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Health Policy Advisory Committee on Technology Technology Brief: Update MR-guided focussed ultrasound for cancer of the brain, liver, bone, breast and prostate November 2013 © State of Queensland (Queensland Health) 2013 This work is licensed under a Creative Commons Attribution Non-Commercial No Derivatives 3.0 Australia licence. In essence, you are free to copy and communicate the work in its current form for non-commercial purposes, as long as you attribute the authors and abide by the licence terms. You may not alter or adapt the work in any way. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/3.0/au/deed.en For further information, contact the HealthPACT Secretariat at: HealthPACT Secretariat c/o Clinical Access and Redesign Unit, Health Service and Clinical Innovation Division Department of Health, Queensland Level 13, Block 7 Royal Brisbane and Women’s Hospital HERSTON QLD 4029 Postal Address: GPO Box 48, Brisbane QLD 4001 Email: [email protected] Telephone: +61 7 3646 9100 For permissions beyond the scope of this licence contact: Intellectual Property Officer, Department of Health, GPO Box 48, Brisbane QLD 4001, email [email protected], phone (07) 3328 9824. Electronic copies can be obtained from: http://www.health.qld.gov.au/healthpact DISCLAIMER: This Brief is published with the intention of providing information of interest. It is based on information available at the time of research and cannot be expected to cover any developments arising from subsequent improvements to health technologies. This Brief is based on a limited literature search and is not a definitive statement on the safety, effectiveness or costeffectiveness of the health technology covered. The State of Queensland acting through Queensland Health (“Queensland Health”) does not guarantee the accuracy, currency or completeness of the information in this Brief. Information may contain or summarise the views of others, and not necessarily reflect the views of Queensland Health. This Brief is not intended to be used as medical advice and it is not intended to be used to diagnose, treat, cure or prevent any disease, nor should it be used for therapeutic purposes or as a substitute for a health professional's advice. It must not be relied upon without verification from authoritative sources. Queensland Health does not accept any liability, including for any injury, loss or damage, incurred by use of or reliance on the information. This Brief was commissioned by Queensland Health, in its role as the Secretariat of the Health Policy Advisory Committee on Technology (HealthPACT). The production of this Brief was overseen by HealthPACT. HealthPACT comprises representatives from health departments in all States and Territories, the Australian and New Zealand governments and MSAC. It is a sub-committee of the Australian Health Ministers’ Advisory Council (AHMAC), reporting to AHMAC’s Hospitals Principal Committee (HPC). AHMAC supports HealthPACT through funding. This Brief was prepared by Linda Mundy from the HealthPACT Secretariat. Technology, Company and Licensing Register ID WP048 Technology name (MRgFUS) Magnetic resonance-guided focussed ultrasound Patient indication For the treatment of patients with cancer of the brain, liver, bone, breast and prostate. Reason for assessment Innovative, less invasive treatment with major expected health benefits to a large patient group. MRgFUS (or MR-guided high intensity ultrasound, MRgHIFU) may reduce the number or severity of adverse events associated with conventional cancer treatment options (open surgery, chemotherapy and/or radiotherapy) and in so doing, may reduce inpatient hospital stay and patient recovery time. In addition, MRgFUS can provide real-time evaluation of the treatment.1 Stage of development in Australia Yet to emerge Experimental _ Investigational for these indications Nearly established Technology type Device Technology use Therapeutic Established Should be taken out of use Patient Indication and Setting Speciality Oncology and radiotherapy Technology setting Specialist hospital Impact Alternative and/or complementary technology Substitution technology: New technology is a direct substitute for current technology, or will substitute to a great extent. Diffusion of technology in Australia Unchanged since writing the original Brief. Cost infrastructure and economic consequences Unchanged since writing the original Brief. MRgFUS for cancer of the brain, liver, bone and breast: November 2011 1 Evidence and Policy Safety and effectiveness Prostate cancer Focal therapies for the treatment of prostate cancer include cryotherapy, laser and photodynamic therapy, and ultrasound or MR-guided high intensity focussed ultrasound (HIFU).2 Focal therapy for prostate cancer relies on the assumption that treatment of the index lesion will prevent disease recurrence, whilst at the same time reducing damage to surrounding tissues and organs. Current treatment options for prostate cancer include radical prostatectomy or radiotherapy, which may result in high rates of erectile dysfunction (30–90%), incontinence (5-20%) and rectal toxicity (5–20%).3 Results of studies evaluating ultrasound-guided HIFU focal therapy have reported markedly reduced rates of adverse events post-treatment including urinary incontinence, reported in approximately one per cent of men, and erectile dysfunction in 5–10 per cent3, 4 after treating the entire gland. Although the majority of clinical experience of focal therapy for prostate cancer has been with ultrasoundguided HIFU, the technique is limited by the inability to monitor temperature distribution in the prostate gland during treatment.5 In May 2013 the Urological Society of Australia and New Zealand issued a position statement on the use of focal therapy to treat prostate cancer. The Society concluded that “due to the lack of long-term data on focal therapy regarding the ability to accurately target a lesion, on the long-term cancer control, on the side effects of treatment , and on the ability to provide safe salvage options should treatment failure occur – USANZ believes that focal therapy for prostate cancer remains an experimental technique.”6 MRgFUS for prostate cancer is a relatively new procedure, with MRI providing improved spatial and contrast resolution when compared to guidance provided by ultrasound. It is thought that MRgFUS provides a good alternative for the surveillance of patients with low-risk prostate cancer, especially those with localised disease and those not suitable, or those who refuse radical prostatectomy.1 MRI, with its superior anatomical resolution, can be used to accurately identify the index lesion in addition to accurately guiding the ablation.1, 7 MRgFUS for prostate cancer was first performed under general anaesthesia but is now usually performed using a spinal block.7 To date, two methods have been used and it is unclear which method is most favoured, with both methods having some advantages. In one method, a transurethral ultrasound transducer is inserted with the patient lying in a supine position until located in the prostate gland (Figure 1). A water-filled balloon inserted into the rectum provides cooling to the transducer as a MRgFUS for cancer of the brain, liver, bone and breast: November 2011 2 means of protecting the rectal wall during ablation. This method only allows treatment of angular sectors within the prostate gland but treatment time is shorter compared to method two due to the ability to treat continuously. However, only this method can provide real-time thermometric monitoring during treatment.5 Method two involves the insertion of an endorectal coil while the patient is lying in a supine position. The coil is surrounded by a water-filled balloon, providing cooling to the rectal wall during ablation (Figure 2).7 The transrectal approach uses a highly focused beam which allows selective treatment of small volumes of the prostate (<0.1 mL). However, long treatment times of up to 3-4 hours may result if a larger volume requires treatment due to delays between exposures that are required to avoid thermal damage to the rectum.5 Unlike ultrasound guided HIFU, MRgFUS is used for targeted ablation, rather than treating the whole prostate gland.7 Figure 1 The ultrasound transducer is inserted via the urethra until positioned in the 5 prostate gland Water-filled balloon for cooling of coil during ablation Figure 2 The endorectal probe in position, with MRI guiding the ultrasound beam to 7 the area of interest MRgFUS for cancer of the brain, liver, bone and breast: November 2011 3 To date, there have only been a few, small case series published describing the results of MRgFUS of the prostate in humans, with the majority of published studies reporting on the results in canines. An early feasibility study was conducted to assess the accuracy of MRgFUS for the ablation of the prostate using the transurethral approach, building on the early work in canines and five patients that were reported in 2010 by the same authors.8 Eight patients (mean age 60 years, range 49-70 years) with localised prostate cancer (Gleason score ≤7, PSA1 ≤15 μg/L) were recruited (level IV intervention evidence). All patients were scheduled to undergo radical prostatectomy within 2-hours of MRgFUS. A 1.5 tesla (1.5-T) MRI unit was used to locate the ultrasound transducer in the prostate and to guide treatment. A target temperature of a maximum of 55°C at the prostate boundary was attained using temperature feedback provided by the MR, using images acquired every 5-seconds. 5 All patients tolerated the procedure without pain or discomfort. The overall treatment time ranged from 104 to 218 minutes, which included administration of anaesthesia, device insertion, device localisation, treatment planning, treatment delivery and post-treatment imaging. Total time spent in the MR unit was an average of 106 minutes (range 62-143 minutes). One patient experienced a 3 mm shift in the position of the prostate between the time treatment planning images were obtained and the time treatment commenced. A biopsy was conducted on the resected gland, indicating that thermal coagulation was continuous and confined to the area of treatment. The mean treatment rate was 0.5 ± 0.1 mL/min, with a mean targeting accuracy of -1.0 ± 2.6 mm, which the authors stated indicated a tendency for under treatment. The mean temperature measured along the boundary of thermal coagulation was 52.3 ± 2.1°C. 5 A similar feasibility study was conducted by Napoli et al, who reported on the use of an endorectal probe to perform MRgFUS using the ExAblate system and a 3-T MRI. Five consecutive patients (median age 65.4 years, range 50-75 years) with biopsyproven localised prostate cancer (Gleason score 6/7) consented to undergo MRgFUS prior to scheduled radical prostatectomy (level IV intervention evidence). The endorectal probe was inserted under spinal anaesthesia and a threshold temperature of 65°C was set in the target area. Radical prostatectomy took place an average of nine days (range 7-14 days) post-MRgFUS treatment. 9 The average procedure time was 84 minutes (range 30-120 minutes) with no technical difficulties or severe patient complications reported. The mean maximum temperature measured in the target lesions was 81 ± 2°C, with a rectal wall 1 PSA= prostate-specific antigen MRgFUS for cancer of the brain, liver, bone and breast: November 2011 4 temperature of 35°C. The number of sonications required for each patient ranged between seven and eleven, with a mean time of 13 seconds for each sonication. A single pathologist examined the resected glands and results indicated negative surgical margins in all cases. No residual viable tumour tissue was evident in the ablation area or along the safety margins, however three patients had nonsignificant residual tumour and two had significant bilateral tumour visible outside the treated area.9 These small case series demonstrated that MRgFUS of the prostate, using either the transurethral or endorectal approach, is feasible and safe for patients, with accurate thermal control and ablation. MRgFUS did not affect the morbidity and oncological outcome of a subsequent radical prostatectomy. However, no conclusions can be made on the effectiveness of MRgFUS on disease progression and patient outcomes as these studies were designed to determine if surgery could be safely adopted after treatment with MRgFUS, rather than using MRgFUS as an alternative treatment option to surgery. In their review, Zini et al referred to the largest case series to date of 18 patients with localised prostate cancer treated with MRgFUS alone, reported by Cheng2 et al to the European Congress of Radiology conference in 2011. A copy of this abstract could not be obtained.10 Turkevich et al (2012) presented an abstract to the World Conference on Interventional Oncology on the use of the ExAblate system with a 1.5 T MRI in patients with localised, low-risk prostate cancer (Gleason score <6, PSA <10 ng/mL).11 Seven patients underwent eight MRgFUS treatments under epidural anaesthesia with conscious sedation (level IV intervention evidence). One patient required an additional treatment session for a newly detected cancerous focus at 6-month follow-up. Adverse events such as haematuria, perineal pain, post-treatment urinary incontinence or bowel related symptoms were not reported by any of the patients. Before treatment, six patients were potent, and four patients had returned to baseline sexual and erectile function within 3-months of treatment. Ongoing research: prostate cancer Three ongoing or completed non-comparative studies describing the use of MRgFUS for the treatment of prostate cancer were identified on the Clinical Trials database. The one completed study (June 2012) built on the earlier work by Napoli et al, and enrolled 12 men with localised prostate cancer, with a Gleason score <7 and PSA Cheng CWS, Kwek JW, Thng CH, Lau W, Ho H, Khoo JBK. Initial experience with MRg FUS focal therapy for low risk prostate cancer. European Congress of Radiology 2011; Mar 3-7; Vienna, Austria 2 MRgFUS for cancer of the brain, liver, bone and breast: November 2011 5 levels <10 ng/mL. All patients were scheduled for radical prostatectomy and the study was designed to determine if surgery could be safely adopted after treatment with MRgFUS, rather than using MRgFUS as an alternative treatment option to surgery (ClinicalTrials.gov Identifier: NCT01522118). The two remaining ongoing feasibility studies were sponsored by the manufacturer, InSightec and are currently recruiting patients. One is a multicentre study expecting to recruit a total of 80 patients from five centres: Toronto, Canada; Tel Hashomer, Israel; Rome, Italy; Singapore and London, United Kingdom (NCT01226576). Patients must be aged between 50 and 75 years with localised, low-risk prostate (Gleason score <6, PSA <10 ng/mL). Patients will be followed-up for a total of 24-months, with the primary outcomes measured at six months being: safety of the procedure – the number of adverse events related to the procedure; and the effectiveness of the procedure - adequate tumour control. At 24-months patients will be assessed for quality of life issues including function and satisfaction with the procedure, in addition to effectiveness of the procedure, i.e. tumour control as measured by periodic PSA measurements and transperineal biopsy. The study expects to be finalised by December 2013. The last study is being conducted in the United States of America (USA) and expects to recruit 40 patients (NCT01657942). The inclusion criteria are similar the previous study, however safety and effectiveness follow-up of treatment-related incontinence and impotence as well as tumour control (confirmed by transperineal biopsy results) at only 6-months. Expected completion date of this study is December 2014. An additional study was identified that was currently recruiting patients to be treated with MRI guided focal prostate cancer laser ablation, aiming to recruit 60 men (NCT01094665). MRgFUS for cancer of the brain, liver, bone and breast: November 2011 6 Breast cancer No studies describing the use of MRgFUS for breast cancer have been published since the 2011 Brief. One study reported on the effect of MRgFUS ablation and thermal exposure on cadaver breast tissue. Ablations were performed in three nonembalmed cadaveric breast specimens. Anatomical images were obtained and breast tissue temperature was measured. Following ablation the breast tissue samples underwent histopathology. The authors concluded that as MRgFUS could successfully be used to monitor tissue ablation and that cell death occurred after 5minutes at 75°C, MRgFUS is feasible as a non-invasive treatment of breast tumours.12 Another study reported on the use of MRgFUS as a surgical guide for non-palpable breast tumours cadaveric breast tissue.13 Previously published studies describing the use of MRgFUS for breast cancer have used the ExAblate system, which consists of a spherically-shaped transducer embedded in a water bath, built into an MR table top .Ultrasound waves are directed at the breast anteriorly using a “point-by-point” method. Merkel et al. (2013) described the development of a dedicated MRgFUS breast platform, the Sonalleve (Philips Healthcare, Finland), a system currently used for the ablation of uterine fibroids and for pain palliation for patients with bone metastases. As with the ExAblate, patients are positioned on the MR table with their breast inside a cup that is filled with water to ensure conduction of the ultrasound beams to the breast (Figure 3a). The breast cup, however, consists of eight separate focused ultrasound modules with 32 transducer elements, which means that 270° of the breast is surrounded by the structure (Figure 3b). The breast is laterally targeted by the ultrasound, which has the effect of increasing the focal point to rib cage, heart and lungs, reducing heating of critical structures (Figure 4). Results in women with breast cancer treated with this system have yet to be reported.14 Figure 3 a (a) The MRI table top, demonstrating the placement of 14 the breast cup (b) b MRgFUS for cancer of the brain, liver, bone and breast: November 2011 7 a Figure 4 b a) Conventional breast MRgFUS demonstrating the short distance between focal point and ribs b) Lateral targeting of the breast, demonstrating a greater distance between 14 focal point and ribs A group from the USA recently reported on refinements to published techniques for the treatment of breast cancer with MRgFUS. Previously described techniques use a single coil around the breast, positioned at the chest wall, which has the advantage that it does not interfere with the ultrasound beam during treatment. However, this technique has a relatively low signal-to-noise ratio and gives limited coverage of the breast. This study used a dedicated 11-channel radiofrequency phased array coil that was incorporated into a breast MRgFUS apparatus, for use in a 3-TMRI unit. Phased arrays will improve signal-to-noise ratios and the multiple channels provide an increase in signal sensitivity, which enables parallel image acquisition techniques. Temporal resolution of temperature monitoring in the breast tissue should be enhanced tissue, which may reduce motion artefacts such as breathing. The array was tested in breast phantoms and five normal human volunteers. Signal-to-noise ratios were improved in the phantom studies when the 11-channel breast coil was compared to the single chest-loop coil. There was a 131 per cent improvement at the centre of the breast, a 295 per cent improvement at lateral edge of the breast, and a 173 and 108 per cent improvement at the superior and inferior edge of the breast, respectively. In addition, there was a 247 per cent improvement at the nipple area. In the normal volunteers, the 11-channel breast coil provided better signal-to-noise ratio coverage over the entire breast region. The increase in signal-to-noise ratio translates to improved spatial and temporal resolution. In addition, the 11-channel coil gave more precise temperature measurements throughout a larger volume of the breast tissue compared to the single chest-loop coil.15 Of interest is the proof-of-concept study by Oerlemans et al. (2011), who described using a combination of fluorescein-containing liposomes which, when the dye is released by the heat of MRgFUS, acts as a means of lesion demarcation making surgical resection of non-palpable breast lesions easier. To date, this technique has only been used in phantoms.16 MRgFUS for cancer of the brain, liver, bone and breast: November 2011 8 Ongoing research: breast cancer Although no ongoing trials were identified on the United States’ National Institutes of Health clinical trials database, the manufacturer advises that they are sponsoring two ongoing trials: BC004 (excision-less trial) and BC006 (treat and resect protocol). In addition, InSightec advise that several hospitals around the world (mainly Japan and Europe) are currently treating patients under these protocols (personal communication). MRgFUS for cancer of the brain, liver, bone and breast: November 2011 9 Bone metastases In October 2012, the United States’ Food and Drug Administration (FDA) approved the use of the ExAblate MRgFUS system for pain palliation of metastatic bone cancer in patients for whom radiation therapy is not an alternative. This is only the second clinical indication that the system has obtained FDA approval for, after uterine fibroids.17 In addition, the ExAblate 2100 system received CE Mark approval in June 2013 for the treatment of bone metastases, multiple myeloma, local tumour control, bone denervation for local treatment of cancerous and benign primary and secondary bone tumours or facet joint syndrome. One peer-reviewed study and three conference abstracts were identified for inclusion in this Brief, in addition to the safety and effectiveness data submitted to the FDA for the approval of the ExAblate system for the treatment of bone metastases. The non-comparative study by Napoli et al. (2013) enrolled 18 consecutive patients (mean age 62.7 ± 11.5 years) with painful bone metastases from primary tumours of the lung (n=5), breast (n=4), kidney (n=3), prostate (n=3), colon/rectum (n=2) and melanoma (n=1) (level IV intervention evidence). Seven patients had a single bone lesion. In four patients the bone was the only secondary organ involved, with the remaining 14 patients having additional metastatic disease to the brain, lung or liver. All patients were undergoing chemotherapy at the time of enrolment and 11 patients had undergone resection of the primary tumour. Computed tomography and MR imaging were performed to determine the size and location of the lesions to be treated. MRgFUS was performed using the ExAblate 2100 system and a 3-T MRI unit.18 Treatment was performed as a day procedure with patients anaesthetised (deep sedation (n=5), epidural (n=8) or general anaesthesia (n=5)) for pain management and to avoid patient movement. Patients were placed on the specially designed MR table, with the transducer attached to the patient’s skin using a moist gel pad to exclude any air which may interfere with the ultrasound signal. A single lesion per patient was treated and ablation at the focal point was considered successful when the temperature reached at least 60 to 70 C. Patients were monitored for one to two hours before discharge. All patients were followed up at 1- and 3-days, 1- and 2weeks, and at 1-, 2- and 3-months post-MRgFUS treatment. The mean number of sonications was 23.5 ± 4 (range 15-29) with a mean maximum sonication energy used per sonication of 2736.8 ± 911.4 Joules (range 980-6677 Joules). The total time spent in the treatment room ranged between 55 and180 minutes. MRgFUS for cancer of the brain, liver, bone and breast: November 2011 10 Pain severity and pain interference scores were assessed3 at baseline and at followup, in addition to the non-perfused volume of tumour. Pain severity was assessed using a 10-point scale questionnaire, where one corresponds to the absence of pain and 10 to the worst pain experienced, with a decrease of two points considered to be clinically significant. Pain interference score relate to the degree in which pain interferes with the patient’s feeling and function across seven daily activities: general activity, walking, work, mood, enjoyment of life, relations with others and sleep. The non-perfused volume of tumour was assessed using contrast-enhanced MR images by a blinded radiologist and defined as the volume of cancer tissue enhancing at baseline that did not show any contrast uptake after treatment. No treatment related adverse events were reported. The 3-month follow-up results are summarised in Table 1. Mean pain severity scores decreased significantly at one and three month follow-up when compared to baseline values. A pain severity score of zero, requiring no medication intake, was reported in 13/18 (72.2%) of patients (responders). Of the remaining five patients, three reported a partial response with a pain reduction of at least two points without an increase in analgesic intake. Two patients reported pain recurrence requiring a 25 per cent increase in pain medication when compared to baseline (non-responders). Both of these patients had a complete response at 2-months but presented with disease progression at 3months. Similarly, the pain interference scores decreased significantly at one and three months when compared to baseline. The non-perfused volumes remained stable after treatment when compared to imaging taken immediately after MRgFUS treatment. There was no difference in the non-perfused volume when responders were compared to partial or non-responders.18 Table 1 Evaluation of pain and tumour volume at baseline and follow-up Baseline 1-month follow-up 3-month follow-up Pain severity score 7.1 ± 2.08, range 4-10 95% CI [6.07, 8.15] 2.5 ± 1.4, range 0-5 95% CI [1.81, 3.2], p=0.001 1 ± 1.1, range 0-3 95% CI [0.0, 1.85], p=0.001 Pain interference score 4.8 ± 1.8, range 2.1-8.7 95% CI [3.86, 5.67] 1.8 ± 1.0, range 0.3-4.6 95% CI [1.32, 2.32], p=0.001 0.7 ± 0.6, range 0-2.6 95% CI [0.06, 0.92], p=0.001 45.2 ± 22.1%, range 20-93% 95% CI [34.19, 56.14], p=0.08 43.7 ± 21.3%, range 20-93% 95% CI [33.17, 54.38], p=0.08 Non-perfused volume 3 18 Pain scores were assessed using the Brief Pain Inventory-Quality of Life criteria MRgFUS for cancer of the brain, liver, bone and breast: November 2011 11 This small study demonstrated that MRgFUS was a safe and effective tool for pain palliation in patients with painful bone metastases, however longer follow-up would be required to determine the length of effect time. A recent conference abstract reported on the results of a multicentre study4 that randomised patients 3:1 to treatment with MRgFUS (n=107) or sham treatment (n=35) (level III-1 intervention evidence – method of randomisation was unclear). All patients had painful bone metastases where radiation therapy was ineffective or contraindicated. Patients in the sham arm who did not report any pain relief within 2-weeksof treatment were allowed to cross over for salvage MRgFUS treatment. The primary outcome was pain response and quality of life5, in addition to safety of the procedure.19 At 3-month follow-up, 67 per cent (95% CI[57.5, 76.0%]) of patients in the MRgFUS treatment arm reported a clinically significant improvement in pain scores compared to 20 per cent of the patients in the sham arm (p<0.0001). At baseline, both groups had a median pain score of 7.0, whereas at 3-month follow-up median pain scores for the MRgFUS group were reduced to 2.0 compared to 6.0 in the sham group. Similarly, the MRgFUSgroup reported a clinically significant improvement in pain scores compared to the sham arm, with an average decrease in pain score of 2.4 versus 0.2 (p<0.0001). No adverse events associated with the treatment were reported.19 The same research group reported on the same patients at a different conference.20 However, only the results from 122 patients treated for 125 lesions with MRgFUS were reported, which may possibly include the results from some of patients in the sham group who crossed over (this was not explicitly stated). Responders were considered to be those patients who reported a reduction of two or more points on the pain scale, without a significant increase in pain medication (<25% difference from baseline). Using these criteria, 87 treatments produced a response. Univariate and multivariate analyses identified five factors that were related to response rate: sex (p<0.001), with a higher likelihood of response associated with being female (odds ratio (OR) = 4.55, 95% CI [1.63, 12.68]); history of radiation therapy (p=0.001), associated with a decreased likelihood of response (OR = 0.33, 95% CI [0.12, 0.91]); 4 Philadelphia, Tampa, Boston, San Diego and Virginia, USA; Rostov-on-Don and St Petersburg, Russia; Toronto, Canada; Haifa and Ramat-Gan, Israel; and Rome, Italy. 5 Pain scores were assessed using the Brief Pain Inventory-Quality of Life criteria (BPI-QOL) and quality of life (QOL) by the numerical rating scale (NRS) MRgFUS for cancer of the brain, liver, bone and breast: November 2011 12 primary tumour site (p=0.009), with metastases from breast cancer (n=46) showing the best response at 87 per cent; treated tumour location (p=0.021) with a higher likelihood of response associated with osteoblastic tumour (OR = 4.0, 95% CI [1.13, 14.2]);and treatment energy (p<0.001), with higher energy densities associated with an increased chance of a response.20 This study was the pivotal study in the application for approval from the FDA. 21 Although the conference abstracts reported no adverse events, the safety and effectiveness data in the FDA application is more comprehensive, with a total number of 82 adverse events reported in 62 patients. Results were divided into those patients from the Russian cohort (ExAblate n=50, sham n=18) and the nonRussian cohort (ExAblate n=83, sham n=19). All of the Russian patients were treated under general anaesthesia, whereas patients in the non-Russian cohort were treated under local or conscious sedation. This resulted in a much higher number of adverse events reported in the non-Russian cohort that were related to pain during the procedure. A total of 77 adverse events in 57 patients were reported in the nonRussian cohort, of which 48 per cent were transient pain and discomfort during treatment. A total of 71 patients (53%) experienced no adverse events. Four significant adverse events were reported, including a third degree skin burn, leg neuropathy in one patient and two events of fracture, which may be considered a complication of bone metastases rather than as a result of treatment. Interestingly, a higher proportion of patients in the Russian cohort were responders (Table 2). These patients were treated with a higher mean energy compared to the non-Russian cohort (6.9 ± 2.8 versus 4.5 ± 3.0 Joules/mm2); however their treatment time was less (54 ± 38.8 versus 78.1 ± 48.5). Table 2 Proportion of responders in the pivotal FDA study Responders N ExAblate Sham Non-Russian cohort 83 55% (35/64) 26% (5/19) p=0.04 Russian cohort 56 90% (36/40) 13% (2/16) p<0.0001 Opioid medication use at 3-months was compared to baseline intake for those patients considered responders. The majority of responders in the non-Russian cohort either stopped (10/35, 29%) or reduced (10/35, 29%) their medication, with 43 per cent reporting no change. In contrast, the majority of responders in the Russian cohort reported no change in their medication (25/36, 69%). MRgFUS for cancer of the brain, liver, bone and breast: November 2011 13 The FDA concluded that data from this study supported that the ExAblate system was safe and effective for the palliation of pain resulting from bone metastases, and does not represent an increased risk to patients who are already at significant risk due to their underlying disease. In approving the ExAblate system, the Center for Devices and Radiological Health required that the performance of the device continue to be monitored in actual clinical use, requiring a post-approval study to evaluate the safety and effectiveness when the device is used in the intended patient population.21 The results from another small case series (n=31) were presented at the World Conference on Interventional Oncology (level IV intervention evidence). Patients (mean age 55 years, range 19-76 years) with painful bone metastases resulting from primary tumours of the breast (n=19), stomach (n=4), bronchus (n=2), bladder (n=2) and other (n=4) were treated with MRgFUS and follow-up for 3-months. No treatment-related adverse events were reported. Three patients died during the follow-up period from progression of their disease. Of the remaining 28 patients, all reported a clinically significant reduction in pain as described in previous studies at 3-months. The mean worst pain score decreased gradually over time from a baseline value of 6.9 to 0.9 at 3-months (Figure 5). As with other studies, MRgFUS appeared to be effective at reducing pain, however longer term follow-up is required to ascertain length of treatment effect and if re-treatment would be required.22 Figure 5 Average pain score reduction versus time 22 Of interest are two small case series that describe the innovative use of MRgFUS for the treatment of chronic musculoskeletal pain (level IV intervention evidence). Izumi et al. (2013) reported the results of eight patients with osteoarthritis (OA) of the knee (mean age 78 ± 6.4 years). All patients had grade 4 medial knee OA and were eligible for a total knee replacement. The primary outcome measure was VAS 6 scores 6 VAS = visual analogue scale MRgFUS for cancer of the brain, liver, bone and breast: November 2011 14 during walking, with zero representing no pain and 100 representing maximum pain, with a 50 per cent decrease in pain scores considered to be a successful response. The mean treatment time was 74 minutes (range 50-120 minutes), with a mean number of sonications of 12.4 (range 10-20) per patient. Six of the eight patients were considered responders with a decrease in VAS scores at one month follow-up compared to baseline values. However, two patients proceeded to a total knee replacement and one patient switched to opioid therapy at one month. Four patients had long lasting pain alleviation with a mean VAS reduction of 72.6 per cent at 6months.23 Weeks et al. described the use of MRgFUS to treat chronic pain emanating from facet joint OA of the lower back (level IV intervention evidence). Although 18 patients (mean age 48.2 years, range 33-60 years) with chronic back pain underwent treatment, only 13 patients were enrolled for follow-up. Patients underwent treatment in an outpatient setting with the ExAblate 2000 system, with (n=10) or without (n=3) sedation. Five patients reported claustrophobia when first placed inside the MRI unit; however this was resolved after administration of sedation. Four patients with a body mass index >30 reported discomfort despite sedation due to difficulty fitting them into the MRI aperture. The mean time spent in the MR unit was 188 minutes (range 102-265) and the mean treatment time was 97 minutes (range 58-186). Treatment consisted of a mean of 23 sonications (range 10-35).24 No adverse events related to the treatment were reported. Pain and quality of life scores were reported at baseline and 1-week, and 1-, 2-, 3- and 6-months. At baseline, the average NRS pain score was 6.42, with a worst pain score of 7.96. At 6months there was a reduction of 3.87 (60.2%) in the average pain score and the reported worst pain score was 4.08, a reduction of 51 per cent. At the same time, improvements in the Oswestry Disability score were noted (45.88%) and a reduction in the BPI-QOL score (61.9%). These results indicate that MRgFUS may be a safe treatment option for patients with chronic facet joint pain with treatment effects lasting for at least 6-months. Ideally this pilot study should be followed up with a larger, randomised controlled trial.24 Ongoing research: Bone metastases cancer Three InSightec-sponsored trials have been identified. One small randomised trial identified in the 2011 Brief (ClinicalTrials.gov Identifier: NCT01091883) comparing MRgFUS to external beam radiation therapy for the palliation of pain in patients with metastatic and myeloma bone tumours was last updated in September 2012. The estimated study completion date was March 2013, however the current status of the trial is unclear. A Phase IV study (NCT01833806) aims to study the safety and efficacy of ExAblate treatment of metastatic bone tumours for the palliation of pain. The MRgFUS for cancer of the brain, liver, bone and breast: November 2011 15 primary outcome of the study is the proportion of responders at 3-months, i.e. those patients with reduced pain after treatment. The secondary outcome is the number and type of adverse event associated with the treatment. This study intends to recruit 70 patients beginning September 2013, with an estimated completion date of October 2016. Another small phase IV post approval registry study (BM019-Registry) (NCT01834937) aims to examine adverse events reported in patients undergoing ExAblate treatment for palliation of pain from metastatic bone tumours during the first 2-years of commercial experience in the USA. Although the planned start date was June 2013, the study has not yet started recruitment, which is estimated to be 50 patients. The estimated study completion date is December 2015. Two studies sponsored by Phillips were identified. A small pilot study (NCT01309048) aims to confirm the safety and technical of MRgFUS for palliation for pain of skeletal metastases. The primary outcome measures include reduction of pain score, reduction of pain medication use, and complications and adverse events at 90 days. Secondary outcomes are changes in bone density and quality of life measure at 90 days. The study enrolled 10 patients and has been completed, however no results have been published to date. Another ongoing multi-centre, non-comparative study is evaluating MRgFUS for palliation of painful skeletal metastases. The primary outcome is pain response to therapy using the BPI questionnaire at 30 days after treatment. Secondary outcome measures include the total number of adverse events at 90 days after treatment, quality of life at baseline (before treatment) and at 7, 14, 30, 60, and 90 days after treatment, pain response in radiation-naïve patients at 30 days and temporal evolution of pain response during the first 30 days after treatment. The study began in September 2012 and hopes to recruit 64 patients with an estimated completion date of December 2014. MRgFUS for cancer of the brain, liver, bone and breast: November 2011 16 Diseases of the brain No recent published studies since the original Brief reporting the use of MRgFUS for the treatment of brain cancer were identified. However, several novel potential intracranial applications of MRgFUS have been described in the literature including the treatment of: chronic neuropathic pain, essential tremor, clot lysis in ischaemic stroke, epilepsy, trigeminal neuralgia and hydrocephalus.25 Lipsman et al. (2013) reported the results of a proof-of-concept study, using MRgFUS to treat four patients (mean age 70.8 years, range 58-77 years) with medication resistant essential tremor. Surgical options for these patients included thalamotomy, gamma knife treatment or deep brain stimulation. The mean duration of illness in the four patients was 17.8 years, with a range of 6-25 years. Although 10 patients were originally screened for inclusion in the study, six were excluded due to age, minimal tremor severity or previous neurosurgery. Patients were followed up for 3months and the primary effectiveness outcome was tremor severity and functional impairment, in addition to any adverse events from the procedure.26 The thalamus contralateral to the most disabled hand was targeted. Although patients were awake during the procedure, a local anaesthetic was used to fix the stereotactic frame to the skull. Treatment was performed with the ExAblate system in conjunction with a 3-T MRI scanner. The mean number of sonications was 22.5, with a range of 12-29. The procedure lasted 5-6 hours including fitting of the frame, positioning of the patient, pre- and post-treatment imaging, as well as treatment time.26 All four patients demonstrated an immediate improvement in tremor in the dominant hand, which was sustained over the 3-month follow-up period. Mean reduction in tremor score of the treated hand was 89.4 and 81.3 per cent at one and three month follow-up, respectively. Patients also had improvements in their selfrated functional impairment scores, with a reduction of 51 per cent in their perceived functional disability relating to their tremor. One patient developed a lower limb deep vein thrombosis at 1-week after the treatment which may have been related to the length of the procedure. No other adverse events were reported. An example of functional ability before and after treatment is given in Figure 6, with the patient demonstrating a clear improvement post-treatment in their ability to draw free-hand and to follow pre-existing lines. This study demonstrates the potential for the non-invasive treatment of essential tremor with MRgFUS, however larger studies are required, with longer follow-up.26 MRgFUS for cancer of the brain, liver, bone and breast: November 2011 17 Figure 6 Functional ability pre-and post-treatment. A: One patient completed a freehand drawing before treatment (LHS) and immediately after treatment (RHS). In addition patients were asked to draw between the lines of the diagrams in B before treatment (LHS) and immediately after treatment 26 (RHS). A similar study was conducted by Elias et al (2013) who enrolled 15 patients (mean age 66.6 ± 8.0 years, range 53 to 79 years) with medication resistant essential tremor. Patients were excluded if they had previously undergone stereotactic or cranial surgery or if they had another neurological condition such as Parkinson’s disease. Patients had a mean history of tremor of 32.0 ± 21.3 years (range 4 to 60 years), with a mean baseline score on the Clinical Rating Scale for Tremor (CRST) of 54.9 ± 14.4. The procedure was conducted using a 3T MRI and the ExAblate Neuro. Follow-up assessments were performed at 1-day, 1-week, 1, 3 and 12-months.27 It should be noted that although this study was funded by the Focused Ultrasound Surgery Foundation, InSightec made financial contributions to this foundation and oversaw the study. As with the previous study, patients were awake during the procedure and a local anaesthetic was used to fix the stereotactic frame to the skull. Patients received a mean number of 17.9 ± 4.6 (range 11 to 26) sonications. Final sonication energies of 10,320 ± 4,537 J (range 6,500 to 20,800) which produced a maximal temperature voxel of 58.5 ± 2.5°C in the lesion. A number of adverse events were reported, some of which were transient and related to the use of the stereotactic frame (headache, scalp numbness). In addition, transient adverse events related to sonication and MRI were reported in a number of patients including nausea (n=5), head pain (n=9) and syncope (n=1). Of those adverse events related to thalamotomy, the most common was paresthesia of the lip (n=9) or fingers (n=5). At 12-months follow-up, four patients experienced persistent MRgFUS for cancer of the brain, liver, bone and breast: November 2011 18 paresthesia. In addition, four patients experienced ataxia that resolved by one month and one patient dysmetria for the same time. There was a significant improvement in tremor in the contralateral hand from a mean baseline CRST score of 20.4 ± 5.2 to a score of 4.3 ± 3.5 at 3-months and 5.2 ± 4.8 at 12-months (p=0.001), representing a 75 per cent reduction from baseline at 12-months (Figure 7). There was no significant difference in tremor score for the ipsilateral hand from baseline to 12-months. Total tremor scores were also reduced significantly from 54.9 ± 14.4 at baseline to 24.3 ± 14.8 at 12-month follow-up (p=0.001). Disability scores improved from 18.2 to 2.8 (p=0.001) and patient’s perception of their quality of life improved with scores reduced from 37 to 11 per cent (p=0.001). 27 As with the previous study, these results are encouraging but further randomised controlled trials are required to assess the clinical effectiveness of this procedure. Figure 7 Individual hand tremor CRST scores 27 A small case series reported on the use of MRgFUS to treat chronic therapy-resistant neuropathic pain using the ExAblate 4000 system with a 3-T MRI. Patients were aged between 45 and 75 years with a duration of pain ranging from 1.5 years to 21 years. Pain was located in the face (n=3), thorax (n=1), lower extremity (n=3), upper extremity (n=4). The cause of pain varied. As in the previous studies, the patient’s head was immobilised in a stereotactic frame. The posterior of the thalamic central lateral nucleus was targeted. Patients were fully awake during the procedure. The procedure was performed unilaterally in five patients and bilaterally in six.28 Pre and post-treatment data is summarised in Table 3. In the first two patients the therapeutic lesions were too small, and therefore only the results of nine of the 11 patients deemed to have successful treatment are presented. Pain was assessed MRgFUS for cancer of the brain, liver, bone and breast: November 2011 19 using the visual analogue scale, with 1 representing the least amount of pain and 100 representing the worst pain. At baseline, the mean VAS score was 59.5, which was reduced at 3-month and maintained at 1-year follow-up. This translated to an approximate 40 per cent post-operative improvement. Significant pain relief was reported immediately following treatment, however this diminished over time. Of the eight patients with data available at 1-year follow-up, five had stopped taking pain relief medication; however three patients had an unchanged medication regimen.28 During the procedure, one patient experienced a displacement of the head frame, which was repositioned without any negative consequences. In addition, one patient experienced a bleed with ischaemia in the motor thalamus.28 Table 3 Summary of the post-treatment data of the 11 patients who underwent MRgFUS for neuropathy Pain relief (%) Patient VAS score (lowest-highest, mean) 1-year drug intake Acute 2-days 3month s 1-year Baseline 3-months 1-year 1 100 70 0 LFU 70-80 16-79 UN Reduced 2 30 30 0-30 LFU 72-100 40-70 UN No change 3 10 100 80 80 52-73, 62.5 5-20, 12.5 9-16, 12.5 Ceased 4 70 50 50 95 40-80, 60 0-72, 36 9-36, 22.5 Ceased 5 100 80 0 Died 12-78, 45 0-50, 25 UN UN 6 30 100 90 100 39-62, 50.5 0-11, 5.5 0 Ceased 7 30 50 50 40 22-85, 53.5 15-84, 49.5 21-86, 53.5 No change 8 100 100 70 50 56-85, 70.5 13-80, 46.5 77 No change 9 0 10 0 0 67-90, 78.5 54-89, 71.5 11-84, 47.5 No change 10 100 75 90 80 44-91, 67.5 0-14, 7 0-28, 14 Ceased 75 15 10 25-70, 47.5 30-80, 55 30-80, 55 Ceased 71.1 49.4 56.9 59.5 34.3 35.3 UN 11 Overall mean* 55 * The mean values were only calculated for cases 3-11 LFU = lost to follow-up, UN = unavailable, VAS = visual analogue scale Although the ExAblate 4000 transcranial MR system has not received FDA approval for the treatment of brain cancer, in December 2012 it received the CE Mark for the MRgFUS for cancer of the brain, liver, bone and breast: November 2011 20 thermal ablation of targets in the thalamus, subthalamus and pallidum regions of the brain. To this end, it can be used for the treatment of neurological disorders such as essential tremors and tremor dominant idiopathic Parkinson’s disease; and neuropathic pain in the brain. Ongoing research: brain cancer One InSightec-sponsored single-group study evaluated the safety and feasibility of ExAblate in the treatment of glioma or metastatic brain tumours (ClinicalTrials.gov Identifier: NCT01473485), with an intended patient number of 10. No primary or secondary outcome measures have been reported. The last update of the study (March 2012) indicated that the study is currently recruiting however the intended finishing date was April 2012. Although not listed on the National Institutes of Health clinical trials database, the manufacturer advises they are sponsoring a large, doublearm blinded study (treatment vs. sham) to evaluate the effectiveness and safety of ExAblate transcranial MRgFUS thalamotomy in the treatment of medication refractory essential tremor (IDE number G120246) (personal communication). MRgFUS for cancer of the brain, liver, bone and breast: November 2011 21 Cancer of the liver In the 2011 Brief, no human studies describing the use of MRgFUS for the ablation of liver cancer were identified despite several reviews discussing the possibility. Since that time, de Senneville et al. have reported on the use of MRgFUS in porcine livers.29 One group in Italy described the results of ultrasound-guided HIFU in 22 patients with mixed indications, including pancreatic solid lesions, and liver and/or bone metastases from breast cancer. The effect of treatment was assessed by MRI.30 Ongoing research: liver cancer No ongoing trials identified. Economic evaluation No economic evaluation of MRgFUS for an indication other than uterine fibroids could be identified. Economic evaluations, especially on the use of MRgFUS for the treatment of bone metastases are required. Summary of findings MRgFUS potentially offers a unique, non-invasive, radiation-free way of treating many types of cancer, which would appeal to many patients. However, apart from the pain palliation for patients with bone metastases, the technology remains immature. In the treatment of prostate cancer, research is still ongoing to decide which method is more effective and/or acceptable to patients: the endorectal or transurethral approach. Only small human case series have been published. Several non-comparative studies for prostate cancer are ongoing. Similarly with breast cancer, methods of imaging and technique are still developing. There appeared to be no advancement of the evidence base for the use of MRgFUS to treat liver cancer. Although this was also true for the treatment of brain cancer, the interest in neurology appears to lie in the use of MRgFUS for the treatment of other conditions such as essential tremor and neuropathic pain. The small proof-of-concept studies included in this Brief indicate that the use of MRgFUS for these conditions may be a feasible option, however larger comparative studies are required. The most mature evidence base was that for the palliation of pain from bone metastases. The FDA approved the use of the ExAblate system for this indication in late 2012, based on the results of a RCT. It would appear that not all patients will respond to this treatment, with pain relief reported in 67-100 per cent of patients, with a corresponding reduction in intake of pain medication. All case series and the RCT included in this Brief only reported on the effectiveness of treatment, that is, a reduction in pain at 3-months post treatment. Longer-term follow-up would be required to determine the length of treatment effectiveness. There were differences MRgFUS for cancer of the brain, liver, bone and breast: November 2011 22 in treatment modality reported when the RCT was stratified into those patients treated in Russian and non-Russian centres. These differences included the method of sedation, which impacted on the amount of procedure pain reported by patients, and the level of energy used for the sonications. These differences in technique need to be clarified. Of interest is the potential use of MRgFUS for the treatment of osteoarthritis. HealthPACT assessment The evidence base for the use of MRgFUS to treat cancers is currently immature, requiring more studies to demonstrate its effectiveness, especially in terms of longterm follow-up of patients. The use of MRgFUS to treat neurological conditions, such as essential tremor, appears to be promising. It is likely that, as the technology matures; further evidence will be published and identified by routine horizon scanning activities. Therefore it is recommended that no further research on behalf of HealthPACT is warranted at this time. Number of studies included All evidence included for assessment in this Technology Brief has been assessed according to the revised NHMRC levels of evidence. A document summarising these levels may be accessed via the HealthPACT web site. Total number of studies Total Level IV intervention evidence studies for prostate cancer Total number of studies for breast cancer Total level IV intervention evidence studies for bone metastases cancer Total level III-1 intervention evidence studies for bone metastases cancer Total number of studies for liver cancer Total number of Level studies for brain cancer 8 3 0 4 1 0 0 References 1. Napoli, A, Anzidei, M et al (2013). 'MR-Guided High-Intensity Focused Ultrasound: Current Status of an Emerging Technology'. Cardiovasc Intervent Radiol, 36 (5), 1190-203. 2. Da Rosa, MR, Trachtenberg, J et al (2011). 'Early experience in MRI-guided therapies of prostate cancer: HIFU, laser and photodynamic treatment'. Cancer Imaging, 11 Spec No A, S3-8. 3. Dickinson, L, Ahmed, HU et al (2013). 'A multi-centre prospective development study evaluating focal therapy using high intensity focused ultrasound for localised prostate cancer: The INDEX study'. Contemp Clin Trials, 36 (1), 68-80. 4. Ahmed, HU, Freeman, A et al (2011). 'Focal therapy for localized prostate cancer: a phase I/II trial'. J Urol, 185 (4), 1246-54. MRgFUS for cancer of the brain, liver, bone and breast: November 2011 23 5. Chopra, R, Colquhoun, A et al (2012). 'MR imaging-controlled transurethral ultrasound therapy for conformal treatment of prostate tissue: Initial feasibility in humans'. Radiology, 265 (1), 303-13. 6. USANZ (2013). Position Statement on Focal Therapy for Prostate Cancer. [Internet]. Urological Society of Australia and New Zealand. Available from: http://www.usanz.org.au/uploads/29168/ufiles/Focal_Therapy_Position_Stat ement2.pdf [Accessed 10th Oct 2013]. 7. Ellis, S, Rieke, V et al (2013). 'Clinical applications for magnetic resonance guided high intensity focused ultrasound (MRgHIFU): present and future'. J Med Imaging Radiat Oncol, 57 (4), 391-9. 8. Siddiqui, K, Chopra, R et al (2010). 'MRI-guided transurethral ultrasound therapy of the prostate gland using real-time thermal mapping: initial studies'. Urology, 76 (6), 1506-11. 9. Napoli, A, Anzidei, M et al (2013). 'Real-time magnetic resonance-guided high-intensity focused ultrasound focal therapy for localised prostate cancer: preliminary experience'. Eur Urol, 63 (2), 395-8. 10. Zini, C, Hipp, E et al (2012). 'Ultrasound- and MR-guided focused ultrasound surgery for prostate cancer'. World J Radiol, 4 (6), 247-52. 11. Turkevich, VG, Nosov, AK et al (2012). 'Preliminary clinical experience with the use of the exablate magnetic resonance guided focused ultrasound surgery (MRgFUS) system for focal treatment of organ-confined low-risk prostate cancer'. Journal of Vascular and Interventional Radiology, Conference: World Conference on Interventional Oncology, WCIO 2012 Chicago, IL United States 23 (6), 853.e20. 12. Merckel, LG, Deckers, R et al (2013). 'The effects of magnetic resonance imaging-guided high-intensity focused ultrasound ablation on human cadaver breast tissue'. Eur J Pharmacol, 717 (1-3), 21-30. 13. Bitton, RR, Kaye, E et al (2012). 'Toward MR-guided high intensity focused ultrasound for presurgical localization: focused ultrasound lesions in cadaveric breast tissue'. J Magn Reson Imaging, 35 (5), 1089-97. 14. Merckel, LG, Bartels, LW et al (2013). 'MR-guided high-intensity focused ultrasound ablation of breast cancer with a dedicated breast platform'. Cardiovasc Intervent Radiol, 36 (2), 292-301. 15. Minalga, E, Payne, A et al (2013). 'An 11-channel radio frequency phased array coil for magnetic resonance guided high-intensity focused ultrasound of the breast'. Magn Reson Med, 69 (1), 295-302. 16. Oerlemans, C, Nijsen, F et al (2011). 'A novel approach to identify nonpalpable breast lesions combining fluorescent liposomes and magnetic resonance-guided high intensity focused ultrasound-triggered release'. Eur J Pharm Biopharm, 77 (3), 458-64. 17. FDA (2012). Magnetic Resonance guided Focused Ultrasound Surgery System (MRgFUS), ExAblate Model 2000/2100 - P110039. [Internet]. US Food and Drug Administration. Available from: http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/Device MRgFUS for cancer of the brain, liver, bone and breast: November 2011 24 ApprovalsandClearances/Recently-ApprovedDevices/ucm327521.htm [Accessed 17th Oct 2013]. 18. Napoli, A, Anzidei, M et al (2013). 'Primary pain palliation and local tumor control in bone metastases treated with magnetic resonance-guided focused ultrasound'. Investigative Radiology, 48 (6), 351-8. 19. Hurwitz, M, Meyer, JE et al (2013). 'Magnetic resonance guided focused ultrasound surgery for palliation of painful bone metastasis: Results of a multicenter phase III trial'. Journal of Clinical Oncology Conference, 31 (15 SUPPL. 1). 20. Meyer, JE, Pfeffer, R et al. Pain Palliation of Bone Metastases Using Magnetic Resonance Guided Focused Ultrasound: Analysis of Factors Predicting Success. . American Society for Radiation Oncology 55th Annual Meeting; Georgia, Atlanta: International Journal of Radiation Oncology, Biology, Physics; 2013. p. S565. 21. FDA (2012). Summary of safety and effectivness data: Magnetic Resonance guided Focused Ultrasound Surgery System (MRgFUS). [Internet]. US Food and Drug Administration. Available from: http://www.accessdata.fda.gov/cdrh_docs/pdf11/P110039b.pdf [Accessed 17th Oct 2013]. 22. Turkevich, VG, Savelyeva, VV et al (2012). 'Result of Treatment Painful Bone Metastases with Magnetic Resonance Guided Focused Ultrasound'.Conference Proceeding: World Conference on Interventional Oncology; Chicago, Illinois., Paper 13, 23, 853e4, 23. Izumi, M, Ikeuchi, M et al (2013). 'MR-guided focused ultrasound for the novel and innovative management of osteoarthritic knee pain'. BMC musculoskeletal disorders, 14 (1), 267. 24. Weeks, EM, Platt, MW&Gedroyc, W (2012). 'MRI-guided focused ultrasound (MRgFUS) to treat facet joint osteoarthritis low back pain--case series of an innovative new technique'. Eur Radiol, 22 (12), 2822-35. 25. Monteith, S, Sheehan, J et al (2013). 'Potential intracranial applications of magnetic resonance-guided focused ultrasound surgery'. J Neurosurg, 118 (2), 215-21. 26. Lipsman, N, Schwartz, ML et al (2013). 'MR-guided focused ultrasound thalamotomy for essential tremor: a proof-of-concept study'. Lancet neurology, 12 (5), 462-8. 27. Elias, WJ, Huss, D et al (2013). 'A pilot study of focused ultrasound thalamotomy for essential tremor'. N Engl J Med, 369 (7), 640-8. 28. Jeanmonod, D, Werner, B et al (2012). 'Transcranial magnetic resonance imaging-guided focused ultrasound: noninvasive central lateral thalamotomy for chronic neuropathic pain'. Neurosurgical focus, 32 (1), E1. 29. Denis De Senneville, B, Ries, M et al (2011). 'Non-invasive thermotherapy of abdominal organs'. IRBM, 32 (2), 109-12. MRgFUS for cancer of the brain, liver, bone and breast: November 2011 25 30. Orgera, G, Monfardini, L et al (2011). 'High-intensity focused ultrasound (HIFU) in patients with solid malignancies: evaluation of feasibility, local tumour response and clinical results'. Radiol Med, 116 (5), 734-48. MRgFUS for cancer of the brain, liver, bone and breast: November 2011 26 TECHNOLOGY BRIEF 2011 Register ID: WP048 Name of Technology: MRI guided, high intensity focussed ultrasound Purpose and Target Group: For indications other than uterine fibroids, including cancer of the brain, liver, breast and bone Stage of Development (In Australia): Yet to emerge Experimental _ Investigational for these indications Nearly established Established Should be taken out of use Australian Therapeutic Goods Administration approval Yes ARTG number (s) 118009 MEDITRON P/L - Hyperthermia system, ultrasound 128137 GE Medical Systems Australia Pty Ltd - Hyperthermia system, ultrasound No Not applicable International Utilisation: COUNTRY LEVEL OF USE Trials Underway or Completed Limited Use Widely Diffused Liver Korea 9 Germany 9 MRgFUS for cancer of the brain, liver, bone and breast: November 2011 1 Bone Canada 9 China 9 Israel 9 United States 9 Korea 9 United States 9 Breast Brain Prostate 9 Impact Summary: In August 2008, an horizon scanning update was completed on the use of MRIguided, high-intensity focussed ultrasound (MRgFUS) for the treatment of symptomatic uterine fibroids. The Royal Woman's Hospital, Melbourne, Australia, began treating women in September 2008 using a 3T MRI and the ExAblate 2000 with a uterine fibroids application. All data on patient treatment and outcomes are being collected for future analysis. There has been a great deal of interest in the use of MRgFUS for the treatment of other indications including cancer of the breast, liver, prostate, brain and bone. This summary will present a brief overview of the evidence for these indications. Currently there are two high-intensity focussed ultrasound systems registered on the TGA: one distributed by Meditron Pty Ltd (Victoria) and manufactured by Focus Surgery (Indianapolis, USA), which was registered on the ARTG in 2005 (ARTG 118009); the other is distributed by GE Healthcare Australia Pty Ltd and manufactured by InSightec Ltd (Israel), registered on the ARTG in 2006 (ARTG 128137). This technology would be made available through specialised hospitals by interventional radiologists in conjunction with a treating specialist. Background High-intensity focussed ultrasound (FUS) is a non-invasive means of focusing thermal energy to ablate deep soft tissue targets such as tumours, which otherwise may only be excised using open surgery. The high-intensity ultrasound deposits localised energy, causing rapid vibration of molecules within the focal spot. This results in localised heating (65-95°C) at the focal point of the target tissue, avoiding damage to MRgFUS for cancer of the brain, liver, bone and breast: November 2011 2 the surrounding tissue but resulting in tissue necrosis, apoptosis and cell death of the target. Magnetic resonance imaging (MRI) is superior for imaging soft tissue compared to other modalities, in addition to being able to monitor temperature and tissue coagulation and therefore avoid damage to the surrounding normal tissue. MRI clearly visualises the boundaries between the normal and cancerous tissue and when combined with FUS allows for precise targeting of tumours. In addition, MRI does not utilise radiation, which safely allows for repeat procedures to be performed if required.1, 2 InSightec Ltd manufactures three systems for the use of magnetic resonance guided FUS (MRgFUS): the ExAblate One, which uses a transducer embedded in the patient bed for the treatment of uterine fibroids, adenomyosis and breast cancer (requires a special coil). The depth and angle of focus of the ultrasound beam can be altered by adjusting the position of the transducer within the water bath using a robotic system; the ExAblate OR, which has separate cradles and accessories depending on the indication. Cradle 1 is used for uterine fibroids, bone and breast cancer and uses the transducer embedded in the patient bed. Cradle 2 is used for prostate cancer and uses a 990-element endorectal transducer. The treatment of liver and pancreatic cancer currently uses the transducer embedded in the patient table, however it is expected that specialised transducers will have to be developed for these indications. A conformal transducer, which is strapped to the body, may be used to treat bone cancer.; and the ExAblateNeuro, which uses a helmet-like 1000-element transducer. This system cannot be upgraded from the ExAblate One or ExAblate OR (personal communication InSightec Ltd). The main components of the ExAblate system are the MR scanner (1.5 or 3.0 T) and the focused ultrasound table, which contains a transducer and cooling water bath. In addition, the FUS work station is linked to the MR work station, with all electronics stored in a large equipment cabinet, which resides in the MRI equipment room. All systems use a transducer (as described above), which focuses the ultrasound energy. Detachable cradles, which contain the transducers, are connected to the patient table to hold the area of clinical interest in place. Good acoustic coupling must be maintained between the part of the body to be treated and the transducer in order to minimise the presence of residual gas bubbles. The entire assembly of patient table and detachable cradle is then moved into the MRI scanner. The patient table MRgFUS for cancer of the brain, liver, bone and breast: November 2011 3 and detachable cradles must be MR compatible. Prior to treatment, a full MRI scan is conducted targeting the tissue of interest and the margins for the procedure are planned on the FUS work station, targeting the tumour and sparing normal tissue. A phase-shift MR thermal map, which requires a specialised software add on to the basic MRI, is used to measure the result of the FUS sonications and monitor progress in near real-time. Each heating period or sonication lasts approximately 20 seconds followed by a cooling period, however during this cooling time treatment may continue in another, not adjacent, area, which reduces treatment time. Total treatment time will vary according to the organ and size of the area being treated and may consist of multiple sonications, with the brain, bone and prostate requiring fewer sonications compared to uterine fibroids. Patients are treated under conscious sedation allowing for communication between patient and the interventional radiologist, especially in regard to any discomfort that may be experienced.2, 3 Existing MRI scanners may be upgraded to be used with the ExAblate system, and can be used interchangeably for diagnostic and therapeutic use, taking approximately 10 minutes to change from diagnostic to ExAblate mode. Of importance to note is that the ExAblate system can only currently be used with GE MRI scanners (personal communication InSightec Ltd). Clinical Need and Burden of Disease The most commonly diagnosed cancer in females in 2007 was breast cancer, with 12,567 cases at an age-standardised incidence rate (ASR) of new breast cancer cases 109.2 per 100,000. The leading cause of burden of disease from cancer in females during 2010 was breast cancer, representing a total of 24 per cent of the total cancer burden and four per cent of the total burden of disease in Australia, accounting for 61,100 DALYs.7 In 2007, breast cancer was the second most common cancer causing death in Australian females, accounting for 2,680 deaths with an ASR of 22.1 per 100,000. The 5-year relative survival for breast cancer in females has increased from 72 per cent in 1982–1986 to 88 per cent in 1998–2004.4 In comparison, cancer of the brain was the 8th ranked cancer in terms of burden of disease in females, associated with 8,800 DALYs and four per cent of the total cancer burden. The overall ASR for cancer of the brain was 6.7 per 100,000, with the rate slightly higher in males (8.6) compared to females (5.0). Death from cancer of the brain was ranked the 9th most common cancer in Australian females with an ASR of 3.9 per 100,000, accounting for a total of 457 deaths in 2007. The ASR for the same period was higher for males at 6.3 deaths per 100,000. Although 5-year relative 7 DALYs = disability affected life year MRgFUS for cancer of the brain, liver, bone and breast: November 2011 4 survival rates for many cancers have improved over time, the 5-year relative survival rate for brain cancer has remained low at approximately 20 per cent.4 In 2007, the ASR for cancer of the liver was 8.0 and 2.7 per 100,000 for males and females, respectively and this rate was expected to increase in 2010. Cancer of the liver is associated with a poor prognosis and contributes to a high burden of disease due to premature death. During the same period, cancer of the liver was the 10th most common cancer causing death in males with 717 attributed deaths and an ASR of 6.9 per 100,000.4 Cancer of the bone represents a small proportion of the total burden of cancer disease with 195 new cases reported in 2007 at an ASR of 0.9 per 100,000. Death from bone cancer remains relatively high in comparison to many cancers, with 118 deaths reported in the same year at a rate of 0.5 per 100,000. 4 In New Zealand in 2007, the number of new breast cancer cases registered was 90.3 per 100,000 females, representing 2,575 women diagnosed with the disease. The number of deaths from breast cancer in the same year was 643 at an ASR of 20.8 per 100,000. As in Australia, rates for liver cancer were markedly higher in males than females with an ASR of 6.1 compared to 2.3 per 100,000, respectively. Similar high rates of mortality were observed for cancer of the liver, with an ASR of 5.3 for males and 1.8 for females per 100,000. The age-standardised incidence rate for cancer of the brain was similar for males and females in New Zealand, with an overall rate of 5.3 per 100,000. Rates of mortality also remain high for these patients with an overall ASR of 4.2 per 100,000. The number of new registrations for cancer of the bone was relatively small at 38 cases (ASR 0.9 per 100,000), however mortality remains high with 22 deaths in 2007.5 Diffusion There are currently two ExAblate systems operating in Australia: one situated in The Royal Woman's Hospital, Melbourne and the other situated at the private clinic Future Medical Imaging, Melbourne. Both centres currently treat women with symptomatic uterine fibroids or adenomyosis. The clinic at Future Medical Imaging has also recently started treating painful bone metastases. The Royal Women’s Hospital is currently in final preparations prior to the launch of a breast cancer clinical trial. Both systems could be upgraded for additional treatment applications for other indications (personal communication InSightec Ltd). Comparators In the majority of cases of brain, breast and liver cancer, the only alternative to MRgFUS would be invasive surgery combined with post-surgical chemotherapy MRgFUS for cancer of the brain, liver, bone and breast: November 2011 5 and/or radiotherapy. Bone metastases are associated with a high degree of pain and palliative therapy is offered as a means to improve the quality of life of patients. External beam radiation would be considered the standard therapy; however 20-30 per cent of patients would not gain sufficient pain relief using this modality. Other therapeutic options may also include chemotherapy, hormonal therapy, pharmaceuticals including bisphosphonates and opiates for pain management, radiation, surgery, cryotherapy and radiofrequency percutaneous ablation.6 Safety and Effectiveness Issues Breast cancer In 2007, MRI was approved by the Medical Services Advisory Committee for interim public funding for the diagnosis of breast cancer in young, high-risk, asymptomatic women. When used in this group of women, MRI was found to be more sensitive and less specific compared to mammography.7 Using MRgFUS therefore allows for accurate targeting of breast lesions for ablation as the breast may be isolated relatively easily, avoiding potential damage to other organs and structures (Figure 8). MRgFUS may potentially be used to replace surgical procedures such as lumpectomy and wide local incision, in so doing conserving the breast with the added cosmetic and psychological benefits.8 Several issues have been identified with the use of MRgFUS for the ablation of breast cancer, specifically the importance of adequate tumour-free margins following ablation and appropriate patient selection. Patients with large tumours >5cm and those with tumours close to the chest wall should not be selected.9 Figure 8 Positioning of the patient for the treatment of breast cancer 9 with MRgFUS (printed with permission InSightec Ltd) MRgFUS for cancer of the brain, liver, bone and breast: November 2011 6 A small case series by Zippel et al (2005) enrolled 15 women (mean age 56 years, range 45-72) with biopsy proven infiltrating breast carcinomas less than 3cm in diameter (mean size 22mm) (level IV intervention evidence). Lesions were all more than 10mm away from the skin and chest wall. The MRgFUS procedure was conducted using the ExAblate 2000 system. The treatment plan included ablation of a minimum boundary of 0.5cm of healthy tissue in all dimensions from the tumour edge. The effect of all sonications was monitored with MR thermal mapping. Although 15 women were enrolled, only 10 completed the protocol with the procedure halted in five patients who experienced extreme anxiety in the MRI. Total procedure time was expected to be 240 minutes; however the actual procedure time was not reported. All patients underwent successful lumpectomy 7-10 days postablation procedure and the resected lesion underwent histopathological examination. Compete ablation was observed in two patients, with no residual tumour left behind. Varying degrees of residual tumour were left behind in the remaining eight patients: three had 10 per cent residual tumour; three had 10-30 per cent and two had microscopic foci of residual carcinoma. Patients were administered analgesics for pain during the procedure and one patient experienced a second degree burn which required skin excision prior to lumpectomy. In addition, the authors noted that the effect of MRgFUS on sentinel node biopsy is largely unknown, however there was no difficulty identifying and removing the sentinel node in the two patients who required this procedure.10 A recent review reported on the results of one of the largest case series of MRgFUS ablation of biopsy-proven breast cancer to date presented by Furusawa et al at the International Symposium on MR-guided Focused Ultrasound (results unpublished at time of writing). Results were presented for 47 out of 57 enrolled women with small breast tumours ≤ 1.5cm (mean 11mm, range 6.0-15mm) with a distance of more than 1.0cm from the skin (level IV intervention evidence). All patients underwent core needle biopsy three weeks after the MRgFUS (1.5T) procedure. Mean MRgFUS treatment duration was 108 minutes (range 65-209 minutes). Mean follow-up was 44 months (range 3-64 months) with all women with no residual viable tumour receiving radiation therapy and breast examination by mammography and MRI every six months. No local recurrences or significant adverse events were reported.11 Bone cancer Up to 30 per cent of all cancer patients will develop secondaries in the bone and approximately half of these patients will go on to develop pain from these lesions. The current treatment option for these lesions is radiotherapy; however 20-30 per cent of patients will gain no relief from pain from radiotherapy and of those who do experience relief, 27 per cent will have recurring pain once radiotherapy ceases. MRgFUS for cancer of the brain, liver, bone and breast: November 2011 7 Bone actively absorbs FUS and a large area at the periosteal margin8 of the bone can be rapidly heated and in so doing may destroy neural pain fibres in the periosteum, resulting in palliation of painful bone lesions. Large areas of the periosteum may be treated with a broader portion of the FUS beam rather than adopting the usual focussed approach described for the ablation of tumours.2, 3 To treat bone metastases, the patient may be situated above the transducer located within the cradle (as depicted in Figure 8) or by using a conformal transducer which can be strapped to the region of interest (Figure 9). Figure 9 Patient being treated for bone metastases indicating the use of a strap on transducer (printed with permission InSightec Ltd) A small case series by Catane et al (2006) reported on the use of MRgFUS for the palliation of pain in 13 patients with 14 symptomatic bone lesions (level IV intervention evidence). Patients were treated under conscious sedation with the ExAblate system, utilising a 1.5T MRI and were followed-up at 3-days, 2-weeks and one, three and six months (mean follow-up 59 days). One patient underwent two treatment sessions due to insufficient energy being used in the first treatment, with another patient undergoing two treatments but targeting two different lesions. All of the remaining patients underwent only one treatment session. The average time for 15 treatments was 80 minutes (range 22-162 minutes), with an average of 25 sonications delivered at an average acoustic energy of 1080 joules (J). One patient was unable to tolerate the pain of the MRgFUS procedure and treatment was halted after 14 sonications and 30 minutes. This patient did not report an improvement in visual analogue scale (VAS) or a reduction in pain medication. No other adverse events were reported during or post-treatment. Follow-up data was not collected from two patients who experienced a rapid 8 Periosteum is a membrane that lines the outer surface of all bones, except at the joints of long bones MRgFUS for cancer of the brain, liver, bone and breast: November 2011 8 progression of disease after MRgFUS treatment, with one patient dying prior to 3month follow-up. The remaining 10 patients reported a reduction in pain scores and the use of pain medication.12 The initial results reported by Catane et al (2006) provided the basis for the largest multicentre case series reported to date. Liberman et al (2009) described the results of 31 patients who had failed to respond to radiotherapy or refused to undergo radiotherapy (level IV intervention evidence). Patients were treated under conscious sedation with the ExAblate system, utilising a 1.5T MRI and were followed-up for three months. The most common treatment site was the iliac bone (18/31, 58%) and the most common primary tumour type was breast cancer (11/31, 35%). Thirty-six treatments in 31 patients with 32 metastatic lesions were administered, with an average treatment time of 66 minutes (range 22-162 minutes). An average of 17.3 sonications (range 8-32) were delivered at an average acoustic energy of 1,135 J (range 440-1,890). The only adverse events reported in this larger study were those reported by Catane et al. Twenty-five patients received the full treatment and completed the 3-month follow-up. Overall, pain reported by one patient worsened during the 3-month follow-up period, six patients (24%) had no response to MRgFUS treatment and 18 patients (72%) reported a significant reduction in VAS scores (>2 points), with nine of these patients reporting a VAS score of zero. The average VAS score decreased from 5.9 at baseline to 1.8 at three months post-MRgFUS. Over 50 per cent of patients reported a reduction in pain within three days of MRgFUS treatment. In addition, the majority of patients reported a decrease in pain medication use, however follow-up data was incomplete for this outcome. A complete response, defined as a VAS score of zero without an increase in medication, was observed in nine patients (36%). A partial response, defined as a decrease in VAS score of two points without a decrease in pain medication, or a decrease of 25 percent or more in medication use without an increase in pain score, was reported in nine patients.13 Gianfelice et al (2008) reported the results of 11 consecutive patients (mean age 58.6 years, range 38-84) with painful bone metastases who had exhausted other treatment options including chemotherapy, radiotherapy and pain medication (level IV intervention evidence). Primary tumour origins included breast (n=5) kidney (n=4), lung (n=1) and liver (n=1). MRgFUS was delivered using the ExAblate system and a 1.5T MRI. Patients underwent MRgFUS treatment under conscious sedation in an outpatient setting and were followed-up at 3-months. Ten patients underwent one treatment session; however one diabetic patient required a second session due to a rapid drop in blood sugar during the procedure. Ten patients had a single lesion treated and one patient had two adjacent lesions treated during the same session. MRgFUS for cancer of the brain, liver, bone and breast: November 2011 9 Treated lesions originated in the iliac (n=7), scapula (n=2), clavicle (n=1) and ischium (n=1). No adverse events related to the procedure were reported. Total treatment time ranged from 28 to 103 minutes, with the number of sonications delivered per patient ranging from 12 to 18 and the energy of sonications varying between 466 and 1853 J. Some patients reported pain relief by 3-days post-treatment, however by day 14 all patients had reported a reduction in pain, with 7/11 (63.6%) patients reported a VAS score of zero at 3-months. The remaining four patients who experienced some pain at end of follow-up had a marked reduction in pain ranging from 3.5-6.5 points on the VAS scale. The average VAS score prior to treatment was 6.0 (range 4-9), which was reduced by 39 per cent to 3.7 three days post-treatment. Further reductions in VAS scores were noted at 14 and 30 days post-treatment, with a significant mean decrease of 92 per cent to a mean VAS score of 0.5 at 3-month follow-up (p<0.01). Seven patients (63.6%) no longer required pain medication at end of follow-up and the remaining four patients had reduced their pain medication intake by at least 50 per cent. MR imaging conducted at end of follow-up indicated that the majority of patients exhibited necrosis of the enhancing medullary component of the metastases and CT imaging revealed increased bone density at the treated site in five patients.6 Brain cancer Previous attempts to use transcranial focused US have been unsuccessful due to the increase in the acoustic attenuation of the skull, which is 30-60 times higher than in soft tissue. To avoid this issue, a hemispherical transducer operating at a lower frequency to produce the US beam, combined with a specialised cradle capable of holding the head in place in a cooling water bath (15-20°C) has been developed, as demonstrated by this short video and Figure 10.14 a MRgFUS for cancer of the brain, liver, bone and breast: November 2011 10 b Figure 10 Positioning of the patient for transcranialMRgFUS 14 a) , b) printed with permission InSightec Ltd Only one small phase I feasibility study was identified for inclusion in this assessment that reported the results of using transcranial MRgFUS for the treatment of three patients with glioblastoma (level IV intervention evidence). Two patients had inoperable tumours whilst the remaining patient had recurrent metastatic cancer. The tumours were all located in the thalamus, relatively deep and central within the brain. All patients underwent chemotherapy and radiation therapy prior to treatment with MRgFUS. Patients were treated under conscious sedation. Prior to treatment patients underwent a CT and MRI scan for treatment planning purposes. Once treatment commenced, MR temperature imaging was used to verify the target location within the tumour and acoustic power was increased to reach thermal coagulation at approximately 55°C peak temperature.14 Treatment was limited by the maximum acoustic power available, with one patient only achieving a maximum power of 650 watts (W) due to software settings. Another patient reached this power level but due to sonication-related pain higher power was not reached. The remaining patient reached a maximum of 800 W. Sufficient tumour ablation was not possible due to the power limitations. Some patient motion was observed in all patients (2-4mm). Focal heating within the tumour was observed during 3 of 12, 14 of 16 and 11 of 17 sonications, and the maximum temperature achieved was 42, 51 and 48°C for patients 1-3, respectively. Ultimate patient outcomes were not reported, however the authors concluded that transcranial MRgFUS was feasible but may require further modifications.14 An interesting development in the use of MRgFUS for the treatment of brain tumours such as gliomas is the potential to deliver therapeutic magnetic nanoparticles across the blood brain barrier. Low-energy FUS is used to increase the MRgFUS for cancer of the brain, liver, bone and breast: November 2011 11 permeability of the blood brain barrier in a localised and reversible manner, allowing for the diffusion of magnetic nanoparticles containing chemotherapeutic agents. Diffusion of nanoparticles is usually passive, however the application of an external magnetic force allows concentration of a therapeutic dose at the target site, with MRI used to monitor the procedure (Figure 11). The integrity of the blood brain barrier is re-established within 24-36 hours. To date only animal studies have been conducted.15-17 Figure 11 Schematic of the procedure demonstrating the localised permeability of the BBB using FUS flowed by the diffusion of the magnetic nanoparticles, 17 which are then guided and concentrated by an external magnetic force Liver cancer Invasive radiofrequency or laser ablation has recently been used as a method to treat local tumours of the liver, with probes being inserted percutaneously into the target tissue. Application of power causes local heating followed by the thermal destruction of tissue. MRgFUS has been suggested as a non-invasive approach for the destruction of localised areas of the liver, especially when underlying liver disease is present, which is common in patients with hepatocellular carcinoma. MRgFUS of the liver presents technical difficulties due to the presence of the rib cage and movement of the liver with respiration. Treating patients under general anaesthesia overcomes the latter problem, however a MRI-compatible ventilator is required. Currently MRgFUS treatment can only be applied to areas of the liver not covered by the rib cage, however it is anticipated that modified transducers will allow treatment between the ribs in the near future.2, 3 Many reviews describing the potential use of MRgFUS for tumours of the liver, however no human studies were identified. MRgFUS for cancer of the brain, liver, bone and breast: November 2011 12 Prostate cancer Phase I and II protocols have been finalised for the treatment of prostate cancer, with studies set to commence in 2012. Cost Impact The cost of the complete ExAblate system varies between AUD$2-4 million depending on the configuration of the MRI (1.5 or 3 Tesla) (personal communication CPR Communications on behalf of InSightec Ltd). All ExAblate systems come complete with the patient table and at least one cradle, depending on the configuration of the system. If new indications are planned for treatment, systems may be upgraded to cater for this except for in the case of the ExAblateNeuro, which is a standalone system. In addition, there would be a cost for the disposable treatment kits required for each procedure that include gel pads and the degassed water (personal communication InSightec Ltd). Ethical, Cultural or Religious Considerations No issues were identified/raised in the sources examined. Other Issues Two studies evaluating the use of magnetic resonance-guided focused ultrasound surgery in patients with metastatic bone cancer are listed on the Current Controlled Trials register. One study, a multi-centre (United States, United Kingdom, Canada, Israel, Italy and Russia) randomised controlled trial, aims to compare the use of the ExAblate 2000 MRgFUS to a sham procedure for the palliation of pain in adult patients with metastatic and multiple myeloma bone tumours, who are not candidates for radiation therapy (ClinicalTrials.gov Identifier: NCT00656305). The trial, sponsored by InSightec, began recruiting patients in 2008 and aims to be finalised by December 2011 with 148 patients enrolled. The primary outcome measure is an improvement in pain scores within three months of treatment, with the secondary outcome measure being a change in pain medication. A smaller randomised controlled trial, also sponsored by InSightec, aims to compare MRgFUS to external beam radiation therapy for the palliation of pain in patients with metastatic and myeloma bone tumours (ClinicalTrials.gov Identifier: NCT01091883). The trial is currently recruiting up to 60 Israeli adult patients and aims to be finalised by March 2012. The primary outcome measure is the number and severity of adverse events associated with the use of MRgFUS compared to external beam radiation therapy. Secondary outcome measures include the assessment of pain relief, determined by a pain scale and by a reduction in the use of pain medication, and an assessment of quality of life within six months of treatment. MRgFUS for cancer of the brain, liver, bone and breast: November 2011 13 Of interest is a clinical trial that has commenced in the United States using MRgFUS for the treatment of patients with chronic neurological conditions, including essential tremor and Parkinson’s Disease.18 It is worth noting that in January 2012, the Journal of Neurosurgery’s online website magazine will be publishing a special issue devoted to the use of MRgFUS (personal communication InSightec Ltd). A summary of talks given at the 2010 Focused Ultrasound Foundation meeting on MRgFUS may be accessed via this link. Summary of findings The use of MRI guided high-intensity ultrasound for the treatment of symptomatic uterine fibroids is an established technique. This technology brief has presented the preliminary evidence on the use of MRgFUS for other indications including tumours of the brain, breast and bone. Small proof of concept studies conducted on patients with breast and brain cancer indicate that the technique is feasible. However, patient selection, especially when treating breast cancer, is an important consideration to ensure optimal outcomes. One of the more interesting and promising fields of research is the use of MRgFUS to target and deliver magnetic nanoparticles to tumours of the brain. It would appear that partial or complete palliation of pain using MRgFUS in patients with painful bone metastases is possible for the majority of patients, increasing the quality of life in these patients. Purchasing the various cradles required to use MRgFUS for indications other than fibroids may increase the utilisation of existing (or those purchased in the future) MRgFUS units to a maximum level. However, this may raise workforce issues in relation to the number of trained interventional radiologists capable of performing this type of procedure, in addition to the role that current specialists (oncologists, hepatologistsetc) may play in this procedure. HealthPACT assessment: Based on the low-level, preliminary evidence it would appear that MRgFUS may be a useful tool for the treatment of patients with tumours who may have limited treatment alternatives available to them. The range of applications for this technology are potentially wide-ranging and therefore HealthPACT have recommended that a New and Emerging Health Technology Report be commissioned late-2012 to allow sufficient time for the results from the randomised controlled trials to be published in addition to the publication of initial studies into the use of MRgFUS for the treatment of prostate cancer and neurological conditions. MRgFUS for cancer of the brain, liver, bone and breast: November 2011 14 Number of included Studies Total number of studies 6 Level IV intervention evidence Breast Bone Liver 6 2 3 0 Brain 1 Search Criteria: Magnetic Resonance Imaging/ methods Sonication Ultrasonic Therapy/adverse effects/ methods Ultrasonography Neoplasms References: 1. Fennessy, FM&Tempany, CM (2005). 'MRI-guided focused ultrasound surgery of uterine leiomyomas'. Acad Radiol, 12 (9), 1158-66. 2. Gedroyc, WM&Anstee, A (2007). 'MR-guided focused ultrasound'. Expert Rev Med Devices, 4 (4), 539-47. 3. Dick, EA&Gedroyc, WM (2010). 'ExAblate magnetic resonance-guided focused ultrasound system in multiple body applications'. Expert Rev Med Devices, 7 (5), 589-97. 4. AIHW&AACR (2010). Cancer in Australia: an overview, 2010, Australian Institute of Health and Welfare and Australasian Association of Cancer Registries, Canberra Available from: http://www.aihw.gov.au/publicationdetail/?id=6442472459&tab=2. 5. Ministry of Health (2010). Cancer: New Registrations and Deaths 2007, New Zealand Ministry of Health, Wellington Available from: http://www.moh.govt.nz/moh.nsf/indexmh/cancer-reg-deaths-2007-jun10. 6. Gianfelice, D, Gupta, C et al (2008). 'Palliative treatment of painful bone metastases with MR imaging--guided focused ultrasound'. Radiology, 249 (1), 355-63. 7. Lord, S, Lei, W et al (2007). Breast magnetic resonance imaging, Medical Services Advisory Committee, Canberra Available from: http://www.msac.gov.au/internet/msac/publishing.nsf/Content/2CDBC3816 FDE8D20CA2575AD0082FD8E/$File/1098%20%20Breast%20MRI%20Report.pdf. MRgFUS for cancer of the brain, liver, bone and breast: November 2011 15 8. Wu, F, ter Haar, G&Chen, WR (2007). 'High-intensity focused ultrasound ablation of breast cancer'. Expert Rev Anticancer Ther, 7 (6), 823-31. 9. Schmitz, AC, Gianfelice, D et al (2008). 'Image-guided focused ultrasound ablation of breast cancer: current status, challenges, and future directions'. Eur Radiol, 18 (7), 1431-41. 10. Zippel, DB&Papa, MZ (2005). 'The use of MR imaging guided focused ultrasound in breast cancer patients; a preliminary phase one study and review'. Breast Cancer, 12 (1), 32-8. 11. Brenin, DR (2011). 'Focused ultrasound ablation for the treatment of breast cancer'. Ann Surg Oncol, 18 (11), 3088-94. 12. Catane, R, Beck, A et al (2007). 'MR-guided focused ultrasound surgery (MRgFUS) for the palliation of pain in patients with bone metastases-preliminary clinical experience'. Ann Oncol, 18 (1), 163-7. 13. Liberman, B, Gianfelice, D et al (2009). 'Pain palliation in patients with bone metastases using MR-guided focused ultrasound surgery: a multicenter study'. Ann Surg Oncol, 16 (1), 140-6. 14. McDannold, N, Clement, GT et al (2010). 'Transcranial magnetic resonance imaging- guided focused ultrasound surgery of brain tumors: initial findings in 3 patients'. Neurosurgery, 66 (2), 323-32; discussion 32. 15. Chen, PY, Liu, HL et al (2010). 'Novel magnetic/ultrasound focusing system enhances nanoparticle drug delivery for glioma treatment'. Neuro Oncol, 12 (10), 1050-60. 16. Liu, HL, Hua, MY et al (2010). 'Blood-brain barrier disruption with focused ultrasound enhances delivery of chemotherapeutic drugs for glioblastoma treatment'. Radiology, 255 (2), 415-25. 17. Liu, HL, Hua, MY et al (2010). 'Magnetic resonance monitoring of focused ultrasound/magnetic nanoparticle targeting delivery of therapeutic agents to the brain'. Proc Natl Acad Sci U S A, 107 (34), 15205-10. 18. PR Newswire (2011). ExAblate® Neuro has Been Used to treat 30 Patients with Chronic Neurological Disorders Such as Essential Tremor, Neuropathic Pain and Parkinson's Disease. Available from: http://www.prnewswire.com/news-releases/exablate-neuro-has-been-usedto-treat-30-patients-with-chronic-neurological-disorders-such-as-essentialtremor-neuropathic-pain-and-parkinsons-disease-130254303.html [Accessed 17th October 2011]. MRgFUS for cancer of the brain, liver, bone and breast: November 2011 16