Introduction

This review discusses the theory, animal experiments, and clinical results using high intensity focused ultrasound (HIFU) ablation for managing primary bone tumors. Some issues of most concern such as outcome, imaging assessment, and immune responses after the therapy are discussed. By summarizing the present situations of HIFU ablation, this review intends to provide some ideas for further studies.

Surgical removal and radiation therapy are commonly used strategies to treat bone tumors. The former is often used for primary bone tumors, whereas the latter is more often than not adopted for bone metastases. After surgical removal of primary bone tumors, the limb reconstruction could be done using the removed tumor-bearing bone section after extracorporeal tumor inactivation. Some physicaland chemical methods are used to inactivate tumorbearing bone sections, including hyperthermia and high pressure [1,2], hypothermal processing [3], high-dose radiation therapy [4], and alcohol inactivation and replantation [5]. For the past 20 years, some surgeons exposed tumor lesions to microwave after surgical procedure and had the tumor cells killed in situ, and the inactivated tumor-bearing bone sections were used for limb reconstruction.This technique is beneficial to adhesion of ligaments and tendons [6,7]. Percutaneous radio frequency for osteoid osteoma was a surprising start for minimally invasive treatment of bone tumors [8•,9•]. Although intraoperative hyperthermia has been considered as an efficient therapy for managing bone tumors, the surgical procedures are complex and appear to be an invasive or minimally invasive method. High intensity focused ultrasound is a new attractive extracorporeal method of noninvasive tissue ablation.High intensity ultrasound beams can be introduced to target sites lying deep within the patient’s body. If sufficient sound energy is concentrated within focal volume, temperature at a specific location may be raised to 56–80_C in a few seconds [10]. As a result, a welldelineated coagulative necrosis can be obtained in the target tissue, whereas surrounding normal tissues remain almost undamaged.

The targeted tissue necrosis produced using HIFU was first reported in the 1940s [11]. Fry et al. [12] successfully destroyed small regions in the human brain without damaging surrounding tissues by HIFU in the 1950s. Since then, a number of reports indicated that HIFU could be used to selectively induce coagulative necrosis of target tissue in animal experiments [13–17]. Numerous patients with primary liver tumors, breast cancers, renal cancers, and uterine myomas have been treated with HIFU since 1997 [18•,19–21].We have successfully treated 96 cases of bone tumors using HIFU technology until 2002 in China[22•].

 
[%page%]

History and rationale of high intensity focused ultrasound treatment of bone tumors

Since an ultrasound beam attenuates sharply in osseous tissues, ultrasonic energy has limited ability to penetrate and accumulate in bone tissue. Furthermore, the acoustic impedance of bone differs greatly from that of the surrounding soft tissue, which leads to strong reflection to the therapeutic ultrasound beams. Therefore, HIFU was not considered as a suitable modality to treat bone diseases. However, Smith et al. [23] found that focused ultrasound beams can target bone tissues and induce necrosis of osteocyte in normal rabbits. In fact, after the bone was destroyed by a lesion, such as an aneurysmal bone cyst, the lesion inside the marrow cavity could be verified by diagnostic ultrasound imaging [24]. Most malignant bone tumors or osteosarcomas are osteolytic and tend to destroy the normal structure of bone. This suggests that ultrasound beams at lower frequencies may penetrate osseous tissues and thus, it may be possible to use focused ultrasound to treat bone tumors. Recent studies have shown that focused ultrasound at frequencies of 1 MHz or lower could create a sharp focal point and induce tissue destruction in rabbit brain after propagation through a segment of human skull [25,26]. We have reported that a HIFU beam at 0.8 MHz operating frequency could induce coagulation necrosis of VX2 neoplastic tissue in the medullary cavity of rabbit tibia [27]. Within the treated region, tissue became completely necrotic encapsulated with a congestion rim (Fig. 1). The margin between the treated and untreated region was quite clear and definitive. In the same study, coagulative necrosis was found at the destroyed cortex bone, as well as in tumor tissue at deep layer of cortex bone. These findings indicated that HIFU might penetrate through the destroyed bone tissue to ablate tumor tissue at deeper layers. Microscopic histologic examination showed coagulative necrosis in the treated region, and the distance between treated and untreated region was of several cells in thickness [28], suggesting that the delivery of HIFU for the management of bone tumors was relatively precise and controllable. In the targeted region, the destruction of endothelium cells of microvessels and thrombosis was readily detected, suggesting that HIFU could potentially prevent hematogenous dissemination of the tumor cells [28].

Another study further demonstrated that the treatable diameters of bone tumor increased with absorption ratio of bone marrow to tumor, acoustic window of surface skin, and diameter of bone, but decreased with muscle depth and specific absorption rate ratio (SARR) of the bone tumor to the surface skin, bone marrow, and bone [29]. In addition, the optimal driving frequency was dependent on the tumor depth, ultrasound absorption of bone marrow, and bone diameter, but was independent on the acoustic window area and SARR ratio under the three SARR criteria [29]. The findings are helpful to make quick assessment on whether the bone tumor is treatable or not in the multilayer tissue conditions, as well as to choose the optimal operating frequency of the ultrasound transducer and the acoustic window on the skin surface once the parameters, such as the tumor size, tumor depth, and diameter of bone, are known.

                                   Figure 1. Coagulative necrosis and congestion rim surrounding ablated tissue.

                    After exposure to high intensity focused ultrasound, targeted tissue became coagulative necrosis

                                and there was a congestion rim surrounding the ablated tissue. Original photo.

[%page%]
Clinical study of bone tumors treated with high intensity focused ultrasound

To explore the feasibility and safety of HIFU for managing malignant bone tumors, we conducted a pilot HIFU study on tumor lesions in five patients with osteosarcoma who were undergoing amputation [30]. Clinical symptoms, imaging changes, and functions of vital organs were evaluated before and after HIFU procedure. Samples were retrieved after the patients received amputation procedures and evaluated histologically. Authors found that ECG had no change before, during, and after HIFU procedure, and there were no significant changes in renal function and blood electrolytes before and after HIFU. We did note that the ALP activity (a measure of liver function) increased 3 days after HIFU, but returned to the same or lower pre-HIFU level 1 week later. These preliminary findings indicated that HIFU ablation had no significant influence on the vital organs. Using digital subtraction angiography (DSA), we found that tumor staining in the treated areas disappeared, while small arteries and the blood vessels >2 mm remained intact, suggesting that HIFU ablation of bone tumors did not damage these vessels. Histopathological findings of these five patients also revealed that the actual damage area was the same as that planned, indicating that that the HIFU-induced coagulative necrosis was controllable. The above findings demonstrated that HIFU ablation of malignant bone tumors was a well tolerated and noninvasive procedure. Clinically, after HIFU bone pain disappeared or was significantly relieved, the range of motion of the inflicted joints was improved. Color Doppler flow imaging (CDFI) indicated the reduction or disappearance of blood flow in the treated region. 99mTc-MDP bone scan showed the disappearance of radioactive uptake and formation of radioactive cold region, and a reduction of radioactivity ratio of the treated region at the affected limb over that at the contralateral unaffected limb, indicating the decline of osteogenesis at the treated region. Pathologic examination found that there was a massive necrosis in the treated regions. In fact, 103 of the analyzed 120 samples exhibited complete necrosis, suggesting HIFU could produce a large volume of necrosis within the tumor lesions.Histologically, 10 samples obtained from the margin of the treated regions had residual tumor cells, and in seven additional samples, inflammatory cell infiltration and fibrous connective tissue proliferation were detected at the margin of the treated regions, indicating that absorption of necrotic tumor tissue starting from the margin. Taken together, these encouraging results strongly suggest that that HIFU management of malignant bone tumors is feasible.

Based on the aforementioned studies, we went on using HIFU procedure on four patients with primary stage II malignant bone tumors, including three chondrosarcoma and one malignant giant cell tumor of bone, and on four patients with breast cancer bone metastases with HIFU ablation alone [31]. Magnetic resonance imaging (MRI) and 99mTc-MDP bone scan before and after HIFU ablation were obtained and compared. We found that all treated regions after HIFU had no intensification and there was an even, thin intensification rim around the region. In 99mTc-MDP bone scan, disappearance of radioactive uptake was found and a radioactive cold region was produced; the treated region covered the entire lesion, suggesting possibly complete inactivation of the tumor foci. Among the eight patients, two chondrosarcoma patients received HIFU treatment twice and another received HIFU just once. After an average follow-up of 23.1 months, no local recurrence was found in any of the cases. These results suggest that HIFU can be used as an effective stand-alone therapy to manage malignant bone tumors. We also conducted further studies using the combination of HIFU and chemotherapy for managing malignant bone tumors. A total of 44 patients with osteosarcomas were treated using HIFU in combination with chemotherapy [32]. Tumor types are included in Table 1. After a mean follow-up time of 17.6 months, the overall survival rate of 44 cases was 84.1%. For the 34 cases of stage IIb, 30 cases continued to survive disease-free, two died of lung and brain metastases, and the other two had local recurrence. Among 10 of the stage IIIb cases, five survived with tumor, one had local recurrence, and five died of lung metastases. The complication occurrence rate was 18.2%, including two cases with secondary infection, three with pathologic fracture, one with epiphysis separation, and two with common peroneal nerve injury. Enneking comprehensive function scoring of the 36 cases was not less than 15 points. It is conceivable that a limb salvage procedure can be carried out to treat malignant bone tumors of limbs using HIFU and chemotherapy because our results demonstrated that HIFU is effective and well tolerated. We expected that HIFU ablation would result in fewer complications and well-preserved limb function because there were no surgical traumas and blood vessels >2 mm in diameter were retained, which could be beneficial to revascularization and repair of inactivated tumor bones. Additionally, because surgical trauma and repair of the trauma are not involved for HIFU treatment, there would be no delay of postoperative chemotherapy, which is beneficial to ensure the efficacy of chemotherapy and to improve the prognosis. All three pathologic fracture complications occurred in osteolytic cases, indicating that patient selection could be important. Revascularization and repair of inactivated bones usually require a long period of time, and it is crucial to protect the affected limb. Since real-time diagnostic ultrasound was used for guidance of HIFU treatment, nerves might not always be clearly detected. This was believed to be the reasons for nerve injury in HIFU treatment of bone tumors. Nevertheless, our studies have relatively short follow-up time. Further studies are necessary to investigate the role that HIFU ablation may play for tumor control, functional status of conserved limbs, incidence of complications, biomechanical performance of repaired limb, and the indication of HIFU. Other researchers have obtained similar results, and concluded that it was important to carefully choose indication to reduce HIFU-related complications, such as pathologic fracture [33].

 
[%page%]
 

             Figure 2. 99mTc-MDP SPECT before high intensity                            Figure 3. Fourteen days after high intensity

                             focused ultrasound treatment.                                                              focused ultrasound