Annals of Oncology Advance Access originally published online on October 9, 2006
Annals of Oncology 2007 18(1):163-167; doi:10.1093/annonc/mdl335
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© 2006 European Society for Medical Oncology
supportive care |
MR-guided focused ultrasound surgery (MRgFUS) for the palliation of pain in patients with bone metastases—preliminary clinical experience
1 Sheba Medical Center, Department of Oncology, Tel-Hashomer, Israel
2 Charite-Universitetsmedizin Berlin, Klinik for Strahlenheilkunde, Berlin, Germany
3 Sheba Medical Center, Department of Diagnostic Imaging, Tel-Hashomer
4 InSightec Ltd, Haifa
5 Sheba Medical Center, Division of Orthopedic Surgery, Tel-Hashomer
6 HaEmek Medical Center, Department of Surgery B', Afula
7 Tel-Aviv University, Tel-Aviv
8 Technion, Israel Institute of Technology, Haifa, Israel
* Correspondence to: Dr D. Kopelman M.D., 30 Kanamt Street, Caesarea, 38900, Israel. E-mail kopelmand{at}bezeqint.net
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Abstract |
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Background: Magnetic resonance-guided focused ultrasound surgery (MRgFUS) is a noninvasive thermal ablation technique, shown to be clinically effective in the treatment of uterine fibroids and is being evaluated as a method of thermal ablation of benign and malignant breast tumors. To evaluate the safety and initial efficacy of MRgFUS for the palliation of pain caused by bone metastases, in patients for whom other treatments are either not effective or not feasible.
Materials and methods: Thirteen patients suffering from symptomatic bone metastases underwent MRgFUS procedure. Treatment safety was evaluated by assessing the incidence and severity of device-related complications up to 6 months after treatment. Effectiveness of pain palliation was evaluated by visual analog scale, pain questionnaires and changes in the patients' medication.
Results: Fifteen procedures were carried out. Mean follow-up was 59 days. Twelve patients received adequate treatment and were available for follow-up. Two patients died due to disease progression during the first month after treatment. No severe adverse events were recorded. The remaining 10 patients reported prolonged improvement in pain score and/or reduced analgesic dosage.
Conclusion: MRgFUS may provide a safe and effective noninvasive alternative for the palliation of pain, caused by bone metastases.
Key words: magnetic resonance-guided focused ultrasound surgery, bone metastases, pain management, thermal ablation
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introduction |
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Bone is the third most common organ to which cancer metastasizes, after the lungs and liver. Almost all patients with metastatic prostate cancer harbor skeletal metastases and in breast cancer, bone is the second most common site of metastatic spread, with bone metastases found in 90% of patients dying of breast cancer. Palliation of symptoms is the primary goal of therapy, with multidisciplinary efforts yielding the best results [1]. The increasing longevity of the population coupled with better therapeutic management of cancer patients contributes to the high incidence and prevalence of metastatic bone lesions. Pain from bone metastases is the most common cause of cancer pain and as more patients are living with bone metastases, improving their quality of life (QoL) becomes a major challenge. Current treatment options for pain control consist of systemic therapy (analgesics, chemotherapy, hormonal therapy and biphosphonates) and local treatments [radiation, surgery and more recently laser ablation and radiofrequency percutaneous ablation (RFA)] [2]. Unfortunately, most medical therapies do not achieve long-lasting efficacy, frequently cause side effects or need chronic administration. Although external beam radiation therapy is the current standard of care for cancer patients who present with localized bone pain, 20%–30% of patients treated with this modality do not experience pain relief and in others the palliation is only temporary. QoL of patients with bone metastases is often poor due to unrelenting pain [3–7].
Magnetic resonance-guided focused ultrasound surgery (MRgFUS) is a completely noninvasive thermal ablation modality. The surgeon can correctly localize tumors, optimally deliver acoustic energy (‘sonicate’), monitor energy deposition in real time and accurately control the deposited thermal dose. This combined technology, real-time magnetic resonance imaging (MRI) and thermography with focused ultrasound ablation, has been presented by Jolesz and Hynynen [8, 9]. It has been shown to be clinically effective in the treatment of soft tissue tumors, such as uterine fibroids [10, 11]. In recent studies, MRgFUS has also been evaluated as a source of noninvasive, controlled thermal energy for the coagulation of benign and malignant breast tumors [12–14]. Additional studies are investigating the use of this method for other indications such as solid tumor ablation in the liver, brain or other organs [15–17]. The ablation of bone metastatic lesions by focused ultrasound energy presents special considerations due to the special characteristics of the interaction of ultrasound beam with bony tissue. The acoustic absorption of bone tissue is 
50 times higher than that of soft tissue and the penetration of ultrasonic energy into the bone is minimal. In addition to these facts, the thermal conductivity of the bone is relatively low. The aim of this study was to evaluate the safety and initial efficacy of MRgFUS ablation for the palliation of pain caused by bone metastases reaching the superficial aspect of the bone.
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materials and methods |
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For a period of 6 months, 13 patients were treated at two sites: Sheba Medical Center (Tel-HaShomer, Israel) and Charite Hospital (Berlin, Germany). This study was conducted in full accordance of the local Internal Review Board's and the National Helsinki Committee approval and guidelines. Patients were eligible for MRgFUS treatment only if they had exhausted all other treatment alternatives and had a localized painful tumor in a non-weight-bearing bone. See Table 1 for a list of tumor origin, type and location. MRgFUS treatments were carried out using a focused ultrasound phased array system (ExAblate® 2000 system, InSightec Ltd, Haifa, Israel) integrated with a clinical MRI Scanner (GE 1.5 T MRI, GE, Milwaukee, WI, USA).
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the MRgFUS procedure
The patients were treated under conscious sedation and analgesia was induced by i.v. Midazolam 5 ml/5 up to 10 mg (Taro Pharmaceutical International, Israel) and i.v. morphine sulfate in doses between 2 and 40 mg (according to patients' current opioid requirement). One patient required the use of regional epidural anesthesia. Pretreatment magnetic resonance (MR) screening images were used to localize the painful lesion and dictate the patient's position lying on the MRgFUS table. The targeted lesion was positioned directly above a water bath within the MR bed, containing the multiple elements ultrasonic transducer. Acoustic coupling was accomplished by placing a coupling gel pad between the patient and the chamber containing the transducer. The skin above the targeted bone was carefully shaved in order to avoid any air bubbles trapped in the hair that could block the ultrasonic beam. A new set of MR images confirmed the patient's position and was used for planning the treatment parameters: (i) Drawing the treatment area borders on the MR images, (ii) Defining the number of adjacent sonications required for the thermal ablation of the marked target, (iii) Analyzing the energy beam pathway for avoidance of any heat-sensitive organ within it (bowel, nerve), or anything that might cause ultrasonic aberrations (scars, surgical clips and air bubbles). Pretreatment verification of accuracy was carried out by a few low-energy, sub-therapeutic sonications followed by the required adjustments of the system parameters. When a mild increase of temperature, exactly at the targeted volume, was observed, the actual treatment was started at a full therapeutic power. Each sonication was monitored in real time using MRI thermometry, on the basis of proton resonance frequency (PRF) shift method of temperature mapping. Temperature elevation of the soft tissue adjacent to the bone and thermal dose for that tissue were calculated in real time on the basis of these images (Figure 1). In response to the resulting temperature map, sonication parameters could be modified including power, length of ‘sonication’, spot size and frequency.
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post-treatment evaluation and follow-up
Immediately following treatment, proton density-weighted and T1-weighted contrast enhanced images were used to evaluate the extent of the ablated area (Figure 2). Patients were followed for a period of up to 6 months. The follow-up sessions were at 3 days after treatment, 2 weeks and 1, 3 and 6 months. The follow-up included evaluation of the patient status including by anamnesis, and full physical examination. Patients completed visual analog scale (VAS) pain questionnaires to monitor changes in pain levels and medication forms to track the changes in their medication and assess the efficacy of pain palliation. Recording and assessing the incidence and severity of any related morbidity during the follow-up period evaluated treatment safety.
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results |
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Fifteen MRgFUS treatments, targeting 14 metastatic bone lesions, were carried out on 13 patients. The first patient in the study was treated twice within 3 weeks due to insufficient energy levels in the first treatment. Another patient was also treated twice, targeting two different lesions. Twelve of the 13 patients in the study were able to tolerate the treatment using only conscious sedation. Average treatment length was 80 min. Average acoustic energy was 1025 J. Table 2 lists a detailed summary of treatment parameters.
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follow-up
One patient's general health (#6) deteriorated very quickly following treatment, thus no follow-up data were collected. Another patient (#7) died before reaching the 3-month follow-up visit. In both of these cases, patient deterioration was due to the natural progression of their illness and not related to the procedure. Immediately following treatment and throughout the follow-up period, no device-related severe adverse events were recorded. One patient (#9) was unable to tolerate the sonication-related pain and the treatment was stopped. Mean follow-up period was 59 days.
During this period, the 12 patients who had received adequate treatment and for whom there were follow-up data improved in both VAS score and pain-relieving medication. In most cases, improvement was already noted at the visit, 3 days following treatment. A few patients have reported a slight increase of pain in the immediate post-procedural period. This pain has subsided before the first follow-up session. In the case of the patient whose treatment was prematurely terminated due to the inability to tolerate the sonication-related pain, the patient did not improve in any of the above criteria following treatment.
VAS score data during the follow-up period are graphically described in Figure 3.
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discussion |
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Pain related to bone metastases is intense and is one of the major reasons for the poor QoL for these patients. Palliation of this kind of pain was the aim of this new technology. The noninvasive use of focused ultrasound energy was meant to achieve localized analgesia by thermal ablation of tissue at the bone–soft tissue interface of bone metastases.
This treatment is a totally noninvasive procedure. The use of focused ultrasound without MR guidance for deep noninvasive ablation has been known for many years [18]. The only effect on tissue is thermal. When a high-intensity focused ultrasound beam propagates in a tissue, it is converted into heat and the temperature rises in the focus [19, 20]. When the temperature at the target is raised to >56°C for 1 s, protein denaturation occurs, resulting in cell death and creation of coagulative necrosis lesion [21, 22]. The tissue in the path of the ultrasound beam, away from the focus, is warmed, but only to sub-lethal temperatures. Among sonications, the heat is dissipated by the conduction and perfusion cooling effects. The excellent soft tissue resolution provided by the MRI enables accurate treatment planning. Real-time thermal mapping at and around the target can be achieved using phase imaging on the basis of the shift in PRF caused by temperature rise [23, 24]. Sequential phase-shift MR images are acquired during the sonication. Those images are automatically compared with a reference image obtained immediately before the sonication to create a real-time thermal map [23–25]. By integrating the focused ultrasound therapeutic system with an MRI (MRgFUS), the MR images can be used for localization and targeting of lesions and for temperature measurement of the soft tissue adjacent to the targeted bone. This approach affords the treating physician a kind of ‘closed loop’ monitoring of the treatment in real time, as it is carried out, resulting in a high level of safety and efficacy. Pioneering experimentations applying focused ultrasound to bone tissue were conducted a few years ago [26]. Thanks to the high acoustic absorption and low thermal conductivity of the bone cortex, it is possible to use a low level of energy (compared with soft tissue MRgFUS treatment) and still achieve a localized heating effect without damaging adjacent tissue. The adjacent tissue, through which the ultrasonic energy propagates toward the focal points, is not damaged. There is no upper limit to the accumulated acoustic energy allowed to pass through the adjunct soft tissue of the pathway, as long as tissue temperature is kept at a safe level. Recurrent sonications at the same target is probably possible and this may represent an advantage of focused ultrasound surgery (FUS) over ionizing radiation.
The possible complications of this treatment are of a thermal nature: skin burns, thermal damage to adjacent heat-sensitive organs such as nerves or bowel wall. None of these were recorded in this study. The real-time image control and thermal feedback of the procedure, together with the ability to verify the accuracy of the expected therapeutic effect, make these complications relatively rare.
A possible mechanism for this analgesic effect may be thermal periostial denervation, thereby eliminating the pain originating from the treated area. Another possible mechanism may be related to the thermal ablation of the tumoral tissue mass itself, diminishing the mass effect, pressure, on adjacent healthy tissues. A combined mechanism is of course a possibility. The immediate nature of pain relief that was achieved in this study supports the thermal denervation hypothesis. The continuous nature of the analgesic effect that was demonstrated may be attributed to both mechanisms.
RFA is a relatively new modality used for the control of metastatic bone pain. RFA is an image-guided thermal therapy, carried out by passing a specialized needle device through the skin and into the target lesion, using computed tomography scan, ultrasound, MRI or fluoroscopy to guide access. When the needle is in the target, a controlled electrical current is applied through the tip, heating the needle tip and destroying the adjacent target tissues. This procedure is usually carried out under general anesthesia, less commonly with heavy sedation and i.v. pain medication. Compared with MRgFUS, RFA is an invasive procedure, less expensive but less accurate due to the lack of real-time thermal feedback, unless it is carried out under MR guidance.
In this study, 13 patients were treated for palliation of pain due to metastatic cancer. However, since one patient health deteriorated quickly and another was unable to tolerate treatment, we have follow-up data of 11 patients. All these patients reported improvement in both pain score and dosage of pain-reducing medication. MRgFUS can be carried out as an outpatient procedure, using conscious sedation for most patients. It has no limitations on the permitted dose amount and was occasionally administered repeatedly.
We conclude that these results are promising. The noninvasive MRgFUS technology has the potential to become an alternative among other modalities in the armamentarium for the management of pain that is related to bone metastasis. Further studies are required to evaluate the local effect of MRgFUS treatment on the progression of bone metastasis, on the long-term durability of pain palliation and bone strength.
Received for publication July 31, 2006. Accepted for publication August 14, 2006.
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