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Radiofrequency ablation as first-line treatment for small solitary hepatocellular carcinoma: Long-term results
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EJSO 36 (2010) 1054e1060
www.ejso.com
Radiofrequency ablation as first-line treatment for small solitary hepatocellular carcinoma: Long-term results Z.-W. Peng a,b,d, Y.-J. Zhang a,b,d, M.-S. Chen a,b,*, X.-J. Lin a,b, H.-H. Liang c, M. Shi a,b a
Department of Hepatobiliary Surgery, Cancer Centre of Sun Yat-Sen University, 651 Dongfeng Road East, Guangzhou 510060, China b State Key Laboratory of Oncology in Southern China, Guangzhou 510060, China c The Second Affiliated Hospital of Guangzhou Medical College, China Accepted 19 August 2010 Available online 16 September 2010
Abstract Aims: To evaluate long-term results of patients with small solitary hepatocellular carcinoma (HCC) and well-preserved liver function who received radiofrequency ablation (RFA) as first-line treatment. Materials and methods: Between November 1999 and June 2007, 247 patients with solitary HCC 5 cm and liver status scored as ChildPugh class A were enrolled. RFA was performed in 224 patients as first-line treatment; 23 patients excluded from RFA because of unfavorable tumor location or their unwillingness, and all of these patients converted to surgical resection. Results: In the 224 patients treated with RFA, the overall 5-, 7-, 10-year survival rates were 59.8%, 55.2%, 33.9%, respectively, and the median of overall survival was 76.1 months. Complete ablation was achieved in 216 patients (96.4%). Major complications occurred in two patients (0.9%), with no treatment-related death or needle track seeding. Indocyanine green retention rate in 15 min (ICGR15) (P ¼ 0.014) and prothrombin activity (P ¼ 0.004) were associated with overall survival. A subgroup of patients with ICGR15 10% and prothrombin activity >75% had 5-, 7-, 10-year survival rates of 67.1%, 64.2%, 57.1%, respectively, with a median survival of 87.7 months. The 10-year recurrence-free, tumor-free survival rates were 17.5%, 28.2%, respectively. Serum albumin was the only factor that significantly impacted recurrence-free and tumor-free survival (P ¼ 0.008, 0.002, respectively). Conclusion: RFA is considered to be the treatment of first choice for patients with solitary HCC 5 cm and well-preserved liver function. Surgery can be used as second-line therapy for few patients if RFA is unfeasible. Ó 2010 Elsevier Ltd. All rights reserved. Keywords: First-line treatment; Radiofrequency ablation; Hepatocellular carcinoma; Survival
Introduction As routine screening of high-risk patient has been implemented, more and more patients are being diagnosed with hepatocellular carcinoma (HCC) at an early stage (solitary 5 cm in diameter or 3 nodules, 3 cm in diameter) allowing radical treatment.1e3 Liver transplantation can eliminate tumors and cirrhosis at the same time, and is considered to be the most appropriate treatment for these patients. But, the lack of liver donors is a major * Corresponding author. Department of Hepatobiliary Oncology, Cancer Center, Sun Yat-sen University, Guangzhou 510060, Tel./fax: þ86 20 8734 3117, þ86 1390 224 1061 (mobile). E-mail address: [email protected] (M.-S. Chen). d Both authors contributed equally to this article. 0748-7983/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2010.08.133
limitation.4,5 Until now, surgical resection (SR) has been still considered as the first choice treatment for these patients, which may offer a 5-year survival rate above 50%.1 However, SR is used only in about 5% of Western patients, and about 40% of Asian patients.6,7 In some centers, radiofrequency ablation (RFA) is considered to be a safe and effective first-line treatment of early stage HCC, with a 5-year survival rate of 40%e57%.8e10 Recently, a clinical trial has shown that RFA was as effective as SR for small solitary HCC with well-preserved liver function in terms of overall survival and disease-free survival.11 Some authors consider that RFA can be used as an alternative treatment to surgery for resectable HCC.10,12 Actually, patients with resectable disease can achieve 5-year survival >70% after RFA in some centers.9,10 However, other authors maintain that SR should
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be the first choice treatment for resectable HCC because RFA has not been shown to be superior to SR, and some tumors (adjacent to intestinal loops or main bile ducts) may be unsuitable for RFA because of the risk of bleeding, tumor seeding, bile leakage, and perforation.13 Therefore, the appropriate treatment strategy for resectable HCC is still under debate. To clarify this issue, we conducted a large cohort study that included a consecutive series of patients with single HCC 5.0 cm or less in diameter accompanying well-preserved liver function who received RFA as first-line treatment.
Patients and methods Patients Patients were enrolled between November 1999 and June 2007 according to the following inclusion criteria: (1) presence of solitary HCC measuring 5.0 cm in diameter, (2) liver status scored as Child-Pugh class A, (3) no extrahepatic metastasis, and no imaging evidence of invasion into the portal/hepatic vein branches, (4) no history of encephalopathy, ascites refractory to diuretics or variceal bleeding, (5) no severe coagulation disorders (prothrombin activity <40% or a platelet count of <40,000/mm3), and (6) no previous treatment. The diagnosis of HCC was based on the diagnostic criteria used by the European Association for the Study of the Liver (EASL)14: two imaging techniques showing typical features of HCC or positive findings on one imaging study together with an alpha fetoprotein level of >400 ng/ mL in a patient, or if a cytological/histological diagnosis of HCC. The treatment selection for HCC in our study was made at patients’ request after a full discussion with the team of multimodality specialists for HCC in our center. During the study period, 247 consecutive patients who met the aforementioned inclusion criteria were enrolled in the study. Twenty three patients excluded from RFA (non-RFA group) because:(1) their tumors located adjacent to intestinal loops or main bile ducts (n ¼ 11), (2) their tumors were poor or absent visualization on ultrasound (n ¼ 5), (3) they refused to received RFA (n ¼ 7) (Fig. 1). These 23 patients all received SR. The remaining 224 patients received RFA (RFA group) as the first-line treatment. The baseline characteristics of the patients in RFA group were reported in Table 1. For each case, we recorded gender, age, total bilirubin level (TBIL), g-glutamyltranspeptidase (GGT), AFP, serum albumin (ALB), indocyanin green retention at 15 min (ICGR15), prothrombin activity, platelet, ascites and tumor size. These parameters were evaluated as possible predictors of overall, recurrence-free, and tumor-free survival.
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RF ablation procedures Expandable electrodes RFA Before September 2004, we used a commercially available system (RF 2000; RadioTherapeutics Mountain View, CA), and a needle electrode with a 15 gauge insulated cannula with 10 hook-shape expandable electrode tines with a diameter of 3.5 cm at expansion (LeVeen; RadioTherapeutics). A 15 gauge RFA needle was first inserted into the tumor. After the ten tines of the needle were deployed, the RF generator was activated and initiated with 10 W of power. The power was increased 10 W per minute to 90 W. RFA was applied until either there was a marked increase in impedance or 15 min had elapsed. If a marked increase in impedance was not achieved, a second application of RF was given. No more than 3 applications of RFA were given in a treatment session. For tumors 3.0 cm in greatest dimension, a single ablation was performed. For tumors >3.0 cm in greatest dimension, multiple overlapping ablations as described by Chen et al15 were performed. The first ablation started at the location farthest away from the skin puncture site. After ablation was completed, the electrode tines were retracted; the needle was withdrawn to the second predetermined location. The electrode tines were then re-expanded and the RF generator was reactivated. This process was repeated until the entire lesion was adequately covered. Perfusion electrode RFA Since September 2004, we used a commercially available system with a 375-KHz computer-assisted radiofrequency generator (Elektrotom HiTT 106, Berchtold, Medizinelektronik, Germany) and an open-perfused electrode (Berchtold, Tuttlingen, Germany) of 15 cm, 14 gauge, and a 15 mm active electrode tip with microbores. The 15 gauge needle was introduced into the tumor, 60 W of the radiofrequency energy was delivered by the generator with the duration of 8 min for every single energy application. During the RFA application, continuous perfusion of the open-perfused electrode with 0.9% sodium chloride solution was administered automatically by means of a syringe pump (Pilot C, Fresenius Medical Care, Alzenau, Germany) linked to the radiofrequency generator. The saline solution was administered at a base rate of 120 mL/h. A saline solution bolus of 600 mL/h was administered for 1e2 s if the impedance increased more than 900 U. For tumors 3.0 cm in greatest dimension, single applicator position with 1e2 duration was adopted for RFA. For tumors >3.0 cm in greatest dimension, different applicator positions were adopted for RFA to create overlapping coagulation zones.16,17 During the RFA, a hyperechoic area was observed around the electrode tip on ultrasonic monitoring. The aim of the treatment was to have this hyperechoic area covering an area larger than 1 cm around the HCC. At the end of the procedure, the generator was reactivated to ablate the needle tract to prevent bleeding.
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Patients meeting inclusion criteria n = 247
converted to resection
n=23
Located in a high-risk area for RFA n=11 Refused to received RFA n=5 Tumors poor or absent on US n=7
Patient received RFA n = 224
Complete tumor ablation
Complete tumor ablation after two or
Viable tumor after two or
after one session
three sessions
three sessions
n = 208
n=8
n=8
Resection n=7 Tumor-free
Complete tumor ablation
TACE n=1
n=216
n=81
Tumor recurrence n=135
Local recurrence
Intrahepatic recurrence
n=28
n=23
n=94
Alive n=145
n=2
n=2 n=71
Repeat RFA
Extrahepatic metastasis
n=105
n=3 n=3
n=25
n=6
Resection
TACE
Supportive care
n=5
n=28
n=8
Death n=99
Lost to follow up n=3
Tumor progression n=26
Tumor progression n=73
Tumor progression n=2
Tumor free n=119
Tumor free n=26
Tumor free n=1
Figure 1. A patient flow diagram for the study.
Follow-up A dual-phase spiral computed tomography (CT) was done 4 weeks after treatment and thereafter every 2 months for the first 2 years. At each of these follow-up visits, blood tests including serum liver enzyme tests, and serum alpha fetoprotein were done. Chest radiography was done every 6 months. Follow-up visits were extended to once every 3 months after 2 years. Magnetic resonance imaging (MRI) was carried out if CT did not provide definite evidence regarding the presence of residual viable tumor. Complete ablation was defined as no areas of enhancement seen within or at the periphery of the ablation zone.
Incomplete ablation was defined as enhancing tissue was still observed at the tumor site. For such cases, up to three applications of RFA were performed. Therefore, treatment failure was defined as persistence of enhancing tissue at the tumor site after a maximum of three iterative RFA procedures. In this setting, other treatment options including SR, transarterial chemoembolization (TACE) or supportive care were performed. After complete ablation was achieved, local recurrence was defined as the development of tumor staining at the margins of the tumor on CT/MRI. Intrahepatic recurrence was defined as a separate new lesion in the liver more than 2.0 cm away from the primary lesion, and extrahepatic
Z.-W. Peng et al. / EJSO 36 (2010) 1054e1060 Table 1 Demographic data for 224 patients received RFA. Factors
Value
Median Age in years, (range) 60 >60 Sex (M/F) HBsAg()b AFPd, ng/ml Median (range) 400 >400 GGTa, m/L Median (range) Serum albumin, g/L Median (range) TBILc, mmol/L Median (range) ICGR15e, % Median (range) 10 >10 Platelet, 109/L Median (range) 100 >100 Tumor size, cm Median (range) 3 >3 Ascites (yes/no) Prothrombin activity Median (range) 75 >75
55(25e80) 139 85 196/28 203/11
a b c d e
562.3(3.0e121000) 56 168
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categorical data. The overall survivals were calculated using a life-table method and compared with ManteleCox test. The survival curves were constructed by KaplaneMeier method and compared by log-rank test. The relative prognostic significance of the variables in predicting survival rates was assessed using multivariate Cox proportional hazards regression analysis. Results were given as mean S.D. All statistical tests were two-sided, and p < 0.05 were considered statistically significant. Results
108.6(10.8e605.4) 39.5(32.5e45.7) 11.5(5.0e29.5) 6.5(3.0e20.5) 177 47 131(80e300) 136 88 2.5(1.0e5.0) 189 35 11/213 76.2(65e97) 50 174
g-Glutamyltranspeptidase. Hepatitis B surface antigen. Total bilirubin. Alpha fetoprotein. Indocyanine green retention rate in 15 min.
metastasis was defined as a metastatic lesion outside the liver. For local and intrahepatic recurrence, RFA was repeated if the patients still met the inclusion criteria. If the patients were beyond the inclusion criteria, SR, TACE or supportive care were given, depending on the tumor, the liver function, and the general condition of the patient. For extrahepatic metastasis, supportive care was given.
Treatment efficacy of RFA Two hundred forty nine total RFA sessions were performed. One session was required for 208, 2 for 7, and 3 for 9 patients. Complete ablation was achieved in 216 patients (96.4%). Treatment failure was observed in eight patients (3.6%), including 5 patients with nodules larger than 3 cm, and 3 patients with nodules located near a large blood vessel. In this setting, seven patients received SR, and one patients received TACE. Overall survival At the time of the analysis, three patients were lost to follow-up after 5, 9, 16 months. The mean follow-up time was 43.6 27.4 months, with a range of 2e123 months. A total of 99 patients died in the follow-up period: 73 patients died of HCC progression, 21 patients of liver failure, and 5 patients of other disease (Fig. 1). The estimated overall 5-, 7-, 10-year survival rates for all patients in the study were 60.1%, 53.7%, 32.6%, respectively, and the median of overall survival was 74.6 3.5 months. For RFA group, after a mean follow-up time of 44.1 28.1 months, the estimated overall 5-, 7-, 10-year survival rates were 59.8%, 55.2%, 33.9%, respectively, and the median of overall survival was 76.1 3.8 months. The difference between the survival curve for all patients including non-RFA group
Statistical analysis Overall survival was defined as the interval between the beginning of treatment and death or the date of the last follow-up. Recurrence-free survival was defined as the interval between treatment and the date of local, intrahepatic or extrahepatic recurrence. Tumor-free survival was defined by the absence of a detectable tumor at the endpoint date. The statistical analyses were performed using the SPSS 10.0 statistical software (SPSS Company, Chicago, Illinois, USA, 2005). Comparisons between the 2 groups were done using Student’s t-test for continuous data and the Chi square test for
Figure 2. Overall survival curves for all patients and for patients received RFA as first-line treatment.
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and the survival curve for patients treated with RF ablation was not statistically significant (P ¼ 0.724, Fig. 2). In patients who underwent RFA, ALB (P < 0.001), ICGR15 (P < 0.001), prothrombin activity (P < 0.001) were found to be associated with overall survival by univariate analysis. After entered into multivariate analysis, ICGR15 [HR 1.800 (1.126e2.878); P ¼ 0.014], prothrombin activity [HR 0.492 (0.305e0.794); P ¼ 0.004] was found as independent predictors of overall survival (Table 2). Patients with ICGR15 10% and prothrombin activity > 75% had 5-, 7-, 10-year survival rates of 67.1%, 64.2%, 57.1%, respectively; the median survival was 87.7 4.4 months. Patients with ICGR15 > 10% and, or, prothrombin activity 75% had 5-, 7-, 10-year survival rates of 44.3%, 37.6%, 33.2%, respectively; median survival was 51.2 5.7 months. The difference between survival curve for patients in the former group and survival curve for patients in the latter group was statistically significant ( p < 0.001). Recurrence-free survival of RFA During follow-up time, tumor recurrence was observed in 135 patients, including 28 local, 105 intrahepatic, and two extrahepatic recurrences. Only four patients experienced multiple recurrences. In this setting, a recurrence interval >1 year was observed in 84 patients. These patients had better survival rates than patients with recurrence interval 1 year (P ¼ 0.001) (Fig. 3). The estimated overall 3-, 5-, 7-year survival rates were 70.6%, 53.0%, 48.2% for patients with recurrence intervals >1 year, and the median of overall survival was 71.5 6.1 months. Tumor size was the only factor associated with local recurrence (P ¼ 0.04). Mean tumor size was larger in patients with local recurrence than that in patients without local recurrence (3.1 1.0 cm versus 2.4 1.1 cm, P ¼ 0.019). Among the 28 patients with local recurrence, 23 patients were successfully treated by repeated RFA, two by resection, and three by TACE. Among the 105 patients with intrahepatic Table 2 Cox survival analysis of predictors of overall survival for 224 patients. Univariate Factors
P
Age (y), Median (range) Sex (M/F) AFP, ng/ml GGT, u/L Serum albumin, g/L TBIL, mmol/L ICGR15, % PLT, 109/L Tumor size, cm Ascites (yes/no) Prothrombin activity
0.654 0.598 0.220 0.054 <0.001 0.219 <0.001 0.137 0.135 0.055 <0.001
Multivariate HR
95%CI
P
1.800
1.126e2.878
0.014
Figure 3. Overall survival curves for patients with recurrence intervals 1 year or >1 year.
recurrence, 71 patients were treated by repeated RFA, three by SR, 25 by TACE, and the other treated by supportive care. Two patients with extrahepatic metastases received supportive care. The estimated 5-, 7-, 10-year recurrence-free survival rates were 36.3%, 29.2%, 17.5%, respectively, and the median of recurrence-free time was 47.8 3.7 months. By univariate analysis, ALB (P < 0.001), ICGR15 (P ¼ 0.015), prothrombin activity (P ¼ 0.036) were associated with recurrence-free survival. By multivariate analysis, ALB [HR 1.989 (1.040 3.802); P ¼ 0.008] was found to be the only independent predictor of recurrence-free survival. After RFA, 22 patients in this study received nucleoside analog treatment for hepatitis B virus. In the subgroup, all patients achieved complete ablation. After a mean survival of 70.1 15.4 months, three patients had intrahepatic recurrence, and died of tumor progression; the other were alive and tumor-free. Tumor-free survival of RFA At time of the analysis, 136 patients were alive. Among these patients, 114 were tumor-free. In total, 74 patients received repeated RFA. Among these patients, 62 patients were tumor-free. The estimated 5-, 7-, 10-year tumor-free survival rates were 42.4%, 36.5%, 28.2%, respectively, and the median of tumor-free time was 54.9 4.2 months. By univariate analysis, platelets (P ¼ 0.042), ALB (P < 0.001), ICGR15 (P ¼ 0.006), TBIL (P ¼ 0.036) were associated with recurrence-free survival. By multivariate analysis, ALB [HR 2.182 (1.172 4.066); P ¼ 0.002] was found as the only independent predictor of tumor-free survival. Complications of RFA
0.492
0.305e0.794
0.004
GGT, g-glutamyltranspeptidase; TBIL, total bilirubin; AFP, alpha fetoprotein; ICGR15, indocyanine green retention rate in 15 min.
Including 72 RFA sessions for treatment of recurrence, 321 total RFA sessions were performed. There was no treatment-related death in the study. Two major complications
Z.-W. Peng et al. / EJSO 36 (2010) 1054e1060
were observed, including moderate/severe ascites (n ¼ 1), and peritoneal bleeding (n ¼ 1). Pain and fever were the most commonly seen minor complications after treatment. Post-treatment fever, >38.5 C, was observed in 113 patients. Post-treatment pain requiring administration of analgesics was observed in 97 patients. Discussion At the end of the study, 224 patients received RFA as first choice, and 23 patients received SR as their choice. The major findings of this study in patients with resectable HCC (5 cm or less in diameter with well-preserved live function) was the treatment strategy’s efficacy and feasibility. There was no treatment-related death, and a 10-year overall survival rate was 32.6% with a median survival of 74.6 months. For patients who received RFA, the 10-year overall survival rate was 33.9% with a median survival of 76.1 months. The outcome seemed somewhat better in patients with ICGR15 10% and prothrombin activity >75%, who had 5-year survival rates of 67.1% with a median survival of 87.7 months which was equal to that reported in other studies, including for patients with similar criteria either treated by RFA or resection.8e10,18 The RFA procedure was associated with acceptable morbidity (only two major complications) and no tumor seeding along needle tracks, which compares favorably with the results of other large series of RFA.9,10,19 Complete ablation were achieved in 96.4% of the treated patients. However, some tumors remain difficult to treat with RFA because of their location. Some patients (18/247) had to be excluded from this study because their tumors could not be visualized on US (n ¼ 7) or were adjacent to intestinal loops or main bile ducts (n ¼ 11) might be damaged by the treatment. All these patients all converted to received SR as second choice treatment. Moreover, 8 treatment failures were observed in patients whose tumors were large than 3 cm in diameter or located near a large blood vessels whose flow probably caused excessive heat loss in the ablation zone (the so-called “heat sink effect”20). These patients were successfully treated by SR, which suggested that SR may used as salvage treatment after RFA. The major problem with RFA is the high recurrence rate.9,10,12 Some authors have suggested that iterative RFA may be suitable for limited recurrence. They point out iterative RFA is associated with tumor-free survival.9 Actually, iterative RFA can be performed for limited recurrence more easily than resection.21,22 In our study, iterative RFA was easy to perform and achieved effective results. During follow-up, most of patients with recurrence (94/ 135) received iterative RFA. We observed that, the median recurrence-free survival was 47.8 months, after iterative RFA, the median tumor-free survival was 54.9 months. According to a recent report, the recurrence interval of HCC after SR is associated with survival outcomes for RFA.23 However, whether the recurrence interval is associated
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with survival results after RFA is not known. We observed that, for patients with recurrence, the recurrence interval after RFA affected overall survival. So, we think that combined treatments such as TACE, cytokine-induced killer cells therapy, and percutaneous ethanol injection to prolong recurrence time may be necessary.24e27 In the current study, we found ICGR, prothrombin activity independently impacted overall survival after RFA in this group. We also found that ALB was the only factor that impacted recurrence- and tumor-free survival. ICGR, ALB, prothrombin activity were factors reflective of liver function. As shown in previous reports, liver function strongly influenced survival.8,28,29 These results confirmed the importance of liver function in the treatment of HCC by RFA. It was worth to noting that tumor size was only associated with local recurrence. The currently available RFA systems produce an ablation zone of up to 5.0 cm in diameter. As it is generally accepted that the ‘safety margin’ of ablation for small HCC is at least 1.0 cm,5,30 it is, therefore, not surprising that the recurrence rate was higher for patients with larger tumors in our study. In conclusion, our results indicate that RFA is considered to be the treatment of first choice for patients with solitary HCC 5 cm and well-preserved liver function. Surgery can be used as second-line and salvage therapy for few patients if RFA is unfeasible or unsuccessful. Conflict of interest There is no conflict of interest in our study.
Acknowledgements This work was supported by the grant of Sciences and Technology Committee of Guangdong Province, China, (2006B36002008).
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Radiofrequency ablation as first-line treatment for small solitary hepatocellular carcinoma: Long-term results Z.-W. Peng a,b,d, Y.-J. Zhang a,b,d, M.-S. Chen a,b,*, X.-J. Lin a,b, H.-H. Liang c, M. Shi a,b a
Department of Hepatobiliary Surgery, Cancer Centre of Sun Yat-Sen University, 651 Dongfeng Road East, Guangzhou 510060, China b State Key Laboratory of Oncology in Southern China, Guangzhou 510060, China c The Second Affiliated Hospital of Guangzhou Medical College, China Accepted 19 August 2010 Available online 16 September 2010
Abstract Aims: To evaluate long-term results of patients with small solitary hepatocellular carcinoma (HCC) and well-preserved liver function who received radiofrequency ablation (RFA) as first-line treatment. Materials and methods: Between November 1999 and June 2007, 247 patients with solitary HCC 5 cm and liver status scored as ChildPugh class A were enrolled. RFA was performed in 224 patients as first-line treatment; 23 patients excluded from RFA because of unfavorable tumor location or their unwillingness, and all of these patients converted to surgical resection. Results: In the 224 patients treated with RFA, the overall 5-, 7-, 10-year survival rates were 59.8%, 55.2%, 33.9%, respectively, and the median of overall survival was 76.1 months. Complete ablation was achieved in 216 patients (96.4%). Major complications occurred in two patients (0.9%), with no treatment-related death or needle track seeding. Indocyanine green retention rate in 15 min (ICGR15) (P ¼ 0.014) and prothrombin activity (P ¼ 0.004) were associated with overall survival. A subgroup of patients with ICGR15 10% and prothrombin activity >75% had 5-, 7-, 10-year survival rates of 67.1%, 64.2%, 57.1%, respectively, with a median survival of 87.7 months. The 10-year recurrence-free, tumor-free survival rates were 17.5%, 28.2%, respectively. Serum albumin was the only factor that significantly impacted recurrence-free and tumor-free survival (P ¼ 0.008, 0.002, respectively). Conclusion: RFA is considered to be the treatment of first choice for patients with solitary HCC 5 cm and well-preserved liver function. Surgery can be used as second-line therapy for few patients if RFA is unfeasible. Ó 2010 Elsevier Ltd. All rights reserved. Keywords: First-line treatment; Radiofrequency ablation; Hepatocellular carcinoma; Survival
Introduction As routine screening of high-risk patient has been implemented, more and more patients are being diagnosed with hepatocellular carcinoma (HCC) at an early stage (solitary 5 cm in diameter or 3 nodules, 3 cm in diameter) allowing radical treatment.1e3 Liver transplantation can eliminate tumors and cirrhosis at the same time, and is considered to be the most appropriate treatment for these patients. But, the lack of liver donors is a major * Corresponding author. Department of Hepatobiliary Oncology, Cancer Center, Sun Yat-sen University, Guangzhou 510060, Tel./fax: þ86 20 8734 3117, þ86 1390 224 1061 (mobile). E-mail address: [email protected] (M.-S. Chen). d Both authors contributed equally to this article. 0748-7983/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2010.08.133
limitation.4,5 Until now, surgical resection (SR) has been still considered as the first choice treatment for these patients, which may offer a 5-year survival rate above 50%.1 However, SR is used only in about 5% of Western patients, and about 40% of Asian patients.6,7 In some centers, radiofrequency ablation (RFA) is considered to be a safe and effective first-line treatment of early stage HCC, with a 5-year survival rate of 40%e57%.8e10 Recently, a clinical trial has shown that RFA was as effective as SR for small solitary HCC with well-preserved liver function in terms of overall survival and disease-free survival.11 Some authors consider that RFA can be used as an alternative treatment to surgery for resectable HCC.10,12 Actually, patients with resectable disease can achieve 5-year survival >70% after RFA in some centers.9,10 However, other authors maintain that SR should
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be the first choice treatment for resectable HCC because RFA has not been shown to be superior to SR, and some tumors (adjacent to intestinal loops or main bile ducts) may be unsuitable for RFA because of the risk of bleeding, tumor seeding, bile leakage, and perforation.13 Therefore, the appropriate treatment strategy for resectable HCC is still under debate. To clarify this issue, we conducted a large cohort study that included a consecutive series of patients with single HCC 5.0 cm or less in diameter accompanying well-preserved liver function who received RFA as first-line treatment.
Patients and methods Patients Patients were enrolled between November 1999 and June 2007 according to the following inclusion criteria: (1) presence of solitary HCC measuring 5.0 cm in diameter, (2) liver status scored as Child-Pugh class A, (3) no extrahepatic metastasis, and no imaging evidence of invasion into the portal/hepatic vein branches, (4) no history of encephalopathy, ascites refractory to diuretics or variceal bleeding, (5) no severe coagulation disorders (prothrombin activity <40% or a platelet count of <40,000/mm3), and (6) no previous treatment. The diagnosis of HCC was based on the diagnostic criteria used by the European Association for the Study of the Liver (EASL)14: two imaging techniques showing typical features of HCC or positive findings on one imaging study together with an alpha fetoprotein level of >400 ng/ mL in a patient, or if a cytological/histological diagnosis of HCC. The treatment selection for HCC in our study was made at patients’ request after a full discussion with the team of multimodality specialists for HCC in our center. During the study period, 247 consecutive patients who met the aforementioned inclusion criteria were enrolled in the study. Twenty three patients excluded from RFA (non-RFA group) because:(1) their tumors located adjacent to intestinal loops or main bile ducts (n ¼ 11), (2) their tumors were poor or absent visualization on ultrasound (n ¼ 5), (3) they refused to received RFA (n ¼ 7) (Fig. 1). These 23 patients all received SR. The remaining 224 patients received RFA (RFA group) as the first-line treatment. The baseline characteristics of the patients in RFA group were reported in Table 1. For each case, we recorded gender, age, total bilirubin level (TBIL), g-glutamyltranspeptidase (GGT), AFP, serum albumin (ALB), indocyanin green retention at 15 min (ICGR15), prothrombin activity, platelet, ascites and tumor size. These parameters were evaluated as possible predictors of overall, recurrence-free, and tumor-free survival.
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RF ablation procedures Expandable electrodes RFA Before September 2004, we used a commercially available system (RF 2000; RadioTherapeutics Mountain View, CA), and a needle electrode with a 15 gauge insulated cannula with 10 hook-shape expandable electrode tines with a diameter of 3.5 cm at expansion (LeVeen; RadioTherapeutics). A 15 gauge RFA needle was first inserted into the tumor. After the ten tines of the needle were deployed, the RF generator was activated and initiated with 10 W of power. The power was increased 10 W per minute to 90 W. RFA was applied until either there was a marked increase in impedance or 15 min had elapsed. If a marked increase in impedance was not achieved, a second application of RF was given. No more than 3 applications of RFA were given in a treatment session. For tumors 3.0 cm in greatest dimension, a single ablation was performed. For tumors >3.0 cm in greatest dimension, multiple overlapping ablations as described by Chen et al15 were performed. The first ablation started at the location farthest away from the skin puncture site. After ablation was completed, the electrode tines were retracted; the needle was withdrawn to the second predetermined location. The electrode tines were then re-expanded and the RF generator was reactivated. This process was repeated until the entire lesion was adequately covered. Perfusion electrode RFA Since September 2004, we used a commercially available system with a 375-KHz computer-assisted radiofrequency generator (Elektrotom HiTT 106, Berchtold, Medizinelektronik, Germany) and an open-perfused electrode (Berchtold, Tuttlingen, Germany) of 15 cm, 14 gauge, and a 15 mm active electrode tip with microbores. The 15 gauge needle was introduced into the tumor, 60 W of the radiofrequency energy was delivered by the generator with the duration of 8 min for every single energy application. During the RFA application, continuous perfusion of the open-perfused electrode with 0.9% sodium chloride solution was administered automatically by means of a syringe pump (Pilot C, Fresenius Medical Care, Alzenau, Germany) linked to the radiofrequency generator. The saline solution was administered at a base rate of 120 mL/h. A saline solution bolus of 600 mL/h was administered for 1e2 s if the impedance increased more than 900 U. For tumors 3.0 cm in greatest dimension, single applicator position with 1e2 duration was adopted for RFA. For tumors >3.0 cm in greatest dimension, different applicator positions were adopted for RFA to create overlapping coagulation zones.16,17 During the RFA, a hyperechoic area was observed around the electrode tip on ultrasonic monitoring. The aim of the treatment was to have this hyperechoic area covering an area larger than 1 cm around the HCC. At the end of the procedure, the generator was reactivated to ablate the needle tract to prevent bleeding.
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Patients meeting inclusion criteria n = 247
converted to resection
n=23
Located in a high-risk area for RFA n=11 Refused to received RFA n=5 Tumors poor or absent on US n=7
Patient received RFA n = 224
Complete tumor ablation
Complete tumor ablation after two or
Viable tumor after two or
after one session
three sessions
three sessions
n = 208
n=8
n=8
Resection n=7 Tumor-free
Complete tumor ablation
TACE n=1
n=216
n=81
Tumor recurrence n=135
Local recurrence
Intrahepatic recurrence
n=28
n=23
n=94
Alive n=145
n=2
n=2 n=71
Repeat RFA
Extrahepatic metastasis
n=105
n=3 n=3
n=25
n=6
Resection
TACE
Supportive care
n=5
n=28
n=8
Death n=99
Lost to follow up n=3
Tumor progression n=26
Tumor progression n=73
Tumor progression n=2
Tumor free n=119
Tumor free n=26
Tumor free n=1
Figure 1. A patient flow diagram for the study.
Follow-up A dual-phase spiral computed tomography (CT) was done 4 weeks after treatment and thereafter every 2 months for the first 2 years. At each of these follow-up visits, blood tests including serum liver enzyme tests, and serum alpha fetoprotein were done. Chest radiography was done every 6 months. Follow-up visits were extended to once every 3 months after 2 years. Magnetic resonance imaging (MRI) was carried out if CT did not provide definite evidence regarding the presence of residual viable tumor. Complete ablation was defined as no areas of enhancement seen within or at the periphery of the ablation zone.
Incomplete ablation was defined as enhancing tissue was still observed at the tumor site. For such cases, up to three applications of RFA were performed. Therefore, treatment failure was defined as persistence of enhancing tissue at the tumor site after a maximum of three iterative RFA procedures. In this setting, other treatment options including SR, transarterial chemoembolization (TACE) or supportive care were performed. After complete ablation was achieved, local recurrence was defined as the development of tumor staining at the margins of the tumor on CT/MRI. Intrahepatic recurrence was defined as a separate new lesion in the liver more than 2.0 cm away from the primary lesion, and extrahepatic
Z.-W. Peng et al. / EJSO 36 (2010) 1054e1060 Table 1 Demographic data for 224 patients received RFA. Factors
Value
Median Age in years, (range) 60 >60 Sex (M/F) HBsAg()b AFPd, ng/ml Median (range) 400 >400 GGTa, m/L Median (range) Serum albumin, g/L Median (range) TBILc, mmol/L Median (range) ICGR15e, % Median (range) 10 >10 Platelet, 109/L Median (range) 100 >100 Tumor size, cm Median (range) 3 >3 Ascites (yes/no) Prothrombin activity Median (range) 75 >75
55(25e80) 139 85 196/28 203/11
a b c d e
562.3(3.0e121000) 56 168
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categorical data. The overall survivals were calculated using a life-table method and compared with ManteleCox test. The survival curves were constructed by KaplaneMeier method and compared by log-rank test. The relative prognostic significance of the variables in predicting survival rates was assessed using multivariate Cox proportional hazards regression analysis. Results were given as mean S.D. All statistical tests were two-sided, and p < 0.05 were considered statistically significant. Results
108.6(10.8e605.4) 39.5(32.5e45.7) 11.5(5.0e29.5) 6.5(3.0e20.5) 177 47 131(80e300) 136 88 2.5(1.0e5.0) 189 35 11/213 76.2(65e97) 50 174
g-Glutamyltranspeptidase. Hepatitis B surface antigen. Total bilirubin. Alpha fetoprotein. Indocyanine green retention rate in 15 min.
metastasis was defined as a metastatic lesion outside the liver. For local and intrahepatic recurrence, RFA was repeated if the patients still met the inclusion criteria. If the patients were beyond the inclusion criteria, SR, TACE or supportive care were given, depending on the tumor, the liver function, and the general condition of the patient. For extrahepatic metastasis, supportive care was given.
Treatment efficacy of RFA Two hundred forty nine total RFA sessions were performed. One session was required for 208, 2 for 7, and 3 for 9 patients. Complete ablation was achieved in 216 patients (96.4%). Treatment failure was observed in eight patients (3.6%), including 5 patients with nodules larger than 3 cm, and 3 patients with nodules located near a large blood vessel. In this setting, seven patients received SR, and one patients received TACE. Overall survival At the time of the analysis, three patients were lost to follow-up after 5, 9, 16 months. The mean follow-up time was 43.6 27.4 months, with a range of 2e123 months. A total of 99 patients died in the follow-up period: 73 patients died of HCC progression, 21 patients of liver failure, and 5 patients of other disease (Fig. 1). The estimated overall 5-, 7-, 10-year survival rates for all patients in the study were 60.1%, 53.7%, 32.6%, respectively, and the median of overall survival was 74.6 3.5 months. For RFA group, after a mean follow-up time of 44.1 28.1 months, the estimated overall 5-, 7-, 10-year survival rates were 59.8%, 55.2%, 33.9%, respectively, and the median of overall survival was 76.1 3.8 months. The difference between the survival curve for all patients including non-RFA group
Statistical analysis Overall survival was defined as the interval between the beginning of treatment and death or the date of the last follow-up. Recurrence-free survival was defined as the interval between treatment and the date of local, intrahepatic or extrahepatic recurrence. Tumor-free survival was defined by the absence of a detectable tumor at the endpoint date. The statistical analyses were performed using the SPSS 10.0 statistical software (SPSS Company, Chicago, Illinois, USA, 2005). Comparisons between the 2 groups were done using Student’s t-test for continuous data and the Chi square test for
Figure 2. Overall survival curves for all patients and for patients received RFA as first-line treatment.
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and the survival curve for patients treated with RF ablation was not statistically significant (P ¼ 0.724, Fig. 2). In patients who underwent RFA, ALB (P < 0.001), ICGR15 (P < 0.001), prothrombin activity (P < 0.001) were found to be associated with overall survival by univariate analysis. After entered into multivariate analysis, ICGR15 [HR 1.800 (1.126e2.878); P ¼ 0.014], prothrombin activity [HR 0.492 (0.305e0.794); P ¼ 0.004] was found as independent predictors of overall survival (Table 2). Patients with ICGR15 10% and prothrombin activity > 75% had 5-, 7-, 10-year survival rates of 67.1%, 64.2%, 57.1%, respectively; the median survival was 87.7 4.4 months. Patients with ICGR15 > 10% and, or, prothrombin activity 75% had 5-, 7-, 10-year survival rates of 44.3%, 37.6%, 33.2%, respectively; median survival was 51.2 5.7 months. The difference between survival curve for patients in the former group and survival curve for patients in the latter group was statistically significant ( p < 0.001). Recurrence-free survival of RFA During follow-up time, tumor recurrence was observed in 135 patients, including 28 local, 105 intrahepatic, and two extrahepatic recurrences. Only four patients experienced multiple recurrences. In this setting, a recurrence interval >1 year was observed in 84 patients. These patients had better survival rates than patients with recurrence interval 1 year (P ¼ 0.001) (Fig. 3). The estimated overall 3-, 5-, 7-year survival rates were 70.6%, 53.0%, 48.2% for patients with recurrence intervals >1 year, and the median of overall survival was 71.5 6.1 months. Tumor size was the only factor associated with local recurrence (P ¼ 0.04). Mean tumor size was larger in patients with local recurrence than that in patients without local recurrence (3.1 1.0 cm versus 2.4 1.1 cm, P ¼ 0.019). Among the 28 patients with local recurrence, 23 patients were successfully treated by repeated RFA, two by resection, and three by TACE. Among the 105 patients with intrahepatic Table 2 Cox survival analysis of predictors of overall survival for 224 patients. Univariate Factors
P
Age (y), Median (range) Sex (M/F) AFP, ng/ml GGT, u/L Serum albumin, g/L TBIL, mmol/L ICGR15, % PLT, 109/L Tumor size, cm Ascites (yes/no) Prothrombin activity
0.654 0.598 0.220 0.054 <0.001 0.219 <0.001 0.137 0.135 0.055 <0.001
Multivariate HR
95%CI
P
1.800
1.126e2.878
0.014
Figure 3. Overall survival curves for patients with recurrence intervals 1 year or >1 year.
recurrence, 71 patients were treated by repeated RFA, three by SR, 25 by TACE, and the other treated by supportive care. Two patients with extrahepatic metastases received supportive care. The estimated 5-, 7-, 10-year recurrence-free survival rates were 36.3%, 29.2%, 17.5%, respectively, and the median of recurrence-free time was 47.8 3.7 months. By univariate analysis, ALB (P < 0.001), ICGR15 (P ¼ 0.015), prothrombin activity (P ¼ 0.036) were associated with recurrence-free survival. By multivariate analysis, ALB [HR 1.989 (1.040 3.802); P ¼ 0.008] was found to be the only independent predictor of recurrence-free survival. After RFA, 22 patients in this study received nucleoside analog treatment for hepatitis B virus. In the subgroup, all patients achieved complete ablation. After a mean survival of 70.1 15.4 months, three patients had intrahepatic recurrence, and died of tumor progression; the other were alive and tumor-free. Tumor-free survival of RFA At time of the analysis, 136 patients were alive. Among these patients, 114 were tumor-free. In total, 74 patients received repeated RFA. Among these patients, 62 patients were tumor-free. The estimated 5-, 7-, 10-year tumor-free survival rates were 42.4%, 36.5%, 28.2%, respectively, and the median of tumor-free time was 54.9 4.2 months. By univariate analysis, platelets (P ¼ 0.042), ALB (P < 0.001), ICGR15 (P ¼ 0.006), TBIL (P ¼ 0.036) were associated with recurrence-free survival. By multivariate analysis, ALB [HR 2.182 (1.172 4.066); P ¼ 0.002] was found as the only independent predictor of tumor-free survival. Complications of RFA
0.492
0.305e0.794
0.004
GGT, g-glutamyltranspeptidase; TBIL, total bilirubin; AFP, alpha fetoprotein; ICGR15, indocyanine green retention rate in 15 min.
Including 72 RFA sessions for treatment of recurrence, 321 total RFA sessions were performed. There was no treatment-related death in the study. Two major complications
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were observed, including moderate/severe ascites (n ¼ 1), and peritoneal bleeding (n ¼ 1). Pain and fever were the most commonly seen minor complications after treatment. Post-treatment fever, >38.5 C, was observed in 113 patients. Post-treatment pain requiring administration of analgesics was observed in 97 patients. Discussion At the end of the study, 224 patients received RFA as first choice, and 23 patients received SR as their choice. The major findings of this study in patients with resectable HCC (5 cm or less in diameter with well-preserved live function) was the treatment strategy’s efficacy and feasibility. There was no treatment-related death, and a 10-year overall survival rate was 32.6% with a median survival of 74.6 months. For patients who received RFA, the 10-year overall survival rate was 33.9% with a median survival of 76.1 months. The outcome seemed somewhat better in patients with ICGR15 10% and prothrombin activity >75%, who had 5-year survival rates of 67.1% with a median survival of 87.7 months which was equal to that reported in other studies, including for patients with similar criteria either treated by RFA or resection.8e10,18 The RFA procedure was associated with acceptable morbidity (only two major complications) and no tumor seeding along needle tracks, which compares favorably with the results of other large series of RFA.9,10,19 Complete ablation were achieved in 96.4% of the treated patients. However, some tumors remain difficult to treat with RFA because of their location. Some patients (18/247) had to be excluded from this study because their tumors could not be visualized on US (n ¼ 7) or were adjacent to intestinal loops or main bile ducts (n ¼ 11) might be damaged by the treatment. All these patients all converted to received SR as second choice treatment. Moreover, 8 treatment failures were observed in patients whose tumors were large than 3 cm in diameter or located near a large blood vessels whose flow probably caused excessive heat loss in the ablation zone (the so-called “heat sink effect”20). These patients were successfully treated by SR, which suggested that SR may used as salvage treatment after RFA. The major problem with RFA is the high recurrence rate.9,10,12 Some authors have suggested that iterative RFA may be suitable for limited recurrence. They point out iterative RFA is associated with tumor-free survival.9 Actually, iterative RFA can be performed for limited recurrence more easily than resection.21,22 In our study, iterative RFA was easy to perform and achieved effective results. During follow-up, most of patients with recurrence (94/ 135) received iterative RFA. We observed that, the median recurrence-free survival was 47.8 months, after iterative RFA, the median tumor-free survival was 54.9 months. According to a recent report, the recurrence interval of HCC after SR is associated with survival outcomes for RFA.23 However, whether the recurrence interval is associated
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with survival results after RFA is not known. We observed that, for patients with recurrence, the recurrence interval after RFA affected overall survival. So, we think that combined treatments such as TACE, cytokine-induced killer cells therapy, and percutaneous ethanol injection to prolong recurrence time may be necessary.24e27 In the current study, we found ICGR, prothrombin activity independently impacted overall survival after RFA in this group. We also found that ALB was the only factor that impacted recurrence- and tumor-free survival. ICGR, ALB, prothrombin activity were factors reflective of liver function. As shown in previous reports, liver function strongly influenced survival.8,28,29 These results confirmed the importance of liver function in the treatment of HCC by RFA. It was worth to noting that tumor size was only associated with local recurrence. The currently available RFA systems produce an ablation zone of up to 5.0 cm in diameter. As it is generally accepted that the ‘safety margin’ of ablation for small HCC is at least 1.0 cm,5,30 it is, therefore, not surprising that the recurrence rate was higher for patients with larger tumors in our study. In conclusion, our results indicate that RFA is considered to be the treatment of first choice for patients with solitary HCC 5 cm and well-preserved liver function. Surgery can be used as second-line and salvage therapy for few patients if RFA is unfeasible or unsuccessful. Conflict of interest There is no conflict of interest in our study.
Acknowledgements This work was supported by the grant of Sciences and Technology Committee of Guangdong Province, China, (2006B36002008).
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