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Early-Stage Hepatocellular Carcinoma: Radiofrequency Ablation Combined with Chemoembolization versus Hepatectomy¹

¹ From the Department of Radiology (K.Y., A.N., H.T., K.T.), First Department of Surgery (H.Y., M.U., H.S., S.I.), and Department of Liver and Gastrointestinal Medicine (K.S., H.F.), Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan; and Department of Surgery, Kyoto University, Kyoto, Japan (S.U.). From the 2006 RSNA Annual Meeting. Received May 9, 2007; revision requested July 13; revision received July 17; accepted August 16; final version accepted October 4. Address correspondence to K.Y. (e-mail: yama{at}clin.medic.mie-u.ac.jp).

	ABSTRACT

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Purpose: To retrospectively evaluate the long-term results of radiofrequency (RF) ablation combined with chemoembolization (combination therapy) as compared with hepatectomy for the treatment of early-stage hepatocellular carcinoma (HCC).

Materials and Methods: The study was approved by the institutional review board, and informed consent was waived. Patients with early-stage HCC were included if they underwent either combination therapy or hepatectomy and met the following inclusion criteria: no previous treatment for HCC, three or fewer tumors with a maximum diameter of 3 cm or less each or a single tumor with a maximum diameter of 5 cm or less, Child-Pugh class A liver profile, no vascular invasion, and no extrahepatic metastases. The primary endpoint was overall survival, and the secondary endpoint was recurrence-free survival.

Results: One hundred four patients (mean age, 66.5 years ± 8.7 [standard deviation]; 79 men, 25 women) underwent combination therapy, and 62 patients (mean age, 64.5 years ± 9.6; 51 men, 11 women) underwent hepatectomy. The 1-, 3-, and 5-year overall survival rates following combination therapy (98%, 94%, and 75%, respectively) were similar (P = .87) to those following hepatectomy (97%, 93%, and 81%, respectively). The 1-, 3-, and 5-year recurrence-free survival rates were also comparable (P = .70) for combination therapy (92%, 64%, and 27%, respectively) and hepatectomy (89%, 69%, and 26%, respectively).

Conclusion: RF ablation combined with chemoembolization in patients with early-stage HCC provides overall and disease-free survival rates similar to those achieved by hepatectomy.

© RSNA, 2008

	INTRODUCTION

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Surgical resection has been considered to be the best treatment for early-stage hepatocellular carcinoma (HCC), but only 9%–29% of patients with HCC are candidates for surgery owing to either underlying chronic liver disease resulting in poor hepatic reserve or a multifocal distribution of tumor nodules (1–7).

Percutaneous ethanol injection (PEI) has been reported to be as effective as surgery for single small lesions in some studies (8,9), although the largest retrospective analysis of which we are aware failed to support this finding (6). Radiofrequency (RF) ablation has been reported to be more effective than PEI in achieving complete tumor necrosis in a single treatment session and plays an important role in the treatment of unresectable HCC (9). Some studies (10–12) have shown that overall survival rates 3 or 4 years after treatment with either hepatectomy or RF ablation are comparable when small tumors are treated. However, recurrence-free survival rates are lower when RF ablation is used (10–12). The combined use of chemoembolization and percutaneous ablation therapy, such as RF ablation or PEI, enhances the therapeutic effect on HCC and reduces the local progression rate (13–15). Given that local tumor progression is an important prognostic factor in patients with HCC, therapy that combines chemoembolization and RF ablation may improve both overall and recurrence-free survival rates in such patients.

The purpose of our study was to retrospectively evaluate the long-term results of RF ablation combined with chemoembolization (combination therapy) as compared with hepatic resection for the treatment of early-stage HCC. The primary endpoint was overall survival, and the secondary endpoint was recurrence-free survival.

	MATERIALS AND METHODS

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Patients
Our retrospective study was approved by the institutional review board of Mie University School of Medicine, and informed consent was waived. Combination therapy employing RF ablation and chemoembolization began in June 2000. The records of all patients with HCC who underwent combination therapy or hepatectomy at Mie University Hospital between June 2000 and May 2006 were reviewed for inclusion in our study.

All patients suspected of having HCC had undergone a routine physical examination, laboratory tests, and imaging studies (including three-phase contrast-enhanced computed tomography [CT], digital subtraction angiography, CT during arterial portography, and CT hepatic arteriography) to establish the diagnosis before treatment. The diagnosis of HCC was made on the basis of a positive serum -fetoprotein result (>20 µg/L) combined with positive imaging findings or on the basis of at least two coincident imaging findings compatible with HCC in high-risk patients (1). Indocyanine green tests were performed to assess the functional hepatic reserve if the HCC was considered to be resectable (16).

Requirements for inclusion in our study were (a) no previous treatment for HCC, (b) a single HCC of less than or equal to 5 cm in diameter or up to three HCCs that were each less than or equal to 3 cm in diameter, (c) liver cirrhosis classified as Child-Pugh class A, (d) no vascular invasion, and (e) no extrahepatic metastases. The exclusion criteria were (a) a Zubrod performance status of greater than or equal to 2 (17), (b) a platelet count of less than 50 000/µL and an international normalized ratio of greater than 1.5, and (c) the presence of an uncontrollable malignancy other than HCC.

Chemoembolization and RF Ablation
Both chemoembolization and RF ablation were performed on an inpatient basis. Two radiologists (K.Y. and A.N., with 12 and 9 years, respectively, experience performing interventional radiology procedures at the beginning of the study period) performed both chemoembolization and RF ablation starting in 2000. Another author (H.T., with 5 years experience performing interventional radiology procedures when he joined the protocol) performed both chemoembolization and RF ablation starting in 2003. Before chemoembolization, celiac and superior mesenteric arteriography was performed by using a 4-F catheter introduced via the femoral artery. Then, a 3-F (MicroPheret; William Cook Europe, Bjaevevskov, Denmark) or a 2.7-F (Progreat; Terumo, Tokyo, Japan) microcatheter was placed in the hepatic arteries that were feeding the HCC. After 1–5 mL of an emulsion of iodized oil (Lipiodol Ultra Fluid; Mitsui, Tokyo, Japan) and 40 mg of epirubicin (Farmorubicin; Kyowa-Hakko, Tokyo, Japan) were injected into the feeding arteries, embolization was performed with gelatin sponge particles 1–2 mm in diameter (Spongel; Yamanouchi, Tokyo, Japan).

RF ablation was performed during the 2 weeks after chemoembolization, following recovery of liver function. Fentanyl citrate (Fentanest; Sankyo, Tokyo, Japan) was used for analgesia at a dose of 0.1–0.2 mg, and lidocaine (Xylocaine; Fujisawa, Tokyo, Japan) was used for local anesthesia. Cefazolin (Astellas, Tokyo, Japan) was administered prophylactically and for 1–2 days following RF ablation. Real-time CT fluoroscopy (X-Vigor or Aquilion; Toshiba, Tokyo, Japan) was used to guide placement of the RF electrode in the tumors. A 15-gauge multitined expandable electrode with 10 expandable hook-shaped electrode tines (Radiotherapeutic RF Ablation System; Boston Scientific, Natick, Mass) was used during the first 6 months of the study period, and a 17-gauge internally cooled electrode with a 3-cm exposed tip (Cool-tip RF Ablation System; Valleylab, Boulder, Colo) was used starting in January 2001 and for the remainder of the study period (18). The electrode was placed in the center of the tumor when the tumor diameter was 2 cm or less. When the tumor diameter was larger than 2 cm, the electrode was placed sequentially at two to four sites in the tumor, which were determined on the basis of tumor size and shape. The electrodes were then connected to a generator (RF 3000 Generator, Boston Scientific; or Series CC-1, Valleylab). For the Radiotherapeutic RF Ablation System, RF energy was applied until roll off was achieved with a ramped energy deposition algorithm. For the Cool-tip Ablation System, RF energy was applied for 12 minutes by using an impedance control algorithm.

The technical success of RF ablation combined with chemoembolization was evaluated by using contrast-enhanced three-phase CT images acquired within 1 week after RF ablation. Three radiologists (K.T. and two nonauthors, with 13–22 years of specialization in abdominal imaging at the start of the study) evaluated the CT images. The presence of a hypoattenuating nonenhancing area surrounding an ablated HCC with an ablative margin of 5 mm or larger in both arterial and portal venous phase images was considered to be indicative of technical success. If the ablative margin was insufficient, a second RF ablation session was performed in the week following the initial RF ablation.

Hepatectomy
Surgeons (H.Y., M.U., H.S., S.I., and S.U.) determined the need for liver resection on the basis of the liver profile (Child-Pugh class, bilirubin level, ascites, and indocyanine green retention rate at 15 minutes [ICGR₁₅]). In patients with a normal bilirubin level and no ascites, the number of tumors and tumor locations were used. The extent of liver resection was mainly determined on the basis of ICGR₁₅ results. Trisegmentectomy and right hepatic lobectomy were considered possible when ICGR₁₅ was 0%–10%; left hepatic lobectomy, at 0%–19%; and subsegmentectomy and partial resection, at 0%–29% (16). Liver resection was performed by means of laparotomy from 2000 to 2004, and a laparoscopic procedure was adopted in 2005. When HCCs were located on the liver surface, laparoscopic liver resection was performed (19).

Complications
Major complications were assessed in the two patient groups on the basis of the previously described guideline for image-guided tumor ablation (20). Complication rates were evaluated for the total number of ablation sessions and hepatectomies performed. We defined a major complication as an event that led to substantial morbidity and disability, increased the level of care required, resulted hospital admission, or substantially lengthened the hospital stay. All other complications were considered minor.

Follow-Up
The follow-up was performed by two radiologists (K.Y. and H.T.) and three surgeons (H.Y., M.U., and H.S.). The follow-up protocol included routine physical examination, laboratory tests (blood count and liver function tests, see Table 1), and measurement of -fetoprotein levels every month, as well as three-phase contrast-enhanced CT studies every 3–4 months. CT images were evaluated by the same three diagnostic radiologists (K.T. and two nonauthors) who interpreted the images for technical success after treatment. Local tumor progression was defined as the appearance of tumor enhancement around the ablated tumor in the combination-therapy group and at the resected liver surface in the hepatectomy group. Distant recurrence was defined as the appearance of new HCC in the untreated liver or extrahepatic regions.

Statistical Analysis
Comparisons between groups were conducted by using the Wilcoxon rank sum test for continuous variables and the ² test for categoric variables. The percentage of complications and the causes of death were compared with the Fisher exact test. Cumulative overall survival and disease-free survival curves were generated according to the Kaplan-Meier method and were compared by using the log-rank test. Cox proportional hazards regression model was used to assess the baseline predictors for overall and disease-free survival. A P value of less than .05 was considered to indicate a significant difference. Statistical analysis was performed with commercially available software (SPSS, version 15; SPSS Japan, Tokyo, Japan).

	RESULTS

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Patients
Between June 2000 and May 2006, 176 consecutive patients underwent combination therapy and 81 consecutive patients underwent hepatectomy for the initial treatment of HCC. One hundred six patients in the combination-therapy group (60.2%) and 63 patients in the hepatectomy group (77.8%) met the inclusion criteria. However, two patients in the combination-therapy group and one in the hepatectomy group were lost to follow-up. Therefore, 104 patients who underwent combination therapy and 62 who underwent hepatectomy were included in the study (Table 1). Tumor characteristics were similar between the two patient groups, but the percentage of patients who were -fetoprotein–positive and the mean -fetoprotein values were higher in the combination-therapy group. The results of liver function tests (except for albumin and percent prothrombin time) were substantially worse in the combination-therapy group. RF ablation was selected as the initial treatment due to an insufficient postoperative hepatic reserve as determined by the indocyanine green test in 54 patients, refusal to undergo surgery in 24 patients, presence of tumors in both lobes of the liver in 16 patients, and unacceptably high surgical risk because of preexisting cardiovascular or pulmonary disease in 10 patients.

Technical Success of RF Ablation
A multitined expandable electrode was used in eight patients, and an internally cooled electrode was used in the other 96. Technical success was achieved in all 104 patients. It was achieved after one RF ablation session in 80 patients (76.9%), after two RF ablation sessions in 18 (17.3%), and after three RF ablation sessions in six (5.8%). Therefore, a total of 134 RF ablation sessions were performed.

Hepatectomy
Hepatectomy was performed in 62 patients. It was performed by means of laparotomy in 58 patients (93.5%) and laparoscopically in four (6.5%). Partial resection was performed in 38 patients (61.3%); segmentectomy, in 15 (24.2%); and lobectomy, in nine (14.5%). All procedures were considered to be curative.

Complications
There were no deaths directly related to either combination therapy or hepatectomy. Three major complications (2.2%, three of 134 procedures) were observed in the combination-therapy group. Intraperitoneal bleeding that required blood transfusion and hepatic arterial embolization occurred in one patient. Immediately after RF ablation, another patient had a pneumothorax and required chest tube placement. In a third patient, diaphragmatic injury that resulted in gastric herniation and required surgical intervention developed 6 months after RF ablation. Two major complications (3.2%, two of 62 procedures) were recorded in the hepatectomy group. Postoperative pneumonia that required intensive care developed in one patient. A hemorrhagic duodenal ulcer that necessitated a blood transfusion occurred in a second patient.

In the combination-therapy group, three minor complications were noted (2.2%, three of 134 procedures); pneumothorax occurred in two patients, and a self-limited portal venous thrombosis was observed in one. No (0%, zero of 62 procedures) minor complications were found in the hepatectomy group. There were no significant differences in either major or minor complication rates between the two patient groups (P = .65 and .55, respectively).

Survival
The mean follow-up period was 37 months ± 18 in the combination-therapy group and 38 months ± 20 in the hepatectomy group.

During the follow-up period, 12 patients (11.5%, 12 of 104) in the combination-therapy group and eight patients (12.9%, 8 of 62) in the hepatectomy group died (Table 2). There were no significant differences in the cause of death between the two patient groups. The survival rates at 1, 3, and 5 years were 98%, 94%, and 75%, respectively, in the combination-therapy group and 97%, 93%, and 81%, respectively, in the hepatectomy group (Fig 1). There was no significant difference in survival rates between the two patient groups (P = .87). No significant prognostic factors, including treatment allocation, were found by using Cox proportional hazards regression model.

View larger version (12K): [in this window] [in a new window] [Download PPT slide]   Figure 1: Kaplan-Meier curve shows overall survival rates for patients who received combination therapy and for those who underwent hepatectomy.

View larger version (7K): [in this window] [in a new window] [Download PPT slide]   Figure 2: Graph shows local tumor progression rate following combination therapy.

View larger version (13K): [in this window] [in a new window] [Download PPT slide]   Figure 3: Kaplan-Meier curve shows recurrence-free survival rates for patients who received combination therapy and for those who underwent hepatectomy.

	DISCUSSION

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RF ablation is accepted as a safe and useful technique for the local-regional treatment of unresectable HCC. Given that hepatectomy is also a locoregional treatment, comparable overall and recurrence-free survival rates would be expected following RF ablation, assuming that the hepatic function and the tumor burden are similar and that the local tumor progression rate is near 0%. Some studies have suggested that incomplete ablation or local tumor progression are significant prognostic factors after patients with HCC have been treated by means of microwave coagulation therapy or RF ablation (21,22). However, the local progression rate following RF ablation has been reported to be as high as 17%–35% over a mean follow-up period of 16–25.7 months in previous studies (10–12). In our study, the local tumor progression rate following RF ablation combined with chemoembolization (combination therapy) was lower than the rates in previous studies (10–12) that used RF ablation alone. Low local tumor progression rates have already been reported following combination therapy for the treatment of unresectable HCC in short-term follow-up periods (13,14).

Blood flow promotes heat loss, and reducing or eliminating blood flow during the RF ablation procedure is known to increase the volume of the ablative zone (13). Because HCCs are supplied almost entirely by the hepatic arteries, it seems reasonable to perform RF ablation after chemoembolization.

Chemoembolization is also effective for the treatment of satellite lesions adjacent to the main lesion. Previously, Yamakado et al (13) performed combination therapy in 64 patients, and, when the tumor was 5 cm or smaller, no recurrences were observed during a mean follow-up of 12.5 months.

We defined early-stage HCC on the basis of the transplantation criteria (Milan criteria) (23). The 5-year overall and recurrence-free survival rates in patients who met the Milan criteria and underwent hepatectomy have been reported to be as high as 69%–76.7% and 28.9%–48%, respectively (24,25). Both the overall and recurrence-free survival rates are comparable to the results of our study, even though our patients had undergone either hepatectomy or combination therapy. In previous comparative studies (11,12), there was a tendency for the recurrence-free survival rate following RF ablation alone to be lower than that following hepatectomy. In our study, the low local tumor progression rate following combination therapy appears to be one of the reasons that comparable results were achieved.

The serum aspartate aminotransferase level was found to be a significant factor affecting recurrence-free survival. In addition to intrahepatic metastases, de novo carcinogenesis is considered to be a reason for the development of new HCC lesions (26,27). Close follow-up is required to detect recurrent HCC lesions. Considering that the serum aspartate aminotransferase level is a significant factor for recurrence-free survival, interferon treatment following combination therapy may improve recurrence-free survival in the same fashion as hepatectomy (28).

It is noteworthy that combination therapy was the most frequent treatment option employed for recurrent tumors, regardless of the patient's initial treatment group. RF ablation has been reported to be a useful treatment option for recurrent HCC after hepatectomy in order to enhance survival (29).

Our study had limitations. Since most patients who undergo hepatectomy have a Child-Pugh class A liver profile, our study was conducted in patients with this type of profile. However, the patients' baseline characteristics were not the same in the two patient groups. A randomized controlled trial would be ideal but difficult to conduct for ethical reasons, owing to the lack of data suggesting that combination therapy is truly equivalent to hepatectomy. Lack of histologic proof in the combination therapy group was another limitation.

Our study results show that RF ablation combined with chemoembolization provides overall and recurrence-free survival rates comparable to those achieved with hepatectomy in patients with early-stage HCC. A randomized controlled study is warranted to clarify whether this combination therapy could provide the same results as hepatectomy over long-term periods.

	ADVANCES IN KNOWLEDGE

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• Local tumor progression rate was as low as 5% 5 years after radiofrequency ablation combined with chemoembolization (combination therapy).
  
• The 5-year overall and recurrence-free survival rates seen following combination therapy (75% and 27%, respectively) were similar to those seen following hepatectomy (81% and 26%, respec-tively).
  

	IMPLICATION FOR PATIENT CARE

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• Our results suggest that outcomes similar to hepatectomy can be achieved with combination therapy in patients with early-stage hepatocellular carcinoma.
  

	FOOTNOTES

 

Abbreviations: HCC = hepatocellular carcinoma • RF = radiofrequency

Author contributions: Guarantors of integrity of entire study, all authors; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; literature research, K.Y., A.N., S.I., K.S., H.F., S.U., K.T.; clinical studies, K.Y., A.N., H.T., H.Y., M.U., H.S., S.I., K.S.; statistical analysis, K.Y., K.T.; and manuscript editing, K.Y., S.I., K.S., K.T.

Authors stated no financial relationship to disclose.

	References

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