International consensus on use of focused ultrasound for painful bone metastases: Current status and future directions

Abstract

Focused ultrasound surgery (FUS), in particular magnetic resonance guided FUS (MRgFUS), is an emerging non-invasive thermal treatment modality in oncology that has recently proven to be effective for the palliation of metastatic bone pain. A consensus panel of internationally recognised experts in focused ultrasound critically reviewed all available data and developed consensus statements to increase awareness, accelerate the development, acceptance and adoption of FUS as a treatment for painful bone metastases and provide guidance towards broader application in oncology. In this review, evidence-based consensus statements are provided for (1) current treatment goals, (2) current indications, (3) technical considerations, (4) future directions including research priorities, and (5) economic and logistical considerations.

• Bone neoplasms
• cancer
• consensus
• high-intensity focused ultrasound
• palliative care

Introduction

Focused ultrasound surgery (FUS), which uses acoustic energy to ablate tissue focally, is a rapidly emerging image-guided non-invasive treatment modality that has many potential applications in oncology [1,2]. Image-guidance of FUS treatment can be provided by either ultrasound (US) or magnetic resonance (MR) imaging. In MR-imaging-guided focused ultrasound (MRgFUS, also known as MRgHIFU), precise tumour targeting and non-invasive real-time temperature monitoring are possible [3–5]. These features, which have generally been lacking in traditional percutaneous thermal ablation modalities such as radiofrequency ablation, may enhance treatment efficacy while reducing complications. MRgFUS has been investigated for a number of malignant tumours, including those arising from the prostate, breast, liver, and pancreas, as well as sarcomas [2]. The first phase III trial of MRgFUS in oncology established its safety and efficacy as a palliative treatment option for painful bone metastases [6]. In light of this milestone, an international panel of experts was convened to address logistic and research issues pertinent to the adaptation of FUS for treatment of bone metastases. The aim of the presented consensus statements is to increase awareness, accelerate the development, acceptance and adoption of FUS as a treatment for painful bone metastases, and provide guidance towards broader application in oncology, warranted by future clinical evidence of benefit.

Materials and methods

Under the auspices of the Focused Ultrasound Foundation, a panel of internationally recognised investigators and other experts with a declared interest in the field of focused ultrasound was constituted (n = 14). A consensus meeting was held at the Focused Ultrasound Therapy Second European Symposium on 9 October 2013 in Rome, Italy. The panel completed a survey prior to the meeting (Appendix 1). A systematic literature review of image-guided focused ultrasound and bone metastases was performed. MEDLINE, Embase, Web of Science and the Cochrane Collaboration Library electronic databases were searched to identify publications on focused ultrasound in bone metastases published between 1980 and June 2014. The overall strategy included search terms and their synonyms for FUS and bone metastases (Appendix 2). Published reports with full or abstract results were included, as were relevant preclinical studies. Publications which did not contain original data, and studies on hyperthermia, primary bone cancer or benign conditions, were excluded. Based on the literature and international expert opinion, consensus statements regarding the following topics were generated: (1) current treatment goals (2) current indications (3) technical considerations (4) future directions including research priorities and (5) economic and logistical considerations.

Results

Current status of the field

Clinical results to date

Preliminary clinical studies have concluded that MRgFUS offers a potentially safe and effective non-invasive treatment option for radiation refractory metastatic bone pain, with more than 70% of patients experiencing pain reduction after MRgFUS treatment [7–9]. In a recent phase III trial by Hurwitz et al. [6] in which 147 patients with radiation refractory metastatic bone pain were randomised to MRgFUS treatment or placebo, a pain response rate of 64% in the MRgFUS treated arm vs. 20% in the placebo arm was found 3 months after treatment. Complete pain relief was observed in 23% of treated patients, compared to 6% of patients who received placebo treatment. In about two thirds of responders pain relief was observed within 3 days of treatment, establishing the ability of MRgFUS to induce fast pain response. The most common complication was pain during MRgFUS treatment (32%) and major complications (third degree skin burn, fracture) occurred in 3% of treated patients [6]. In the study of Napoli et al. [10] in which 18 radiation-naïve patients were treated with MRgFUS, the overall pain response rate was 89% with complete pain relief in 72% of patients. Six of 18 (33%) patients showed partial or complete tumour response including remineralisation, according to the MD Anderson cancer response criteria [11]. These findings suggest that MRgFUS may have a value in tumour control as well as pain relief. An overview of all clinical studies and abstract results on image-guided FUS for painful bone metastases is presented in Table 1. These combined results indicate that MRgFUS is a safe and effective palliative treatment option for patients with painful bone metastases. Currently, a randomised controlled trial (RCT) of MRgFUS vs. radiotherapy for the primary palliative treatment of metastatic bone pain is open to accrual in Europe (trial registry no. NCT01091883). A multicentre cohort study on MRgFUS for bone metastases is open to accrual in Europe and Asia (trial registry no. NCT01586273) and a post-approval study is currently running in the USA (trial registry no. NCT01833806).

Table 1. Clinical studies of image-guided FUS for painful bone metastases.

Study	Study design	Primary end points	Patients (n)	Patient selection	Guidance	Duration of follow-up	Outcome assessment	Outcome
Hurwitz et al. [6]	Randomized controlled trial multicentre	Pain response, QoL, safety	147	Secondary treatment	MR	3 months	IBMCWP guidelines, BPI	OR rate at 3 months 64.3%
Napoli et al. [10]	Prospective single-arm monocentre	Pain response, local control	18	Primary treatment	MR	3 months	IBMCWP guidelines, BPI, MDA criteria	OR rate at 3 months 89%
Chen et al. [12]	Single-arm monocentre (abstract)	Safety, pain response	6	–	MR	3 months	VAS	Mean VAS 1.8 ± 1.1 at 3 months (baseline 8.2 ± 0.8)
Catane et al. [13]	Prospective single-arm multicentre (abstract)	Pain response	93	–	MR	3 months	NRS and analgesics	Mean NRS 2.6 at 3 months (baseline 6.9)
Candiano et al. [18]	Case-report	Metabolic changes, pain response	1	Primary treatment	MR	12 months	VAS and analgesics	VAS 2 at 12 months (baseline 9)
Turkevic et al. [14]	Single-arm monocentre (abstract)	Safety, pain response	31	–	MR	3 months	IBMCWP guidelines	OR rate at 3 months 100%
Orgera et al. [49]	Single-arm monocentre (abstract)	Safety, efficacy in solid tumours	3*	Secondary treatment	US	3 months	–	Complete remission in all patients <48 h
Kawasaki et al. [19]	Prospective single-arm monocentre (abstract)	Pain response, safety	6	–	MR	9 months	BPI, imaging, adverse events	Mean NRS 1.2 ± 1.0 at end of FU (baseline 6.0 ± 1.3)
Carteret et al. [50]	Single-arm study monocentre (abstract)	Safety, technical pain response	1	–	MR	2 weeks	VAS and analgesics	Decrease in VAS (1 point), stable analgesics at 2 weeks
Orgera et al. [51]	Case-series (abstract)	Safety, pain response	7*	Secondary treatment	US	5 months	VAS and analgesics	Mean VAS 1.9 (baseline 6.5)
Li et al. [52]	Single-arm monocentre	Safety, effects	12*	Primary treatment	US	–	VRS	VRS 0.17 ± 0.39 (baseline 1.75 ± 0.97)
Liberman et al. [8]	Single-arm multicentre	Safety, pain response	31	Secondary treatment	MR	3–6 months	IBMCWP guidelines	OR rate at 3 months 72%
Gianfelice et al. [9]	Single-arm monocentre	Safety, pain response	11	Secondary treatment	MR	3 months	IBMCWP guidelines	OR rate at 3 months 100%
Catane et al. [7]	Single-arm multicentre	Safety, pain response	13	Secondary treatment	MR	6 months	VAS and analgesics	Improvement in pain score and pain medication at 3 months

MR, magnetic resonance; US, ultrasound; IBMCWP, International Bone Metastasis Consensus Working Party; BPI, Brief Pain Inventory; MDA criteria, MD Anderson Cancer Centre criteria; NRS, Numeric Rating Scale; VAS, Visual Analogue Scale; VRS; Verbal Rating Scale; OR, overall response

*In these studies patients were treated with FUS for different indications, only those with painful bone metastases were listed.

Current treatment goals

The biological mechanism of pain relief induced by FUS treatment has not been completely elucidated, although it is generally assumed that periosteal denervation induced by cortical heating plays a major role [8,9]. It has been established that targeting the bone–soft tissue interface results in a significant benefit in terms of fast pain response, with duration of pain relief of at least 3 months [7–10,12–14]. More aggressive ablation may lead to local tumour control and improved pain relief [10], but possibly also results in more adverse events. In patients with advanced disease and limited survival (≤6 months) local tumour control should not be pursued since the potential additional risks of more aggressive treatment strategies do not outweigh the benefits for these patients [15]. There is consensus that the current treatment goal is pain control through periosteal ablation, without complete tumour ablation, to ensure the safety of palliative FUS treatments.

Current indications

The primary palliative treatment for uncomplicated metastatic bone pain is radiotherapy, which can be repeated (re-irradiation) if additional pain relief is needed [16,17]. Although the body of evidence for both re-irradiation and MRgFUS for painful bone metastases remains relatively limited, and comparative studies are not available, MRgFUS has proven to be a safe and effective alternative to re-irradiation [6]. Important benefits of FUS compared to radiotherapy are the absence of ionising radiation and its ability to induce pain relief within 3 days of treatment, whereas radiotherapy may have a delay in response of up to 4 weeks [6,8,13]. Other possible benefits of FUS compared to re-irradiation include a higher response rate, longer response duration [6,8,17–19], and fewer side effects [1,6,20]. In addition, FUS treatment may occur without interrupting chemotherapy. Generally, only a single session is needed for treatment, although repeat exposures are possible if there are residual symptoms. Disadvantages of FUS include the need for anaesthesia, and for patients to be able to undergo MRI for MRgFUS. Contraindications for MRI include certain metallic implants or devices (e.g. pacemakers). In MRgFUS, the table-mounted system requires careful patient positioning and sometimes the acoustic window cannot provide full access to the target area. Possible solutions are a conformal MRgFUS system or US-guided FUS. Other disadvantages are mainly linked to the current status of clinical FUS development, and include the current lack of device availability and logistical challenges such as long treatment duration when compared to single fraction radiotherapy. FUS can currently not be given to patients with skull metastases or spinal metastases (except for the posterior elements below the level of the conus medullaris). A summary of radiotherapy and FUS for painful bone metastases is provided in Table 2. Based on the evidence currently available, consensus has been reached that FUS is an acceptable secondary treatment option for patients who have painful bone metastases in a non-spinal site, for whom radiotherapy has not been effective. Consensus exists that at this stage, FUS can be considered a primary palliative treatment option in patients for whom radiotherapy may be contraindicated (e.g. due to prior radiation to the same site) or has been refused.

Table 2. Radiotherapy and focused ultrasound for painful bone metastases.

	Radiotherapy	FUS
Indication	Primary/secondary palliation	Mostly secondary palliation
Locations	No restrictions	No spinal or skull metastases, lesions within 1 cm of skin or critical normal tissues/organs
Ionising radiation	Yes	No
Concurrent chemotherapy possible	Yes	Yes
Sessions	1–10 typical	1
Onset of response	1–4 weeks	±3 days
Retreatment	Re-treatment may be possible on a case by case basis	Yes
Conscious sedation or anaesthesia required	No	Yes
Availability	Widely available	Limited
MRI required	No	Yes (in MRgFUS)
Treatment duration	15 min	2–3 h

Technical considerations

Both ultrasound (US)-guided and MR-guided FUS systems are available. Clinical study results pertain primarily to MRgFUS (Table 1). MR guidance provides superior 3D anatomical imaging and non-invasive temperature monitoring, but is more technically challenging than US guidance. In MRgFUS, the treatment effects can be visualised directly after treatment using contrast-enhanced MR-imaging, whereas in US-guided FUS, the treatment effects are depicted by greyscale or perfusion changes. In MRgFUS, real-time temperature monitoring, calculation of the deposited dose and prediction of the extent of thermal damage are achieved using proton resonance frequency shift (PRFS) MR thermometry sequences [4,21]. In bone, MR thermometry has some limitations mainly due to the lack of signal in cortical bone. Furthermore, MR thermometry is sensitive to (motion) artefacts [22]. Nonetheless, thermal mapping based on the temperature rise in the soft-tissue adjacent to the cortical bone allows adequate real-time treatment guidance.

Visualisation of the cortical bone is important for treatment planning. In USgFUS, inherent to the fact that ultrasound does not penetrate bone cortex, imaging capabilities of and beyond the cortical bone are limited. Currently, a computed tomography (CT) scan generates the most optimal visualisation of cortical bone [23]. Ideally, the cortical bone would be reliably visualised with MRI in MRgFUS. Further development and validation of a bone-dedicated sequence would greatly contribute to MRgFUS treatments in bone [24].

Treatment simulation in a similar fashion to that used for treatment planning in radiation oncology would optimise treatment efficiency and facilitate quality assurance. First steps towards treatment simulation should include the development and validation of a thermal model that predicts cortical temperatures during FUS exposure. This model should involve both a patient-specific ultrasound propagation model and a bioheat model to assess treatment feasibility, different potential treatment approaches including risk assessment or full treatment simulation. If treatment simulation includes MR images, protocols aimed at eliminating difficulties associated with the differences between diagnostic and treatment planning images should be designed.

Future directions

Indications

Local tumour control and role in primary treatment

In addition to pain palliation, the ability of FUS to induce local tumour control is a notable consideration [10]. When pain palliation is the only treatment goal, some of the tumour may be ablated, but, since radical tumour ablation is not sought, symptoms may recur as the tumour continues to grow. Local tumour control is of interest in selected patient populations, such as breast or prostate cancer patients with prolonged survival (>12 months) [25,26] or those with oligometastatic disease [27–30]. These patients could benefit from local tumour control in terms of potential durable symptom management and prevention of future skeletal-related events (e.g. pathological fracture or nerve compression). Both local tumour control, directly, and symptom management, indirectly, may increase survival in selected patient groups [29,31,32]. There was consensus that targeting the periosteum remains the treatment approach of choice for FUS when used as a secondary palliative treatment. Local tumour control, in addition to pain palliation, could be of added value in selected patient populations.

Vertebral metastases

Treatment of spinal metastases is not carried out in clinical practice at the moment, because of concerns about thermal damage to the spinal cord, and for technical and accessibility challenges. Since approximately one third of patients with painful bone metastases have lesions in the thoracic or lumbar spine [33], the ability to treat these patients would considerably enhance the clinical utility of FUS. Although significant engineering development is required to accomplish this goal, it is anticipated that in the future it will be technically possible to treat metastases in the entirety of the vertebral column. Consensus was reached that in the future the treatment of vertebral metastases should be an achievable goal.

Research priorities

Local tumour control and role in primary treatment

As was agreed, local tumour control is desirable especially if FUS is to be used as a primary treatment option in the future. Importantly, there are still some challenges to be met when complete tumour ablation with FUS is intended. Firstly, because of the high acoustic impedance of cortical bone, full ablation of the lesion in osteoblastic or mixed metastases is likely to be difficult, and more knowledge of ultrasonic interaction with cortical bone in these lesions is required. When radiotherapy is omitted, and full tumour ablation cannot be achieved, the patient is potentially put at risk of pathological fractures since the untreated tumour may continue to grow. Local tumour control requires a different treatment strategy from periosteal ablation, needing higher acoustic energies and longer exposure times in order to reach higher temperatures within tumour deep below the bone surface. Secondly, risks arising from more aggressive ablation include pathological fractures and damage to surrounding structures from the higher energies used to heat the bone. From in vivo studies, it is known that MRgFUS ablation induces bone weakness. This is most prominent 6 weeks after treatment and returns to normal at 3 months [34,35]. Currently, fracture rates following palliative MRgFUS treatment compare favourably with those from radiotherapy (2% vs. 3%) [6,36]. The fracture risk may be higher for local tumour control than for pain palliation, especially in weight-bearing bones. Lastly, to achieve complete tumour ablation, analgesia during treatment is important, and general anaesthesia may be needed.

Consensus exists that the value of FUS incorporated into primary therapeutic options should be investigated, initially in patients with painful bone metastases in non-weight-bearing bones.

FUS in a multimodality setting

The combination of FUS with radiotherapy is an interesting concept, especially when primary treatment is intended. There are several hypotheses about the possible synergistic effect of FUS and radiotherapy. FUS could enhance radiotherapy by providing early onset of 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 [37–40]. It might be that systemic responses can be augmented by local ablation. Another merit of combination therapy could be that hyperthermia beyond the ablated area results in complementary radiosensitisation [41]. To date, these two treatments have not been tested together in vivo to evaluate for safety or synergistic effect. Consensus has been reached that the combination of FUS with radiotherapy should be investigated in the future. Other topics of interest that could be explored in phase II studies include systemic combination treatments, for example targeted drug delivery in oligometastatic disease [42] or a combination of FUS and radium-223 in castration-resistant prostate cancer [43].

Approach to future research: registry

Although MRgFUS for bone metastases has proven to be an effective treatment in terms of pain palliation, large-scale evidence of secondary outcomes (e.g. response durability) for greater acceptance of the treatment is still required. Patient accrual rates for palliative care studies are generally poor and trials are costly [44–46]. Therefore, a pragmatic approach would be to create a registry that accrues data on clinical FUS treatments prospectively to provide information on rare adverse events and long-term effectiveness of FUS treatment for painful bone metastases in clinical practice. Consensus has been reached that such an international bone registry of FUS for painful bone metastases should be set up to generate large-scale evidence for safety, response durability and effectiveness.

Approach to future research: trial design

A phase III trial has generated level 1 evidence on the safety and efficacy of MRgFUS for treatment of painful bone metastases [6]. However, several clinical questions remain to be answered. Firstly, it is not yet known how MRgFUS compares to radiotherapy for primary palliative treatment of painful bone metastases. Secondly, an additional study would be needed to estimate the effectiveness of combined radiotherapy and MRgFUS as a primary treatment.

A possible study design is a three-arm RCT to assess the efficacy of MRgFUS, radiotherapy and a combination of the two modalities as a primary palliative treatment. Such a trial would allow several hypotheses to be tested, including the potential superiority of combined treatment over either modality alone with regard to overall pain response. Additional end points could include onset and durability of response, local tumour control, delay in skeletal-related events, quality of life, toxicity, cost-effectiveness, and exploratory information on sensitisation and immune response. Radiotherapy would be carried out within a few hours of MRgFUS ablation to maximise any possible sensitisation effect [41]. The advantage of a large three-arm RCT is that this is likely to generate convincing evidence on the clinical value of MRgFUS in primary treatment and many different clinical questions can be answered. The disadvantage of this trial design is the cost associated with the need for large patient numbers.

An alternative to a three-arm trial would be a two-arm trial to assess the superiority of MRgFUS and radiotherapy vs. radiotherapy alone as a primary treatment. Such a trial may be more practical in terms of the number of subjects required and of greater acceptance in terms of routine clinical practice, but would not address the value of MRgFUS used alone as a primary treatment.

Another option could be an additional RCT to study MRgFUS vs. radiotherapy with the hypothesis that MRgFUS is as effective as radiotherapy in terms of overall pain response, but is superior to radiotherapy on secondary end points (e.g. time to onset of response and response durability). Alternatively, an RCT comparing MRgFUS vs. re-irradiation for patients who have failed initial radiotherapy could be carried out. However, the main disadvantage of these trial designs is that the outcome is unlikely to have an impact on the standard of care, despite the expected outcome that MRgFUS is not inferior to re-irradiation. Unless compelling evidence indicates that MRgFUS has clear benefits over re-irradiation, it is expected that single-fraction re-irradiation will remain the treatment of choice in most institutions. Compared to MRgFUS, radiotherapy is more widely available and requires less effort from physicians in planning and performance.

There is consensus that a three-arm RCT to assess the efficacy of MRgFUS, radiotherapy and a combination of these two modalities as a primary palliative treatment is the preferred study design at this moment. If a three-arm trial is not considered feasible, the preferred two-arm trial would be a randomisation between radiotherapy and radiotherapy + MRgFUS. For all future studies, the authors recommend the use of validated measurements of pain response, quality of life and imaging such as those described in the International Bone Metastases Consensus Working Party (IBMCWP) end points [47,48] and the MD Anderson criteria [11].

Economic considerations

Currently, palliative treatment of bone metastases is the only application in oncology for which FUS has received approval in the USA. Other geographical regions for which FUS for bone metastases has received approval include India, Israel, Korea, China, Russia and Europe. In Europe, FUS is also approved for treatment of prostate, breast, liver, pancreatic and renal cancers and for soft tissue tumours. MRgFUS treatments of bone metastases are now being reimbursed by both the government and private payers in the USA. FUS treatments are also reimbursed in Italy and Germany. In other countries, coverage may be available on a case-by-case or site basis. Reimbursement by insurance companies is essential for adoption of any treatment in most countries and it is expected that the recently reported phase III trial will provide strong impetus for broader reimbursement of MRgFUS for treatment of painful bone metastases. Since MRgFUS treatment comes with additional costs, a cost-effectiveness analysis should be performed since a more effective combined therapy may prove more cost effective in the long-term, despite greater initial expense.

Logistical considerations

FUS treatment is performed by a radiation oncologist or interventional radiologist, aided by medical physicists, depending on the institution. Radiation oncologists and interventional radiologists have experience with this patient population and with image-guided interventions. If the procedure is primarily carried out by the interventional radiologist, medical oncologists and radiation oncologists need to be made aware of the existence of FUS in order to increase referrals. Ideally, patient selection and treatment planning should be carried out by a multidisciplinary team in collaboration with an anaesthetist.

The use of moderate sedation/analgesia (‘conscious sedation’) during treatment enables patient feedback to prevent skin burns, although pain and movement during treatment represent major drawbacks. Given the current safety profile of the treatment [6], it was agreed that patient feedback is no longer regarded as a requirement for safe treatment. The optimal anaesthesia strategy varies with each patient, and depends on local regulations and practice. General anaesthesia offers ideal pain and motion control during treatment but makes the treatment more intrusive and logistically challenging. Deep sedation/analgesia (e.g. propofol and fentanyl/ketamine) may prevent pain during treatment, although patients may still move and the presence of an anaesthetist is required in most countries. Epidural anaesthesia or peripheral nerve block may be suitable for certain lesion locations, but needs to be carefully monitored to ensure adequate effect.

Conclusion

Based on a review of the literature and the experience of an international panel of experts, consensus was reached on issues pertaining to the clinical advancement of FUS for treatment of bone metastases. The consensus statements presented here are intended to provide guidance with regard to logistical and treatment considerations pertinent to the future applications of FUS in oncology, and to benefit patients, clinicians, investigators and industry interested in realising the full potential of FUS for the treatment of bone metastases.

Consensus statements

• (1) Current treatment goals

  • (i) In patients with painful bone metastases, the current treatment goal is pain control through periosteal ablation, without complete tumour ablation, to ensure safety of palliative FUS treatments.

• (2) Current indications

  • (i) FUS is a secondary treatment option for patients who have a painful bone metastasis in a non-spinal site, for whom radiotherapy has not been effective.

  • (ii) FUS can be considered a primary palliative treatment option in patients for whom radiotherapy is contraindicated or refused.

• (3) Technical considerations

  • (i) MR guidance offers several advantages over US guidance, including target visualisation, non-invasive thermometry, and immediate post-treatment assessment.

  • (ii) MR thermometry has some limitations in bone; however, thermal mapping based on the temperature rise in the soft-tissue adjacent to the cortical bone allows adequate real-time treatment guidance.

  •   (iii) Treatment simulation would optimise treatment efficacy, and facilitate quality assurance.

• (4) Future directions including research priorities

  • (i) Targeting the periosteum remains the preferred treatment approach for FUS as a secondary palliative treatment for painful bone metastases.

  • (ii) Local tumour control, in addition to pain palliation through periosteal ablation, could be of added value in selected patient populations.

  • (iii) Treatment of vertebral metastases would considerably enhance the clinical utility of FUS and although significant engineering development will be required, treatment of vertebral metastases should be an achievable goal.

  • (iv) The value of FUS incorporated into primary therapeutic options should be investigated, initially in patients with lesions in non-weight-bearing bones.

  • (v) The combination of FUS with radiotherapy should be investigated.

  • (vi) An international registry of FUS for painful bone metastases should be set up to generate large-scale evidence for safety, response durability and effectiveness.

  • (vii) The recommended trial design is a three-arm randomised controlled trial (RCT) to assess the efficacy of MRgFUS, radiotherapy and a combination of these two modalities as a primary palliative treatment for bone metastases.

• (5) Economic and logistical considerations

  • (i) The recently reported phase III trial provides strong impetus for routine reimbursement of MRgFUS for treatment of painful bone metastases.

  • (ii) Cost-effectiveness analyses should be included in future studies.

  • (iii) Ideally, patient selection and treatment planning should be carried out by a multidisciplinary team involving a radiation oncologist, (interventional) radiologist, medical physicist and an anaesthetist.

  • (iv) Patient feedback is no longer regarded as a requirement for safe treatment and optimal anaesthesia is key to success.

Acknowledgements

The authors wish to thank Susan Klees and Heather Huff Simonin from the Focused Ultrasound Foundation for their contributions. The authors wish to thank the Focused Ultrasound Foundation for initiating and funding the workshop from which this work started.

Declaration of interest

M.H. was supported by the Centre for Translational Molecular Medicine (www.ctmm.nl), project HIFU-CHEM, the Netherlands. A.H. is currently employed by the Focused Ultrasound Foundation and is a shareholder at InSightec, Tirat Carmel, Israel. V.R. has received a grant from InSightec. M.D.H. has served as a consultant to InSightec. The authors alone are responsible for the content and writing of the paper.

Appendix 1. Survey

Survey questions

Part I: Open questions on radiotherapy practice patterns

1. What radiation protocols are most commonly used for pain palliation of bone metastases at your institute (fractions and Gy)?

2. When a patient with painful bone metastases fails to respond to radiotherapy, what is the next step at your institution?

3. At your institution, what percentage of patients with bone metastases treated with radiotherapy fail to respond, i.e. fail to achieve the desired reduction in pain requiring other interventions?

4. What percentage of patients with painful bone metastases are not eligible for radiotherapy?

Part II: Questions on (possible) features of focused ultrasound (FUS) therapy for painful bone metastases (5-point scale ranging from very unimportant to very important)

1. How important is the ability of FUS to provide single-session pain relief?

2. How important is the ability of FUS to provide rapid pain relief?

3. How important is the ability of FUS to be delivered during the course of radiation or chemotherapy?

4. How important would be the ability of FUS to generate localised tumour control in addition to pain palliation?

Part III: Open questions on timing and position of focused ultrasound therapy for painful bone metastases within the current standard of care

1. At what point should FUS treatment be used?

2. What could be the place for FUS in the future management of painful bone metastases, given more evidence?

Survey results

Part I

1. Fractionation schedules varied from single-fraction schedules (mostly 1 × 8 Gy) to multi-fraction schedules (5 × 4 Gy, 4 × 5 Gy, 5 × 3 Gy, 10 × 3 Gy, 15 × 2.5 Gy and 20 × 2 Gy).

2. For secondary treatment of metastatic bone pain, most patients are generally referred to the radiation oncologist for re-irradiation or to a pain clinic for palliative treatment (supported by 8 out of 13 responses – 8/13). Patients are referred to the interventional radiologist in none of the institutions (0/13).

3. Respondents estimated that 30% of patients failed to respond to radiation treatment in their centre (median, range 15–50%, 11 responders).

4. From the survey it followed that about 9% of patients with painful bone metastases in the participating centres were not eligible for radiotherapy (median, range 5–20%, 8 responders).

Part II

1. It is regarded as important/very important that FUS provides pain relief in a single session (14/14).

2. An important/very important benefit of FUS is its ability to induce fast pain relief (14/14).

3. It is regarded as important that FUS can be given during a course of chemo- or radiotherapy (14/14).

4. It is regarded as important/very important that FUS would be able to induce local tumour control in addition to palliation (13/14).

Part III

1. FUS is an acceptable secondary treatment option for patients who have persistent or recurrent pain after radiotherapy (10/13).

2. There is interest in combining FUS with radiotherapy as a primary treatment in the future (6/13).

The results presented here have fluctuating denominators due to ‘blank responses’ by the responders.

Appendix 2. Search strategy

‘high intensity focused ultrasound’ OR ‘HIFU’ OR ‘MRgFUS’ OR ‘focused ultrasound’ AND ‘bone’ OR ‘bony’ OR ‘osseous’ OR ‘skeletal’

(Title and abstract search, no language restrictions.)