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Originally published as Ann Surg Oncol Early Release 10.1245/ASO.2004.02.026 on November 15, 2004

Annals of Surgical Oncology 11:1061-1069 (2004)
© 2004 Society of Surgical Oncology
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ORIGINAL ARTICLES

Extracorporeal High Intensity Focused Ultrasound Ablation in the Treatment of Patients with Large Hepatocellular Carcinoma

Feng Wu, MD, PhD, Zhi-Biao Wang, MD, PhD, Wen-Zhi Chen, MD, Hui Zhu, MD, Jin Bai, MD, Jian-Zhong Zou, MD, Ke-Quan Li, MD, Cheng-Bing Jin, MD, Fang-Lin Xie, MD and Hai-Bing Su, MD

From the Institute of Ultrasonic Engineering in Medicine, and Clinical Center for Tumor Therapy of 2nd Affiliated Hospital, Chongqing University of Medical Sciences, Chongqing, China.

Correspondence: Address correspondence and reprint requests to: Feng Wu, MD, Chongqing University of Medical Sciences, Box 153, Institute of Ultrasonic Engineering in Medicine, 1 Medical College Road, Chongqing 400016, China; Fax: +86-23-6372-5784; E-mail: mfengwu{at}yahoo.com


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: High intensity focused ultrasound (HIFU) is a noninvasive treatment modality that induces complete coagulative necrosis of a deep tumor through the intact skin. The current study was conducted to determine the safety, efficacy, and feasibility of extracorporeal HIFU in the treatment of patients with hepatocellular carcinoma (HCC).

Methods: A total of 55 patients with HCC with cirrhosis were enrolled in this prospective, nonrandomized clinical trial. Among them, 51 patients had unresectable HCC. Tumor size ranged from 4 to 14 cm in diameter with mean diameter of 8.14 cm. According to tumor, node, metastasis (TNM) classification, 15 patients corresponded to stage II, 16 to stage IIIA, and 24 to IIIC. All patients had HIFU, and the median number of HIFU session was 1.69. Safety and efficacy of HIFU were assessed in this trial.

Results: No severe side effect was observed in the patients treated with HIFU. Follow-up imaging showed an absence of tumor vascular supply and the shrinkage of treated lesions. Serum {alpha}-fetoprotein returned to normal level in 34% of patients. The overall survival rates at 6, 12, and 18 months were 86.1%, 61.5%, and 35.3%, respectively. The survival rates were significantly higher in patients in stage II than those in stage IIIA (P = .0132) and in stage IIIC (P = .0265).

Conclusion: As a noninvasive therapy, HIFU appears to be effective, safe, and feasible in the treatment of patients with HCC. It may play an important role in the ablation of large tumors.

Key Words: High intensity focused ultrasound • Hepatocellular carcinoma • Cirrhosis • Thermal ablation


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world.1 More than 80% patients with HCC are not good candidates for curative surgical resection because of advanced liver cirrhosis caused by underlying chronic hepatitis virus (B or C) infection.2–4 Therefore, nonsurgical local treatments, including percutaneous ethanol injection,5,6 microwave,7,8 laser,9,10 cryotherapy,11,12 and radiofrequency ablation,13,14 have been used for patients with HCC. These therapeutic energy modalities, however, are principally performed in patients with small volume HCC <5 cm in diameter.15

High intensity focused ultrasound (HIFU) is a noninvasive technique for local thermal ablation of solid tumors. With an external source of focal ultrasonic energy, ultrasound can be used to induce a well-delineated volume of coagulation deep to the skin. Three-dimension, conformal ablation of a large lesion can be achieved under the guidance of real-time imaging techniques by moving the therapeutic transducer—the focus—extracorporeally. Experimental results revealed that HIFU could ablate normal liver tissue in vivo and achieve local control of implanted liver tumors.16–21 Until now, the clinical application of HIFU for HCC treatment was limited. Therefore, we performed this prospective, nonrandomized clinical trial to investigate the safety, efficacy, and feasibility of HIFU in the treatment of patients with HCC.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
Between November 1998 and October 2001, 78 consecutive patients with HCC were enrolled in this clinical study. Among them, 55 patients (43 men, 12 women; age range, 24 to 73 years; average age, 51.6 ± 13.05 years) had extracorporeal HIFU ablation. A total of 23 patients were not included in this study because they had either more than four HCC foci (n = 15) or hepatic dysfunction (Child-Pugh class C, n = 8). Our university ethics committee approved this study, and each patient signed an informed consent form at the time of enrollment.

All patients were evaluated initially by a team that consisted of three senior surgeons, a senior oncologist, and a senior interventional radiologist. The selection criteria for the patients in this study were as follows: the number of HCC lesions was less than five (excluding five); lesion was detected on ultrasound imaging; Karnofsky performance scale ≥70%; no detected extrahepatic metastasis; Child-Pugh class A or B cirrhosis; and no history of hepatic encephalopathy. HCC diagnosis was confirmed by ultrasound-guided, fine-needle biopsy (n = 23) or made on both the characteristic findings of either computerized tomography (CT) or magnetic resonance imaging (MRI) and a high level (>200 ng mL–1) of serum {alpha}-fetoprotein (AFP) (n = 32).

Almost all patients in this study had large HCC. The tumor size ranged from 4 to 14 cm in diameter; average diameter was 8.18 ± 3.37 cm. Tumor diameter in 2 patients was <5 cm, 5.1 to 10 cm in 32, and >10.1 cm in 21. A total of 28 patients had multiple lesions (2 lesions in 8 patients, 3 lesions in 9, and 4 lesions in 11), and the remaining 27 had a solitary lesion. A total of 33 patients had HCC lesions located in the right lobe, 4 in left lobe, and 18 in both lobes. According to the tumor, node metastasis (TNM) classification,22 15 patients corresponded to stage II (T2N0M0), 16 to stage IIIA (T3N0M0), and 24 to IIIC (T3N1M0). Of patients, 48 had tumors with vascular invasion and 16 had tumor thrombosis or tumor invasion in main branches of intrahepatic blood vessels.

All patients had hepatic cirrhosis with evidence of either chronic hepatitis B (n = 48) or hepatitis C (n = 5), and of unknown origin (n = 2). The diagnosis of cirrhosis was based on imaging changes of the liver on CT, MRI, and Doppler ultrasound. A total of 48 patients corresponded to Child class A and 7 to class B. A total of 51 patients were considered to have unresectable tumor because of severe hepatic cirrhosis with hepatic function at reserve insufficient to tolerate conventional HCC resection (n = 19), advanced stage of tumor (n = 16), or both of them (n = 16). The remaining four patients were suitable for surgical resection, but they refused surgery. A total of 21 patients had a previous history of unsuccessful treatment with 2 to 6 sessions (average 3.6 sessions) of transcatheter arterial chemoembolization (TACE), 1 patient had prior local radiation therapy, and 33 patients did not have any intervention before entry into the study. The interval time between the latest TACE and HIFU ranged from 11 to 19 weeks.

Pretreatment Preparation
Preoperative clinical assessment included the following: the patient’s history, a physical examination, hematologic evaluation (baseline hematocrit, platelet count, prothrombin time, and partial thromboplastin time tests), routine serum chemistry examination (electrolytes, liver, and renal function), serum AFP measurement, chest radiography, electrocardiogram, and a bone scan. CT or MRI, and Doppler ultrasound were performed in all patients before each treatment episode.

HIFU System and Therapeutic Procedure
The HIFU therapy system (Chongqing Haifu [HIFU] Tech Co., Ltd, Chongqing, China) used in this study is guided by real-time ultrasound imaging. This has been described in detail.23,24 The HIFU device has the following main elements: a real-time diagnostic ultrasound device; integrated ultrasound therapy transducers; a six-direction movement and therapeutic planning system; computer units for automated control; an ultrasound generator for therapy; and a degassed water circulation unit. The focused ultrasound is produced by a transducer operating at 0.8 MHz (aperture 120 mm, focal length 135 mm). Tumors are identified and targeted using an integral central 3.5-MHz diagnostic ultrasound probe (Esaote, Genoa, Italy), which is integrated in the center of the therapeutic transducer (Fig. 1). The integrated transducer is mounted in a reservoir of degassed water; it is driven by electric motors and can be moved smoothly in all planes. Both diagnostic and therapeutic ultrasound beams are directed upward. The degassed water provides acoustic coupling between transducer and patient. The focal region of the HIFU transducer is ellipsoid or cigar-shaped, with dimensions of 9.8 mm along the beam axis and 1.3 mm in the transverse direction.



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  		FIG. 1. Photograph of integrated ultrasound therapy transducer within water reservoir. A 3.5-MHz imaging probe (I) is integrated in the center of the therapeutic transducer (T).

 
Treatment by HIFU is performed under either epidural anesthesia (n = 31) or general anesthesia (n = 24). The anesthetist selects the anesthetic, primarily on the basis of ablation time, patient position, tumor location, and therapeutic ultrasound exposure. Endotracheal intubation and mechanical ventilation during the HIFU procedure enables single lung ventilation on the left and, therefore, controls the liver movement caused by respiration. After suitable anesthesia, the patient is positioned prone or in the right lateral position. The skin overlying the lesion to be treated is then in contact with the degassed water used as a coupling medium (Fig. 2). A detailed planning session is performed, in which the target tumor is identified and divided into parallel slices of 5-mm separation by moving the diagnostic probe. Using provisional therapeutic parameters based on the depth and vascular supply of target region, the tumor on each slice is completely ablated, and this process is repeated slice by slice to achieve entire tumor treatment. During the procedure, gray-scale changes on the ultrasound images obtained after each therapeutic exposure are used to evaluate the extent of coagulative necrosis on each slice.



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  		FIG. 2. Photograph of Model-JC high intensity focused ultrasound tumor therapy system during treatment procedure. A patient lies on the treatment bed.

 
In this study, 26 of the 55 patients had HIFU treatment alone at our center. Among them, 21 patients had previously received TACE (2 to 6 sessions, average 3.6), 1 had local radiation therapy at other hospitals. Both therapeutic modalities were performed 11 to 19 weeks before HIFU failed to either control tumor growth (n = 18) or cause a complete necrosis (n = 4). Four patients received HIFU alone as TACE was impossible because of technical failure. The remaining 29 patients received the combination of TACE (either 80 to 120 mg cisplatin or 40 to 60 mg adriamycin, plus 10 to 20 mL iodized oil) and HIFU treatment, which was performed 2 to 4 weeks after TACE. The main purposes of TACE before HIFU were that TACE can cause a decreased tumor blood supply that could reduce the heat loss in a target tumor and iodized oil deposited in a lesion resulted in increased deposition of ultrasonic energy in the target region. Both effects could obviously shorten HIFU treatment time for large HCC in this study. The number of HIFU session ranged from 1 to 3 (median 1.69 sessions). The target tissue was exposed at the various acoustic focal peak intensities from 5000 to 20,000 W cm–2. HIFU treatment time was 2 to 8 hours (mean time, 5.5 hours).

Two to three sessions of HIFU were performed in 19 patients because follow-up imaging showed partial viable tumor still remained after the first ablation, usually in the deep portion of the tumor. Before th second HIFU ablation, a section of the ribs overlying the lesion were resected in 14 patients [stage II (3); stage IIIA (6); stage IIIC (5)] to achieve a complete tumor ablation by obtaining an "acoustic window."

Assessment of Therapeutic Safety and Efficacy
Potential complications and side effects related to HIFU were recorded for each patient; these included pain, fever, skin burn, local infection, tumor bleeding or large vessel rupture, hepatic dysfunction, and bowel perforation. During their hospital stay, patients were monitored weekly with hematologic evaluation and routine serum chemistry examination.

Follow-up imaging examination and serum AFP measurement were performed to evaluate the therapeutic efficacy of HIFU and to detect evidence of residual tumor in treated lesions or the growth of new tumors in the liver. At the time of this study, no clear evidence indicated which imaging modality was best at evaluating coagulative necrosis induced by HIFU. A total of 55 patients received pre- and posttreatment Doppler ultrasound [Q-2000, 3.5-MHz probe (Siemens, Erlangen, Germany)]. A total of 29 patients had follow-up nonenhanced and contrast-enhanced CT scan (Sytec 4000, GE Medical System, Milwaukee, Wisconsin), and the remaining 26 patients received postoperative nonenhanced and gadolinium contrast-enhanced MRI (1.5-T scanner, Signa, GE Medical System). The follow-up images were performed 3 to 6 months postoperatively. Three radiologists reviewed the pre- and postprocedural imaging and reached a consensus in each patient.

A cumulative survival rate is calculated by using the Kaplan-Meier method. Changes in tumor size are calculated by using following formula: (a x b-a’ x b’)/ (a x b) x 100%, in which the coefficients a and a’ are the largest diameter, and b and b’ are the perpendicular diameter of the tumor before and after HIFU ablation.

Statistical Analysis
All the data are reported as the mean ± standard deviation. The statistical significance of any observed difference is evaluated by an unpaired Student t-test, and the differences in percentage data are analyzed by using the Fisher exact test. The difference in cumulative survival rate is evaluated by using a log-rank test. Statistical significance is defined as a P value of < .05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Follow-up Imaging
During the HIFU procedure, real-time ultrasound imaging showed obviously increased gray-scale changes in the targeted lesion in 49 of 55 patients, as shown in Figure 3. These hyperechoic zones in the targeted tissue corresponded mainly to the extent of the coagulation necrosis.25,26 They became gradually less evident and sometimes disappeared within a few minutes following the ablation. Compared with images obtained before HIFU, postprocedural imaging, including Doppler ultrasound, CT, and MRI, showed an absence or obvious decrease in tumor vascular supply, as well as shrinkage of the treated lesions. In this study, 55 patients received Doppler ultrasound as follow-up imaging. A heterogeneous increase in gray-scale changes was noted within the treated tumor in 24 patients, but no gray-scale change was observed in the remaining 31 patients. Reduced or absent blood supply was seen in 32 patients after HIFU treatment. In the remaining 23 cases, however, it was not sufficiently sensitive to detect the destruction of the tumor blood vessels, particularly in hypovascular HCC.



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  		FIG. 3. Gray-scale changes of large high intensity focused ultrasound (HIFU) obtained on real-time ultrasound (US) images during HIFU procedure. (A) US image obtained before HIFU shows a large hepatocellular carcinoma lesion present in left lobe of liver (arrows). (B–C) US images obtained during the HIFU procedure show hyperechogenicity in the treated tumor (arrows). (D) US images obtained immediately after the one-slice HIFU procedure show the hyperechogenicity of treated tumor in the one-slice lesion (arrows).

 
Follow-up enhanced CT was performed in 29 patients every 3 to 6 months postoperatively; hypoattenuating region without contrast enhancement was seen in the treated region after HIFU ablation, as shown in Figure 4. Also, in patients with end-stage HCC, HIFU had obvious efficacy in the control of tumor growth. Figure 5 shows the regression of large HCC in a patient with vascular occlusion of the portal vein by tumor. After HIFU, blood flow was observed in the distal part of portal vein, which we can surmise is the effect of HIFU on the tumor occlusion. Most patients in this study, received at least one TACE treatment before HIFU, however, and the retention of iodized oil caused the evaluation of HIFU efficacy to become more difficult as the tumor that retained iodized oil had a high attenuation on CT.



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  		FIG. 4. Enhanced computed tomography scans obtained in a patient 49 years of age who had one-session high intensity focused ultrasound (HIFU) treatment alone for hepatocellular carcinoma. (A) Before treatment, the lesion, 4 cm in diameter, is located in the left lobe of the liver (arrow). (B) Three months after HIFU, no tumor blood supply is seen in target region (arrow). (C) Twelve months after HIFU, an obvious shrinkage of treated lesion is seen with an absence of blood supply (arrow). (D) Twenty-four months after HIFU, the treated lesion became very small, without vascular supply (arrow).

 


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  		FIG. 5. Enhanced computed tomography scans obtained in a patient 56 years of age who received one-session high intensity focused ultrasound (HIFU) treatment alone for advanced-stage HCC. (A) Before HIFU, the patient had three transcatheter arterial chemoembolization treatments that had failed to control tumor growth. Hepatocellular carcinoma lesion, 12 cm in size, invaded the right branch of the portal vein (black arrow) and the inferior vena cava was compressed with the change in shape (black arrow). Small amount of ascites is seen. (B) Four months after HIFU, the treated lesion regressed (black arrow), the compression of vessel disappeared, and the shape of inferior vena cava became normal (black arrow). Blood flow is seen in the distal part of the portal vein (white arrow), indicative of the portal vein occluded by tumor reopened after the tumor was controlled by HIFU.

 
The remaining 26 patients had contrast-enhanced MRI examinations before and after HIFU. Postprocedural MRI revealed an obvious absence of contrast enhancement in the treated region (Fig. 6), which is indicative of coagulative necrosis. It was noted that contrast-enhanced MRI was more accurate than either Doppler ultrasound or CT scan in demonstrating changes in tumor vascular perfusion and in distinguishing the difference between nonviable and residual viable tumor directly in the treated tumor. MRI demonstrated a complete ablation induced by HIFU in 18 of 26 patients, >80% ablation of tumor volume in 5, and <80% ablation of tumor volume in 3, in whom tumor size was >10 cm in diameter.



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  		FIG. 6. Enhanced magnetic resonance scans of patient 62 years of age with hepatocellular carcinoma who received the combination of transcatheter arterial chemoembolization (TACE) and one-session high intensity focused ultrasound (HIFU). (A) Before TACE, tumor, located in the right lobe of the liver, was 11 cm in size. Rich tumor blood supply was seen (arrow). (B) Four weeks after TACE, just before HIFU, tumor vascular perfusion was decreased (arrows), but large viable tumor volume still remained. (C) Two weeks after HIFU, the blood supply in the tumor disappeared completely (arrows).

 
Serum AFP Level
Of patients, 32 had a high level (>200 ng mL–1) of serum AFP before HIFU treatment. During the follow-up period, serum AFP level was decreased in 29 patients (89%), unchanged in 2 (7%), and increased in 1 (4%). Among the patients with a decrease of serum AFP level, 25 patients (78%) had a reduced level of >25%, 15 (47%) reduced by >50%, and 11 patients (34%) showed a level within normal limits. The change of AFP level coincided with the tumor response to HIFU treatment as imaging seen radiologically.

Changes in Tumor Size
Tumor size was assessed in each patient from both maximal transverse and longitudinal dimensions of the lesion. The changes in tumor size were expressed as a percentage of the initial size of the tumor. During the follow-up period, tumor disappearance was seen in 2 patients, reduction in size in 50, stable in 2, and increased in 1. The average reduction in tumor size at 6, 12, and 18 months in 55 patients, and in patients with II-III stage disease, respectively, are shown in Table 1. During the first 6 months, a gradual reduction in tumor size was noted. But, between 6 and 18 months, this change was less marked, and in some cases the size was stable.


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  		TABLE 1. Reduction in tumor size in HCC patients treated with HIFU as a percentage of the initial tumor volume
 
Survival
No patients have been lost to follow-up. After the median follow-up time of 18 months (range 6 to 34 months), 32 of 55 patients had died and 23 patients were still alive. The overall survival rates at 6, 12, and 18 months were 86.1%, 61.5%, and 35.3%, respectively (median survival 17 months). Also, the survival curves in patients with stage II, stage IIIA, and stage IIIC disease are shown in Figure 7. The survival rates were significantly higher in those with stage II disease than those with stage IIIA (P = .0132) and stage IIIC (P = .0265).



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  		FIG. 7. Cumulative survival curves for 55 patients with hepatocellular carcinoma according to tumor, node, metastasis stage.

 
Among the 32 patients who have died, 17 did so as a result of recurrent HCC: local recurrence in HIFU-treated region in 7 patients and recurrence in other sites of liver in 10 patients. In those patients who had recurrence at the HIFU-treated region, two patients had lesions close to the main branch of the bile duct and, therefore, incomplete HIFU ablation was performed to avoid potential damage to it. Five of seven patients had two to four sessions of TACE at the time of enrollment, and their lesions were >10 cm in diameter before HIFU. Local recurrence was detected at the regions close to large hepatic vessels in four patients and at deep margin of tumor in one patient. Five patients died of respiratory failure caused directly by lung metastases. Seven patients died of hepatic failure occurring between 14 and 27 months after HIFU, and two patients died of bleeding gastroesophageal varices at 11 and 17 months after HIFU, respectively, which were not related to HCC. In one patient, cause of death was undetermined.

Complications
A transient increase of serum aspartate transaminase, alkaline phosphatase, and alanine aminotransferase was observed in 29 of 55 patients on the third and seventh postoperative day. No significant differences were statistically observed in these data between the preoperative and the postoperative mean values. Furthermore, no significant change was seen in platelet count pre- and postoperatively.

No deaths occurred during the initial 3 months in the treated group. HIFU-related complications and side effects were observed in 13 patients (23.6%). Two patients had low-grade fever up to 38.5°C, which persisted for about 3 to 5 days after HIFU treatment. Six patients had superficial skin burns that healed by 7 to 10 days after HIFU, but one patient, who had received local radiation therapy 3 months before HIFU, had a third-degree skin burn (the extent of burn, 3 x 4 cm). Four patients had transient pain, only one of them was given 5 days prescription for oral analgesics. Local infection, tumor bleeding, large vessel rupture, and bowel perforation were not detected following HIFU treatment in this group.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Using thermal energy to treat human neoplasm has a long history. It is reported that approximately five thousand years ago, physicians in Egypt used cautery with heated implements to destroy tumors.27 In the past several decades, new thermal therapies (e.g., microwave, laser, cryotherapy, and radiofrequency) have been developed to ablate solid tumors by a minimally invasive route. As most patients are not suitable for surgical resection at the time of diagnosis with HCC, these therapeutic modalities can be mainly applied for them.28 The main limitation of these treatments is the difficulty in ablating HCC >5 cm in diameter.

The HIFU procedure is an extracorporeal technology for the thermal ablation of tumors. An ultrasound beam can be focused while it passes through soft tissues, allowing an extracorporeal transducer to thermally ablate a large tumor without requiring surgical exposure or insertion of instruments into the lesion. The main advantages of HIFU are that it is noninvasive and conformal and can ablate large volume of tumor. Our previous clinical studies have shown that HIFU can induce complete coagulation in large HCC lesions, ranging in size from 5 to 12 cm in diameter.23,29–32 In this group, only two patients had HCC lesions <5 cm in diameter, and almost all patients had large HCC (5.1 to 10 cm in 32 patients; >10.1 cm in 21 patients).

One major complication was caused directly by HIFU in the 55 treated patients: a skin burn at the site of previous radiotherapy that required skin grafting. Six minor complications (also skin burns not requiring treatment) and two episodes of postablation syndrome (fever) also occurred. It was postulated that chronic damage of vascular vessels by radiation on skin and subcutaneous structures made these tissues more sensitive to ultrasound energy deposition and thermal absorption. Therefore, patients who have received radiotherapy in the 6 months before HIFU should probably be excluded from treatment. Also, our clinical experiences reveal that cautious review of pretreatment imaging (Doppler ultrasound, CT, or MRI) and careful therapeutic planning are important for patients in order to avoid thermal injury to surrounding structures.

As patients with HCC often present with symptoms in an advanced stage, the prognosis for them is extremely poor. In this study, 51 (93%) of 55 patients had unresectable HCC lesions, and tumor size was >5 cm (range 5.1 to 14 cm in diameter) in 53 patients (95%). According to TNM classification, 40 patients (73%) had advanced disease (n = 16 in stage IIIA; n = 24 in stage IIIC). A total of 21 (38%) patients were considered as failure cases treated with TACE before HIFU, and 16 patients had tumor invading the main branches of intrahepatic blood vessels. Our results reveal, however, that HIFU can be used as an effective modality in all of these patients with HCC, even in those who have failed a prior therapy. HIFU is an effective means of controlling the disease even at an advanced stage, for which no useful conventional therapy exists, and thus it may have widely clinical applications as a palliative treatment, both to impede tumor growth and to improve the quality of life in patients. The overall survival rates at 6, 12, and 18 months in this group were 86.1%, 61.5%, and 35.3%, respectively. Patients treated with HIFU had a long-term survival benefit in this study. We found that the TNM stage directly correlated with survival figures, and statistical significance was seen in the survival data among patients with stage II, IIIA, and IIIC diseases. Survival rates at 1 year and 2 years were 87% and 47% in stage II, 44% and 25% in stage IIIA, and 55% and 14% in stage IIIC, respectively. Survival appeared significantly better in patients with stage II disease than in patients with stage IIIA and stage IIIC disease.

Transcatheter arterial chemoembolization is a widely used treatment for large, unresectable HCC. As HCC receives 95% of their blood supply from the hepatic artery, selective embolization of the hepatic artery induces ischemic necrosis in the tumors. This modality is rarely as curative, however. Some tumor cells can remain viable and tumor can recur through the blood supply from the collateral circulation and portal vein.33–35 Our results indicate that HIFU can clearly induce coagulative necrosis of residual viable tumor cells after failed TACE to achieve complete necrosis of HCC.

Treatment time for HIFU ranged from 2 hours to 8 hours (average, 5.5 hours) in this study. This long treatment time can be explained by the fact that most treated tumors were large HCC. It is still necessary to shorten HIFU treatment time in clinical application. Chen et al.36 found that HIFU produced a higher and faster temperature rise in a target tissue ex vivo following local injection of iodized oil than HIFU alone. Subsequent in vivo experiments demonstrated that HIFU used in combination with TAE improved survival benefit in nude mice with liver cancer.36 Our previous study revealed that iodized oil could reduce the time taken to achieve HIFU-induced coagulative necrosis of normal liver in vivo in experimental goats, compared with HIFU alone.37 As a consequence of these experimental findings, 29 patients in this study received TACE before HIFU treatment, aiming to improve treatment efficacy and reduce treatment duration. It should be recognized that the number of TACE given to these patients was considerably lower than would have been the case if TACE had been given alone. In these cases, the specific intentions of TACE were to reduce the blood supply to the target tumors and to increase the tissue’s absorption of ultrasound energy. In this regimen, the limited TACE sessions may contribute to any observed benefit. After TACE, however, MRI demonstrated large residual tumor volume in almost all cases. It is our opinion, therefore, that HIFU was predominantly responsible for the beneficial effects.

Several problems are encountered in the use of HIFU to treat large HCC. Prolonged general anesthetic time can be problematic in patients who are elderly or in a poor physical condition; ultimately, the choice between general or regional anesthesia is made by the anesthetist and is related to preoperative patient parameters. That having been said, no problems related to anesthetic were experienced within the trial group. During epidural anesthesia, it is impossible to breath hold; however, greater liver movement did not hinder treatment as the scanning speed of HIFU transducer is adjusted to match ventilatory excursion of the liver and to keep the target tumor within the therapeutic zone. Under general anesthesia with endotracheal intubation, liver movement can be reduced during the procedure by ventilating the left lung, as necessary, to ablate the tumor behind the ribs.

Ribs overlying lesions can attenuate acoustic power deposited in target tumors, and the ribs’ reflection of therapeutic ultrasound can cause damage to skin and subcutaneous tissue. In this study, viable tumor remained at depth after the first HIFU treatment in 19 patients with huge HCC. For such patients, we found that by resecting a portion of the ribs overlying the lesion, we could provide an adequate "acoustic window" before HIFU treatment. This invasive procedure can reduce the noninvasiveness of HIFU ablation. As a single therapeutic transducer was used in this study, it was impossible to avoid the ultrasonic reflection from ribs. Therefore, phased array transducers and time-reversal technique are being investigated to overcome this problem.38,39 Similar to adaptive optics, this technology uses the phase information available from the reflected beam to reconstruct the focus behind the bone. If achieved, HIFU can treat large HCC without any removal of ribs. Furthermore, a laparoscopic HIFU device used in partial kidney ablation is another option to avoid acoustic delivery impedance by the ribs for HCC ablation.40 To counter the criticism that we added a surgical intervention into an otherwise extracorporeal therapy, we felt that rib resection was a relatively minor procedure that allowed potentially curative ablation of tumors that otherwise would not be amenable to this form of therapy.

In conclusion, our results demonstrate that HIFU is effective, safe, and feasible in the treatment of patients with large volume HCC. Several preparative therapies before HIFU treatment in this study may weaken this assertion, however. One is that rib resection was performed in some patients with huge HCC. In itself, this can detract from the status of HIFU as a noninvasive therapy, although this surgery is relatively minor. Another is that pre-procedural TACE was carried out in half the patients. We acknowledge that this is not a randomized clinical trial and that TACE can have an independent effect on tumor volume. Thus, it will be necessary to perform large randomized clinical trials in the future to assess this further. HIFU technology is still in development and its clinical applications are in the preliminary stage. We are currently undertaking further clinical trials to improve this technology and solve the problems we had in this study both in the HIFU therapeutic system and clinical therapy strategies.


   ACKNOWLEDGMENTS
 
This work was supported by Ministry of Science and Technology of China (grant No. 96-905-02-01) and National Natural Science Foundation of China (grant No. 39300125, 39630340, 39630340, 39670749, 39770841, 39770712, 30070217, 30171060). We thank the Chongqing Haifu Technology Company Ltd. (Chongqing, China) for technical support, and Dr. Rowland Illing and Dr. James Kennedy at the Churchill Hospital of Oxford, UK, for the help with linguistic revision of the manuscript.


   FOOTNOTES
 
Extracorporeal high intensity focused ultrasound (HIFU) was performed for the thermal ablation of patients with large hepatocellular carcinoma (HCC). The results indicated that as a noninvasive therapy, HIFU appears to be effective, safe, and feasible in the treatment of large HCC.

Received for publication February 23, 2004. Accepted for publication September 3, 2004.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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