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Keywords:

  • hepatocellular carcinoma;
  • liver;
  • radiofrequency ablation;
  • transcatheter arterial chemoembolization

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

BACKGROUND:

Radiofrequency ablation (RFA) is becoming a well-known local therapy for hepatocellular carcinoma (HCC). Transcatheter arterial chemoembolization (TACE) is expected to enhance the effects of subsequent RFA by reducing arterial blood flow. However, the long-term efficacy of this combined therapy has not been elucidated. In this study, the survival rates of patients who received TACE combined with RFA (TACE + RFA) were compared with those of patients treated surgically.

METHODS:

The study included consecutive patients who received TACE + RFA or surgical resection as the initial curative treatment for HCC between 2000 and 2005 at Tokai University Hospital. Inclusion criteria were a single HCC ≤50 mm or up to 3 HCCs ≤30 mm, presence of cirrhosis classified as Child-Pugh class A, no vascular invasion, and no extrahepatic metastasis.

RESULTS:

Sixty-two patients (23 women, 39 men; aged 67.5 ± 8.4 years [mean ± standard deviation]) received TACE + RFA, and 55 patients (15 women, 40 men; aged 66.1 ± 8.4 years) underwent surgical resection. Median follow-up periods were similar (50 months in the TACE + RFA group vs 49 months in the resection group). The probabilities of overall survival at 1, 3, and 5 years in the TACE + RFA group (100%, 94.8%, and 64.6%, respectively) were similar (P = .788) to those in the resection group (92.5%, 82.7%, and 76.9%, respectively). Two major RFA-related complications were observed (1.5%).

CONCLUSIONS:

RFA combined with TACE is an efficient and safe treatment that provides overall survival rates similar to those achieved with surgical resection. Cancer 2010. © 2010 American Cancer Society.

Hepatocellular carcinoma (HCC) is a common cancer, and its incidence is increasing.1 Although surgical resection is considered the main curative treatment, many data have accumulated on the efficacy and safety of a wide array of locoregional therapies. Radiofrequency ablation (RFA) is an emerging technology, and its superiority over microwave coagulation therapy2, 3 and percutaneous ethanol injection (PEI)4-8 was reported.

Transcatheter arterial chemoembolization (TACE) prolongs survival9-11 by the arterial injection of anticancer drugs and embolizing agents, which subsequently induces ischemic necrosis. The synergistic effect of TACE and RFA has been demonstrated.12 The decrease in blood flow caused by TACE reduces heat loss, thus permitting larger lesions to be ablated by RFA. A combination of chemotherapy and hypoxia also reduces the temperature at which coagulative necrosis occurs, which enables formation of larger thermal lesions. A combination of RFA and TACE is increasingly used, but data on the efficacy and safety of this therapy are still insufficient.

In this study, we compared the survival rate after RFA combined with TACE with that after surgical resection as the initial curative treatment for early stage HCC.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Patients

This is a cohort study conducted as a retrospective analysis of a prospective database in a single institution. The records of consecutive patients who received TACE followed by RFA or surgical resection as the initial curative treatment for HCC between January 2000 and December 2005 at Tokai University Hospital were reviewed. The diagnosis of HCC was based on histological findings or the European Association for Study of the Liver consensus conference criteria.13 Inclusion criteria were (1) no previous treatment for HCC, (2) a single HCC ≤50 mm or up to 3 HCCs ≤30 mm, (3) presence of cirrhosis classified as Child-Pugh class A, (4) no vascular invasion, and (5) no extrahepatic metastasis. Exclusion criteria were (1) an Eastern Cooperative Oncology Group performance status ≥214 and (2) the presence of an uncontrollable malignancy other than HCC. Written informed consent was obtained from all patients before treatment.

TACE Procedure

TACE was performed using the Seldinger technique followed by arterial embolization. After introducing a 4-F catheter through the femoral artery, hepatic arteriography and superior mesenteric arterial portovenography were performed to evaluate portal flow and localize the tumors. When portal flow was adequate, a 2- or 3-Fr microcatheter was placed in the arteries that were feeding the HCC. An emulsion consisting of 30 to 60 mg epirubicin (Kyowa-Hakko, Tokyo, Japan) and 2 to 6 mL iodized oil (Lipiodol Ultrafluid; Terumo, Tokyo, Japan) was injected into the segmental artery supplying blood to the tumor, followed by embolization with gelatin sponge particles (Gelfoam; Pfizer, Tokyo, Japan). After embolization, angiography was performed to determine the extent of vascular occlusion and to assess blood flow in other arterial vessels. Patients were observed carefully, and analgesia (pentazocine) was administered if necessary.

RFA Procedure

Within 2 months after the procedure of TACE, RFA was performed using 2 systems. From January 2000 to January 2002, a 15-gauge needle with 10 expandable hook-shaped electrode tines (LeVeen needle, Radiotherapeutic RF 2000 generator system; Boston Scientific, Natick, Mass) was used. Since January 2002, a 17-gauge internally cooled electrode with a 2- or 3-cm exposed tip (Cool-tip RF Ablation System; Valleylab, Boulder, Colo) was primarily used. After administration of analgesia (pethidine hydrochloride) and local anesthesia (10 mL of 1% lidocaine), the electrode needles were introduced into the tumor under ultrasonographic guidance. RFA was performed percutaneously according to the common technique. When withdrawing the RFA electrode, track ablation was performed to prevent bleeding and tumor seeding. The treatment response was evaluated by subsequent dynamic computed tomography (CT) or magnetic resonance imaging (MRI), and additional RFA was performed until the tumor was completely ablated.

Surgical Resection

The indication and extent of surgical resection were decided on the basis of tumor locations, the number of tumors, and indocyanine green retention rate at 15 minutes.15 For the patients with an indocyanine green retention rate at 15 minutes below 10%, 20%, and 30%, trisegmentectomy/right hepatic lobectomy, left hepatic lobectomy, and subsegmentectomy/partial resection, respectively, were considered to be performed safely.

Assessment and Follow-Up

Patients were assessed every 3 months by serum biochemistry, dynamic CT, dynamic MRI, or ultrasonography. Local tumor progression was defined as the appearance of viable tumors within the ablation region or <2.0 cm from its borders. When recurrence was recognized, patients were treated by surgical resection, RFA, PEI, or TACE. Patients were followed until loss to follow-up, death, or July 31, 2008.

Statistical Analysis

Pearson chi-square and Fisher exact probability tests were performed to compare the frequency distributions of categorical variables between groups. One-way analysis of variance was used to test the differences in means between groups for continuous variables. Survival probabilities were estimated using the Kaplan-Meier method, and differences between groups were compared using the log-rank test. A Cox proportional hazards regression model was used to assess the baseline predictors for overall survival. Patients who died of diseases unrelated to the liver were censored. All statistical analyses were performed using SPSS version 16 (SPSS Japan, Tokyo, Japan). All reported P values are 2-sided, with P < .05 considered statistically significant.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Baseline Characteristics of the Patients

A total of 190 patients received TACE and subsequent RFA (89 patients) or surgical resection (91 patients) as an initial treatment for HCC. Of these, 117 patients who met the inclusion criteria were enrolled in this study. Sixty-two patients received TACE and subsequent RFA within 2 months (median, 11.5 days; range, 4-39 days) (TACE + RFA group). Of these, 30 (48.4%) patients progressed from cirrhosis to HCC during follow-up at the Department of Gastroenterology, Tokai University Hospital. The remaining 32 (51.6%) patients were referred to the Department of Gastroenterology for HCC treatment. HCC was diagnosed pathologically in 19 (30.6%) patients and by radiological characteristics in the remaining 43 (69.4%) patients.

Fifty-five of the patients who were referred to the Department of Surgery underwent surgical resection (resection group). Of these, 16 (29.1%) patients were referred to the Department of Surgery from the Department of Gastroenterology either because of high-risk tumor location for RFA (12 patients) or by choice of the patient (4 patients). The diagnosis of HCC was pathologically confirmed in all patients.

The distributions of sex and age were not different between the 2 groups (Table 1). Forty-nine (79.0%) and 8 (12.9%) patients in the TACE + RFA group were infected with hepatitis C virus (HCV) and hepatitis B virus (HBV), respectively (1 patient was infected with both viruses). Thirty-six (65.5%) and 10 (18.2%) patients in the resection group were infected with HCV and HBV, respectively.

Table 1. Demographic and Baseline Characteristics of the Patients
VariablesTACE-RFA (n = 62)Resection (n = 55)P
  1. TACE indicates transcatheter arterial chemoembolization; RFA, radiofrequency ablation; SD, standard deviation; HCV, hepatitis C virus; HBV, hepatitis B virus; AFP, α-fetoprotein; CLIP, Cancer of Liver Italian Program; JIS, Japan Integrated Staging.

Sex  .324
 Women23 (37.1%)15 (27.3%) 
 Men39 (62.9%)40 (72.7%) 
Age, mean y ± SD67.5 ± 8.466.1 ± 8.4.372
Etiology  .360
 HCV48 (77.4%)36 (65.5%) 
 HBV7 (11.3%)10 (18.2%) 
 HCV + HBV1 (1.6%)0 (0%) 
 Alcohol3 (4.8%)3 (5.5%) 
 Unknown3 (4.8%)6 (10.9%) 
AFP  .165
 <400 ng/mL57 (91.9%)45 (81.8%) 
 ≥400 ng/mL5 (8.1%)10 (18.2%) 
Tumor size  .085
 <20 mm19 (30.6%)9 (16.4%) 
 ≥20 mm43 (69.4%)46 (83.6%) 
Number of tumors  .974
 149 (79.0%)44 (80.0%) 
 29 (14.5%)8 (14.5%) 
 34 (6.5%)3 (5.5%) 
CLIP score  .176
 043 (69.4%)36 (65.5%) 
 119 (30.6%)16 (29.1%) 
 20 (0%)3 (5.5%) 
JIS score  .553
 015 (24.2%)9 (16.4%) 
 136 (58.1%)34 (61.8%) 
 211 (17.7%)12 (21.8%) 

The tumor size was not significantly different between the 2 groups; 19 (30.6%) patients in the TACE + RFA group and 9 (16.4%) patients in the resection group had HCC with a diameter <20 mm. The median (min-max) tumor size was 24 (8-50) mm in the TACE + RFA group and 28 (10-50) mm in the resection group. Serum α-fetoprotein (AFP) levels and the number of tumors were not significantly different between the 2 groups.

When patients were classified by the Cancer of Liver Italian Program score,16 43 (69.4%) and 19 (30.6%) patients in the TACE + RFA group had scores of 0 and 1, respectively, whereas 36 (65.5%), 16 (29.1%), and 3 (5.5%) patients in the resection group had scores of 0, 1, and 2, respectively. The proportions of patients with particular Cancer of Liver Italian Program scores were not significantly different between the 2 treatment groups. The proportions of patients with particular Japan Integrated Staging scores17 did not differ significantly.

The follow-up period was similar between the 2 groups: 50 (9-95) (median [min-max]) and 49 (1-102) months in the TACE + RFA and resection groups, respectively.

Overall Survival

At the end of follow-up, 19 and 18 patients had died in the TACE-RFA and resection groups, respectively. Most of them (14 and 16 patients in the TACE+RFA and resection groups, respectively) died as a result of progression of liver disease. One patient in each group died from rupture of esophageal varices. The death of 1 and 2 patients was related to RFA and resection, respectively. Five patients in the TACE+RFA group and 2 in the resection group died of diseases unrelated to the liver; causes of death included lung cancer, pancreatic cancer, malignant lymphoma, ruptured abdominal aorta aneurysm, cerebral hemorrhage, cerebral infarction, and pneumonia.

The probabilities of overall survival at 1, 3, and 5 years were 100%, 94.8%, and 64.6% in the TACE+RFA group and 92.5%, 82.7%, and 76.9% in the resection group, respectively. Overall survival rate was not significantly different between the 2 groups (P = .788 by log-rank test; Fig. 1). Cancer of Liver Italian Program score is closely associated with the prognosis. In this study, the overall survival rate was significantly better in patients with Cancer of Liver Italian Program score of 0 than in those with scores of 1-2 (P < .05, data not shown). We compared survival rates between the TACE+RFA and resection groups after stratification by Cancer of Liver Italian Program score. Analysis revealed no significant difference in each subgroup (score of 0, P = .927; score of 1-2, P = .530; data not shown). Similarly, stratification by Japan Integrated Staging score did not reveal any significant difference (data not shown).

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Figure 1. Overall survival curves are shown for patients who received transcatheter arterial chemoembolization (TACE)-radiofrequency ablation (RFA) and for those who underwent surgical resection.

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We analyzed the factors that were associated with overall survival using a Cox regression model. The variables studied were sex, age, etiology, serum AFP level, tumor size, tumor number, treatment, and recurrence. Recurrence was the only independent factor related to survival (hazard ratio [HR], 3.77; 95% confidence interval [CI], 1.08-13.16; P = .037). Analysis was performed for each treatment group. In the resection group, recurrence was the only independent factor related to survival (HR, 3.57; 95% CI, 1.01-12.5; P = .049), whereas in the TACE + RFA group, no significant factors were found in this study.

Recurrence

The probabilities of recurrence-free survival at 1, 3, and 5 years were 64.5%, 40.1%, and 18.0% in the TACE-RFA group, and 75.6%, 41.1%, and 36.4% in the resection group, respectively (P = .010 by log-rank test; Fig. 2). This difference was attributable to a difference in local tumor progression, which was observed in 9 (14.5%) patients in the TACE + RFA group and no patients in the resection group. The tumor size was not significantly different between those with and those without local tumor progression: 25.9 ± 5.1 mm (mean ± standard deviation) and 23.9 ± 8.8 mm, respectively. There was a trend toward more frequent occurrence of local tumor progression (6 of 21, 28.6%) in patients treated with the LeVeen needle than that in those treated with the Cool-tip needle (3 of 41, 7.3%) (P = .062).

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Figure 2. Recurrence-free survival curves are shown for patients who received transcatheter arterial chemoembolization (TACE)-radiofrequency ablation (RFA) and for those who underwent surgical resection.

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When recurrence was recognized, surgical resection was performed in 5 (8.1%) and 3 (5.5%) patients in the TACE + RFA and resection groups, respectively. One patient in the TACE + RFA group received surgical resection twice. RFA was performed in 34 (54.8%) and 11 (20.0%) patients in the TACE + RFA and resection groups, respectively. A total of 71 sessions of RFA were performed. Fourteen (22.6%) patients in the TACE + RFA group and 3 (5.5%) patients in the resection group received RFA more than twice. PEI was performed in 13 (21.0%) and 1 (1.8%) patients in the TACE + RFA and resection groups, respectively. TACE was performed in 43 (69.4%) and 24 (43.6%) patients of the TACE + RFA and resection groups, respectively. Fourteen (22.6%) patients in the TACE + RFA group and 4 (7.3%) patients in the resection group received TACE 5× or more.

Complications

Common complications of TACE and RFA were fever, pain, vomiting, and increased serum alanine aminotransferase or aspartate aminotransferase levels. No serious complications were observed after the initial TACE and RFA treatment. Two serious RFA-related complications were observed among sessions performed for recurrent tumors (2 of 133, 1.5%). One patient in the TACE + RFA group died of duodenal perforation because of RFA. Because a total of 133 sessions of RFA were performed, the rate of RFA-related death was 0.8%. The other patient progressed to hemothorax that was treated with chest-tube drainage. A total of 227 sessions of TACE were performed. The serious complications of liver failure and gastric ulcer were observed in 2 (0.9%) and 1 patients (0.4%), respectively. These complications subsided after palliative treatment. Tumor seeding by RFA was not observed in this study.

Two deaths were considered surgery-related. Both patients died of liver failure. Because a total of 64 surgical operations were undertaken, the rate of surgery-related death was 3.1%. Other serious complications included liver failure (1 case, 1.6%), pleural effusion (1 case, 1.6%), pneumonia (1 case, 1.6%), and biliary leakage (2 cases, 3.1%), but the patients recovered.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

In this study, the probabilities of overall survival at 1, 3, and 5 years in patients with Child-Pugh class A liver profile and early stage HCC were similar between the TACE+RFA and resection groups (TACE+RFA, 100%, 94.8%, and 64.6%; resection, 92.5%, 82.7%, and 76.9%, respectively). Therefore, we concluded that the efficacy of RFA combined with TACE was similar to that of surgical resection in the treatment of early stage HCC. These rates are comparable to the 5-year overall survival rates in patients with early stage HCC who undergo hepatic resection, which have been reported to be as high as 56% to 81%.18-21 Yamakado et al retrospectively compared the efficacy of RFA combined with TACE with that of surgical resection in early stage HCC patients with a Child-Pugh class A liver profile.20 The 5-year overall survival rates were similar between these 2 treatments (72% in the TACE + RFA group and 81% in the surgical resection group), which is in accordance with our study.

Local tumor progression was observed in 14.5% of patients treated by TACE and RFA in the present study, comparable to the previously reported rates (2.4%-30%).5, 20-27 Surprisingly, a histological study in patients who underwent liver transplantation after an RFA procedure revealed residual tumor tissue in 37% and 71% of patients with HCC ≤3 cm and HCC >3 cm, respectively.28 The combination with TACE is expected to reduce such microscopic local tumor progression. In our study, local tumor progression was observed more frequently when HCC was treated with the LeVeen needle (28.6%) than when it was treated with the Cool-tip needle (7.3%), although this difference did not reach significance. The former was used from January 2000 to January 2002, and subsequently the latter was primarily used. Because no differences in efficacy among types of RFA device have been reported,29 more frequent local recurrence after ablation with the LeVeen needle might be because of the surgeon's lack of proficiency. In our study, relatively frequent local tumor progression was observed, but it did not affect overall survival. This might be explained by the finding that local tumor progression was immediately treated in an appropriate way, including RFA, PEI, or surgical resection.

Total recurrence, including local tumor progression and the appearance of a new HCC, was the only independent predictor for overall survival. The rate of total recurrence was considerably high. Therefore, the development of drugs that suppress HCC recurrence is desirable. Long-term interferon-alpha administration after resection of HCC decreased the recurrence rate, although this Japanese study included a relatively small number of patients.30 Recently Di Bisceglie et al reported that low-dose maintenance therapy with peginterferon failed to reduce the incidence of HCC in HCV-positive patients with bridging fibrosis.31 However, the annual incidence rate of HCC was approximately 1% in their study, in which the patients were around 50 years old. A Japanese retrospective study found that interferon therapy reduced the annual incidence of HCC from 6%-8% to 4%-5% in cirrhotic patients aged about 60 years.32 Larger randomized controlled studies are required to determine the effect of interferon on the prevention of HCC incidence or recurrence in elderly patients, who are expected to have substantial risk for HCC.33

The major complication rate after RFA was 1.5%, which is comparable to the rates in other studies (1.9%-16%).5, 7, 20, 21, 23, 27, 34, 35 RFA-related death was observed in 1 (0.8%) patient. A low mortality rate after RFA was reported, ranging from 0% to 2.9%.5, 7, 20, 21, 23, 27, 34, 35 The mortality rate related to surgical resection was 3.1%, which is comparable to other studies (0%-15%).36-39 These results demonstrate that RFA combined with TACE is safe.

Twelve (16.2%) of 74 patients for whom TACE+RFA was planned eventually underwent surgical resection because of high-risk tumor location for RFA. Livraghi et al40 reported that RFA was not feasible in 6.0% of patients because of high-risk tumor location or poor detection on ultrasonography. Although new technologies, such as artificial pleural effusion or ascites, increase the number of patients eligible for RFA,7, 27, 41 surgical resection should be chosen for the treatment of patients with high-risk tumor location.

A limitation of this study is that it was not randomized. A large-scale randomized controlled trial would be ideal but might be difficult to perform, because in general practice, factors such as tumor location and body constitution affect the choice of treatment. Other limitations of this study were that it was conducted at a single center and that some of the patients who underwent TACE + RFA did not have a histological diagnosis.

In conclusion, we demonstrated that RFA combined with TACE is an efficient and safe treatment resulting in an overall survival rate similar to that achieved with surgical resection. Although a large-scale randomized controlled study is required, RFA combined with TACE could be an alternative modality in the treatment of HCC.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

We thank Naoko Ochiai, Reiko Toda, Misako Shirasu, Sayuri Kowata, and Tomoyuki Sakiyama for their technical assistance.

CONFLICT OF INTEREST DISCLOSURES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Supported in part by a Japanese Grant-in-Aid for Scientific Research (to T.K.).

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES