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Vascular and Interventional Radiology |
1 From the Institute of Ultrasonic Engineering in Medicine and Clinical Center for Tumor Therapy of the 2nd Affiliated Hospital, Chongqing University of Medical Sciences, 1 Medical College Rd, Box 153, Chongqing 400016, China. Received June 20, 2003; revision requested August 29; final revision received August 5, 2004; accepted August 6. Supported by grants from the Ministry of Science and Technology of China (96–905-02–01) and the National Natural Science Foundation of China (39300125, 39630340, 39630340, 39670749, 39770841, 39770712, 30070217, 30171060). Address correspondence to F.W. (e-mail: mfengwu@yahoo.com).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained. From November 1998 to May 2000, 50 consecutive patients with stage IVA HCC (TNM classification, T4N0–1M0) were alternately enrolled in one of two treatment groups: group 1 (n = 26), in which TACE was performed alone, and group 2 (n = 24), in which transcutaneous ablation of HCC with high-intensity focused ultrasound was performed 2–4 weeks after TACE. The tumors were 4–14 cm in diameter (mean, 10.5 cm). Immediate therapeutic effects were assessed at follow-up with Doppler US and computed tomography or magnetic resonance imaging. All patients were followed up for 3–24 months (mean, 8 months) to observe long-term therapeutic effects and complications in both groups. Tumor reduction rates, median survival time, and cumulative survival rates in both groups were calculated by using the unpaired Student t test and Kaplan-Meier method.
RESULTS: No severe complication was observed after focused ultrasound ablation, and no unexpected side effects were noted after TACE. Follow-up images showed absence or reduction of blood supply in the lesions after focused ultrasound ablation when compared with blood supply after TACE alone. The median survival time was 11.3 months in group 2 and 4.0 months in group 1 (P = .004). The 6-month survival rate was 80.4%–85.4% in group 2 and 13.2% in group 1 (P = .002), and the 1-year survival rate was 42.9% and 0%, respectively. Median reductions in tumor size as a percentage of initial tumor volume at 1, 3, 6, and 12 months after treatment, respectively, were 28.6%, 35.0%, 50.0%, and 50.0% in group 2 and 4.8%, 7.7%, 10.0%, and 0% in group 1 (P < .01).
CONCLUSION: The combination of high-intensity focused ultrasound ablation and TACE is a promising approach in patients with advanced-stage HCC, but large-scale randomized clinical trials are necessary for confirmation.
© RSNA, 2005
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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Several minimally invasive techniques have been used for the local ablation of liver lesions. Ablation with high-intensity focused ultrasound is one such treatment, but others, including laser, microwave, radiofrequency, cryo-, and ethanol ablation therapy have been developed in past 2 decades (10). As stand-alone treatments, these alternative energy modalities are principally performed in patients with small-volume HCCs no larger than 3–4 cm in diameter (11–13). Transcatheter arterial chemoembolization (TACE) is a widely used treatment for patients with large-volume HCC. Since HCC is supplied by both arterial and portal blood, the purpose of performing TACE is to achieve the cytoreduction of vital tumor tissue (14,15). It is almost impossible to achieve complete necrosis of HCC with embolization of the hepatic artery alone. After TACE, viable tumor cells still remain and may cause local recurrence and distant metastasis (16–19). For these reasons, TACE has recently been used in combination with ablative therapies to exterminate residual tumor cells after TACE (20).
High-intensity focused ultrasound ablation is a conformal extracorporeal treatment method that can noninvasively cause complete coagulation necrosis of large lesions without surgical exposure or insertion of instruments (21,22). With the extracorporeal motion of a therapeutic transducer, well-delineated coagulation necrosis can be induced at depth in the focal area of the ultrasound beam, through the intact skin. In recent years, high-intensity focused ultrasound has been applied experimentally to ablate normal liver tissue and implanted liver tumors in vivo (23–29), as well as human breast cancer (30). In this study, we hypothesized that focused ultrasound ablation combined with TACE would be more effective than TACE alone in the treatment of advanced-stage HCC. Thus, the purpose of our study was to evaluate the use of high-intensity focused ultrasound ablation combined with TACE in the treatment of advanced-stage HCC in patients.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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), and rotation along the long or short axis of the bed (
, 
). Through computer control, the imaging probe is placed either against the skin or at a distance from the skin in the water for pretreatment imaging. The integrated transducer is mounted in a water reservoir with the ultrasound beam directed upward. The water bag is filled with degassed deionized water. The ultrasound beams of the therapeutic transducer and the imaging probe completely overlap so that the longitudinal axis of the high-intensity focused ultrasound beam is in the two-dimensional US imaging plane. A calibrated polyvinylidene fluoride–membrane hydrophone with a spot diameter of 0.5 mm is used to map the acoustic pressure field of the focused transducer at the focal peak intensities from 200 to 300 W · cm–2. The focal region of the 0.8-MHz transducer with 135-mm focal length is cigar-shaped, with dimensions of 9.8 mm along the beam axis and 1.3 mm in the transverse direction. The absorbing target method is used to measure the total acoustic power output in degassed water at 21°C.
Patients
From November 1998 to May 2000, 50 consecutive patients with advanced-stage HCC (stage IVA) were enrolled in a prospective controlled clinical protocol that was approved by the ethics committee at Chongqing University of Medical Sciences. A detailed written description of the procedure was provided to all patients before enrollment. At the time of enrollment, an informed consent form (in accordance with the specifications stipulated by the Helsinki Committee) was obtained from all patients and also from their relatives, as is the custom in China.
Each patient was initially evaluated by three senior liver surgeons working together, each of whom had more than 20 years of clinical experience, to determine suitability for surgery. Patients in whom lesions were not suitable for surgical resection were referred to this trial. Patients were excluded from undergoing surgical resection on the basis of the following criteria: presence of multiple lesions; tumor proximity to major vascular structures, which precluded the resection of a tumor-free margin; or presence of severe cirrhosis with an insufficient hepatic functional reserve to tolerate conventional HCC resection. The selection criteria for enrollment in our study were as follows: HCC diagnosis confirmed at US-guided fine-needle biopsy or made on the basis of both the characteristic findings of HCC lesions shown at imaging (including Doppler US, computed tomography [CT], and magnetic resonance [MR] imaging [32]) and a high level (more than 200 ng · mL–1) of serum 
-fetoprotein; four or fewer lesions detectable at US imaging; stage IVA disease (T4N0–1M0 in TNM classification); Karnofsky performance scale score of 70% or greater; Child-Pugh class A or B cirrhosis; no history of hepatic encephalopathy; and few or no ascites detected at Doppler US. All patients had stable hematogenic parameters and no active infection.
Patients with extrahepatic metastases, Child-Pugh class C cirrhosis, or severe coagulation disorders were excluded from this study. The exclusion criteria were as follows: lesions undetectable at US imaging, five or more lesions present at US imaging, Child-Pugh class C disease, extrahepatic metastases detected on bone scans and chest radiographs, and/or severe coagulation disorders. On the basis of these criteria, 73 patients were initially evaluated, of whom 50 (69%) were enrolled in this study. The remaining 23 (31%) patients were excluded because of extrahepatic metastases (n = 12), advanced cirrhosis (n = 7), or severe coagulation disorders (n = 4).
Patients were consecutively enrolled at clinical presentation and were alternately assigned to one of the following two treatment groups: group 1, the TACE group (n = 26), in which TACE alone was performed; or group 2, the combined treatment group (n = 24), in which extracorporeal focused ultrasound ablation was performed after TACE. There were two fewer patients in group 1 than in group 2, because one patient in group 2 refused to undergo ultrasound ablation after TACE. Patient characteristics assessed in both groups are shown in the Table. The differences between data in these two groups were analyzed by using the Fisher exact test and an unpaired Student t test. The two patient groups were comparable (P > .05) with respect to age, sex, type of cirrhosis, TNM classification, position of lesion, portal vein involvement, number of lesions, lesion diameter, and Child-Pugh class. Therefore, there was no reason to consider that the alternating method that we chose for determining whether patients would undergo TACE or TACE plus focused ultrasound ablation would cause a statistically obvious bias in the results.
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-fetoprotein. All patients had hepatitis B–related liver cirrhosis. Patient ranged in age from 28 to 72 years. There were 36 men and 14 women. Fifteen patients (30%) had a solitary lesion (group 1, nine patients [35%]; group 2, six patients [25%]), and the remaining 35 patients (70%) had multinodular HCC (group 1, 17 patients [65%]; group 2, 18 patients [75%]). Distribution of lesions in multinodular HCC was as follows: Four patients (15%) in group 1 and four (17%) in group 2 each had two lesions present; eight patients (31%) in group 1 and six (25%) in group 2 each had three lesions; five patients (19%) in group 1 and eight (33%) in group 2 each had four lesions. The tumors were 4–14 cm in diameter (mean, 10.5 cm). Lesion size was less than 5 cm in diameter in one patient (2%), 5.1–10.0 cm in diameter in 20 patients (40%), and larger than 10 cm in diameter in the remaining 29 patients (58%). Tumor thrombosis of the portal vein was present in 21 patients (42%). Forty-eight patients (96%) had Child-Pugh class A disease and two (4%) had class B disease. All patients were assessed at CT or MR imaging as having disease corresponding to stage IVA (T4N0–1M0), including 28 patients (56%) with regional lymph node metastasis (13 patients in group 1 and 15 in group 2) and 22 patients (44%) without regional lymph node metastasis (13 patients in group 1 and nine in group 2).
TACE Procedures
TACE was performed in all patients by two interventional radiologists, each of whom had more than 10 years of clinical experience. They worked together for each patient but were blinded to the allocation of patients to each study group. After the introduction of a 5-F pigtail catheter through the femoral artery, an angiographic survey of the abdominal vessels was performed. Depending on the size, location, and arterial supply of the tumor and its satellite lesions, the tip of the catheter was advanced toward tumor-feeding arteries for selective embolization of all tumors detected at digital subtraction angiography by using a 3–5-F tracker catheter. Segmental embolization was also performed in small tumors. Either 80–120 mg of cisplatin (Qilu Pharmaceutical Factory, Jinan, China) or 40–60 mg of adriamycin (Main Luck Pharmaceutical, Shenzhen, China) were mixed in 10–20 mL of iodized oil (Lipiodol; Huaihai Pharmaceutical Factory, Shanghai, China), and the embolization suspension was then slowly injected with fluoroscopic guidance. The 18 patients (nine patients each in groups 1 and 2) treated between November 1998 and December 1999 received adriamycin, and the remaining 32 patients (17 patients in group 1, 15 patients in group 2), who were treated after December 1999, received cisplatin. The reason for this change in regimen was a local shortage of adriamycin.
Embolization of tumor-feeding vessels was performed with use of a 1 x 1 x 10-mm gelatin sponge (Gelfoam; 3rd Pharmaceutical Factory of Nanjing, Nanjing, China) in all patients after injecting the embolization suspension. After embolization, devascularization was confirmed with an additional angiographic study of the hepatic artery. The median number of courses of TACE performed was 1.5 (range, 1–3 courses) per patient in the TACE group and 1.2 (range, 1–2 courses) per patient in the group undergoing combined treatment. In group 1 (the TACE only group), the termination of TACE treatment was based on two criteria: insufficient liver function after TACE, which rendered 19 of 26 patients unable to tolerate further conventional TACE, or extrahepatic metastases detected after TACE treatment, which were found in the remaining seven patients in the form of lung, bone, or other metastases during the follow-up period. In group 2, TACE was performed as neoadjuvant therapy prior to focused ultrasound ablation, not as a stand-alone treatment. For this reason, the criterion for treatment was different. Patients in group 2 underwent either one (n = 20) or two (n = 4) courses of TACE; the number of courses was dictated by the size of the target tumor alone. No extrahepatic metastases were detected between TACE and ultrasound ablation treatments, but it should be emphasized that the interval was very short (2–4 weeks).
High-Intensity Focused Ultrasound Ablation
High-intensity focused ultrasound ablation was always performed after TACE. The interval between TACE and ultrasound ablation was at least 2 weeks (range, 2–4 weeks). Either epidural or general anesthetic was necessary during focused ultrasound treatment to prevent the patient from experiencing deep visceral-type pain and to ensure immobilization. After suitable anesthesia was induced, the patient was carefully positioned, either prone or on his or her right side, so that the skin overlaying the lesion to be treated would be easily put in contact with the degassed water. Then, the coaxial US imaging device was used to establish three-dimensional images of the entire tumor through the movement of the integrated probe. The target tumor was then divided into sections with 5 mm of separation. By scanning the high-intensity ultrasound focus in successive sweeps from the deep to shallow regions of the tumor, the targeted regions on each section were completely ablated. This process was repeated section by section to achieve complete tumor ablation (Fig 1). During focused ultrasound ablation of each section, the real-time US images obtained before and after each exposure were immediately compared to determine whether the echogenic changes, which indicated the extent of coagulation necrosis, had covered the desired treatment area.
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Follow-up
No patients were lost to follow-up. Patients were monitored weekly by means of physical examination, complete blood cell counts, and renal and hepatic function tests during their hospital stays. However, the hospital stay for both groups was not recorded as inpatient stay, because inpatient stay in China is related more to social and logical considerations. All patients were followed up after treatment to observe complications related to focused ultrasound ablation and long-term therapeutic effectiveness of treatment in both groups. Results were analyzed when all patients in group 1 died of either disease progression or hepatic dysfunction. At this point, follow-up time ranged from 3 to 24 months (mean, 8 months). Survival was estimated from the date of initial treatment.
Follow-up imaging techniques, including Doppler US, CT, and MR imaging, were used to detect evidence of residual or recurrent tumor in treated lesions, to assess changes in tumor size with time, and to monitor for the development of new hepatic lesions. Imaging was performed before focused ultrasound treatment and at 2 weeks and 3, 6, 9, 12, 18, and 24 months after ultrasound treatment; images were interpreted jointly by three radiologists (J.Z.Z., 20 years of experience; H.B.S., 7 years of experience; H.Z., 8 years of experience) who were blinded to the treatment method used, and a consensus was reached for each patient. The device used for Doppler US was a Q-2000 unit with a 3.5-MHz convex-array probe (Siemens Medical Systems, Erlangen, Germany). With the pulsed Doppler method, tumor vascularity was evaluated as intratumoral flow signals. We detected only whether pulsatile color flow was present or absent within the tumor. Two weeks after TACE or ultrasound ablation, tumor margin could be clearly identified at Doppler US, and tumor size was measured from both maximum transverse and longitudinal dimensions of the lesion in the scanning plane in all patients before and after treatment. Doppler US was performed jointly by two radiologists (J.Z.Z., H.B.S.) in each patient, and the measurements were interpreted by consensus between three observers (J.Z.Z., H.B.S., H.Z.). Consistency of tumor size measurement was ensured by using a fixed examination protocol, and all the data were recorded simultaneously on videotapes.
Forty-two patients (16 in the ultrasound ablation plus TACE group, 26 in the TACE group) underwent follow-up transverse nonhelical CT scanning (Sytec 4000; GE Medical Systems, Milwaukee, Wis). Initial nonenhanced images were acquired with 7-mm section thickness at 10-mm intervals through the liver. For the contrast material–enhanced images, the patients were administered 150 mL of iopamidol solution (Ultravist 370; Schering, Berlin, Germany) by means of power injection at a rate of 2–3 mL/sec.
MR imaging became available at our hospital during the study period, so eight of 24 patients in group 2 (combined treatment group) underwent nonenhanced and contrast-enhanced MR examinations with a 1.5-T imager (Signa; GE Medical Systems) before TACE and before and after ultrasound ablation. Nonenhanced MR imaging included transverse and coronal spin-echo T1-weighted images (500–600/9–16 [repetition time msec/echo time msec], two to four signals acquired, 256 x 128–192 matrix, 8-mm-thick sections with a 2-mm intersection gap) and transverse fast spin-echo T2-weighted images with frequency-selective fat suppression (4,000–5,000/92–105 [repetition time msec/echo time (effective) msec], echo train length of eight, two to four signals acquired, 256 x 192–256 matrix, 8-mm-thick sections with a 2-mm intersection gap). After dynamic intravenous injection of 20 mL gadopentetate dimeglumine (Magnevist; Berlex Laboratories, Wayne, NJ), transverse or coronal fast multiplanar spoiled gradient-recalled-echo breath-hold images (90/2.3, 70° flip angle, 256 x 128 matrix, and one to two signals acquired) were obtained.
Areas of hypoattenuation shown at MR imaging or CT that did not enhance after contrast material administration were considered to represent necrotic tissue. Still-enhancing areas were assumed to reveal residual viable tumor. Chest radiographs and bone scans obtained 3, 6, 12, 18, and 24 months after ultrasound ablation were used to discover lung and bone metastases in all patients. Two radiologists who were blinded to the treatment method interpreted these results and reached a consensus in each patient.
Statistical Analysis
All data are reported as the mean ± standard deviation and were analyzed by three investigators (C.B.J., H.Z., K.Q.L.). Statistical analysis was performed by using a statistical software package (SAS version 6.12, SAS Institute, Cary, NC). The statistical significance of any observed difference between the mean values for the control and treatment groups was evaluated by means of an unpaired Student t test. The differences in percentage data were analyzed by using the Fisher exact test. A cumulative survival rate was calculated by using the Kaplan-Meier method, in which the difference between the treatment and control groups was evaluated by using a log-rank test. The following formula was employed to calculate the changes in tumor size: (a · b)–(a' · b')/(a · b) · 100%. The coefficients a and a' are the largest diameter and b and b' are the perpendicular diameter of the tumor measured at US before and after ablation, respectively. Statistical significance was defined at a P value of less than .05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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Follow-up CT was performed in 42 patients (84%): 26 patients (100%) in group 1 and 16 (67%) in group 2. The evaluation of the effectiveness of high-intensity focused ultrasound ablation was difficult because tumors that retained iodized oil had a high attenuation at CT, as shown in Figure 4. For this reason, no valid assessment could be made regarding the extent of ablation within this patient subset.
Eight patients (33%) in group 2 underwent dynamic contrast-enhanced MR imaging. Dynamic contrast-enhanced MR images revealed an obvious reduction of tumor blood supply after TACE in these eight patients, but tumor vascularity still remained, particularly in the portal venous phase. When images obtained before and after ultrasound ablation were compared, there was an absence of contrast enhancement within the treated region in seven (88%) of eight patients, as shown in Figure 5. This was interpreted as an indication of complete ablation in seven of eight patients.
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After TACE, all patients had transient impairment of hepatic function. Transient fever was observed in 45 patients (90%), and 30 patients (60%) complained of transient pain that lasted 1–2 weeks. No patients developed acute hepatic failure, liver abscess, or renal dysfunction caused directly by either TACE or focused ultrasound treatment.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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Extracorporeal high-intensity focused ultrasound enables the performance of transcutaneous tumor ablation. High-intensity focused ultrasound ablation provides a potential therapeutic method for the precise ablation of entire tumors of different sizes and shapes without damaging overlying and surrounding vital structures. Because ultrasound is a mechanical waveform, its energy deposition can cause several effects, including thermal ablation and cavitation in living tissue. An ultrasound beam can be focused while it is transmitted through soft tissue within the body, which allows the possibility of using focused ultrasound energy noninvasively to induce coagulation necrosis of a target tumor. To date, much of the interest associated with this technique has been concentrated on the ablation of liver malignancies. Results of animal studies (23–27) have demonstrated that high-intensity focused ultrasound can be used to completely ablate target liver carcinomas and improve the survival of animals with implanted liver tumors. Results of our previous clinical studies (22,31,36) have shown that the main histologic changes in human HCC treated with high-intensity focused ultrasound are coagulation necrosis of the target tumor and severe damage of small tumor vessels.
In this study, 6-month and 1-year survival rates in the group that underwent TACE alone were 13.2% and 0%, respectively. Survival in the TACE group was lower than that found in previous reports (15,17,37,38). There is a large discrepancy between survival rates found in different studies, and this is assumed to be caused by variation between populations, which explains why a local study directly comparing different treatment methods within the same population provides the only valid means to assess the survival benefits of a new treatment method. In our own study, the poor survival rate could be caused by two factors. First, patients enrolled in this study had advanced-stage HCC. Despite the fact that there were no statistical differences in the characteristics of patients between the two groups, 61% of patients in group 1 had lesions larger than 10 cm in diameter (mean diameter, 11.26 cm ± 3.89), and the main branch of the portal vein was invaded in 50% of patients. Second, all patients had hepatitis B–related cirrhosis. Objective response to TACE was not obtained with repeated TACE, as normal liver function was very difficult to maintain after TACE. For this reason, treatment was curtailed in 73% (19 of 26) of patients in group 1.
TACE is routinely performed for large HCCs as repeated courses over a period of several months. The reason for this is that sequential courses of TACE can reduce the tumor vascularity over time. The greatest reduction in blood supply is achieved in the first one or two courses of TACE. Our rationale for performing a modified (reduced) regimen of TACE in the combined treatment group was that focused ultrasound ablation could be considered more efficient than repeated TACE courses for destroying residual tumor blood supply. The same rationale has been used to justify a combined approach of embolization and thermal ablation proposed by other authors (10).
Portal vein involvement is regarded by some to be a contraindication of embolization. At our institution, when portal venous flow could be identified, embolization would still be performed with caution if no alternative therapies were available to an individual. To date, we have not noted the complication profile to be adversely affected and, therefore, consider this approach to be acceptable.
One problem with tumor localization is the movement of the liver during normal ventilation. The motion of the target organ can cause misdirected ultrasound energy, which could potentially result in damage to normal tissue, severe therapeutic complications, and insufficient energy delivery, as well as incomplete ablation of the tumor. To solve this problem, in our study we used real-time three-dimensional US imaging to depict the tumor to be treated. If the treated tumor was outside the target zone, ultrasound ablation was automatically stopped. Furthermore, in our focused ultrasound ablation regimen, the transducer was usually scanned in a linear fashion through the tissue while the therapeutic ultrasound was on. The scanning speed was possibly adjusted to match ventilatory excursion of the liver and to keep the target tumor within the therapeutic zone. However, in some patients with HCC, the treated lesion was located just behind ribs, and ultrasound energy could not be easily transmitted through the overlying bone structures. For this condition, general anesthesia with endotracheal intubation and mechanical ventilation was selected. This approach had the supplementary benefit of permitting provisional suspension of respiration with controlled pulmonary inflation, as necessary, to ablate the tumor behind the ribs.
Dynamic contrast-enhanced CT is reliable for the assessment of changes in tumor vascular perfusion. However, CT images could not reveal tumor status in the embolized portion because of the high attenuation of iodized oil. Results of previous pathologic studies have indicated that after TACE, residual cancer tissue still existed around the lesion, despite complete accumulation of iodized oil throughout the entire HCC lesion (39). Therefore, it was emphasized by these results that dynamic contrast-enhanced MR imaging (40–42) was more sensitive in enabling the evaluation of therapeutic effectiveness of TACE in the treatment of HCC. Moreover, this imaging modality can provide complementary information concerning the indication for additional treatment during the follow-up period.
We hypothesized that the combination of high-intensity focused ultrasound ablation and TACE would be more effective than TACE alone in this study. Focused ultrasound ablation can serve to eliminate residual cancer cells after TACE. In animal studies we have found that the reduction of blood supply after TACE allows the use of lower levels of ultrasound energy and irradiation fields, which shorten treatment time with focused ultrasound and so may reduce potential side effects (F.W., unpublished data, 2002). The results of this study show obvious evidence to support our hypothesis that TACE followed by high-intensity focused ultrasound ablation would be better than TACE alone in the treatment of patients with advanced-stage HCC. First, the cumulative survival rates and the median survival times for group 2 were much greater than those for group 1. Furthermore, the tumor response in group 2 was better than that in group 1, with median reductions in tumor size in group 2 that were greater than those in group 1 throughout the study period. Finally, among those patients who died during the follow-up period, median survival times in group 2 were greater than those in group 1. The longer survival times in the combined treatment group could be attributed to a greater tumor necrosis rate or to a reduction in the induced liver damage from this approach. We believe that the former is the more important mechanism, but either could support the use of this combined regimen.
The duration of inpatient stay has not been reported in this study because, in China, inpatient stay is related more to social and logical considerations than to any given procedure. Comparison with Western practice would therefore be inappropriate.
We met several difficulties in conducting this clinical trial. Long treatment times (range, 2–8 hours; mean, 4.9 hours) were noted in this study, and this may be problematic for patients who are in poor physical condition. Prolonged treatment time can be explained by the fact that most treated tumors are large HCCs. Also, in the early development of a new technique, long procedure times are often needed. With technical development, therapy time could be gradually reduced in the future. Ribs overlying lesions may attenuate the energy deposition in target tumors, and reflection of ultrasound beams by the ribs may cause damage to the bone and adjacent tissue. Therefore, the technology of phased-array transducers is being investigated to explore the possibility of overcoming this problem. Another criticism of the methods in this study could be that there was a difference between TACE regimens used in each group. However, the survival benefit in group 2 was achieved with a reduced TACE regimen, and we believe that this fact should serve to strengthen the conclusion that the combination of high-intensity focused ultrasound ablation and TACE is an improvement over TACE alone.
Although the 5-year clinical benefits of high-intensity focused ultrasound ablation for the treatment of HCC in patients are still unproven, the results from this study suggest that this noninvasive technique may play an important role in the treatment of HCC. In summary, our results demonstrate that high-intensity focused ultrasound ablation combined with TACE is a promising approach for the treatment of unresectable HCC. However, large-scale randomized clinical trials are needed to determine the future role of this modality.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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F.W. and W.Z.C are shareholders in and consultants to, Z.B.W. is a shareholder in and full-time employee of, J.B. is a shareholder in, and J.Z.Z. is a consultant to Chongqing Haifu Technology.
See also Science to Practice in this issue.
Author contributions: Guarantors of integrity of entire study, F.W., Z.B.W.; study concepts and design, F.W., Z.B.W., W.Z.C., H.Z.; literature research, F.W., C.B.J.; clinical studies, all authors; data acquisition, C.B.J., H.Z., F.W.; data analysis/interpretation, C.B.J., F.W.; statistical analysis, C.B.J., F.W.; manuscript preparation, C.B.J., F.W.; manuscript definition of intellectual content, editing, revision/review, and final version approval, all authors
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