See editorial on pages 3754-5, this issue.
Noninvasive treatment of malignant bone tumors using high-intensity focused ultrasound†
Article first published online: 28 MAY 2010
Copyright © 2010 American Cancer Society
Volume 116, Issue 16, pages 3934–3942, 15 August 2010
How to Cite
Li, C., Zhang, W., Fan, W., Huang, J., Zhang, F. and Wu, P. (2010), Noninvasive treatment of malignant bone tumors using high-intensity focused ultrasound. Cancer, 116: 3934–3942. doi: 10.1002/cncr.25192
- Issue published online: 4 AUG 2010
- Article first published online: 28 MAY 2010
- Manuscript Accepted: 26 OCT 2009
- Manuscript Revised: 28 JUL 2009
- Manuscript Received: 28 MAY 2009
- high-intensity focused ultrasound;
- malignant bone tumor;
High-intensity focused ultrasound (HIFU) is a new, noninvasive technique with potential to ablate and inactivate tumors. Treatment of solid tumors with HIFU has been reported. In this study, the safety and effects of HIFU in the clinical therapy of malignant bone tumors were assessed.
Biochemical markers and magnetic resonance imaging (MRI) or positron emission tomography (PET)-computed tomography (CT) were used to evaluate 25 patients with malignant bone tumors before and after HIFU treatment.
HIFU resulted in significant improvement in biochemical markers, and no severe complications were observed. After HIFU treatment, 21 (87.5%) patients were completely relieved of pain, and 24 (100%) experienced significant relief. On the basis of MRI or PET-CT, HIFU was effective: For patients with primary bone tumors, 6 (46.2%) had a complete response, 5 (38.4%) had a partial response, 1 (7.8%) had a moderate response, and 1 suffered progressive disease; the response rate was 84.6%. For patients with metastatic bone tumors, 5 (41.7%) had complete response, 4 (33.3%) had partial response, 1 (8.3%) had a moderate response, 1 (8.3%) had stable disease, and 1 suffered progressive disease; the response rate was 75.0%. The 1-, 2-, 3-, and 5-year survival rates were 100.0%, 84.6%, 69.2%, and 38.5%, respectively, for patients with primary bone tumors and 83.3%, 16.7%, 0%, and 0%, respectively, for patients with metastatic bone tumors. The survival rates for patients with primary bone tumors were significantly better than for those with metastatic tumors.
HIFU safely and noninvasively ablated malignant bone tumors and relieved pain. HIFU ablation should be further investigated, as it appears to be successful in the treatment of primary malignant bone tumors. Cancer 2010. © 2010 American Cancer Society.
Malignant bone tumors are usually secondary and often the result from cancer metastasis. Bone is among the most frequent target organs in cancer metastasis, followed by liver and lung.1 The clinical symptoms include indolent bone pain, movement limitations in the affected limb, hypercalcemia, and a tendency for pathological fractures. Clinical treatments for metastatic bone tumors aim to control and relieve bone pain, increase quality of life, prevent complications, improve prognosis, and extend survival time.2 Nonsurgical clinical treatments include radiotherapy, chemotherapy, radionuclide therapy, endocrine therapy, and molecular biology therapy. Radiotherapy provides pain relief but does not extend the patient's survival time.3-6
High-intensity focused ultrasound (HIFU) ablation is a noninvasive method for the treatment of localized tumors.7-9 An ultrasound beam is focused onto the tumor as it passes through tissue. This enables the use of an external ultrasound energy source to induce thermal ablation of a tumor at a depth under the intact skin. Under the guidance of real-time ultrasonographic imaging, the motion of a therapeutic transducer can facilitate ablation of a 3-dimensional target.10-13 The temperature at the targeted position increases to approximately 65 to 100°C in 0.5 to 1.0 seconds.10 The tumor tissues undergo coagulative necrosis with little damage to nearby healthy tissues.13, 14 The main advantages of HIFU are that it is noninvasive, conformal, and enables ablation of large-volume tumors. Here we describe our data on the safety and efficacy HIFU in a group of 25 patients with malignant bone tumors.
MATERIALS AND METHODS
The Ethical Committee at the Cancer Center of Sun Yat-Sen University approved the study design, and informed consent was obtained from patients. A total of 25 patients (13 men, 12 women) with mean age of 39.6 ± 17.2 years (range, 9-72 years) underwent HIFU treatment of malignant bone tumors at our hospital beginning in June of 2001. Thirteen of the patients had primary malignant bone tumors, and 12 had metastatic malignant bone tumors. Pathological or cytological tests confirmed that tumors were malignant. Twelve of the primary tumors were osteosarcomas, 6 were hepatic cancer, 3 were lung cancer, 1 was a malignant fibrous histiocytoma, 1 was a mediastinum signet ring cell carcinoma, 1 was rectal cancer, and 1 was kidney cancer. HIFU was targeted to the primary or metastatic malignant bone tumor in ilium (n = 8), limbs (n = 7), ribs (n = 7), sternum (n = 1), scapula (n = 1), and pubis (n = 1). Primary and metastatic tumor characteristics and patient information are summarized in Tables 1 and 2.
|Patient No./Age, y/Sex||Primary Tumor Type||Bone Tumor Size, mm||Pain Degree (VRS)|
|1/9/F||Distal femur osteosarcoma||42×46×65||1|
|2/25/F||Distal humerus osteosarcoma||23×40×72||2|
|3/32/F||Distal femur osteosarcoma||100×120×160||3|
|4/20/M||Proximal tibia osteosarcoma||20×42×60||1|
|5/17/F||Distal femur osteosarcoma||34×118×133||3|
|6/16/M||Proximal humerus osteosarcoma||60×64×116||1|
|7/60/F||Distal femur osteosarcoma||62×80×120||2|
|8/25/M||Left ilium malignant fibrous histiocytoma||69×71×90||1|
|9/35/F||Right ilium osteosarcoma||66×87×105||2|
|10/53/M||Right scapula osteosarcoma||60×70×80||2|
|11/18/F||Right rib osteosarcoma||80×85×100||2|
|12/53/F||Left pubis osteosarcoma||80×85×90||2|
|13/65/M||Right ilium osteosarcoma||50×60×80||2|
|Patient No./Age, y/Sex||Primary Tumor Type||Bone Tumor Position||Bone Tumor Size, mm||Pain Degree (VRS)|
|1/47/M||Left lung cancer||Left 4th rib||10×10×15||1|
|3/46/F||Mediastinum signet ring cell carcinoma||Left 6th rib||55×58×66||2|
|4/42/M||Colorectal cancer||Right ilium||70×70×90||2|
|5/33/F||Liver cancer||Right ilium||70×70×80||3|
|6/72/M||Lung cancer||Left ilium||85×90×115||3|
|7/47/F||Right kidney cancer||Right 5th rib||40×40×50||2|
|8/47/F||Liver cancer||Left 4th rib||20×20×30||2|
|9/39/M||Liver cancer||Right 4th rib||10×10×20||1|
|10/32/M||Liver cancer||Right 5th rib||10×10×20||0|
|11/53/F||Left lung cancer||Right ilium||40×40×50||1|
|12/37/M||Liver cancer||Right ilium||80×110×125||3|
Physical and iconographical examinations were performed to determine the location, size, and shape of the tumors and the relation of the tumors to nearby nerves, blood vessels, and other organs. Personal HIFU therapeutic schedules were designed on the basis of the results of these examinations and the patients' history.
The tumor therapy system (Model JC, Chongqing Haifu Technology, Chongqing, China) used in this study was guided by real-time ultrasonographic imaging as previously described.11, 12, 15 Focused ultrasound was produced by a piezoelectric ceramic (lead zirconate titanate) transducer (12 cm in diameter with a focal length of 135 mm) at a frequency of 0.8 MHz (continuous wave). The focal region was an ellipsoid with dimensions of 3.3 mm along the beam axis and 1.1 mm in the transverse direction. An AU3 ultrasonographic imaging device (Esaote, Genoa, Italy) was used as the real-time imaging unit of the system. This 3.5- to 5.0-MHz imaging probe was situated in the center of the HIFU transducer.
HIFU treatment was performed with patients under general anesthesia to prevent the patient from experiencing pain and to ensure immobilization. Before HIFU treatment, the skin of the therapy area was prepared, degassed, and defatted to reduce the refraction of ultrasound and enhance the accuracy of focusing. We applied a 75% alcohol swab to the treatment area to defat the skin's surface before treatment. Next, we used a vacuum extractor to degas the skin. Degassed water was applied to the target area to wet the skin, and a disk suction device with holes was connected to the vacuum extractor. Next, degassing was performed from the center of the lump to the margins in a spiral manner. After degassing, a transparent film was applied to the degassed area to block the air. The treated area of skin was greater than the target area by ∼3 to 5 cm. Real-time ultrasonography was used to target the tumor by moving the integrated probe, and the tumor was divided into sections with 5 mm of separation. The targeted regions in each section were completely ablated by the HIFU scanning beam. This process was repeated section by section to achieve complete ablation of the tumor volume. During HIFU ablation, real-time ultrasonographic scans obtained immediately before and after the individual exposures were compared to determine whether the echogenic changes to the HIFU-treated region were indicative of coagulative necrosis and to ensure that treatment covered the desired area.
The excision extension of HIFU included the normal soft tissue 2.0 cm from the edge of tumor and normal bone tissue 2.0 to 3.0 cm from the tumor. Special attention was paid to protecting important nerves. Skin protection was necessary for treatment of the tibia, because these tumors often occurred subcutaneously. The target tissue was exposed at acoustic focal peak intensities from 70 to 160 W/cm2. The treatment power was adjusted according to the tumor position, size, focal distance, and relationship to the nearby nerves, blood vessels, and other organs. The scanning speed ranged from 1 to 3 mm/s. Five patients underwent 2 HIFU sessions, and 2 patients underwent 3 HIFU sessions (mean of 2.29 sessions). Therapeutic times for individual patients ranged from 27.5 to 647.6 minutes (mean 230.9 ± 173.3 minutes). The number of sessions depended on the therapeutic effectiveness, determined based on symptoms, levels of tumor biomarkers, and changes in tumor images. The treatment protocols were design to ensure that the treatment area was fully covered by HIFU and that the skin integrity as well as limb function were protected.
For metastatic bone tumors, adjuvant chemotherapy was given if determined necessary based on the patient's history, such as the previous surgery and chemotherapy results. For the primary osteosarcoma patients, 4 to 6 weeks of neoadjuvant chemotherapy was given before HIFU, followed by 2 to 4 weeks of adjuvant chemotherapy, 10 to 20 days after HIFU. The chemotherapy regimens were high-dose methotrexate/vincristine (8-12 g/m2 methotrexate intravenous drip, 2 mg vincristine, intravenous injection) at 3-week intervals and doxorubicin (Adriamycin) (40-60 mg/m2 intravenous injection) and cisplatin (100-120 mg/m2 intravenous drip) at 3-week intervals.
The patient's physical condition and local symptoms were recorded before and after HIFU. Physical condition included vital signs and physical examination. Local symptoms included tumor size and texture, skin temperature, skin venous engorgement, and motion of the joint closest to the affected limb. The complexion of the skin was also recorded.
Pain degree was classified using verbal rating scales. Patients rated their pain as follows: 0 indicated no pain; 1, mild pain; 2, moderate pain; and 3, severe pain.16
Before HIFU and 1 week after HIFU, liver/kidney marker and blood electrolyte levels were determined. For limb osteosarcoma patients, blood alkaline phosphatase and lactate dehydrogenase levels were measured before HIFU and 1 and 2 months after HIFU.
Radiographic imaging examination
Imaging examinations were performed to evaluate the therapeutic effectiveness of HIFU. Before HIFU and 4 to 6 weeks after HIFU, all patients underwent 99mTc-methane-diphosphonate (99mTc-MDP) (injected doses: 925 MBq) and either contrast-enhanced magnetic resonance imaging (MRI) with a 1.5-T unit (Signa, GE Medical Systems, Waukesha, Wis) or positron emission tomography (PET)-computed tomography (CT) (GE Medical Systems, Discovery ST16 PET/CT).
MRI or PET-CT exams were performed 4 to 6 weeks before and after treatment to evaluate tumor necrosis and lesion size. The World Health Organization standard was adopted to evaluate effectiveness17, 18: 1) complete response (CR), whole tumor was completely necrotic or disappeared for >4 weeks; 2) partial response (PR), tumor necrosis >50% or the decrease of the multiplication of lesion diameters was >50% and lasted >4 weeks; 3) moderate response, >50% necrotic or a decrease in tumors of ≥25%; 4) stable disease (SD), a decrease or increase in tumors of <25%; and 5) progressive disease (PD), increase in tumor ≥25% or new lesions occur. Total effective rate was calculated as cases of CR plus cases of PR divided by the total number of cases.
All values are presented as the mean ± standard deviation. The Wilcoxon nonparametric test was used to compare tumor and ablation volumes with non-normal distributions. Cumulative survival rates were expressed according to the Kaplan-Meier method. The differences in survival were compared using the log-rank test. The pain scale was continuously variable, and t test was used to evaluate the significance of differences (P < .05 indicated significance).
Four metastatic bone tumor patients developed a low-grade fever (37.5-38.4°C) after HIFU treatment that normalized within 3 to 5 days. All other regional body temperatures remained unchanged. Mental status and appetite remained unchanged throughout HIFU treatment. Six patients exhibited venous skin engorgement before HIFU treatment. After treatment, 4 patients no longer exhibited these symptoms, 1 patient improved, and 1 patient had no obvious change. One to 5 days after HIFU treatments, therapy areas showed swelling that disappeared within 1 week.
After chemotherapy but before HIFU treatment, tumors showed low signal intensity on a T1-weighted image (T1WI) MRI, but showed a mixed signal with a slightly high signal on T2WI. The signal of the tumor was somewhat strengthened after gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) was injected. One week after HIFU treatment and 4 to 6 weeks after treatment, the tumors showed a slightly high signal on T1WI. The tumors were of the mixed signal type, mainly showing low signal on T2WI, which was not strengthened by Gd-DTPA injection. There was also a thin, regular, enhanced band that clearly separated the inactivated area from the normal tissue. Furthermore, the therapy area defined in HIFU was bigger than the actual size of the tumor before treatment (Fig. 1).
Bone imaging by PET-CT (or 99mTc-MDP) after chemotherapy, but before HIFU treatment, revealed abnormal radioactivity concentration in all the tumors. Bone imaging by PET-CT (or 99mTc-MDP) 4 to 6 weeks after HIFU showed no abnormal radioactivity concentrations in the tumor areas; the areas were now cold lesions of the size and shape of the original bone tumor. There was a reaction band along with the margins of the inactivated area of the tumor that showed higher radioactivity (Figs. 1-3).
Twenty-four of the 25 patients suffered pain because of their bone tumors. Before HIFU treatment, patients rated their pain on average 1.84 ± 0.85 (on a scale of 0-3). After HIFU treatment, pain was significantly alleviated, and the average pain rating was 0.12 ± 0.33 (P < .001). For the 13 patients with primary bone tumors, the average pain rating before treatment was 1.85 ± 0.69. After HIFU treatment, it was 0.08 ± 0.28 (P < .01). Eleven of the 12 patients with metastatic bone tumors suffered from pain from the bone tumor. Before HIFU treatment, the pain rating was 1.75 ± 0.97. After HIFU treatment, it was 0.17 ± 0.39 (P < .004). In summary, 21 (87.5%) of 24 patients were completely relieved of pain, and all patients had significant pain relief (Table 3).
|Tumor Type||No. of Cases||Pretreatment||Post-treatment||P|
|Bone||25||1.84 ± 0.85||0.12 ± 0.33||.00|
|Primary||13||1.85 ± 0.69||0.08 ± 0.28||.01|
|Metastatic||12||1.75 ± 0.97||0.17 ± 0.39||.00|
Four to 6 months after HIFU treatment, MRI or PET-CT examinations confirmed the effectiveness of the treatment in all patients. The response rate for patients with primary bone tumors was significant: 6 (46.2%) patients had CR, 5 (38.4%) had PR, 1 (7.8%) had moderate response, and 1 (7.8%) had PD. The response rate was 84.6%. For patients with metastatic bone tumors, 5 (41.7%) had CR, 4 (33.3%) had PR, 1 (8.3%) had moderate response, 1 (8.3%) had SD, and 1 (8.3%) had PD; the response rate was 75.0%. There was no significant difference in extent of response between primary bone tumors and metastatic bone tumors (Table 4).
|Group||No. of Cases||CR||PR||MR||SD||PD||RR|
|Primary tumors||13||6 (46.2)||5 (38.5)||1 (7.8)||0||1 (7.8)||11 (84.6)|
|Metastatic tumors||12||5 (41.7)||4 (33.3)||1 (8.3)||1 (8.3)||1 (8.3)||9 (75.0)|
The 1-, 2-, 3-, and 5-year overall survival rates were 100.0%, 84.6%, 69.2%, and 38.5%, respectively, for patients with primary bone tumors, and median overall survival was 43.0 months. For patients with metastatic bone tumors, the 1-, 2-, 3-, and 5-year overall survival rates were 83.3%, 16.7%, 0%, and 0%, respectively. There was significant difference in overall survival rates between patients with primary bone tumors and metastatic bone tumors. The survival curves are shown in Figure 4.
Blood samples were obtained before and after HIFU from the 13 patients with the primary malignant bone tumors. The levels of alkaline phosphatase before treatment ranged from 78 to 412 U/L, with an average of 227.9 U/L (normal value, <110 U/L). The levels of lactic acid dehydrogenase ranged from 136 to 400 U/L, with an average of 263.3 U/L (normal value, <245 U/L). There was no statistical significance in levels of these biomarkers before and 3 days after treatment (P > .05). There was statistical significance found (P < .05) between pretreatment values and the levels 1 to 2 months after HIFU (Table 5). No abnormalities in electrocardiogram, liver, and kidney functions and blood electrolytes were detected in the patients (data not shown).
|Group||Before Treatment||3 Days After Treatment||1 Month After Treatment||2 Months After Treatment|
|Alkaline phosphatase (U/L)||227.9 ± 99.4||229.3 ± 93.9||171.7 ± 71.6a||128.0 ± 54.1a|
|Lactic acid dehydrogenase (U/L)||263.3 ± 82.3||268.9 ± 70.8||212.5 ± 52.0a||178.5 ± 67.6a|
Complications Because of HIFU
During HIFU treatment, 12 patients had first-degree burns; the symptoms faded without intervention within 2 weeks. Two patients had second-degree burns, and the symptoms faded without scars 4 weeks after treatment. Three patients lacked feeling in the affected limb during HIFU treatment, but the symptoms were alleviated after treatment.
Traditionally, HIFU has not been applied in the treatment of bone disease. However, because the equipment for HIFU has improved, recent studies have evaluated use in treatment of osteosarcoma.19-21 Although bone tissue has a high acoustic impedance and attenuation coefficient, the bone surface is a strong reflective area, and malignant bone tumors can destroy the integrity of cortical bone. This can result in significant differences in the acoustic characteristics between normal bone and tumor-laden bone. For bone tumor, the ultrasonic wave transmitted into bone tissue has a lower chance of retransmitting off the bone than off normal tissue, thus allowing for a high efficiency of conversion of sonic energy into heat. Low-frequency ultrasound can be focused on the tumor to form centers of high energy, forcing tumor tissue to undergo coagulative necrosis via instantaneous high temperature and cavitation erosion, with no harm to normal tissue outside of the therapy area. We have applied HIFU to treat malignant bone tumors in 25 patients. The results show that HIFU effectively controlled local tumors and improved symptoms and limb function.
During HIFU therapy, B-type ultrasonography was used to monitor real-time changes in sonograms. Thus, the relationship between dose and temperature and between dose and effect is evident.19, 21 In this study, during HIFU, obvious lamellar or cloud-like strengthening occurred in all sonograms, confirming that real-time monitoring by B-type ultrasonography indicated whether the dose was sufficient. MRI can identify the size of intramedullary pathological changes and nearby soft tissue changes caused by bone tumors, thus guiding determination of the size of the therapy area. MRI can also show the real coverage area of HIFU to determine whether the tumor area has been totally ablated.22, 23 Similarly, whole body bone 99mTc-MDP and PET-CT scans can reflect whether bone tumors have been totally ablated. In summary, B-type ultrasonography, MRI, 99mTc-MDP, and PET-CT can be used to evaluate the effect of HIFU on bone tumor ablation. Moreover, serum alkaline phosphatase levels reflect tumor status. By all these measures, the patients in our study were effectively treated. For patients with primary bone tumors, the response rate based on MRI or PET/CT was 84.6%. For patients with metastatic bone tumors, the response rate was 75.0%. The survival rates for patients with primary bone tumors were significantly better than for those with metastatic tumors (Fig. 4).
Twenty-four of the 25 patients suffered pain because of their bone tumors. After HIFU treatment, pain was significantly alleviated. A possible mechanism for the pain relief may be thermal periosteal denervation. Another possible mechanism may be related to the thermal ablation of the tumor tissue mass itself; through reduction in the mass, the pressure on adjacent healthy tissues might be relieved. A combination of these mechanisms is also a possibility.
The main complications of HIFU therapy in malignant bone tumor included skin burns in the therapy area and local nerve injury. Other potential complications included fracture of the tumor-affected bone, functional loss of nearby joints, and hemorrhagic infection of the tumor; these were not observed in our study. HIFU should not be used or should only be carefully considered when: 1) there is pathological fracture; 2) tumors are located in spine or skull; 3) the distance between tumor and skin is <0.5 cm; 4) tumor crosses a joint; or 5) tumor crosses/surrounds a nerve or blood vessel.
In this study, most patients received chemotherapy before and after HIFU therapy. Chemotherapy may not only inhibit growth of subclinical metastatic foci, preventing recurrence after HIFU therapy, but may also minimize tumor size. Therefore, chemotherapy and HIFU might be synergistic.
HIFU has several advantages:
It is noninvasive; therefore, there is no need for surgery or ultrasound-guided puncture and no risk of bleeding. HIFU can completely destroy lesions in the body, with no harm to ultrasound-penetrated tissues or normal areas lying outside the target.
There is uniform distribution of therapeutic dose. Nonuniform dose distribution is a problem in minimally invasive, interventional therapies like microwave, radiofrequency, laser, and freezing.
Lethal treatment of the targeted area is possible; the target receives lethal ultrasonic doses and all tissues within the target are nonselectively destroyed.
It is a type of conformal treatment; 3-dimensional conformal therapy ensures complete lesions that are unconstrained by tumor shape.
HIFU treatment is not dependent on tumor size; lesions of any size can be completely destroyed.
HIFU allows selective destruction of blood vessels. In general, only tumor blood vessels with a diameter <200 μm are targeted for destruction,24 effectively guaranteeing the safety of the treatment and increasing the scope of treatable lesions. Therefore, HIFU makes it possible to perform local treatment on some cancer patients for whom surgery is complicated by anatomical features of tumor blood vessels.
Real-time treatment is possible; ultrasound monitoring devices offer real-time monitoring of the entire process of HIFU treatment, enabling timely evaluation of treatment efficacy and dose adjustments using imaging changes of the target before, during, and after treatment.
Compared with traditional surgery for malignant bone tumors, HIFU has the advantage of being noninvasive, and it can be used to treat large malignant bone tumors, which cannot be surgically removed. Limb shape and succession are not affected by HIFU, and treatment can be repeated on patients who did not respond fully or who had recurrence. HIFU treatment provides pain relief and can be used in conjunction with chemotherapy. In summary, our preliminary data suggest that HIFU is safe and feasible for the treatment of patients with malignant bone tumors. HIFU ablation is promising and should be investigated in larger numbers of patients with primary malignant bone tumors.
CONFLICT OF INTEREST DISCLOSURES
We thank Wang Lan, PhD and N. Rama Krishna, PhD, Professor, Biochemistry and Molecular Genetics, University of Alabama at Birmingham School of Medicine for help with the linguistic revision of the manuscript.
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- 20High intensity focused ultrasound in the treatment of primary malignant bone tumor [in Chinese]. Zhonghua Zhong Liu Za Zhi. 2002; 24: 612-615., , , et al.