investigator’s Brochure.  
 
6.2 
Summary of findings from non-clinical studies 
See Investigator’s brochure for the summary of findings from non-clinical MR-HIFU studies 
(pages 17 - 24). 
 
6.3 
Summary of findings from clinical studies 
See chapter 1.3 and Investigator’s brochure for the summary of findings from clinical MR-
HIFU studies (pages 25 - 30). 
 
6.4 
Summary of known and potential risks and benefits 
The Profound Sonalleve MRI-HIFU system is able to elevate temperatures at the bone 
interfaces, inside the bone and inside the bone metastasis with fast acquisition of thermal 
maps covering a large volume (including the skin), and with continuous heating of adjacent 
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sufficient information about the location of temperature elevation, volume of the ablation, and 
the temperature and thermal dose behavior of the heated tissue. With the device the 
temperature of the bone surface can be elevated and a part of the soft tissue ablated to the 
extent that provides a significant improvement to the symptoms experienced by the patient. 
 
The risks are HIFU physics and clinical practice dependent rather than specific HIFU device 
dependent. The highest risk is unintended heating of tissue causing burns. 
The Sonalleve device is equipped with several safety measures to reduce the risks.  
The system offers e.g. real-time feedback to inform the operator of various safety 
parameters. The user can monitor for: 
 Undesired temperature elevations in off-focal and focal areas. 
 A significant drop in transmitted power. 
 A significant drop in temperature versus time curve at the focus 
 
The ultrasound system will automatically shut down if: 
 The transducer heats to critical temperatures. 
 The measured output power is higher or substantially lower than the requested power. 
 High levels of reflected/backscattered power are detected in the amplifiers. 
 Any system control element fails to respond correctly to a control request. 
 
The sonication can also be shut down manually by the Patient Emergency Stop Button, the 
operator controlled Safety Device, or the stop button in the User Interface. A sonication shut 
down is indicated both by the user interface and by an indicator light on the operator console. 
A manual reset or other action by the operator is required to continue use of the system after 
a safety shutdown or use of the stop button by a patient. 
 
The duration of the treatment is dependent on the area which needs to be ablated. In 
general, it takes one to two hours to treat the average patient with one or more painful bone 
metastases. Since EBRT only takes up to 20 minutes and there is no need for sedation, 
patients could experience the MR-HIFU treatment as more cumbersome. Based on the 
results from previous studies we have valid reason to tell our patients that, even though 
MR-HIFU is more cumbersome, it is expected to lead to much faster pain relief and 
perhaps even longer lasting pain relief in the majority of patients.  
 
 

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7. METHODS 
 
7.1 
Study parameters/endpoints 
7.1.1 
Main study parameter/endpoint 
The main outcome of this study is the feasibility of the combined procedure in terms of 
 Patient tolerance: assessed with a short patient reported experience measure (PREM).  
 Optimal logistics and standardization of the procedure (treatment planning, extra hospital 
visits). 
 
7.1.2 
Secondary study parameters/endpoints 
The secondary study endpoints of this study are: 
 The pain reducing capabilities of the combined treatment: 
Pain scores related to the target lesion treated as measured by patient’s self-assessment 
on a Numerical Rating Scale (NRS) in the Brief Pain Inventory (BPI) questionnaire 
(Cleeland 1994) post inclusion and post treatment by phone around day 3, 7, 14, 21 and 
28 after the MR-HIFU treatment. The BPI is a well-established, thoroughly validated tool 
for pain self-assessment, which can be considered a gold standard. Patients will rate the 
worst and average pain that they felt from the treated area over the last three days, and 
the pain they feel currently.  
 
 Safety of the combined treatment. 
 
7.1.3 
Other study parameters 
Several patient and tumor related parameters will be assessed such as age, gender, 
primary tumor, Karnofsky performance score (KPS), location of targeted volume, number 
of symptomatic bone metastases, date of diagnosis of primary tumor, date of diagnosis of 
first symptomatic bone metastasis, prior systemic treatments received, current systemic 
therapy, prior radiotherapy received (including dose/fractionation schedule and dates) and 
MR-HIFU treatment data such as treatment duration (time in scanner, sonication time) 
and amount of sonications.  
 
7.2 
Randomisation, blinding and treatment allocation 
This study is a non-randomized pilot study. All eligible subjects will first receive EBRT 
followed by MR-HIFU. As such, there will be no blinding of the study participants and their 
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7.3 
Study procedures 
At least one day after the visit to the outpatient clinic the investigator or an authorized 
delegate will phone the patient to inform him/her about eligibility for the study. In case of 
eligibility the investigator or an authorized delegate will ask the patient for oral informed 
consent. If the patient is willing to participate in the study the investigator or an authorized 
delegate will make an appointment with the patient when the informed consent will be 
signed. This will preferably coincidence with the patient’s next visit to the hospital but latest 
before the preoperative screening and the MR-HIFU treatment. When written informed 
consent is given, the investigator or an authorized delegate will collect standard baseline 
demographic factors, disease history, and previous therapy for bone metastasis from 
participating patients and response to prior radiotherapy when applicable, as well as help the 
patient to fill out the BPI and record total analgesic consumption during the previous 24 
hours. 
 
Patients will be formally enrolled in the study following written informed consent, after 
inclusion criteria are met and none of the exclusion criteria apply. Patient screening and 
enrollment will be recorded on the Screening / Enrollment log.  Information on withdrawal will 
also be recorded in this log. The Screening / Enrollment log will be used for subject 
accountability. 
 
Treatment procedure 
Usually single fraction EBRT is performed on the day of the patient’s first visit to the 
outpatient clinic of the Radiation Oncology Department. The MR-HIFU treatment will be 
subsequently applied within the shortest time interval possible but at the latest 4 days after 
EBRT. 
 
Multiple fraction EBRT is usually started within one to maximally seven days after the 
patient’s first visit to the outpatient clinic of the Radiation Oncology Department. When 
multiple fraction EBRT is indicated, the MR-HIFU treatment will be minimally 3 hours and 
maximally 4 days after the last multiple fraction session. 
 
Planning of MR-HIFU treatment is more challenging than planning of EBRT. Most of the time 
treatment planning can be done on the basis of the available (CT) images.  
During the MR-HIFU treatment procedure, an intravenous catheter will deliver MR contrast 
media and medications (such as sedation and analgesics if required) within the MR room. 
The need for a urinary bladder cathether is determined by the treating physician. The body 
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patients will be asked to lie still on the HIFU patient table inside the MRI magnet. The 
operator will locate the target tissue and mark the volume to be treated using MRI images. 
The operator starts the treatment and monitors the progress of the treatment with MR 
thermal and dose maps according to the Sonalleve Instructions for Use to ensure safety.  
Due to the pain associated with the MR-HIFU procedure, anaesthesiologists/sedation 
specialists need to be involved to provide procedural sedation and analgesia. The pre-
operative screening will be preferably take place on a day that the patients is already in the 
hospital. 
Patients will receive sedation during treatment administered by an anaesthesiologist or 
sedation specialist. Medication given will be a combination of pain medication (e.g. rapifen) 
and anesthetics (e.g. propofol in combination with lidocaine for injection) at the preference of 
the anaesthesiologist/sedation specialist. The use of medication for treatment-related pain 
shall be recorded. 
 
Following the MR-HIFU procedure, a set of MR images of the target region will be acquired 
with the use of a MR contrast agent. When the whole planned volume has been treated, the 
operator stores the full treatment history and technical data as available from the Profound 
Sonalleve MR-HIFU device. The patients are then conducted to the recovery room for 
medical supervision. Before discharge, follow-up instructions will be given to the patient. 
 
We expect that by gaining more clinical experience with the combined treatment, we will be 
able to provide the combined treatment in a faster, patient-friendly way. 
 
Follow-up 
Follow up will be approximately 3, 7, 14, 21 and 28 days after the MR-HIFU treatment. The 
investigator or an authorized delegate will contact patients by phone to ask them whether 
any possible complications/adverse events have occurred. He/she will also interview the 
patient about their pain medication use and fill in the BPI questionnaire. At the third day after 
the MR-HIFU treatment the investigator will also inquire about the patient’s experience with 
the combined treatment.   
 
7.4 
Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without any 
consequences. The investigator can decide to withdraw a subject from the study for urgent 
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7.4.1 
Specific criteria for withdrawal  
Patients will exit the study during the follow-up period if they have been referred to alternative 
palliative treatments 
of the treated metastasis 
for medical reasons 
(such as 
radiopharmaceuticals, surgery, cryotherapy or radio-frequency ablation).  
 
7.5 
Replacement of individual subjects after withdrawal 
If a subject withdraws from the study for any reason prior to MR-HIFU treatment, the subject 
will not count towards total enrollment and may be replaced with another subject. 
 
7.6 
Follow-up of subjects withdrawn from treatment 
Follow-up of withdrawn subjects will take place by their treating physician, according to 
standard clinical practice. 
 
7.7  Premature termination of the study 
The study will be prematurely terminated if any of the following predetermined conditions are 
met; a serious adverse event related to the study procedures resulting in death, a serious 
adverse event related to the study procedures that is life threatening, a serious adverse 
event related to the study procedures that results in persistent or significant disability or an 
obviously higher incidence of (wound) complications than normally anticipated. 
Additionally, the study may be terminated for any other perceived safety concern based on 
clinical judgment, including but not limited to a higher than anticipated rate for any 
component of the primary or secondary endpoints or unexpected serious adverse events.  
 
 
 

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8. 
SAFETY REPORTING 
 
8.1 
Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the study if 
there is sufficient ground that continuation of the study will jeopardise subject health or 
safety.  The sponsor will notify the accredited METC without undue delay of a temporary halt 
including the reason for such an action. The study will be suspended pending a further 
positive decision by the accredited METC. The investigator will take care that all subjects are 
kept informed.  
 
8.2 
Definitions in safety reporting 
According to EU Directive 90/385/EEC, 93/42/EEC (last amended Directive 2007/47/EC) and 
the ‘Guidelines on medical devices: MEDDEV 2.7/3 revision 3’, the following definitions are 
used in the safety reporting: 
8.2.1 
Investigational medical device 
Medical device being assessed for safety or performance in a clinical investigation. The 
investigational medical device in the PRE-FURTHER study is the Sonalleve MR-HIFU 
system. 
8.2.2 
Device deficiency (DD) 
Inadequacy of an investigational medical device related to its identity, quality, durability, 
reliability, safety or performance. This may include malfunctions, use error, or inadequacy in 
the information supplied by the manufacturer. 
8.2.3 
Adverse event (AE) 
Adverse events are defined as any untoward medical occurrence, unintended disease or 
injury or any untoward clinical signs (including an abnormal laboratory finding) in subjects, 
users or other persons whether or not related to the investigational medical device. 
This definition includes events related to the investigational device or the comparator or 
the procedures involved. For users or other persons, this definition is restricted to events 
related to investigational medical device.   
8.2.4 
Adverse device effect (ADE) 
Adverse event related to the use of the investigational medical device. 
This includes any adverse event resulting from insufficiencies or inadequacies in the 
instructions for use, the deployment, the implantation, the installation, the operation, or any 
malfunction of the investigational medical device. This also includes any event that is a result 
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8.2.5 
Serious adverse event (SAE) 
Adverse event that: 
a) led to a death, injury or permanent impairment to a body structure or a body function. 
b) led to a serious deterioration in health of the subject, that either resulted in: 
- 
a life-threatening illness or injury, or 
- 
a permanent impairment of a body structure or a body function, or 
- 
in-patient hospitalization or prolongation of existing hospitalization, or 
- 
a medical or surgical intervention to prevent life threatening illness. 
c) led to foetal distress, foetal death or a congenital abnormality or birth defect. 
A planned hospitalization for a pre-existing condition, or a procedure required by the study 
protocol, without a serious deterioration in health, is not considered a serious adverse event. 
8.2.6 
Serious adverse device effect (SADE) 
Adverse device effect that has resulted in any of the consequences characteristic of a 
serious adverse event. 
8.2.7 
Unanticipated serious adverse device effect (USADE) 
Serious adverse device effect which by its nature, incidence, severity or outcome has not 
been identified in the current version of the risk analysis report. 
Anticipated SADE (ASADE): an effect which by its nature, incidence, severity or outcome has 
been previously identified in the risk analysis report. 
 
8.3 
Safety reporting 
8.3.1 
Recording of adverse events 
All adverse (device) events reported spontaneously by the patient or observed by the 
investigator or his staff will be recorded up to 1 month after the MR-HIFU treatment. 
All complications and adverse events will be documented in detail according to the latest 
version of the Common Toxicity Criteria for Adverse Events (CTCAE). The physicians and 
investigators will evaluate reported (S)AEs for determination of seriousness and causal 
relationship with the fact that EBRT was combined with MR-HIFU. In those instances where 
it cannot be determined if the event is linked to the combined treatment, this will also be 
noted on the patient file event report. The following aspects will be recorded for each event: 
 Grade according of the AE according to the CTCAE;  
 Date of onset; 
 Date of recovery; 
 If possible, attribution factor; 
 Intervention (action taken); 
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8.3.2 
Reportable events 
The following events are considered reportable events in accordance with Annex 7, section 
2.3.5 and Annex X, section 2.3.5 of the above mentioned Directives (18): 
- any SAE; 
- any device deficiency that might have led to a SAE if: 
a) suitable action had not been taken or 
b) intervention had not been made or 
c) circumstances had been less fortunate. 
- new findings/updates in relation to already reported events. 
8.3.3 
Report by whom 
Reportable events will be reported by the sponsor (authorized representative or another 
person or entity). 
8.3.4 
Report to whom 
Reportable events will be reported by the sponsor to the accredited METC that approved the 
study protocol. 
8.3.5 
Reporting timelines 
The investigator will report all SAEs to the sponsor without undue delay after obtaining 
knowledge of the events. The sponsor will report the SAEs to the accredited METC that 
approved the protocol, within 7 days of first knowledge for SAEs that result in death or are 
life threatening followed by a period of maximum of 8 days to complete the initial preliminary 
report. All other SAEs will be reported within a period of maximum 15 days after the sponsor 
has first knowledge of the serious adverse events. 
8.3.6 
Reporting standards 
The METC will be notified through the web portal Toetsingonline. 
 
8.4 
Causality assessment 
The relationship between the use of the medical device (including the medical - surgical 
procedure) and the occurrence of each adverse event will be assessed and categorized. 
Each SAE will be classified according to five different levels of causality. The following 
definitions to assess the relationship of the serious adverse event to the investigational 
medical device or procedures will be used: 
1) Not related: relationship to the device or procedures can be excluded when: 
- the event is not a known side effect of the product category the device belongs to or of 
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- the event has no temporal relationship with the use of the investigational device or the 
procedures; 
- the serious event does not follow a known response pattern to the medical device (if 
the response pattern is previously known) and is biologically implausible; 
- the discontinuation of medical device application or the reduction of the level of 
activation/exposure - when clinically feasible - and reintroduction of its use (or increase 
of the level of activation/exposure), do not impact on the serious event; 
- the event involves a body-site or an organ not expected to be affected by the device or 
procedure; 
- the serious event can be attributed to another cause (e.g. an underlying or concurrent 
illness/clinical condition, an effect of another device, drug, treatment or other risk 
factors); 
- harms to the subject are not clearly due to use error. 
In order to establish the non-relatedness, not all the criteria listed above might be met at the 
same time, depending on the type of device/procedures and the serious event. 
2) Unlikely: the relationship with the use of the device seems not relevant and/or the event 
can be reasonably explained by another cause, but additional information may be 
obtained. 
3) Possible: the relationship with the use of the investigational device is weak but cannot be 
ruled out completely. Alternative causes are also possible (e.g. an underlying or 
concurrent illness/clinical condition or/and an effect of another device, drug or treatment). 
Cases where relatedness cannot be assessed or no information has been obtained 
should also be classified as possible. 
4) Probable: the relationship with the use of the investigational device seems relevant and/or 
the event cannot reasonably explained by another cause, but additional information may 
be obtained. 
5) Causal relationship: the serious event is associated with the investigational device or with 
procedures beyond reasonable doubt when: 
- 
the event is a known side effect of the product category the device belongs to or of 
similar devices and procedures; 
- 
the event has a temporal relationship with investigational device use/application or 
procedures; 
- 
the event involves a body-site or organ that the investigational device or procedures 
are applied to, or have an effect on; 
- 
the serious event follows a known response pattern to the medical device (if the 
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- 
the discontinuation of medical device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of the level of 
activation/exposure), impact on the serious event (when clinically feasible); 
- 
other possible causes (e.g. an underlying or concurrent illness/ clinical condition 
or/and an effect of another device, drug or treatment) have been adequately ruled 
out; 
- 
harm to the subject is due to error in use. 
In order to establish the relatedness, not all the criteria listed above might be met at the 
same time, depending on the type of device/procedures and the serious event. 
 
8.5 
Follow-up of adverse events 
All recorded AEs will be followed until they have abated, or until a stable situation has been 
reached. Depending on the event, follow up may require additional tests or medical 
procedures as indicated, and/or referral to the general physician or a medical specialist. 
SAEs need to be reported till end of study within the Netherlands, as defined in the protocol.  
 
8.6 
Data Safety Monitoring Board (DSMB) / Safety Committee 
The investigators will perform continuous safety monitoring and will evaluate reported 
adverse events for agreement in determination of seriousness and causal relationship with 
the treatment (either procedure and/or device). In those instances where it cannot be 
determined if the event was linked to the treatment, this will also be noted on the patient file 
event report. If at any point during the study, the investigators conclude that continuation of 
the study will endanger the safety of the patients, the study shall be terminated.  
Both EBRT and MR-HIFU have been proven to be safe when applied alone. A time window 
of minimally 3 hours between EBRT and MR-HIFU is taken into account to exclude possible 
detrimental synergistic effects between the two treatments. Moreover, the mechanism of 
action of MR-HIFU and EBRT differs. Therefore, we do not expect any SAE when the two 
treatments are combined.  
However, representatives of the external advisory board of the FURTHER will act as a safety 
committee and evaluate the safety of the combined treatment after the first three patients. 
This committee consists of: 
- Prof. Maurice van den Bosch, chairman OLVG Amsterdam and a MR-HIFU expert; 
- Prof. Yvette van der Linden, radiation oncologist and head of Expertcentre of Palliative 
Care at Leiden University Medical Centre, Leiden; 
- Dr. Jorrit-Jan Verlaan, Spine surgeon at Dept of Othopedic Surgery, UMC Utrecht. 
 

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9. 
STATISTICAL ANALYSIS 
 
In order to reach the objectives, a two stage approach will be used following the IDEAL 
recommendations: IDEAL stage 1, i.e. innovation/proof of concept of EBRT followed by MR-
HIFU within a 3 hours - 4 days time window, followed by IDEAL stage 2a, i.e. development of 
the new treatment strategy.  
In the first stage, we will include three patients in whom the combined treatment will be 
applied and tested for the first time. In this stage, the main objective is to demonstrate the 
feasibility of the combined treatment strategy and describe it in detail. The report will contain 
clear anonymous details of the patient, exact description of the primary tumor, site of 
metastases, extent of the index lesion, rationale for the use of this procedure in these 
particular patients and a very detailed description of technical and clinical aspects of the 
procedures. For all patients, technical success, detailed pain scores (baseline and follow up), 
neurological symptoms (baseline and follow up), complications, toxicity, use of analgesics, 
and other relevant outcomes will be reported on an individual level. The patients reported 
experience will also be used to make adjustments to the logistics and treatment protocol.  
After stage 1, an interval of at least two weeks will be implemented before treating the next 
patient to allow identification of early major problems.  
Progression to stage 2a (Development) will be justified after we have demonstrated feasibility 
of the combined procedure, without major technical problems or safety issues. In stage 2a, 
the main focus is safety and technical feasibility of the combined procedure, which will be 
measured in 3-7 consecutive patients meeting the inclusion criteria and none of the exclusion 
criteria.  
For all patients, we will report toxicity and pain response. The patient-reported worst pain will 
be used. This is consistent with the latest version of the International Consensus for clinical 
trial endpoints on bone pain palliation with radiotherapy.  
Pain responders are defined as patients with: 
1. Pain score (numerical rating scale; NRS) at the treated site of zero without analgesic 
increase (complete response); 
2. Reduction of pain score of at least 2 points at the treated site without analgesic increase 
(partial response); 
3. Analgesic reduction of 25% or more without increase in pain (partial response). 
In addition, pain medication pre- and post-procedure as reported by the patient and in 
medication records are documented. Opioid analgesics are expressed as the oral equivalent 
daily morphine use (OMED). 
Results will be presented as descriptive statistics and no statistical tests will be performed. 
Early terminations and withdrawals, will also be reported.  

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10. ETHICAL CONSIDERATIONS 
 
10.1 Regulation statement 
The study will be conducted according to the principles of the Declaration of Helsinki (2013, 
www.wma.net) and in accordance with:  
 All national and local laws of the pertinent regulatory bodies, including the Medical 
Research Involving Human Subjects Act (WMO) in the Netherlands, 
 Internal Standard Operating Procedures, 
 
and 
 This protocol. 
 
10.2 Recruitment and consent 
In the UMC Utrecht subjects will be recruited from the PRESENT cohort. In Isala patients will 
be recruited from patients that visit the outpatient clinic of the Department of Radiation 
Oncology. 
The radiation oncologist will perform a first eligibility check on the basis of clinical parameters 
and images (PET-CT) which are usually already available when patients with painful bone 
metastases are referred to the Department of Radiation Oncology. If information on medical 
history, indication for treatment and capability to communicate with the physician indicate 
that the patient is likely to satisfy the inclusion and exclusion criteria (section 4.2 and 4.3), the 
radiation oncologist will inform the patient about the PRE-FURTHER study. Patients 
interested in participating in the study will receive a participant information letter including the 
informed consent form explaining the purpose and the details of the study, particularly the 
potential risks and burdens associated with the combined treatment. In case the patient is 
likely to give informed consent, eligibility of the patient is discussed in detail in a 
Multidisciplinary Consultation Meeting with the radiation oncologist and radiologist.  
The investigator or an authorized delegate will conduct the informed consent process. 
He/she will contact the patient by phone at least one day after the initial hospital visit and in 
case of eligibility he/she will provide more details on the study if needed and will ask the 
patient for his/her oral consent to participate in the study.  
The time window of minimally one day for an oral informed consent has been chosen as 
these procedures are almost always planned within one week after first presentation in the 
outpatient clinic. The one-day time window allows us to plan the combined treatment as soon 
as possible. In our opinion, with one day patients have a reasonable amount of time to 
consider this experimental combination without the risk on treatment delay.   
 

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The patients are requested to sign the informed consent form before the preoperative 
screening, the MR-HIFU treatment and before any other data are collected. Thus, patients 
also have the chance to revoke consent at this stage. Signature to the consent form should 
take place in the presence of the principal investigator or an authorized delegate.  
 
10.3 Benefits and risks assessment, group relatedness 
The PRE-FURTHER study is designed to assess the feasibility of the combined EBRT MR-
HIFU treatment of painful bone metastases.  
 
EBRT is the current standard of care. The most common adverse event of EBRT is a 
temporal increase of the pain after the treatment also known as pain flare (Mavrogenis, 
2016). ‘Pain flare’ is observed in 2 to 44 percent of patients and can have an important 
impact on quality of life.  
Pathologic fractures of weight-bearing bones occur in 10-20% of patients with bone 
metastases, with femoral metastases accounting for the largest part of these fractures (Body, 
1992; Eastley, 2012) The risk of pathological fractures after radiotherapy has been well 
documented.  In the most recent systematic review of palliative radiotherapy trials for bone 
metastases, comparing single versus multiple faction regimens, one of the secondary 
outcomes was pathological fracture rate after radiotherapy (Chow, 2007). Several studies 
reported data for pathological fracture rates (Bone Pain Trial Working Party, 1999; Cole, 
1989; Hartsell, 2005; Kaasa, 2006, Nielsen, 1998; Price, 1986; Roos, 2005). The pooled 
pathological fracture rates ranged from 2.8% to 3.2% with no significant differences for 
treatment schedules. Most of these studies excluded patients with (impending) pathological 
fractures, which is also the case in this pilot study. 
 
However, EBRT is only effective in part of the patients and it may take several weeks before 
pain reduction is achieved. The additional MR-HIFU treatment is expected to lead to a more 
rapid pain relief and may even prevent or reduce the pain flare. Besides occasional minor 
thermal skin burns, no serious adverse effects are expected as a result of the additional MR-
HIFU treatment. A detailed summary of the results of the complete risk analysis performed 
by the Supplier is given in the Investigator’s Brochure (chapter 10 and appendix 1).  
The Investigator’s Brochure summarizes the outcomes and reported adverse events of 
previous key MR-HIFU studies. The benefits and positive outcomes reported in these 
previous studies have been weighed against the identified risks. This weighing has led to CE 
labeling of the device in Europe. 
 

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In addition to those procedure- or device-related adverse events the following adverse 
events are anticipated in this patient population, but expected to be unrelated to the 
combined treatment procedure: 
 Death due to progression of the underlying cancer or cancer-related complications; 
 Hospitalization for cancer treatment or due to cancer-related complications; 
 Fracture at site(s) of bone metastases unrelated to treatment requiring hospitalization 
and/or surgical intervention; 
 Increase of cancer-related pain unrelated to treatment; 
 Progression of the underlying disease. 
 
For the combined treatment, patients will in most cases need to pay an extra visit to the 
hospital to undergo a rather lengthy additional intervention (MR-HIFU treatment), under 
conscious sedation.  
 
There is no data available about the possible complications and risk of the combination of 
EBRT and MR-HIFU within 4 days. However, both treatments have proven to be safe when 
applied alone, their mechanism of action differs and the minimal interval of 3 hours between 
the two treatments has been chosen in such a way that a detrimental interaction between the 
two treatments is not to be expected.  
 
10.4 Compensation for injury  
The sponsor/investigator has a liability insurance which is in accordance with article 7 of the 
WMO. 
The sponsor (also) has an insurance which is in accordance with the legal requirements in 
the Netherlands (Article 7 WMO). This insurance provides cover for damage to research 
subjects through injury or death caused by the study. 
The insurance applies to the damage that becomes apparent during the study or within 4 
years after the end of the study. 
 
10.5 Incentives 
Reasonable travel expenses and parking costs arising from an additional or prolonged 
hospital visit because of the MR-HIFU treatment will be reimbursed to enrolled subjects. 
Besides travel expenses and parking costs, there will be no extra compensation for study 
participants. 

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11. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
 
11.1 Handling and storage of data and documents 
A clinical database will be set-up using OpenClinica. As part of the data entry workflow, the 
OpenClinica software will assign a “study ID”. The reference between the Study ID and the 
hospital patient number is listed in the Subject Identification Log per site. The Subject 
Identification Log will only be accessible by authorized personnel. The study ID will also be 
used to tag the inbound technical patient data. Data will be pseudonymized according to the 
applicable regulations and rules. Each eCRF will be completed on site by the investigator or 
an authorized staff member. MRI and HIFU data will be stored on location. 
 
All individual patient data records will be collected on confidential basis and according to the 
applicable national data protection, privacy, and secrecy laws (General Data Protection 
Regulation (GDPR) (In Dutch: Algemene Verordening Gegevensbescherming (AVG)). The 
investigators, auditors, monitors and employees of the ‘Inspectie Gezondheidszorg en Jeugd’ 
may have access to the medical and research data of the patients. It is the investigator’s 
responsibility to complete and approve all treatment related data. 
 
Anonymized data collected from subjects treated under this protocol may be used in 
submissions to regulatory agencies, and for publications. Summaries of data and information 
from each patient data form may be used for reporting of the investigation's findings during 
the study.  
 
Records of the study must be maintained at least as long as local document retention 
regulations require. In the event that the investigator withdraws or relocates, study records 
will be transferred to identified site personnel or to the sponsor. This transfer is subject to the 
sponsor’s approval.  
 
Procedures for data management are detailed in a separate Data Management Plan. 
 
11.2 Monitoring and Quality Assurance  
Each site will be monitored by its own institutional monitor. The clinical monitor will be 
responsible for verifying adherence to the protocol, reviewing subject records and source 
data, maintaining records of all actions taken to correct protocol deficiencies during the 
investigation, and assuring that the data needed to complete the study is complete and 
accurate. Monitoring will be documented to the study files by monitor reports.  
The monitor plan is attached as an addendum. 

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11.3 Amendments  
Amendments are changes made to the research after a favourable opinion by the accredited 
METC has been given. All amendments will be notified to the METC that gave a favourable 
opinion.  
 
11.4 Annual progress report 
The investigator will submit a summary of the progress of the pilot study to the accredited 
METC once a year. Information will be provided on the date of inclusion of the first subject, 
numbers of subjects included and numbers of subjects that have completed the trial, serious 
adverse events, other problems, and amendments.  
 
11.5 Temporary halt and (prematurely) end of study report 
The investigator/sponsor will notify the accredited METC of the end of the study within a 
period of 8 weeks. The end of the study is defined as the last patient’s last follow-up moment 
4 weeks after MR-HIFU.  
The investigator will notify the METC immediately of a temporary halt of the study, including 
the reason of such an action.  
In case the study is ended prematurely, the sponsor will notify the accredited METC within 15 
days, including the reasons for the premature termination. 
Within one year after the end of the study, the investigator/sponsor will submit a final study 
report with the results of the study, including any publications/abstracts of the study, to the 
accredited METC.  
 
11.6 Public disclosure and publication policy 
Data collected from subjects treated under this protocol will be used for conferences and 
publication according to the CCMO statement on publication policy (www.ccmo.nl). This 
statement contains the basic principles of the CCMO’s position on the disclosure/publication 
of research results obtained from studies involving human subjects. It is the opinion of the 
CCMO that the results of scientific research involving human subjects must be disclosed 
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12. STRUCTURED RISK ANALYSIS 
  
12.1 Potential issues of concern 
In the PRE-FURTHER study patients with painful bone metastases will receive both (single 
or multiple fraction) EBRT and MR-HIFU within a rather short interval of 3 hours - 4 days. 
Since EBRT is the current standard of care for these patients this structured risk analysis 
focuses on any risks caused by the MR-HIFU treatment and by the combination of the two 
treatments.  
 
a. Level of knowledge about mechanism of action 
The putative main mechanism of pain relief by EBRT involves the inactivation of osteoclasts 
to change the microenvironment of bone resorption followed by sterilization of cancer cells to 
reduce tumor-induced compression (Hartsell et al 2007). The direct mechanism of action of 
EBRT is damage to DNA of tissues, including both single strand and double strand DNA 
breaks, originating mostly from different oxygen radicals. The mechanism of action of MR-
HIFU is coagulative necrosis and apoptosis of tissue due to heat leading to rapid and durable 
pain relief from immediate periosteal nerve ablation and thermal necrosis of the targeted 
bone tumor followed by remineralization of the trabecular bone and bone healing a few 
months later. Since the mechanism of action of EBRT and MR-HIFU differ, MR-HIFU 
provides an alternative means to overcome radioresistance and is recommended for patients 
with bone metastasis for whom RT is considered to have failed (Hurwitz, 2014). 
 
Since the mechanism of action of EBRT and MR-HIFU differ, the two methods may be 
synergistic in first-line, or when applied nearly simultaneously. Heat-induced coagulative 
ablation is the main action of MR-HIFU, hence its pain palliation effect is expected to be 
rapid. However, heat distribution is often spatially heterogeneous in bone metastases 
because of the fact that absorption of ultrasound energy depends on many factors including 
the degree of bone lysis or formation, and incident ultrasound angle. Therefore, it might be 
that the, more long-term, systemic responses of EBRT of the tumor and its 
microenvironment, reduction of tumor-induced compression and inactivation of osteoclasts, 
can be augmented by local ablation of periosteal nerve ablation by MR-HIFU.  
 
Some other effects should be mentioned.  
- Hyperthermia (temperatures 42-45°C) beyond the ablated area results in complementary 
radiosensitization (reduction of hypoxia; inhibition of DNA repair mechanisms) (van der 
Zee, 2000, Dababou  2018) thereby increasing the risk of damage to surrounding tissue. 

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- Coagulative ablation by MR-HIFU (temperatures around 60°C) also leads to 
reduction/elimination of local perfusion leading to hypoxia of the treated area. This may 
render subsequent EBRT less efficient (less production of oxygen radicals). 
 
b. Previous exposure of human beings with the test product(s) and/or products with a 
similar biological mechanism 
To date, MR-HIFU treatments of uterine fibroids, prostate cancer, breast cancer, bone 
metastases, brain tumors and pancreas-, liver- and kidney tumors are either a clinical 
application or in development. Currently HIFU is mostly used for the ablation of prostate 
cancer and uterine fibroids. Many HIFU treatments are performed under MR-guidance. MRI 
provides accurate guidance during HIFU treatment, as it offers good soft tissue visualization 
and enables treatment planning. Moreover MRI provides temperature maps for excellent 
therapy monitoring and evaluation of treatment results. For these reasons, MRI is considered 
the best and safest method for HIFU guidance. 
 
Results of previous studies are presented in chapter 1.3 and the Investigator’s Brochure. 
 
The combined EBRT MR-HIFU treatment is applied for the first time within the relatively short 
interval of 3 hours - 4 days in human beings. 
 
c. Can the primary or secondary mechanism be induced in animals and/or in ex-vivo 
human cell material? 
Animal studies were focused on: 
 
The Treatment Protocol for sonication on bone 
 
Safety Issues including skin, near field heating, cooling times, targeting accuracy 
 
Cavitation Detection: passive receive technique 
 
Full integrated HIFU system performance in a representative in vivo model 
 
These studies confirmed the potential benefit but their relevance to the clinical situation is 
limited because of the following reasons: 
- The origin of the primary tumor in the PRE-FURTHER and FURTHER projects varies 
(breast, prostate, etcetera), and hence also the genotype and phenotype of the bone 
metastasis. 
- The anatomical location of the bone metastasis varies necessitating an individual 
planning and adaptation of both EBRT and MR-HIFU. 

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- The degree of bone lysis/bone growth differs affecting the ultrasound absorption 
necessitating specific MR-HIFU planning. 
- EBRT efficacy varies with relation to the degree of hypoxia and perfusion. 
- MR-HIFU efficacy differs with respect to ultrasound absorption, incidence angle of the 
ultrasound beam, and degree of bone lysis/bone growth. 
  
In addition, pain scores are difficult to obtain in animal models. Also, the starting pain level in 
drug refractory patients in this trial is at such an elevated level that animal models are 
ethically questionable. 
 
See for more detail page 21-24 of the Sonalleve Investigator’s brochure. 
 
To the best of our knowledge there are no data available from animal studies that combined 
EBRT and MR-HIFU.  
 
d. Selectivity of the mechanism to target tissue in animals and/or human beings 
The mechanism of MR-HIFU thermal ablation does not depend on cell types, receptors or 
other biological characteristics, but merely on the targeted locations of the HIFU beam focal 
point. The targeting precision is in the range of millimeters. MR imaging is used for target 
definition and allows the physician to depict organs at risk of thermal damage (in the HIFU 
beam, i.e. in front of, or behind the focal point). 
 
e. Analysis of potential effect 
Thermal damage can be quantified with the thermal dose concept, which has been validated 
extensively ex vivo, in vivo and in the clinical setting (Chung, 1999; Dewhirst, 2003; 
McDannold, 2000 & 2006; Yarmolenko, 2011). A thermal dose of > 240 cumulative 
equivalent minutes (EM) at 43°C is generally considered lethal. In addition, tissue that is 
heated (for any duration) to > 60°C can be considered coagulated. This is regardless of 
whether malignant or (accidently) healthy tissue is targeted. During the MR-HIFU procedure, 
the thermal dose and temperature are visualized on the HIFU console in real-time. This 
allows the physician to continuously monitor the deposition of thermal energy, and to abort 
the sonication when a temperature elevation or thermal dose deposition is observed outside 
the targeted location. Thus, adjacent healthy organs can be monitored continuously for 
damage, and the physician can act immediately to prevent damaging these organs. 
 
 

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f. Pharmacokinetic considerations 
Not applicable for this study. 
 
g. Interaction with other products 
Not applicable for this study. 
 
h. Study population 
The research subjects are male and female adults (age ≥ 18 years) with painful bone 
metastases. This is a group of (often elderly) patients, with a limited life expectancy. Since 
we will only include patients with a life expectancy longer than 3 months, the condition of 
these patients is expected to be good enough to undergo an additional treatment next to the 
standard EBRT treatment. Eligibility for the study will be assessed by the treating radiation 
oncologist and radiologist, the anesthesiologist and the investigator. 
 
i. Predictability of effect 
MR-HIFU tissue ablation has been demonstrated to have a high predictability of effect. 
Protein denaturation, causing cell death, occurs at temperatures ≥ 60°C, or when a 
cumulative thermal dose is reached of ≥ 240 EM. This mechanism has been demonstrated 
both ex vivo and in vivo in multiple studies, and has been validated in clinical studies on 
uterine fibroid ablation (Chung, 1999; Dewhirst, 2003; McDannold, 2000 & 2006; 
Yarmolenko, 2011). In addition, each treatment is preceded by a test sonication. This is a 
low-powered sonication that only causes a small increase in temperature. It is used to 
validate (and, if required, adjust) the HIFU beam targeting for optimal accuracy of the 
therapeutic shots. 
 
j. Can effects be managed? 
During MR-HIFU sonications, temperature development in the targeted and surrounding 
tissue is closely monitored with the proton resonance frequency shift (PRFS) method. The 
treating physician is able to follow the deposition of thermal energy in real-time. If needed, 
sonications are aborted in order to, for example, prevent lethal heating of surrounding 
healthy tissue. Abortion of the sonications is automatically done by the system or manually 
by the treating physician. Additionally an anesthesiologist will monitor the patient during 
treatments. He or she may abort or pause the treatment in case changes in the patient’s vital 
signs indicate to do so. 
After the MR-HIFU procedure, the patient will be allowed to recover from the procedural 
sedation and analgesia (PSA), after which he/she will be transferred to the ward. Local 
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hospital at the nursing unit for a few hours after the procedure and will be discharged on the 
treatment day, unless clinical indications dictate otherwise. This allows (per)acute 
complications to become overt. In that case, adequate medical and/or surgical support is left 
at the discretion of the attending physician.  
 
12.2 Synthesis 
MR-HIFU ablation is a powerful technique that can rapidly increase the temperature in 
tissues to lethal temperatures. This makes it an useful tool for the treatment of a whole array 
of diseases. However, MR-HIFU can also potentially induce thermal damage to vital tissues 
and organs. For this reason, clinical studies focus on real-time treatment monitoring and 
optimizing the accuracy and precision of the ablation process. Previous MR-HIFU studies for 
painful bone metastases demonstrated that MR-HIFU is sufficiently safe and effective. The 
MR-HIFU procedures are performed under MRI guidance which means that the treated 
tissue is visualized during the entire treatment and that the temperature of the targeted 
region is continuously depicted in temperature maps. 
In the presented literature, minor adverse events occurred in some patients and mainly 
consisted of mild skin burns and mild pain. No severe adverse events were reported. All 
minor adverse events subsided within a maximum of 10 days and had no sequelae. 
 
The use of PSA for the MR-HIFU treatment has two major advantages over using local or no 
anesthesia. First, patients are able to lie still during the entire treatment, which decreases the 
risk of side effects and impaired treatment efficacy due to patient motion. Second, subjects 
experience less discomfort and pain during MR-HIFU treatment. The risks of the sedation 
used are very low. 
 
We cannot fully exclude unexpected complications and (serious) adverse events due to the 
combination of EBRT and MR-HIFU. However, the minimal interval of 3 hours between the 
EBRT and MR-HIFU treatment was chosen in such a way that a detrimental interaction 
between the two treatments is not to be expected. Moreover, their mechanism of action 
differs and both treatments have proven to be safe when applied alone. Therefore, we do not 
expect any SAE.  
Overall, it is deemed that the potential benefits of this study, both to the individual patient, as 
manifested by potential rapid and long lasting pain relief at the treated lesion, and in the end 
to the wider patient community, as manifested by potential wider availability of an additional 
non-invasive option for pain palliation in bone metastases, outweighs the potential risks. 
 
 
 

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