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Vascular and Interventional Radiology |
1 From the Departments of Hepatobiliary Surgery (M.D.L., J.W.C., X.Q.H., L.J.L., J.F.H.) and Medical Ultrasonics (X.Y.X., L.L.), First Affiliated Hospital of Sun Yat-sen University of Medical Sciences, 2 Zhongshan Rd, Guangzhou, People’s Republic of China. Received November 10, 2000; revision requested December 23; revision received March 1, 2001; accepted April 18. Address correspondence to M.D.L. (e-mail: gylumd@public.guangzhou.gd.cn).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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MATERIALS AND METHODS: Fifty patients with 107 hepatocellular carcinoma nodules (mean diameter, 2.7 cm ± 1.5 [SD]; range, 0.8–6.4 cm) were treated with percutaneous microwave coagulation therapy. Single electrode insertion was used in 46 nodules (43.0%) 2 cm or smaller, whereas multiple electrode insertion was applied in 61 (57.0%) nodules larger than 2 cm.
RESULTS: At 1 month after therapy, technical success for tumors 2 cm or smaller and those larger than 2 cm was achieved in 45 (98%) and 56 (92%) nodules, respectively. After follow-up of 9 months or longer, local recurrence was found in one nodule (2%) sized 1.8 cm and in five nodules (8%) larger than 2 cm. At the end of the study, 26 (52%) of 50 patients were free of disease, and disease-free survival rates at 1 and 2 years were 55% and 41%, respectively. Overall survival rates at 1, 2, and 3 years were 96%, 83%, and 73%, respectively.
CONCLUSION: Percutaneous microwave coagulation therapy is an effective and safe therapeutic modality for hepatocellular carcinoma. A multiple electrode insertion technique can enhance the effectiveness of this therapy in tumors 6 cm or smaller.
Index terms: Liver, interventional procedures, 761.12896 • Liver neoplasms, therapy, 761.12896, 761.323 • Microwaves, 761.12896 • Ultrasound (US), guidance, 761.12896
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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The use of percutaneous microwave coagulation therapy (PMCT) was reported by Seki et al (4) in 1994, and it has received much attention because it can induce complete tumor necrosis with minimal invasiveness. Since the coagulation area of a single microwave energy application at 60 W and 120 seconds is limited to 1.6 cm in transverse diameter (4), it is used mainly for HCCs smaller than 2 cm. However, in our country, many potentially treatable tumors are larger than 2 cm at the time of diagnosis. Hence, there is a great need for further advances to enhance its ability in treating large HCC. The purpose of our study was to evaluate the use of PMCT with a multiple electrode insertion technique in tumors larger than 2 cm.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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From August 1997 to December 1999, 562 patients with HCC were treated at our hospital. PMCT was performed in 50 (8.9%) consecutive patients who met the following criteria: (a) They were not surgical candidates due to an advanced tumor stage (n = 18), they had poor liver function (n = 26), or they refused to provide consent for surgery (n = 6); (b) they had four or fewer nodules; (c) the tumor was smaller than 7 cm in diameter; and (d) portal vein thrombosis and extrahepatic metastases were absent. The number and size of the tumor nodules were estimated by use of computed tomography (CT).
The patients comprised 44 (88%) men and six (12%) women (median age, 51 years; age range, 20–71 years) who had 12 (24%) primary cases (newly diagnosed HCC) and 38 (76%) recurrent cases (development of new lesions after curative resection of an initial lesion). Histologic diagnosis was obtained in all patients by means of ultrasonography (US)-guided needle biopsy before treatment. The numbers of the patients with one, two, three, and four tumor nodules were 16 (32%), 14 (28%), 17 (34%), and three (6%), respectively. A total of 107 tumor nodules sized 0.8–6.4 cm in diameter were treated. The diameter of the tumors was 2.7 cm ± 1.5 (mean ± SD). Forty-six (43.0%) nodules were 2 cm or smaller, and 61 (57.0%) nodules were larger than 2 cm. Eighteen (36%) of the 50 patients had an increased serum 
-fetoprotein level (>100 µg/L). Liver function status was classified as Child-Pugh class A in 16 (32%) patients, class B in 30 (60%), and class C in four (8%). None of them received any antitumor therapy before PMCT.
Equipment
A UMC-I microwave delivery system (Institute 207 of the Aerospace Industry Company and PLA General Hospital, Beijing, China) (5) was used in the present study (Fig 1). It consisted of a microwave generator with frequency of 2,450 MHz and power output of 10–80 W, a flexible low-loss cable, a monopolar electrode, and a thermometric system with four 20-gauge thermistor probes. The electrode was 1.6 mm in diameter and 24.7 cm in length. At the electrode terminus was a 2.7-cm exposed antenna. The thermistor probes provided a rapid response (<1 second), and the temperature was monitored with an accuracy of 1.0°C. A 14-gauge PMCT guiding needle (Hakko, Tokyo, Japan) was used for puncture guidance. A US scanner (SSD 2000; Aloka, Tokyo, Japan) with 3.5-MHz transducers was used to monitor the procedure and follow-up examinations. CT (Xpress/SX; Toshiba, Tokyo, Japan) was performed with helical technique (10-mm-thick sections, 10-mm collimation, 1-second scan acquisition, pitch of 1:1, 120 kV, 250 mA). Contrast material–enhanced images were acquired with the power injection of 1.5 mL/kg iopromide (Ultravist 300; Schering, Berlin, Germany) at a rate of 3 mL/sec.
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In tumors with a diameter of 2.0 cm or smaller, PMCT was performed under local anesthesia with 1% lidocaine. In each session, the electrode was inserted into the central portion of the tumor with the tip in the deepest part of the tumor.
In tumors larger than 2.0 cm, a multiple electrode insertion technique was applied, with intravenous anesthetics administered by an anesthetist. Propofol (Diprivan; Zeneca Pharmaceuticals, Wilmington, Del) combined with ketamine (First Pharmaceuticals of Shanghai, China) was used. Since single-energy application with a 60-W output and 300-second duration can create a coagulation volume of 3.7 x 2.6 x 2.6 cm (5), three to four insertions were used in tumors sized 2.1–4.0 cm. The electrodes were placed in the peripheral part of the tumor about 0.5 cm inside the tumor margin. Five to seven electrodes were inserted with an interelectrode distance of about 2.0–2.5 cm in tumors sized 4.1–6.0 cm (Fig 2).
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-fetoprotein levels, and liver function were checked monthly during the first 6 months and every 3 months thereafter. US findings were evaluated by two authors (X.Y.X., L.L.). In cases with suspicious findings, repeat dynamic CT and fine-needle biopsy were performed. Patient survival and disease-free survival rates were calculated by using the Kaplan-Meier method.
Thermal Monitoring
To determine the thermal changes in the tumor during the application of microwave energy, the temperature was measured in nine nodules. These nodules were selected because their locations allowed the insertion of one to four 20-gauge thermistor probes at radial distances of 10, 15, and 20 mm from the electrode. The distance between the electrode and thermistor probes was precisely controlled by using a self-made Plexiglas fixer (Fig 5). The probes were placed 10 mm superficial to the tip of the electrode (maximal transverse diameter of the coagulation determined in our preliminary ex vivo experiment). The temperature of each point was recorded every 20 seconds. A total of 18 measurements was obtained in the nine nodules (six measurements for each distance).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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Technical success, as determined at dynamic CT performed 1 month after PMCT, was achieved in 101 (94.4%) of 107 nodules (Fig 7). The technical success rates for tumors 2 cm or smaller and those larger than 2 cm were 98% (45 of 46 nodules) and 92% (56 of 61 nodules), respectively. The six incompletely ablated tumors were treated with additional PMCT sessions, and technical success was achieved in all. In 18 patients with elevated -fetoprotein levels before treatment, the level decreased markedly at 1 month after PMCT (mean decrease from 3,279 µg/L ± 2,459 to 450 µg/L ± 136.
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After PMCT, three patients whose tumors were located in the liver dome had severe right upper quadrant pain. The pain was relieved with the oral administration of analgesics. Thirty-five (70%) patients had a mild fever, which lasted 1–3 days. In two cases, a small discharge from the puncture wound occurred on the initial days after therapy and cleared up after local treatment. In two patients, confined subcapsular hematoma of the liver was detected at US and was spontaneously absorbed within 2 months. No other clinically relevant complications were observed.
Serum alanine aminotransferase levels were substantially elevated on the 3rd day after PMCT in all patients and returned pretreatment levels within a week. There was no substantial change in serum bilirubin and albumin level after treatment.
Long-term Follow-up
All patients, except one who died 3 months after treatment, were followed up for at least 9 months (range, 3–37 months; mean, 18.1 months ± 8.3). Thirty-six (72%) patients were followed up for at least 1 year; 13 (26%), at least 2 years; and two (4%), at least 3 years. Six (12%) patients died at 3, 10, 15, 19, 20, and 29 months after PMCT. Causes of death were liver failure with tumor progression (n = 3), variceal bleeding (n = 2), and extrahepatic metastasis (n = 1). The survival rates at 1, 2, and 3 years were 96%, 83%, and 73%, respectively.
Local recurrence was suspected in six nodules and confirmed with CT and biopsy at 2-month (two nodules), 3-month (two nodules), 4-month (one nodule), and 11-month (one nodule) follow-up. With respect to tumor location, four nodules were adjacent to the major portal vein, and one was adjacent to the gallbladder. The local recurrence rates for nodules 2 cm or smaller and those larger than 2 cm were 2% (one of 46 nodules) and 8% (five of 61 nodules), respectively. New lesions at other sites of the liver occurred in 24 (48%) patients. By the end of the study, 26 (52%) of 50 patients were free of disease, and disease-free survival rates at 1 and 2 years were 55% and 41%, respectively.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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To date, both PMCT and radio-frequency ablation can provide reliable ablation in tumors smaller than 2 cm (6,15–18). Recently, with the development of cooled-tip and multiprobe-array electrodes, the coagulation volume with radio-frequency ablation has increased, and a single electrode insertion can ensure adequate treatment of small tumors (6,18,19). In the series by Solbiati et al (6), 29 patients with 44 hepatic metastases were treated by using radio-frequency ablation with cooled-tip electrodes; none of the 12 nodules smaller than 2 cm showed evidence of local recurrence. With PMCT, Seki et al (16) reported that complete ablation was achieved in all 48 HCC nodules smaller than 2 cm. The commonly used microwave setting (60 W for 120 seconds) generates a coagulation region of about 1.6 cm in transverse diameter with a single energy application (4). It has been reported (5) that the extent of coagulation can be enlarged with a 300-second duration. In our study, the results of thermal monitoring indicated that the temperature at points 1.0 and 1.5 cm from the electrode increased gradually to the coagulation temperature (55°C) with an ablation duration of 300 seconds. Although this temperature change might be insufficiently sensitive to define the coagulation volume and to determine whether the tissue was destroyed, it suggested that this duration can enlarge the area that reaches the coagulation temperature. By using this technique, 46 HCC nodules smaller than 2 cm were treated with a single insertion technique in our study; only one (2%) nodule developed local recurrence. This result also indicated the usefulness of the longer ablation duration.
Given the limited coagulation region with single insertion and the current ablation techniques, multiple electrode insertions are necessary to ensure adequate ablation of tumors larger than 2 cm. Goldberg et al (19) demonstrated that three insertions with internally cooled radio-frequency electrodes could be used to create an area of coagulation with a mean diameter of 5.3 cm (measured in 10 liver metastases at CT). With PMCT, Sato et al (20) reported that seven insertions could produce a coagulation region as large as 5.0 cm in diameter. In their study, three of the six treated patients underwent curative PMCT, and the tumors in all of them were completely ablated. Murakami et al (21) treated nine HCCs sized 3.5–6.7 cm by using multiple electrode insertion and achieved technical success in all tumors.
During multiple electrode insertion, incomplete ablation of the tissue between each two electrodes is the first item to be considered. Appropriate overlapping of each coagulation volume can overcome this problem, and the overlapping depends on the distance between each pair of adjacent electrodes. In our previous ex vivo liver experiment, an interelectrode distance of 2.5–3.0 cm provided adequate tissue coagulation between the electrodes. Considering the cooling effect of blood flow in clinical practice, we used 2.5 cm as the maximum distance between each pair of adjacent electrodes in our multiple electrode insertion scheme. With this scheme, a coagulation region of about 7 cm in transverse diameter is expected with seven punctures; this region may encompass a 6-cm tumor with a 0.5-cm margin of tumor-free liver tissue.
In the present study, two PMCT sessions were performed in each nodule. This practice may be helpful to overcome the individual variation in the coagulation volume due to discrepancies in blood flow and other biophysical features (22). The second session is likely to be more efficient, since the first PMCT session may destroy blood vessels in the tumor region. Although all patients underwent two treatment sessions, no severe complication was observed, and the changes in liver function were transient and reversible. In this study, 61 tumor nodules sized 2.1–6.4 cm were treated, technical success was achieved in 56 (92%) nodules, and only five (8%) developed local recurrence at follow-up of 9 months or longer. These promising results demonstrate the reliability of this multiple electrode insertion technique.
Dynamic contrast-enhanced CT is useful for assessing the completeness of ablation, in which hypoattenuating change without enhancement represents necrotic tissue (6–9). CT is usually performed immediately or 7–14 days later to determine the technical success of the treatment (6–9). During this period, a hyperemic response surrounding the ablation sites may be confused with peripheral tumor regrowth at CT. This hyperemia usually resolves within 1 month after treatment (8,19). CT performed at 1 month after treatment may help prevent such misinterpretation. Fine-needle biopsy was performed in this study. Although multiple samples were obtained, analysis of these failed to reveal three (50%) of six incompletely ablated nodules, as determined at CT. As Solbiati et al (23) pointed out, assessment of therapeutic effectiveness at biopsy is unreliable due to possible sampling error.
The major benefit of multiple electrode insertion is that it enhances the effectiveness of PMCT in large tumors. However, some limitations in its application exist. First, multiple electrode insertion is influenced by tumor location. Multiple percutaneous punctures are not always feasible because ribs, diaphragm, or major vessels can interfere with the puncture routes. Second, in tumors larger than 6 cm, although more insertions theoretically lead to larger coagulation volumes, multiple insertions are not likely to be performed due to inadequate intercostal or subcostal space in the liver region. In addition, the therapeutic effectiveness of thermal ablation modalities can be unsatisfactory in the treatment of tumors near major vessels because it may be compromised by the cooling effect of the blood flow. Multiple electrode insertion cannot solve this problem.
Seki et al (16) recently reported the long-term results of PMCT for solitary HCCs 2 cm or smaller; the 5-year survival rate is more than 70%. In this study, PMCT was performed in 50 patients with 107 nodules, which included 61 nodules larger than 2 cm. The 1-, 2-, and 3-year survival rates were 96%, 83%, and 73%, respectively. In contrast, the 3-year survival rate in untreated patients with HCCs smaller than 3 or 5 cm is only 12.8%–21% (24,25). These results suggest that PMCT can improve the survival rate in patients undergoing PMCT. Further study with a larger patient sample and longer follow-up is needed.
In conclusion, PMCT is an effective and safe therapeutic modality for HCC. A multiple electrode insertion technique can be used to enhance the effectiveness of PMCT in tumors 6 cm or smaller.
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FOOTNOTES |
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Author contributions: Guarantor of integrity of entire study, M.D.L.; study concepts, M.D.L., J.W.C., J.F.H.; study design, J.W.C., X.Y.X.; literature research, J.W.C.; clinical studies, J.W.C., X.Y.X., L.L., X.Q.H.; data acquisition and analysis/interpretation, J.W.C., L.L.; statistical analysis, J.W.C.; manuscript preparation, J.W.C., M.D.L.; manuscript definition of intellectual content, M.D.L., J.F.H.; manuscript editing, J.W.C.; manuscript revision/review, J.F.H., L.J.L.; manuscript final version approval, M.D.L.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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), and 2.0 (
) cm from the electrode. Each marker represents the mean of six measurements (total measurements, 18). Error bars signify 1 SD. The temperature at a point 1.5 cm from the electrode reached a temperature of more than 55°C within 300 seconds.
