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Hepatology Research 2014; 44: E156–E162
doi: 10.1111/hepr.12264
Original Article
Comparative study of percutaneous radiofrequency ablation and hepatic resection for small, poorly differentiated hepatocellular carcinomas Hiroya Iida, Tsukasa Aihara, Shinichi Ikuta and Naoki Yamanaka Department of Surgery, Meiwa Hospital, Nishinomiya, Japan Aim: Histologically, poorly differentiated hepatocellular carcinomas (HCC) are considered highly malignant. Here, we aimed to evaluate the relative efficacy and safety of hepatic resection or radiofrequency ablation (RFA) for treating this malignancy. Methods: Between April 2004 and May 2011, we enrolled 48 patients who had poorly differentiated HCC that had been diagnosed postoperatively by pathological assessment. All the tumors had a maximum diameter of 3 cm and all patients had three or less tumors. Fifteen of these patients underwent hepatic resection (HR group) and 33 patients underwent RFA (RF group). The patient background, tumor characteristics, overall survival rate and recurrence-free survival rate were assessed in both groups. Results: The mean maximum tumor diameter was 2.5 and 2.0 cm in the HR and RF groups, respectively. The prothrom-
INTRODUCTION
H
EPATOCELLULAR CARCINOMA (HCC) is a common malignancy in Japan, for which hepatic resection is the most effective treatment in patients with good hepatic functional reserve. However, most patients experience recurrence after hepatic resection due to infection with a hepatitis virus. Since the 1990s, the use of radiofrequency ablation (RFA) has become more common for the treatment of
Correspondence: Dr Hiroya Iida, Meiwa Hospital, 4-31 Agenaruo-cho, Nishinomiya, Hyogo 663-8186, Japan. Email: [email protected] Conflict of interest: Drs Hiroya Iida, Tsukasa Aihara, Shinichi Ikuta and Naoki Yamanaka have no conflicts of interest or financial ties to disclose. Received 25 May 2013; revision 14 October 2013; accepted 18 October 2013.
E156
bin activity level was 94% and 86% in the HR and RF groups, respectively. The 1-, 3- and 5-year cumulative survival rates were 89.1%, 68.7% and 68.7%, respectively, in the HR group, and 59.2%, 40.9% and 32.7%, respectively, in the RF group. The 1-, 3- and 5-year recurrence-free survival rates were 85.1%, 64.8% and 48.6%, respectively, in the HR group, and 29.0%, 7.2% and 7.2%, respectively, in the RF group. There was a significant difference between these groups (P < 0.05).
Conclusion: As hepatic resection has greater efficacy than RFA in the treatment of poorly differentiated HCC, even in cases with a small tumor size, we recommend its use for this malignancy. Key words: hepatectomy, hepatic resection, hepatocellular carcinoma, poorly differentiated hepatocellular carcinoma, radiofrequency ablation, tumor seeding
small HCC tumors, particularly because it can be performed repeatedly. Several studies have evaluated the effectiveness and safety of RFA,1–4 and one study has reported that it is particularly effective in cases of recurrent HCC after hepatic resection.5 The Japanese guidelines for HCC treatment state that RFA should be used in cases where the maximum tumor diameter is 3 cm and there are three or less tumors in total.6,7 However, the guidelines do not address tumor differentiation. Some previous studies have shown that RFA, which is used to treat poorly differentiated HCC, is associated with a risk of tumor seeding and diffuse intrahepatic recurrence.8–10 Despite this, it remains unclear as to whether or not tumor differentiation is actually associated with prognosis. In the present study, we aimed to compare the efficacy of hepatic resection and RFA for the treatment of poorly differentiated, small HCC tumors that are histologically diagnosed as being malignant.
© 2013 The Japan Society of Hepatology
Hepatology Research 2014; 44: E156–E162
METHODS Patients
B
RFA or resection for poorly differentiated HCC E157
power (W), RF current (mA), RF voltage (V) and impedance (Ω) simultaneously, and continued ablation until a break occurred, which was considered to be the point of complete ablation. The break was noted when the impedance increased to 25 Ω above the initial impedance of RFA, and at this point, the RF power was automatically decreased to 0 W. All RFA procedures were completed in a single session for each tumor.
ETWEEN APRIL 2004 and May 2011, we enrolled patients who had undergone hepatic resection (HR group; n = 15) or percutaneous RFA (RF group; n = 33) as a first-line treatment for newly developed HCC. No cases of recurrent HCC that had undergone treatment at the time of study initiation were included in this study. Additional inclusion criteria were that the maximum tumor diameter was 3 cm, that there were no more than three HCC tumors in total and that the pathological diagnosis after the procedure was poorly differentiated HCC. Contrast computed tomography (CT) was used to confirm that tumors had been completely resected (HR group) or ablated (RF group).
Evaluation of the safety margin after RFA
Criteria for making the therapeutic decisions
Fine-needle biopsy
The decision on whether to treat using hepatic resection or RFA was based on the location of the tumor. Hepatic resection was used primarily if the tumor was adjacent to major vessels or located on the surface of the liver. It was also selected if there were major vessels between the puncture lines of the RFA needle.
Hepatic resection Hepatic resection was performed under general anesthesia. All patients underwent a J-incision and the transection was performed by using a cavitron ultrasonic surgical aspirator. Four patients underwent partial resection and 11 patients underwent segmentectomy or lobectomy. All patients had a surgical margin of at least 5 mm and none of the patients indicated any evidence of a residual lesion.
RFA The RFA procedure was performed with local anesthesia using Lidocaine (Xylocaine; AstraZeneca, Osaka, Japan). We used the Cool-tip RF system (Covidien, Boulder, CO, USA) for all patients and the entire procedure was performed percutaneously. A 2-cm needle was used if the maximum tumor diameter was less than 2 cm, and a 3-cm needle was used if the maximum tumor diameter was between 2 and 3 cm. Abdominal ultrasound (US) (Nemio; Toshiba, Tokyo, Japan) was used during tumor puncturing. The starting power level for ablation was 40 W for the 2-cm needle and 60 W for the 3-cm needle, and in each case, this was increased by 10 W/min using the impedance control mode. We monitored the RF
The safety margin after RFA was evaluated by a specialized radiologist. We examined the ablation area using contrast CT between 1 and 3 days after the procedure. Complete ablation was defined as the absence of enhancement at the original site of the lesion, including a surrounding safety margin of at least 5 mm.
Fine-needle biopsy was performed just before RFA. We used US and targeted the center of the tumor using a 18 G × 20-cm biopsy system (Monopty; Bard, New Jersey, CO, USA).
Preoperative transarterial embolization (TAE) All of the patients had newly developed HCC for which RFA or resection was the first-line treatment. However, we often perform TAE before RFA or, less frequently, before resection in an attempt to control micrometastasis. TAE was performed 1–2 weeks prior to RFA or resection. There were no set criteria for whether or not TAE was performed.
Pathology All patients included in this study had poorly differentiated HCC. Resected specimens from the HR group and biopsy specimens from the RF group (obtained prior to the procedure) were examined by the same specialized pathologist.
Follow up All patients were examined for the level of serum α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) every 2 months. They were also followed up every 4 months using contrast CT, magnetic resonance imaging or US. We confirmed the presence of recurrent HCC using at least two imaging modalities. However, the AFP and DCP levels were used as supplementary indicators.
© 2013 The Japan Society of Hepatology
E158 H. Iida et al.
Hepatology Research 2014; 44: E156–E162
Statistical analysis The HR group and the RF group were compared with respect to the following variables: age; sex; etiology; rate of preoperative TAE; maximum tumor diameter; number of tumors; serum levels of albumin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), AFP, DCP and total bilirubin; platelet count; prothrombin activity (PT); indocyanine green retention rate at 15 min (ICG-R15); and Child–Pugh score. To compare the two groups, the Mann–Whitney U-test was used for continuous variables and the χ2-test for categorical variables. In addition, the cumulative survival rate and the recurrence-free survival rate were evaluated using the Kaplan–Meier estimator. Differences in the cumulative survival rate and recurrence-free survival rate were analyzed using the log–rank test. Multivariate analysis was performed with some categories using Cox’s proportional hazards model. For each statistical test, P < 0.05 was considered statistically significant. The statistical software used was JMP version 9.0.2 (SAS Institute, Tokyo, Japan).
RESULTS
T
ABLE 1 SUMMARIZES THE patient characteristics of each group. The mean (1 standard deviation) age was 67 1 8 years in the HR group and 69 1 10 years in
the RF group. The HR group consisted of 14 male patients and one female patient and the RF group consisted of 21 male patients and 12 female patients. There were significantly more female patients in the RF group than in the HR group (P = 0.03). In the HR group, positive results were obtained for hepatitis B virus (HBV) surface antigen in two patients and hepatitis C virus (HCV) antibody in 12 patients, whereas one patient indicated a negative result for both the HBV surface antigen and HCV antibody. In the RF group, positive results were obtained for HBV surface antigen in five patients and HCV antibody in 22 patients, whereas six patients indicated a negative result for both the HBV surface antigen and HCV antibody. The rate of preoperative TAE was significantly different between the groups (40.0% in the HR group and 81.8% in the RF group; P = 0.006). The mean maximum tumor diameter was 2.5 1 0.4 cm in the HR group and 2.0 1 1.1 cm in the RF group (P = 0.003), whereas the mean number of tumors was 1.2 1 0.6 in the HR group and 1.5 1 0.9 in the RF group (P = 0.39). None of the biochemical and hematology test results were significantly different between the two groups, with the exception of the mean PT levels that differed significantly between the groups (94% 1 8% in the HR group and 86% 1 9% in the RF group; P = 0.008). Fourteen patients had a Child–Pugh score of A and one patient had a score of B in the HR
Table 1 Univariate analyses comparing several factors between HR group and RF group
Age (years) Sex (male : female) Etiology (HBV : HCV : NBNC) Preoperative TAE (%) Maximum tumor diameter (cm) No. of tumors Albumin level (g/dL) AST (IU/L) ALT (IU/L) Total bilirubin level (mg/dL) Platelet count (×104/μL) Prothrombin activity (%) AFP (ng/mL) DCP (mAU/mL) ICG-R15 (%) Child–Pugh (A:B:C)
HR group (n = 15)
RF group (n = 33)
P-value
67 1 8 14:1 2:12:1 40.0 2.5 1 0.4 1.2 1 0.6 4.0 1 0.4 47 1 26 54 1 55 0.9 1 0.4 14.3 1 4.4 94 1 8 350 1 820 665 1 1750 15.5 1 10.8 14:1:0
69 1 10 21:12 5:22:6 81.8 2.0 1 1.1 1.5 1 0.9 3.8 1 0.3 50 1 19 43 1 22 0.7 1 0.3 12.8 1 6.6 86 1 9 172 1 296 311 1 945 19.9 1 11.1 28:5:0
0.62 0.03 0.54 0.006 0.003 0.39 0.11 0.34 0.84 0.09 0.17 0.008 0.56 0.13 0.14 0.41
AFP, α-fetoprotein level; ALT, alanine aminotransferase; AST, aspartate aminotransferase; DCP, des-γ-carboxy prothrombin; HBV, positive for the hepatitis B virus surface antigen; HCV, positive for the hepatitis C virus antibody; ICG-R15, indocyanine green retention rate at 15 min; NBNC, negative for the hepatitis B antigen and hepatitis C antibody; TAE, transarterial embolization.
© 2013 The Japan Society of Hepatology
RFA or resection for poorly differentiated HCC E159
group, whereas 28 patients had a Child–Pugh score of A and five patients had a score of B in the RF group. None of the patients had a Child–Pugh score of C. In the HR group, only one patient experienced a significant bile leak after the procedure; however, in the RF group, none of the patients developed any complications after the procedure. The 1-, 3- and 5-year cumulative survival rates for the HR group were 89.1%, 68.7% and 68.7%, respectively, whereas those of the RF group were 59.2%, 40.9% and 32.7%, respectively; significant differences in these values were noted between the groups (P = 0.03; Fig. 1). The 1-, 3- and 5-year recurrence-free survival rates for the HR group were 85.1%, 64.8% and 48.6%, respectively, whereas those of the RF group were 29.0%, 7.2% and 7.2%, respectively; significant differences in these values were noted between the groups (P = 0.0002; Fig. 2). Multivariate analysis was performed to identify the independent prognostic factors for survival and recurrence-free survival. We used factors of P 2 0.15 in the univariate analysis. For survival, these included AST (340 vs
Hepatology Research 2014; 44: E156–E162
doi: 10.1111/hepr.12264
Original Article
Comparative study of percutaneous radiofrequency ablation and hepatic resection for small, poorly differentiated hepatocellular carcinomas Hiroya Iida, Tsukasa Aihara, Shinichi Ikuta and Naoki Yamanaka Department of Surgery, Meiwa Hospital, Nishinomiya, Japan Aim: Histologically, poorly differentiated hepatocellular carcinomas (HCC) are considered highly malignant. Here, we aimed to evaluate the relative efficacy and safety of hepatic resection or radiofrequency ablation (RFA) for treating this malignancy. Methods: Between April 2004 and May 2011, we enrolled 48 patients who had poorly differentiated HCC that had been diagnosed postoperatively by pathological assessment. All the tumors had a maximum diameter of 3 cm and all patients had three or less tumors. Fifteen of these patients underwent hepatic resection (HR group) and 33 patients underwent RFA (RF group). The patient background, tumor characteristics, overall survival rate and recurrence-free survival rate were assessed in both groups. Results: The mean maximum tumor diameter was 2.5 and 2.0 cm in the HR and RF groups, respectively. The prothrom-
INTRODUCTION
H
EPATOCELLULAR CARCINOMA (HCC) is a common malignancy in Japan, for which hepatic resection is the most effective treatment in patients with good hepatic functional reserve. However, most patients experience recurrence after hepatic resection due to infection with a hepatitis virus. Since the 1990s, the use of radiofrequency ablation (RFA) has become more common for the treatment of
Correspondence: Dr Hiroya Iida, Meiwa Hospital, 4-31 Agenaruo-cho, Nishinomiya, Hyogo 663-8186, Japan. Email: [email protected] Conflict of interest: Drs Hiroya Iida, Tsukasa Aihara, Shinichi Ikuta and Naoki Yamanaka have no conflicts of interest or financial ties to disclose. Received 25 May 2013; revision 14 October 2013; accepted 18 October 2013.
E156
bin activity level was 94% and 86% in the HR and RF groups, respectively. The 1-, 3- and 5-year cumulative survival rates were 89.1%, 68.7% and 68.7%, respectively, in the HR group, and 59.2%, 40.9% and 32.7%, respectively, in the RF group. The 1-, 3- and 5-year recurrence-free survival rates were 85.1%, 64.8% and 48.6%, respectively, in the HR group, and 29.0%, 7.2% and 7.2%, respectively, in the RF group. There was a significant difference between these groups (P < 0.05).
Conclusion: As hepatic resection has greater efficacy than RFA in the treatment of poorly differentiated HCC, even in cases with a small tumor size, we recommend its use for this malignancy. Key words: hepatectomy, hepatic resection, hepatocellular carcinoma, poorly differentiated hepatocellular carcinoma, radiofrequency ablation, tumor seeding
small HCC tumors, particularly because it can be performed repeatedly. Several studies have evaluated the effectiveness and safety of RFA,1–4 and one study has reported that it is particularly effective in cases of recurrent HCC after hepatic resection.5 The Japanese guidelines for HCC treatment state that RFA should be used in cases where the maximum tumor diameter is 3 cm and there are three or less tumors in total.6,7 However, the guidelines do not address tumor differentiation. Some previous studies have shown that RFA, which is used to treat poorly differentiated HCC, is associated with a risk of tumor seeding and diffuse intrahepatic recurrence.8–10 Despite this, it remains unclear as to whether or not tumor differentiation is actually associated with prognosis. In the present study, we aimed to compare the efficacy of hepatic resection and RFA for the treatment of poorly differentiated, small HCC tumors that are histologically diagnosed as being malignant.
© 2013 The Japan Society of Hepatology
Hepatology Research 2014; 44: E156–E162
METHODS Patients
B
RFA or resection for poorly differentiated HCC E157
power (W), RF current (mA), RF voltage (V) and impedance (Ω) simultaneously, and continued ablation until a break occurred, which was considered to be the point of complete ablation. The break was noted when the impedance increased to 25 Ω above the initial impedance of RFA, and at this point, the RF power was automatically decreased to 0 W. All RFA procedures were completed in a single session for each tumor.
ETWEEN APRIL 2004 and May 2011, we enrolled patients who had undergone hepatic resection (HR group; n = 15) or percutaneous RFA (RF group; n = 33) as a first-line treatment for newly developed HCC. No cases of recurrent HCC that had undergone treatment at the time of study initiation were included in this study. Additional inclusion criteria were that the maximum tumor diameter was 3 cm, that there were no more than three HCC tumors in total and that the pathological diagnosis after the procedure was poorly differentiated HCC. Contrast computed tomography (CT) was used to confirm that tumors had been completely resected (HR group) or ablated (RF group).
Evaluation of the safety margin after RFA
Criteria for making the therapeutic decisions
Fine-needle biopsy
The decision on whether to treat using hepatic resection or RFA was based on the location of the tumor. Hepatic resection was used primarily if the tumor was adjacent to major vessels or located on the surface of the liver. It was also selected if there were major vessels between the puncture lines of the RFA needle.
Hepatic resection Hepatic resection was performed under general anesthesia. All patients underwent a J-incision and the transection was performed by using a cavitron ultrasonic surgical aspirator. Four patients underwent partial resection and 11 patients underwent segmentectomy or lobectomy. All patients had a surgical margin of at least 5 mm and none of the patients indicated any evidence of a residual lesion.
RFA The RFA procedure was performed with local anesthesia using Lidocaine (Xylocaine; AstraZeneca, Osaka, Japan). We used the Cool-tip RF system (Covidien, Boulder, CO, USA) for all patients and the entire procedure was performed percutaneously. A 2-cm needle was used if the maximum tumor diameter was less than 2 cm, and a 3-cm needle was used if the maximum tumor diameter was between 2 and 3 cm. Abdominal ultrasound (US) (Nemio; Toshiba, Tokyo, Japan) was used during tumor puncturing. The starting power level for ablation was 40 W for the 2-cm needle and 60 W for the 3-cm needle, and in each case, this was increased by 10 W/min using the impedance control mode. We monitored the RF
The safety margin after RFA was evaluated by a specialized radiologist. We examined the ablation area using contrast CT between 1 and 3 days after the procedure. Complete ablation was defined as the absence of enhancement at the original site of the lesion, including a surrounding safety margin of at least 5 mm.
Fine-needle biopsy was performed just before RFA. We used US and targeted the center of the tumor using a 18 G × 20-cm biopsy system (Monopty; Bard, New Jersey, CO, USA).
Preoperative transarterial embolization (TAE) All of the patients had newly developed HCC for which RFA or resection was the first-line treatment. However, we often perform TAE before RFA or, less frequently, before resection in an attempt to control micrometastasis. TAE was performed 1–2 weeks prior to RFA or resection. There were no set criteria for whether or not TAE was performed.
Pathology All patients included in this study had poorly differentiated HCC. Resected specimens from the HR group and biopsy specimens from the RF group (obtained prior to the procedure) were examined by the same specialized pathologist.
Follow up All patients were examined for the level of serum α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) every 2 months. They were also followed up every 4 months using contrast CT, magnetic resonance imaging or US. We confirmed the presence of recurrent HCC using at least two imaging modalities. However, the AFP and DCP levels were used as supplementary indicators.
© 2013 The Japan Society of Hepatology
E158 H. Iida et al.
Hepatology Research 2014; 44: E156–E162
Statistical analysis The HR group and the RF group were compared with respect to the following variables: age; sex; etiology; rate of preoperative TAE; maximum tumor diameter; number of tumors; serum levels of albumin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), AFP, DCP and total bilirubin; platelet count; prothrombin activity (PT); indocyanine green retention rate at 15 min (ICG-R15); and Child–Pugh score. To compare the two groups, the Mann–Whitney U-test was used for continuous variables and the χ2-test for categorical variables. In addition, the cumulative survival rate and the recurrence-free survival rate were evaluated using the Kaplan–Meier estimator. Differences in the cumulative survival rate and recurrence-free survival rate were analyzed using the log–rank test. Multivariate analysis was performed with some categories using Cox’s proportional hazards model. For each statistical test, P < 0.05 was considered statistically significant. The statistical software used was JMP version 9.0.2 (SAS Institute, Tokyo, Japan).
RESULTS
T
ABLE 1 SUMMARIZES THE patient characteristics of each group. The mean (1 standard deviation) age was 67 1 8 years in the HR group and 69 1 10 years in
the RF group. The HR group consisted of 14 male patients and one female patient and the RF group consisted of 21 male patients and 12 female patients. There were significantly more female patients in the RF group than in the HR group (P = 0.03). In the HR group, positive results were obtained for hepatitis B virus (HBV) surface antigen in two patients and hepatitis C virus (HCV) antibody in 12 patients, whereas one patient indicated a negative result for both the HBV surface antigen and HCV antibody. In the RF group, positive results were obtained for HBV surface antigen in five patients and HCV antibody in 22 patients, whereas six patients indicated a negative result for both the HBV surface antigen and HCV antibody. The rate of preoperative TAE was significantly different between the groups (40.0% in the HR group and 81.8% in the RF group; P = 0.006). The mean maximum tumor diameter was 2.5 1 0.4 cm in the HR group and 2.0 1 1.1 cm in the RF group (P = 0.003), whereas the mean number of tumors was 1.2 1 0.6 in the HR group and 1.5 1 0.9 in the RF group (P = 0.39). None of the biochemical and hematology test results were significantly different between the two groups, with the exception of the mean PT levels that differed significantly between the groups (94% 1 8% in the HR group and 86% 1 9% in the RF group; P = 0.008). Fourteen patients had a Child–Pugh score of A and one patient had a score of B in the HR
Table 1 Univariate analyses comparing several factors between HR group and RF group
Age (years) Sex (male : female) Etiology (HBV : HCV : NBNC) Preoperative TAE (%) Maximum tumor diameter (cm) No. of tumors Albumin level (g/dL) AST (IU/L) ALT (IU/L) Total bilirubin level (mg/dL) Platelet count (×104/μL) Prothrombin activity (%) AFP (ng/mL) DCP (mAU/mL) ICG-R15 (%) Child–Pugh (A:B:C)
HR group (n = 15)
RF group (n = 33)
P-value
67 1 8 14:1 2:12:1 40.0 2.5 1 0.4 1.2 1 0.6 4.0 1 0.4 47 1 26 54 1 55 0.9 1 0.4 14.3 1 4.4 94 1 8 350 1 820 665 1 1750 15.5 1 10.8 14:1:0
69 1 10 21:12 5:22:6 81.8 2.0 1 1.1 1.5 1 0.9 3.8 1 0.3 50 1 19 43 1 22 0.7 1 0.3 12.8 1 6.6 86 1 9 172 1 296 311 1 945 19.9 1 11.1 28:5:0
0.62 0.03 0.54 0.006 0.003 0.39 0.11 0.34 0.84 0.09 0.17 0.008 0.56 0.13 0.14 0.41
AFP, α-fetoprotein level; ALT, alanine aminotransferase; AST, aspartate aminotransferase; DCP, des-γ-carboxy prothrombin; HBV, positive for the hepatitis B virus surface antigen; HCV, positive for the hepatitis C virus antibody; ICG-R15, indocyanine green retention rate at 15 min; NBNC, negative for the hepatitis B antigen and hepatitis C antibody; TAE, transarterial embolization.
© 2013 The Japan Society of Hepatology
RFA or resection for poorly differentiated HCC E159
group, whereas 28 patients had a Child–Pugh score of A and five patients had a score of B in the RF group. None of the patients had a Child–Pugh score of C. In the HR group, only one patient experienced a significant bile leak after the procedure; however, in the RF group, none of the patients developed any complications after the procedure. The 1-, 3- and 5-year cumulative survival rates for the HR group were 89.1%, 68.7% and 68.7%, respectively, whereas those of the RF group were 59.2%, 40.9% and 32.7%, respectively; significant differences in these values were noted between the groups (P = 0.03; Fig. 1). The 1-, 3- and 5-year recurrence-free survival rates for the HR group were 85.1%, 64.8% and 48.6%, respectively, whereas those of the RF group were 29.0%, 7.2% and 7.2%, respectively; significant differences in these values were noted between the groups (P = 0.0002; Fig. 2). Multivariate analysis was performed to identify the independent prognostic factors for survival and recurrence-free survival. We used factors of P 2 0.15 in the univariate analysis. For survival, these included AST (340 vs
