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doi:10.1111/jgh.12441
H E PAT O L O G Y
Comparison of long-term effectiveness and complications of radiofrequency ablation with hepatectomy for small hepatocellular carcinoma Yong Fang,* Wei Chen,* Xiao Liang,† Da Li,* HaiZhou Lou,* Renbiao Chen,‡ Kaifeng Wang* and HongMing Pan* Departments of *Medical Oncology, †General Surgery and ‡Radiology and Medical Image Center, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China
Key words hepatectomy, prognosis, radiofrequency ablation, small hepatocellular carcinoma. Accepted for publication 16 October 2013. Correspondence Dr HongMing Pan, Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, 3 East QinChun Road, Hangzhou, Zhejiang 310016, China. Email: [email protected] Conflict of interest: None.
Abstract Background and Aim: To determine and compare the adverse events and long-term effectiveness for patients with small hepatocellular carcinoma (HCC) (≤ 3 cm) treated by percutaneous radiofrequency ablation (RFA) or hepatectomy. Methods: Small HCC from 120 patients were randomized into either percutaneous RFA therapy or hepatectomy group, and the effectiveness and complications of two treatment modalities were analyzed. The complications of post-RFA or hepatectomy, the complete treatment rate, treatment-related mortality, and disease-free and overall survival rate were followed up and conducted. Results: In patients with small HCC, complete remission rates were achieved in 95% and 96.7% in the percutaneus RFA and hepatectomy groups, respectively (P > 0.05). Hepatic function at day-7 status post-treatment, including albumin and bilirubin levels, were significantly worse in the hepatectomy group (P < 0.01). Compared with the RFA group, the incidence of postoperative complications (27.5% vs 5.0%) and hospital stay (11.8 ± 3.1 vs 4.3 ± 1.5) were significantly higher in the hepatectomy group (P < 0.01). After a mean follow-up of 40 months, 22 patients (36.6%) in the RFA group and 21 patients (35.0%) in the hepatectomy group developed a recurrence (P > 0.05). There was no significant difference of the disease-free and overall survival rates at 1, 2, and 3 years between the RFA group and the surgical hepatectomy group (P = 0.443 and P = 0.207, respectively). Conclusions: In patients with small HCC, percutaneous RFA showed similar local control and long-term survival compared with hepatectomy. Importantly, percutaneous RFA are accompanied with a lower complication rate and shorter hospital stay day.
Introduction Hepatocellular carcinoma (HCC) is the fifth most common malignancy in the world1 and a prevalent tumor type in mainland China, because of relatively frequent infections by hepatitis B virus (HBV).2 Over the past decade, there has been considerable progress in the diagnosis and surgical treatment of HCC in mainland China.3 The tumors are more often identified at an early stage, in particular through the screening of high-risk patients.4,5 Hence, various local regional therapies including ethanol injection,6,7 microwave coagulation,8 and radiofrequency ablation (RFA)9,10 have been developed for HCC. Hepatectomy11,12 and percutaneous RFA13 are the two best treatment options for small HCC. Hepatectomy is recommended by surgeons and allows for better local control,14,15 with an overall mortality rate less than 5% in cirrhotic patients and long-term survival up to > 50% after adequate anatomical resections.16,17 RFA is one of the most recent local ablative
therapies for small HCC13,14,18, which can be performed by percutaneous or surgical approach.19–21 For small HCC nodules (less than 3 cm), there is still some controversy regarding to the longterm effectiveness between the two treatment modalities, such as overall survive time, disease-free time, and the tumor recurrence rate.13,22 The aim of this randomized study was to determine which treatment modality, hepatectomy, or percutaneous RFA is more beneficial for patients with small HCC in terms of long-term outcomes.
Methods Patients. One hundred twenty patients with HCC ≤ 3 cm between January 1, 2000 and December 30, 2012 were randomized into either percutaneous RFA therapy or hepatectomy group, as initial treatment in Sir Run Run Shaw Hospital. Sixty patients
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who received hepatectomy were treated at Department of General Surgery, and 60 patients who received RFA were treated in Department of Medical Oncology. The treatment and data collection were approved by Ethical Committee of our institution. HCC diagnosis was based on the criteria used by the European Association for the Study of the Liver, confirmed by a core biopsy before therapy. This study included 88 men and 32 women with a median age of 53.4 ± 10.9 years (range: 18–71). All patients were Chinese. Inclusion criteria as follows: (i) ≥ 18 years; (ii) any solitary HCC ≤ 3 cm in diameter and no more than three tumor nodules; (iii) no extrahepatic metastasis at diagnosis; (iv) no radiologic evidence of major portal/hepatic vein branches invasion; (v) liver function equal or better than Pugh–Child Class B, with no history of encephalopathy, ascites refractory to diuretics or variceal bleeding (Patients with Pugh–Child Class C could be enrolled after the liver function was improved to B with the treatment options, including albumin infusion, diuretics, and non-steroidal anti-inflammatory drugs); and (vi) platelet count > 50 × 109/L without clinical significant portal hypertension and esophageal varices. We compared the randomized analysis based on the clinical characteristics, including age, sex, Child–Pugh classification, hepatic cirrhosis, tumor anatomical location, and HBV infection. Treatment modalities. Sixty patients underwent hepatectomy for HCC. Hepatectomy procedures were performed based on the position of HCC under general anesthesia, including nonanatomic hepatectomy in 38 patients, right hepatectomy in 13 patients, and left hepatectomy in 9 patients. A nonanatomic resection aiming at a resection margin of at least 2 cm was performed. All RFA procedures were performed by a dedicated team from the Department of Medical Oncology, using a standard protocol of TYCO RFA device (Valley Lab, Tyco Health Care Group, Boulder, CO, USA) or Rita RFA device (Oncology Products Group Angio Dynamics, Latham, NY, USA) under the ultrasound wave or computed tomography (CT) scan guidance according to the anatomical location of the carcinoma. Each tumor was treated with a single electrode placement and just one ablation. Each patient was discussed in a multidisciplinary team meeting before the appropriate approach was decided. Post-treatment follow-up and CT scans. Operative mortality was defined as death within the same hospital admission after treatment. Mortality rates were compared over a 30-day period, between the two treatment groups. All adverse events, including the pain after treatment, were recorded and compared. Abdominal contrast-enhanced CT (SOMATOMAR-T CT scanner, Siemens AG, Germany) was conducted 1 month later, or magnetic resonance imaging (MRI) (GE Signa HDx 1.5T MRI machine, Milwaukee, WI, USA) was used while patients were allergenic to the Omnipaque Solution (GE Healthcare, Shanghai, China). Patients routinely received plain and triphasic scans from 2 cm above right diaphragm to 2 cm below the inferior pole of the liver. Serum concentrations of α-fetoprotein (AFP) were measured on all the patients approximately 1 month after the treatment. Thereafter, all patients were regularly monitored for any intrahepatic recurrence or distant metastasis every 3 months in the first 2 years with measurement of serum AFP level, liver function tests, chest 194
radiography, and CT or MRI scan. The outcome measures were completed and conducted with complete treatment rate, postRFA and surgery complications, treatment-related mortality, and disease-free and overall survival rates. Complete ablation was defined as the absence of any peripheral enhancement in the contrast-enhanced phase 1 month after the RFA treatment. Local recurrence was defined as recurrences contiguous to or within resection or ablated areas. Distant intrahepatic recurrence was defined as a new tumor that appeared in the liver away from the ablated or operation area. When intrahepatic recurrences were detected, they were treated with either transarterial chemoembolization (TACE), or repeat hepatectomy, or RFA, or liver transplantation after discussed in a multidisciplinary team meeting. Statistical analyses. Results were given as mean ± standard deviation. Clinical features and pathologic tumor-related factors were compared between the two groups using χ2 test or with Fisher’s exact test. The t-test was used for continuous variables in a parametric fashion, whereas the Mann–Whitney U-test was used for non-parametric data. The Kaplan–Meier method was used to estimate the cumulative incidences of events, and differences in these incidences were evaluated using the log–rank test. All statistical evaluations were performed using the SPSS 21.0 software package (SPSS Inc., Chicago, IL, USA). All statistical tests were two-sided, and a significant difference was considered when P < 0.050.
Results Clinicopathologic characteristics according to treatment modality. RFA and hepatectomy groups showed similarities in age, sex, Child–Pugh classification, hepatitis B infection, comorbidity cirrhosis and increased serum AFP level (Table 1, P > 0.05). The mean age for RFA and hepatectomy were 51.4 ± 8.1 and 53.5 ± 11.0 years, respectively (P = 0.527). The majority of 120 patients with small HCC were characterized by HBV infection, increased serum level of AFP, cirrhosis, and Child–Pugh classification A or B, suggesting impaired hepatic functional reserve with active hepatitis in these patients. A total of 86 tumors (range: 1–3 tumors) were treated in patients undergoing percutaneous RFA, and a total of 86 hepatic tumors (range: 1–3 tumors) were resected in patients undergoing hepatectomy. Patients in the surgical group tended to have a lower incidence of multiple tumors, but the difference was not statistically significant (Table 1, P = 0.109). Treatment data, morbidity, major complication, and mortality. Table 2 showed the treatment data, morbidity, and mortality for patients with small HCC. In the RFA group, percutaneous RFA was performed in 49 patients under ultrasonographic guidance after the patient had received local anesthesia and intravenous sedation. Another 11 patients underwent a CT–guidance RFA for lesions not visible on ultrasonography. In the surgical group, all of the 60 patients underwent hepatectomy. Mean tumor size was 22.1 ± 5.2 mm and 22.8 ± 3.5 mm in RFA group and hepatectomy, respectively (P = 0.482). Journal of Gastroenterology and Hepatology 29 (2014) 193–200
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Hepatic function of post-treatment in terms of day-7 albumin and bilirubin levels was significantly worse in the surgical group (P < 0.05). Compared with the RFA group, the incidence of postoperative complications was significantly higher in the surgical group (5.0% vs 27.5%, P = 0.007). In the percutaneous RFA group, patients had a total of two complications, including a minor complication of skin burn at the RFA site (n = 1) and a
Table 1 Baseline clinicopathologic characteristics of 120 patients with small HCC treated with RFA or hepatecomy† Characteristics
RFA group (n = 60)
Hepatectomy (n = 60)
P value
No. of men/women Age (year) Child–Pugh classification A B C HBS Ag (%) Negative Positive Hepatic cirrhosis Absent Present Serum AFP (ng/mL) > 200 ≤ 200 No. of hepatic tumors Solitary Multiple
42/18 51.4 ± 8.1
46/14 53.5 ± 11.0
0.486 0.527
32 23 5
43 17 0
0.021
5 55
8 52
0.380
7 53
12 48
0.213
52 8
50 10
0.611
41 19
49 11
0.555
†
Data are the number of patients. AFP; α-fetoprotein; HBS Ag; surface antigen of the hepatitis B virus; HCC; hepatocellular carcinoma; RFA, radiofrequency ablation.
Table 2
major complication of pleural effusion in the costo-phrenic angle (n = 1). In the surgical hepatectomy group, patients had 17 complications, including 14 major complication such as high fever due to sepsis (n = 3), wound infection with bleeding (n = 2), chest infection (n = 2), pleural effusion (n = 3), ascites requiring treatment (n = 2), thrombosis of the main lobar portal vein (n = 1), and renal failure (n = 1), and three minor complications of atelectasis. Many more patients (71.7%) who received hepatectomy experienced more severe pain and more frequently required usage of analgesic than those in RFA group (5%) (P < 0.001). The proportion of patients (10%) requiring intensive care admission was significantly higher (P = 0.012), and overall hospital stays was significantly longer in the surgical hepatectomy group (P < 0.010). Of note, there was no treatment-related mortality in either group. Complete ablation rate, recurrence, and extrahepatic metastasis after treatment. Table 3 showed the follow-up data of patients according to the treatment modalities. The follow-up period after the treatment was defined as the interval between the date of the initial treatment and that of the last follow-up. Overall, complete tumor treatment rates were achieved in 95.0% and 96.7% of patients in the percutaneus RFA and hepatectomy groups, respectively (P > 0.05). The Figures 1 and 2 compared the changes of CT image and MRI image of small HCC before and 1 month after RFA, respectively. As Table 3 showed, eight patients had intrahepatic recurrence local to the RFA area in RFA group, compared with one patient who had new tumors local to the hepatectomy area in hepatectomy group. In addition, another six patients had new hepatic tumors distant from the ablation site at 3 months post-RFA CT scan in the RFA group. Whereas 10 patients had new hepatic tumors distant to the hepatectomy area at 3 months post-surgery CT scan in the surgical hepatectomy group (P = 0.502). Retreatment was performed in these 11
Treatment data, morbidity, and mortality for small HCC†
Characteristic
No. of tumor lesion (%) 1 2 3 Mean size (mm)† Albumin level Pretreatment, g/dl, mean (SD) Albumin level on 7 days post-treatment, g/dl, mean (SD) Direct bilirubin level pretreatment, mg/dl (mean ± SD) Total bilirubin level post-treatment, mg/dl (mean ± SD) Postoperative complication, No. (%) Major complication Minor complication Serious pain requiring analgesic, No.(%) ICU stay, No. (%) Hospital days (mean ± SD) Hospital mortality, No. (%)
RFA group (n = 60)
Hepatectomy n = (60)
41 (68.3) 12 (20.0) 7 (11.7) 22.1 ± 5.2 4.4 ± 0.5 3.9 ± 0.4 0.61 ± 0.15 1.0 ± 0.19 2 (5.0) 1 (2.5) 1 (2.5) 3 (5.0%) 0 4.3 ± 1.5 0
49 (81.7) 6 (10.0) 5 (8.3) 22.8 ± 3.5 4.3 ± 0.4 2.9 ± 0.3 0.98 ± 0.23 1.73 ± 0.21 17 (27.5) 14 (2.5) 3 (25) 43 (71.7%) 6 (10%) 11.8 ± 3.1 0
P value
0.109
0.482 0.124 0.032 0.013 0.008 0.047 < 0.001 0.012 < 0.001 NA
†
Data are the mean standard deviation; data in parentheses are expressed as number of patients (percentage). NA, not applicable. HCC; hepatocellular carcinoma; RFA, radiofrequency ablation; SD, standard deviation.
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Table 3 Complete ablation rate, recurrence, and extrahepatic metastasis in patients with small HCC† Characteristic
RFA group (n = 60)
Hepatectomy (n = 60)
P value
Complete treatment rate (%) Recurrence during follow-up (%) Intrahepatic recurrence (%) Local Distant Extrahepatic metastasis (%) Lung Bone Lymph node
57 (95.0) 22 (36.6) 14 (23.3) 8 (13.3) 6 (10.0) 8 (13.3) 6 (10.0) 2 (3.3) 0 (0)
58 (96.7) 21 (35.0) 11 (18.4) 1 (1.7) 10 (16.7) 10 (16.6) 8 (13.3) 1 (2.5) 1 (2.5)
0.311 0.850 0.502
0.611
†
Data are expressed as number of patients (percentage). HCC; hepatocellular carcinoma; RFA, radiofrequency ablation.
patients, as shown as Figure 3, including RFA in six patients and chemoembolization in four patients. And two patients among these 11 patients underwent transplantation further after re-recurrence in the Center of Hematology Transplantation, the First Affiliated Hospital, School of Medicine, Zhejiang University. Other 14 patients gave up further treatment because of failure of liver function, multiple intrahepatic recurrences more than three tumors because of microvascular invasion, side-effects, and other reasons. After a mean follow-up of 40 months, 22 patients (36.6%) in the percutaneous RFA group and 21 patients (35.0%) in the hepatectomy group developed recurrence. There was a trend toward a higher incidence of intrahepatic recurrence (23.3% vs 18.4%) with percutaneous RFA group and distant metastases (13.3% vs 16.6%) with surgical hepatectomy group, but the difference was not significant (P > 0.05). Univariate analysis revealed that Child–Pugh classification of the liver functions (P = 0.003), serum AFP level (P = 0.006), HBV infection (P = 0.018), and number of hepatic tumors (P = 0.038) were risk factors for local recurrence.
Follow-up results. The rates of disease-free survival in the RFA group versus the surgical hepatectomy group at 1, 2, and 3 years were 91.6% versus 90.4%, 87.4% versus 85.2%, and 55.4% versus 41.3% (Fig. 4a). There was no significant difference in the rates of disease-free survival between the two groups (P = 0.443, log–rank test). The overall survival rates at 1, 2, and 3 years in the percutaneous group were 97.5%, 91.2%, and 82.5%, respectively; and in the surgical hepatectomy group were 93.7%, 86.2%, and 77.5%, respectively. Thus, there was no significant difference in the overall survival rates between the two groups (P = 0.207, log–rank test, Fig. 4b).
Discussion Our study suggested that percutaneous RFA and hepatectomy provided similar local control and overall disease-free survival for patients with small HCC (tumor size ≤ 3 cm). However, in comparison with hepatectomy, percutaneous RFA showed a lower complication rate and shorter hospital stays. 196
Partial hepatectomy, including liver transplantation, remains the most efficient and treatment “gold standard” for resectable HCC patients with an aim of providing a “cure.”23 And surgical resection and local ablative therapies represent the most frequent first lines therapies adopted when liver transplantation cannot be offered or is not immediately accessible. However, less than 30% of patients with small HCC are eligible for surgery, mainly because of the multiplicity of the lesions that often occurs in a background of chronic liver disease, bad liver function, and deteriorating general condition.24,25 Partial hepatectomy is safe after adequate anatomical resections, with good long-term survival up to > 50% over 5 years.23,26 Unfortunately, a significant proportion of these patients cannot be offered surgery at the time of diagnosis of HCC with a background of chronic hepatitis B cirrhosis. In addition, the role of hepatic resection for treatment of bilobar or multiple small HCCs is more controversial.27,28 Thus, a less invasive procedure with the ability to ablate HCC completely is a necessary and attractive alternative treatment modality. Recently, various thermal ablative therapies have been developed, of which percutaneous RFA has attracted the greatest interest and popularity because of its low morbidity and mortality, effective tumor ablation, and maximal preservation of normal liver parenchyma.19,29,30 RFA has been shown by prospective randomized trials to be superior to ethanol injection for treatment of HCC.31,32 Although recent advances in RFA technology have enabled clinicians to use RFA for larger tumors,33,34 there is controversy regarding the treatment choices for HCC larger than 3 cm in diameter.35 Wakai T et al. 36proved that hepatectomy provides both similar local control and better long-term survival for patients with HCC ≤ 4 cm in comparison with percutaneous ablation. A nonrandomized prospective study suggested that resection is superior to RFA in long-term survival.37,38 However, a recently reported randomized trial showed that RFA can achieve similar long-term overall and disease-free survival compared with resection for HCCs ≤ 5 cm.39 Since January 2000, the safety and minimal invasiveness of RFA had made it an attractive treatment option for small HCC in our hospital, especially in the patients who had high operative risks by surgical resection. As far as we know, there have been rare randomized trials to compare the efficacy of RFA with that of surgical resection for an operable early-stage HCC in terms of survival for HCCs ≤ 3 cm.40,41 In this study, the randomized analysis showed that there was no significant difference of the complete remission rates, recurrence rates, disease-free survival rates, and overall survival rates between the RFA group and hepatectomy group (P > 0.05). Local recurrences after percutaneous RFA may be attributable to insufficient ablation of the primary tumor and/or the presence of portal or hepatic venous tumor thrombi in the adjacent liver.4 Our study also showed that the overall and disease-free survival rates at 1, 2, and 3 years were the same for small HCC patients treated with either RFA or surgical resection (P > 0.05). In contrast, another large retrospective study for HCC patients with tumor less than 5 cm in diameter enrolled in the Liver Cancer Study Group of Japan.41 The results showed that HCC patients who received liver resection (n = 8010) had better survival than RFA (n = 4037) or TACE (n = 841). In the Japan study, the lesions of HCCs measuring > 3 cm were included in this study resulting incomplete Journal of Gastroenterology and Hepatology 29 (2014) 193–200
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Figure 1 Early-phase computed tomography (CT) scans of hepatocellular carcinoma nodule in the diaphragmatic dome area in a 54-year-old man. The hepatic nodule with a 10 mm enhancing tumor (arrows) in the diaphragmatic dome area (a) nodules were diagnosed after transcatheter arterial embolization with iodized oil and biopsy under the CT scan guidance, following treated with RF ablation under the CT guidance. Scan of venous phase obtained 1 month after RF ablation showed no enhancement in the tumor area (arrowshead). As (b) showed that iodized oil injected at the site of previous transcatheter arterial embolization before radiofrequency ablation (RFA) was accumulated in an HCC nodule. Early-phase transverse CT scans of an intrahepatic metastatic nodule located the right hepatic lobes 3 months after the surgical hepatectomy in an 18-year-old man. As (c) showed that the nodule obtained before RF ablation showed a 1.4-cm enhancing tumor (arrows) in the right hepatic lobes. Scan obtained 14 months after RFA of (d) showed no enhancement in the tumor area (arrows). The technique effectiveness was considered complete.
ablation and the proportion of patients with associated cirrhosis was lower in the surgical resection group than in the nonsurgically treated group. The beneficial effect of hepatectomy was due to the removal of venous tumor thrombi and complete eradication of the primary tumor with clean resection margins.35,42 Another similar study from the Hong Kong, China,19 compared the survival outcome and disease-free survival of a total of 228 patients who underwent RFA of small (< 3 cm; n = 155) and medium (3.1– 5 cm; n = 73) HCC by percutaneous or surgical approach. Percutaneous RFA approach achieved similar tumor control with lower morbidity compared with the surgical approach for patients with small HCC. In our study, during a follow-up of 40 months, there was a trend toward a higher intrahepatic recurrence in the percutaneous RFA group as well as extrahepatic metastases in the surgical hepatectomy group, but the difference was not of statistical significance (P = 0.502 and P = 0.611, respectively). Local recurrences after percutaneous RFA might be attributable to insufficient ablation of the primary tumor, and/or the presence of portal or hepatic venous tumor thrombi in the adjacent liver.43 The predominant trend of extrahepatic recurrence in the hepatectomy group was associated with the following factors: compression, separating of the primary tumor, intraoperative blood transfusion, hematogenous dissemination, and/or devascularization.23,44
However, RFA had significant advantages over surgical resection in causing only one major and one minor complications, less severe pain, a shorter intensive care unit stay and hospital stays (P < 0.01). These data were similar to the first large clinical experience with RFA as reported by Rossi et al.45 and other researchers.36,46 Two patients underwent liver transplantation further after re-recurrence, and salvage liver transplantation is an efficacious treatment for patients with recurrent HCC and should be considered when repeated hepatic resection is not feasible.47 There are still a few outstanding issues that are worth pursuing in future studies. First of all, the sample size of 120 patients in this study was relatively small. However, with the strong belief by oncologists and surgeons as well as patients that RFA has become a more commonly used treatment modality for HCC, we believe that a larger sample size will likely be collected for future comparison with surgical resection. Second, in this study, intrahepatic recurrences were treated further with either TACE or repeated hepatectomy or RFA when indicated. Local effective control of intrahepatic recurrence might increase and affect the overall survival time and the progression-free survival time. Nevertheless, we do think that a longer period of follow-up in the future might be beneficial for the comparison of the disease-free and overall survival rates between RFA and hepatectomy group.
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Figure 2 Magnetic resonance imaging (MRI) with hepatobiliary contrast agent of a “typical” small hepatocellular carcinoma. On the blank T1-weighted MRI, the new lesion was visible in the right liver lobe in a male patient, 44 years old, with 25 years of infection of hepatitis B (a). In the contrast artery (b) and portal venous phase (c), the lesion showed markedly enhancement. 1 month later after the RFA treatment of this lesion, the lesion was visible with a central scar in the T1-weighted MRI (d). After contrast the lesion showed no enhancement during the artery phase (e) and portal venous phase (f).
Figure 3 Magnetic resonance imaging (MRI) with hepatobiliary contrast agent of a “typical” hepatocellular carcinoma. On the blank T1-weighted MRI, the new lesion was visible in the right liver lobe in a female patient, 34 years old, 5 months later of hepatectomy (a). In the contrast artery phase, the lesion showed strong enhancement (b). In the portal venous phase, the lesion was slightly hyperintense compared to the normal liver tissue (c). 1 month later after the radiofrequency ablation (RFA) treatment of right liver lobe, on the blank T1-weighted MRI, the lesion was visible with a central scar (d). After contrast the lesion showed no enhancement with exception of the central scar in the artery phase (e) and portal venous phase (f).
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Disease-free-survival curve
Overall-survival curve
(b)
1.0
1.0
0.8
0.8
0.6
0.6
Cum survival
Cum survival
(a)
0.4
0.4
0.2
0.2
0.0
0.0 .00
10.00
20.00 30.00 Time (months)
40.00
.00
10.00
20.00 30.00 40.00 Time (months)
50.00
Figure 4 No significant difference of the rates of disease-free survival between the radiofrequency ablation (RFA) group and the surgical hepatectomy group. The rates of disease-free survival in the RFA group versus the surgical hepatectomy group at 1, 2, and 3 years were 91.6% versus 90.4%, 87.4% versus 85.2%, and 55.4% versus 41.3% (a). No significant difference was noted between the two groups (P = 0.443, log–rank test). And as (b) showed, the overall survival rates at 1, 2, and 3 years were 97.5%, 91.2% and 82.5%, respectively, in the RFA group and, 93.7%, 86.2% and , 77.5%, respectively, in the surgical hepatectomy group. No significant difference was noted between the two groups (P = 0.207, log–rank test). RFA group; , Hepatectomy group.
In conclusion, RFA give similar long-time effectiveness compared with hepatectomy resection for patients with small HCC, including complete tumor treatment rate, and disease-free and overall survival rate. Importantly, other than being less invasive, RFA offers additional advantages over surgical resection in giving better short-term postoperative results such as lower complication rates, and shorter intensive care unit and hospital stays. Further studies such as enlarged multicenter randomized trials are required to validate the results of the current study.
Acknowledgments The authors acknowledge Dr. Gerry Ellis working in Sir Run Run Shaw hospital for the writing assistance and critical revision of the manuscript for important intellectual content. This work was fully supported by grants from Zhejiang Science and Technology Agency funding 2010C13025-1 (H.M. Pan), National Natural Science Foundation of China 81272593 (H.M. Pan), Zhejiang Provincial Natural Science Foundation of China LY13H160013 (Y. Fang) and Zhejiang Provincial Natural Science Foundation of China LQ13H160009 (W. Chen).
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12 Nanashima A, Abo T, Hamasaki KL. Perioperative non-tumorous factors associated with survivalin HCC patients who underwent hepatectomy. Anticancer Res. 2011; 31: 4545–51. 13 Montorsi M, Santambrogio R, Bianchi P. Survival and recurrences after hepatic resection orradiofrequency for hepatocellular carcinoma in cirrhotic patients: a multivariate analysis. J. Gastrointest. Surg. 2005; 9: 62–7. 14 Andreou A, Vauthey JN, Cherqui D. Improved long-term survival after major resection forhepatocellular carcinoma: a multicenter analysis based on a new definition of major hepatectomy. J. Gastrointest. Surg. 2013; 17: 66–77. 15 Toyoda H, Kumada T, Tada T. Prognostic significance of a combination of pre- and post-treatmenttumor markers for hepatocellular carcinoma curatively treated with hepatectomy. J. Hepatol. 2012; 57: 1251–7. 16 Belli G, Fantini C, D’Agostino A, Belli A, Russolillo N. Laparoscopic liver resections forhepatocellular carcinoma (HCC) in cirrhotic patients. HPB (Oxford) 2004; 6: 236–46. 17 Kamiyama T, Nakanishi K, Yokoo H et al. Analysis of therisk factors for early death due to disease recurrence or progression within 1 year after hepatectomy inpatients with hepatocellular carcinoma. World J. Surg. Oncol. 2012; 10: 107–13. 18 Sheiman RG, Mullan C, Ahmed M. In vivo determination of a modified heat capacity of smallhepatocellular carcinomas prior to radiofrequency ablation: correlation with adjacent vasculature andtumour recurrence. Int. J. Hyperthermia 2012; 28: 122–31. 19 Khan MR, Poon RT, Ng KK. Comparison of percutaneous and surgical approaches forradiofrequency ablation of small and medium hepatocellular carcinoma. Arch. Surg. 2007; 142: 1136–43. 20 Kariyama K, Nouso K, Wakuta A. Percutaneous radiofrequency ablation for treatment ofhepatocellular carcinoma in the caudate lobe. AJR Am. J. Roentgenol. 2011; 197: W571–5. 21 Peng ZW, Liang HH, Chen MS. Percutaneous radiofrequency ablation for the treatment ofhepatocellular carcinoma in the caudate lobe. Eur. J. Surg. Oncol. 2008; 34: 166–72. 22 Choi D, Lim HK, Rhim H. Percutaneous radiofrequency ablation for recurrent hepatocellularcarcinoma after hepatectomy: long-term results and prognostic factors. Ann. Surg. Oncol. 2007; 14: 2319–29. 23 Poon RT, Fan ST, Lo CM. Improving survival results after resection of hepatocellular carcinoma: a prospective study of 377 patients over 10 years. Ann. Surg. 2001; 234: 63–70. 24 Verslype C, Van Cutsem E, Dicato M. The management of hepatocellular carcinoma. Currentexpert opinion and recommendations derived from the 10th World Congress on Gastrointestinal Cancer,Barcelona, 2008. Ann. Oncol. 2009; 20 (Suppl 7): vii1–vii6. 25 Zhu AX. Molecularly targeted therapy for advanced hepatocellular carcinoma in 2012: currentstatus and future perspectives. Semin. Oncol. 2012; 39: 493–502. 26 Makuuchi M, Sano K. The surgical approach to HCC: our progress and results in Japan. Liver Transpl. 2004; 10: S46–52. 27 Chen WT, Chau GY, Lui WY. Recurrent hepatocellular carcinoma after hepatic resection: prognostic factors and long-term outcome. Eur. J. Surg. Oncol. 2004; 30: 414–20. 28 Chong CC, Lee K, Ip PC et al. Pre-operative predictors ofpost-hepatectomy recurrence of hepatocellular carcinoma: can we predict earlier? Surgeon 2012; 10: 260–6. 29 Allgaier HP, Deibert P, Zuber I, Olschewski M, Blum HE. Percutaneous radiofrequency interstitialthermal ablation of small hepatocellular carcinoma. Lancet 1999; 353: 1676–7. 30 Lau WY, Leung T, Yu SC, Ho SK. Percutaneous local ablative therapy for hepatocellular carcinoma: a review and look into the future. Ann. Surg. 2003; 237: 171–9.
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31 Orlando A, Leandro G, Olivo M, Andriulli A, Cottone M. Radiofrequency thermal ablation vs.percutaneous ethanol injection for small hepatocellular carcinoma in cirrhosis: meta-analysis ofrandomized controlled trials. Am. J. Gastroenterol. 2009; 104: 514–24. 32 Lin SM, Lin C, Lin CC, Hsu CW, Chen YC. Randomized controlled trial comparing percutaneousradiofrequency thermal ablation, percutaneous ethanol injection, and percutaneous acetic acid injectionto treat hepatocellular carcinoma of 3 cm or less. Gut 2005; 54: 1151–6. 33 Takaki H, Yamakado K, Uraki J et al. Radiofrequencyablation combined with chemoembolization for the treatment of hepatocellular carcinomas larger than5 cm. J. Vasc. Interv. Radiol. 2009; 20: 217–24. 34 Seror O, N’Kontchou G, Ibraheem M et al. Large (> or=5.0-cm) HCCs: multipolar RF ablation with three internally cooled bipolar electrodes—initial experience in 26 patients. Radiology 2008; 248: 288–96. 35 Earl TM, Chapman WC. Conventional Surgical Treatment of Hepatocellular Carcinoma. Clin. Liver Dis. 2011; 15: 353–70, vii–x. 36 Wakai T, Shirai Y, Suda T et al. Long-term outcomes ofhepatectomy vs percutaneous ablation for treatment of hepatocellular carcinoma < or = 4 cm. World J. Gastroenterol. 2006; 12: 546–52. 37 Cho YK, Kim J, Kim WT, Chung JW. Hepatic resection versus radiofrequency ablation for very earlystage hepatocellular carcinoma: a Markov model analysis. Hepatology 2010; 51: 1284–90. 38 Ruzzenente A, Guglielmi A, Sandri M. Surgical resection versus local ablation for HCC oncirrhosis: results from a propensity case-matched study. J. Gastrointest. Surg. 2012; 16: 301–11. 39 Kim YS, Lee W, Rhim H, Lim HK, Choi D, Lee JY. The minimal ablative margin of radiofrequencyablation of hepatocellular carcinoma (> 2 and < 5 cm) needed to prevent local tumor progression: 3Dquantitative assessment using CT image fusion. AJR Am. J. Roentgenol. 2010; 195: 758–65. 40 Chen MS, Li JQ, Zheng Y. A prospective randomized trial comparing percutaneous local ablativetherapy and partial hepatectomy for small hepatocellular carcinoma. Ann. Surg. 2006; 243: 321–8. 41 Arii S, Yamaoka Y, Futagawa S et al. Results of surgicaland nonsurgical treatment for small-sized hepatocellular carcinomas: a retrospective and nationwidesurvey in Japan. The Liver Cancer Study Group of Japan. Hepatology 2000; 32: 1224–9. 42 Tsoulfas G, Mekras A, Agorastou P, Kiskinis D. Surgical treatment for large hepatocellular carcinoma: does size matter? ANZ J. Surg. 2012; 82: 510–17. 43 Sasaki A, Kai S, Iwashita Y, Hirano S, Ohta M, Kitano S. Microsatellite distribution andindication for locoregional therapy in small hepatocellular carcinoma. Cancer 2005; 103: 299–306. 44 Kow AW, Kwon CH, Song S, Shin M, Kim JM, Joh JW. Risk factors of peritoneal recurrence and outcome of resected peritoneal recurrence after liver resection in hepatocellular carcinoma: review of 1222 cases of hepatectomy in a tertiary institution. Ann. Surg. Oncol. 2012; 19: 2246–55. 45 Rossi S, Di Stasi M, Buscarini E. Percutaneous RF interstitial thermal ablation in the treatment of hepatic cancer. AJR Am. J. Roentgenol. 1996; 167: 759–68. 46 Zagoria RJ. “Percutaneous RF interstitial thermal ablation in the treatment of hepatic cancer”—a commentary. AJR Am. J. Roentgenol. 2006; 187: 1149–50. 47 Chan AC, Chan SC, Chok KS et al. Treatment strategy for recurrent hepatocellular carcinoma: salvage transplantation, repeated resection, or radiofrequency ablation? Liver Transpl. 2013; 19: 411–19.
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doi:10.1111/jgh.12441
H E PAT O L O G Y
Comparison of long-term effectiveness and complications of radiofrequency ablation with hepatectomy for small hepatocellular carcinoma Yong Fang,* Wei Chen,* Xiao Liang,† Da Li,* HaiZhou Lou,* Renbiao Chen,‡ Kaifeng Wang* and HongMing Pan* Departments of *Medical Oncology, †General Surgery and ‡Radiology and Medical Image Center, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China
Key words hepatectomy, prognosis, radiofrequency ablation, small hepatocellular carcinoma. Accepted for publication 16 October 2013. Correspondence Dr HongMing Pan, Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, 3 East QinChun Road, Hangzhou, Zhejiang 310016, China. Email: [email protected] Conflict of interest: None.
Abstract Background and Aim: To determine and compare the adverse events and long-term effectiveness for patients with small hepatocellular carcinoma (HCC) (≤ 3 cm) treated by percutaneous radiofrequency ablation (RFA) or hepatectomy. Methods: Small HCC from 120 patients were randomized into either percutaneous RFA therapy or hepatectomy group, and the effectiveness and complications of two treatment modalities were analyzed. The complications of post-RFA or hepatectomy, the complete treatment rate, treatment-related mortality, and disease-free and overall survival rate were followed up and conducted. Results: In patients with small HCC, complete remission rates were achieved in 95% and 96.7% in the percutaneus RFA and hepatectomy groups, respectively (P > 0.05). Hepatic function at day-7 status post-treatment, including albumin and bilirubin levels, were significantly worse in the hepatectomy group (P < 0.01). Compared with the RFA group, the incidence of postoperative complications (27.5% vs 5.0%) and hospital stay (11.8 ± 3.1 vs 4.3 ± 1.5) were significantly higher in the hepatectomy group (P < 0.01). After a mean follow-up of 40 months, 22 patients (36.6%) in the RFA group and 21 patients (35.0%) in the hepatectomy group developed a recurrence (P > 0.05). There was no significant difference of the disease-free and overall survival rates at 1, 2, and 3 years between the RFA group and the surgical hepatectomy group (P = 0.443 and P = 0.207, respectively). Conclusions: In patients with small HCC, percutaneous RFA showed similar local control and long-term survival compared with hepatectomy. Importantly, percutaneous RFA are accompanied with a lower complication rate and shorter hospital stay day.
Introduction Hepatocellular carcinoma (HCC) is the fifth most common malignancy in the world1 and a prevalent tumor type in mainland China, because of relatively frequent infections by hepatitis B virus (HBV).2 Over the past decade, there has been considerable progress in the diagnosis and surgical treatment of HCC in mainland China.3 The tumors are more often identified at an early stage, in particular through the screening of high-risk patients.4,5 Hence, various local regional therapies including ethanol injection,6,7 microwave coagulation,8 and radiofrequency ablation (RFA)9,10 have been developed for HCC. Hepatectomy11,12 and percutaneous RFA13 are the two best treatment options for small HCC. Hepatectomy is recommended by surgeons and allows for better local control,14,15 with an overall mortality rate less than 5% in cirrhotic patients and long-term survival up to > 50% after adequate anatomical resections.16,17 RFA is one of the most recent local ablative
therapies for small HCC13,14,18, which can be performed by percutaneous or surgical approach.19–21 For small HCC nodules (less than 3 cm), there is still some controversy regarding to the longterm effectiveness between the two treatment modalities, such as overall survive time, disease-free time, and the tumor recurrence rate.13,22 The aim of this randomized study was to determine which treatment modality, hepatectomy, or percutaneous RFA is more beneficial for patients with small HCC in terms of long-term outcomes.
Methods Patients. One hundred twenty patients with HCC ≤ 3 cm between January 1, 2000 and December 30, 2012 were randomized into either percutaneous RFA therapy or hepatectomy group, as initial treatment in Sir Run Run Shaw Hospital. Sixty patients
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who received hepatectomy were treated at Department of General Surgery, and 60 patients who received RFA were treated in Department of Medical Oncology. The treatment and data collection were approved by Ethical Committee of our institution. HCC diagnosis was based on the criteria used by the European Association for the Study of the Liver, confirmed by a core biopsy before therapy. This study included 88 men and 32 women with a median age of 53.4 ± 10.9 years (range: 18–71). All patients were Chinese. Inclusion criteria as follows: (i) ≥ 18 years; (ii) any solitary HCC ≤ 3 cm in diameter and no more than three tumor nodules; (iii) no extrahepatic metastasis at diagnosis; (iv) no radiologic evidence of major portal/hepatic vein branches invasion; (v) liver function equal or better than Pugh–Child Class B, with no history of encephalopathy, ascites refractory to diuretics or variceal bleeding (Patients with Pugh–Child Class C could be enrolled after the liver function was improved to B with the treatment options, including albumin infusion, diuretics, and non-steroidal anti-inflammatory drugs); and (vi) platelet count > 50 × 109/L without clinical significant portal hypertension and esophageal varices. We compared the randomized analysis based on the clinical characteristics, including age, sex, Child–Pugh classification, hepatic cirrhosis, tumor anatomical location, and HBV infection. Treatment modalities. Sixty patients underwent hepatectomy for HCC. Hepatectomy procedures were performed based on the position of HCC under general anesthesia, including nonanatomic hepatectomy in 38 patients, right hepatectomy in 13 patients, and left hepatectomy in 9 patients. A nonanatomic resection aiming at a resection margin of at least 2 cm was performed. All RFA procedures were performed by a dedicated team from the Department of Medical Oncology, using a standard protocol of TYCO RFA device (Valley Lab, Tyco Health Care Group, Boulder, CO, USA) or Rita RFA device (Oncology Products Group Angio Dynamics, Latham, NY, USA) under the ultrasound wave or computed tomography (CT) scan guidance according to the anatomical location of the carcinoma. Each tumor was treated with a single electrode placement and just one ablation. Each patient was discussed in a multidisciplinary team meeting before the appropriate approach was decided. Post-treatment follow-up and CT scans. Operative mortality was defined as death within the same hospital admission after treatment. Mortality rates were compared over a 30-day period, between the two treatment groups. All adverse events, including the pain after treatment, were recorded and compared. Abdominal contrast-enhanced CT (SOMATOMAR-T CT scanner, Siemens AG, Germany) was conducted 1 month later, or magnetic resonance imaging (MRI) (GE Signa HDx 1.5T MRI machine, Milwaukee, WI, USA) was used while patients were allergenic to the Omnipaque Solution (GE Healthcare, Shanghai, China). Patients routinely received plain and triphasic scans from 2 cm above right diaphragm to 2 cm below the inferior pole of the liver. Serum concentrations of α-fetoprotein (AFP) were measured on all the patients approximately 1 month after the treatment. Thereafter, all patients were regularly monitored for any intrahepatic recurrence or distant metastasis every 3 months in the first 2 years with measurement of serum AFP level, liver function tests, chest 194
radiography, and CT or MRI scan. The outcome measures were completed and conducted with complete treatment rate, postRFA and surgery complications, treatment-related mortality, and disease-free and overall survival rates. Complete ablation was defined as the absence of any peripheral enhancement in the contrast-enhanced phase 1 month after the RFA treatment. Local recurrence was defined as recurrences contiguous to or within resection or ablated areas. Distant intrahepatic recurrence was defined as a new tumor that appeared in the liver away from the ablated or operation area. When intrahepatic recurrences were detected, they were treated with either transarterial chemoembolization (TACE), or repeat hepatectomy, or RFA, or liver transplantation after discussed in a multidisciplinary team meeting. Statistical analyses. Results were given as mean ± standard deviation. Clinical features and pathologic tumor-related factors were compared between the two groups using χ2 test or with Fisher’s exact test. The t-test was used for continuous variables in a parametric fashion, whereas the Mann–Whitney U-test was used for non-parametric data. The Kaplan–Meier method was used to estimate the cumulative incidences of events, and differences in these incidences were evaluated using the log–rank test. All statistical evaluations were performed using the SPSS 21.0 software package (SPSS Inc., Chicago, IL, USA). All statistical tests were two-sided, and a significant difference was considered when P < 0.050.
Results Clinicopathologic characteristics according to treatment modality. RFA and hepatectomy groups showed similarities in age, sex, Child–Pugh classification, hepatitis B infection, comorbidity cirrhosis and increased serum AFP level (Table 1, P > 0.05). The mean age for RFA and hepatectomy were 51.4 ± 8.1 and 53.5 ± 11.0 years, respectively (P = 0.527). The majority of 120 patients with small HCC were characterized by HBV infection, increased serum level of AFP, cirrhosis, and Child–Pugh classification A or B, suggesting impaired hepatic functional reserve with active hepatitis in these patients. A total of 86 tumors (range: 1–3 tumors) were treated in patients undergoing percutaneous RFA, and a total of 86 hepatic tumors (range: 1–3 tumors) were resected in patients undergoing hepatectomy. Patients in the surgical group tended to have a lower incidence of multiple tumors, but the difference was not statistically significant (Table 1, P = 0.109). Treatment data, morbidity, major complication, and mortality. Table 2 showed the treatment data, morbidity, and mortality for patients with small HCC. In the RFA group, percutaneous RFA was performed in 49 patients under ultrasonographic guidance after the patient had received local anesthesia and intravenous sedation. Another 11 patients underwent a CT–guidance RFA for lesions not visible on ultrasonography. In the surgical group, all of the 60 patients underwent hepatectomy. Mean tumor size was 22.1 ± 5.2 mm and 22.8 ± 3.5 mm in RFA group and hepatectomy, respectively (P = 0.482). Journal of Gastroenterology and Hepatology 29 (2014) 193–200
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Hepatic function of post-treatment in terms of day-7 albumin and bilirubin levels was significantly worse in the surgical group (P < 0.05). Compared with the RFA group, the incidence of postoperative complications was significantly higher in the surgical group (5.0% vs 27.5%, P = 0.007). In the percutaneous RFA group, patients had a total of two complications, including a minor complication of skin burn at the RFA site (n = 1) and a
Table 1 Baseline clinicopathologic characteristics of 120 patients with small HCC treated with RFA or hepatecomy† Characteristics
RFA group (n = 60)
Hepatectomy (n = 60)
P value
No. of men/women Age (year) Child–Pugh classification A B C HBS Ag (%) Negative Positive Hepatic cirrhosis Absent Present Serum AFP (ng/mL) > 200 ≤ 200 No. of hepatic tumors Solitary Multiple
42/18 51.4 ± 8.1
46/14 53.5 ± 11.0
0.486 0.527
32 23 5
43 17 0
0.021
5 55
8 52
0.380
7 53
12 48
0.213
52 8
50 10
0.611
41 19
49 11
0.555
†
Data are the number of patients. AFP; α-fetoprotein; HBS Ag; surface antigen of the hepatitis B virus; HCC; hepatocellular carcinoma; RFA, radiofrequency ablation.
Table 2
major complication of pleural effusion in the costo-phrenic angle (n = 1). In the surgical hepatectomy group, patients had 17 complications, including 14 major complication such as high fever due to sepsis (n = 3), wound infection with bleeding (n = 2), chest infection (n = 2), pleural effusion (n = 3), ascites requiring treatment (n = 2), thrombosis of the main lobar portal vein (n = 1), and renal failure (n = 1), and three minor complications of atelectasis. Many more patients (71.7%) who received hepatectomy experienced more severe pain and more frequently required usage of analgesic than those in RFA group (5%) (P < 0.001). The proportion of patients (10%) requiring intensive care admission was significantly higher (P = 0.012), and overall hospital stays was significantly longer in the surgical hepatectomy group (P < 0.010). Of note, there was no treatment-related mortality in either group. Complete ablation rate, recurrence, and extrahepatic metastasis after treatment. Table 3 showed the follow-up data of patients according to the treatment modalities. The follow-up period after the treatment was defined as the interval between the date of the initial treatment and that of the last follow-up. Overall, complete tumor treatment rates were achieved in 95.0% and 96.7% of patients in the percutaneus RFA and hepatectomy groups, respectively (P > 0.05). The Figures 1 and 2 compared the changes of CT image and MRI image of small HCC before and 1 month after RFA, respectively. As Table 3 showed, eight patients had intrahepatic recurrence local to the RFA area in RFA group, compared with one patient who had new tumors local to the hepatectomy area in hepatectomy group. In addition, another six patients had new hepatic tumors distant from the ablation site at 3 months post-RFA CT scan in the RFA group. Whereas 10 patients had new hepatic tumors distant to the hepatectomy area at 3 months post-surgery CT scan in the surgical hepatectomy group (P = 0.502). Retreatment was performed in these 11
Treatment data, morbidity, and mortality for small HCC†
Characteristic
No. of tumor lesion (%) 1 2 3 Mean size (mm)† Albumin level Pretreatment, g/dl, mean (SD) Albumin level on 7 days post-treatment, g/dl, mean (SD) Direct bilirubin level pretreatment, mg/dl (mean ± SD) Total bilirubin level post-treatment, mg/dl (mean ± SD) Postoperative complication, No. (%) Major complication Minor complication Serious pain requiring analgesic, No.(%) ICU stay, No. (%) Hospital days (mean ± SD) Hospital mortality, No. (%)
RFA group (n = 60)
Hepatectomy n = (60)
41 (68.3) 12 (20.0) 7 (11.7) 22.1 ± 5.2 4.4 ± 0.5 3.9 ± 0.4 0.61 ± 0.15 1.0 ± 0.19 2 (5.0) 1 (2.5) 1 (2.5) 3 (5.0%) 0 4.3 ± 1.5 0
49 (81.7) 6 (10.0) 5 (8.3) 22.8 ± 3.5 4.3 ± 0.4 2.9 ± 0.3 0.98 ± 0.23 1.73 ± 0.21 17 (27.5) 14 (2.5) 3 (25) 43 (71.7%) 6 (10%) 11.8 ± 3.1 0
P value
0.109
0.482 0.124 0.032 0.013 0.008 0.047 < 0.001 0.012 < 0.001 NA
†
Data are the mean standard deviation; data in parentheses are expressed as number of patients (percentage). NA, not applicable. HCC; hepatocellular carcinoma; RFA, radiofrequency ablation; SD, standard deviation.
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Table 3 Complete ablation rate, recurrence, and extrahepatic metastasis in patients with small HCC† Characteristic
RFA group (n = 60)
Hepatectomy (n = 60)
P value
Complete treatment rate (%) Recurrence during follow-up (%) Intrahepatic recurrence (%) Local Distant Extrahepatic metastasis (%) Lung Bone Lymph node
57 (95.0) 22 (36.6) 14 (23.3) 8 (13.3) 6 (10.0) 8 (13.3) 6 (10.0) 2 (3.3) 0 (0)
58 (96.7) 21 (35.0) 11 (18.4) 1 (1.7) 10 (16.7) 10 (16.6) 8 (13.3) 1 (2.5) 1 (2.5)
0.311 0.850 0.502
0.611
†
Data are expressed as number of patients (percentage). HCC; hepatocellular carcinoma; RFA, radiofrequency ablation.
patients, as shown as Figure 3, including RFA in six patients and chemoembolization in four patients. And two patients among these 11 patients underwent transplantation further after re-recurrence in the Center of Hematology Transplantation, the First Affiliated Hospital, School of Medicine, Zhejiang University. Other 14 patients gave up further treatment because of failure of liver function, multiple intrahepatic recurrences more than three tumors because of microvascular invasion, side-effects, and other reasons. After a mean follow-up of 40 months, 22 patients (36.6%) in the percutaneous RFA group and 21 patients (35.0%) in the hepatectomy group developed recurrence. There was a trend toward a higher incidence of intrahepatic recurrence (23.3% vs 18.4%) with percutaneous RFA group and distant metastases (13.3% vs 16.6%) with surgical hepatectomy group, but the difference was not significant (P > 0.05). Univariate analysis revealed that Child–Pugh classification of the liver functions (P = 0.003), serum AFP level (P = 0.006), HBV infection (P = 0.018), and number of hepatic tumors (P = 0.038) were risk factors for local recurrence.
Follow-up results. The rates of disease-free survival in the RFA group versus the surgical hepatectomy group at 1, 2, and 3 years were 91.6% versus 90.4%, 87.4% versus 85.2%, and 55.4% versus 41.3% (Fig. 4a). There was no significant difference in the rates of disease-free survival between the two groups (P = 0.443, log–rank test). The overall survival rates at 1, 2, and 3 years in the percutaneous group were 97.5%, 91.2%, and 82.5%, respectively; and in the surgical hepatectomy group were 93.7%, 86.2%, and 77.5%, respectively. Thus, there was no significant difference in the overall survival rates between the two groups (P = 0.207, log–rank test, Fig. 4b).
Discussion Our study suggested that percutaneous RFA and hepatectomy provided similar local control and overall disease-free survival for patients with small HCC (tumor size ≤ 3 cm). However, in comparison with hepatectomy, percutaneous RFA showed a lower complication rate and shorter hospital stays. 196
Partial hepatectomy, including liver transplantation, remains the most efficient and treatment “gold standard” for resectable HCC patients with an aim of providing a “cure.”23 And surgical resection and local ablative therapies represent the most frequent first lines therapies adopted when liver transplantation cannot be offered or is not immediately accessible. However, less than 30% of patients with small HCC are eligible for surgery, mainly because of the multiplicity of the lesions that often occurs in a background of chronic liver disease, bad liver function, and deteriorating general condition.24,25 Partial hepatectomy is safe after adequate anatomical resections, with good long-term survival up to > 50% over 5 years.23,26 Unfortunately, a significant proportion of these patients cannot be offered surgery at the time of diagnosis of HCC with a background of chronic hepatitis B cirrhosis. In addition, the role of hepatic resection for treatment of bilobar or multiple small HCCs is more controversial.27,28 Thus, a less invasive procedure with the ability to ablate HCC completely is a necessary and attractive alternative treatment modality. Recently, various thermal ablative therapies have been developed, of which percutaneous RFA has attracted the greatest interest and popularity because of its low morbidity and mortality, effective tumor ablation, and maximal preservation of normal liver parenchyma.19,29,30 RFA has been shown by prospective randomized trials to be superior to ethanol injection for treatment of HCC.31,32 Although recent advances in RFA technology have enabled clinicians to use RFA for larger tumors,33,34 there is controversy regarding the treatment choices for HCC larger than 3 cm in diameter.35 Wakai T et al. 36proved that hepatectomy provides both similar local control and better long-term survival for patients with HCC ≤ 4 cm in comparison with percutaneous ablation. A nonrandomized prospective study suggested that resection is superior to RFA in long-term survival.37,38 However, a recently reported randomized trial showed that RFA can achieve similar long-term overall and disease-free survival compared with resection for HCCs ≤ 5 cm.39 Since January 2000, the safety and minimal invasiveness of RFA had made it an attractive treatment option for small HCC in our hospital, especially in the patients who had high operative risks by surgical resection. As far as we know, there have been rare randomized trials to compare the efficacy of RFA with that of surgical resection for an operable early-stage HCC in terms of survival for HCCs ≤ 3 cm.40,41 In this study, the randomized analysis showed that there was no significant difference of the complete remission rates, recurrence rates, disease-free survival rates, and overall survival rates between the RFA group and hepatectomy group (P > 0.05). Local recurrences after percutaneous RFA may be attributable to insufficient ablation of the primary tumor and/or the presence of portal or hepatic venous tumor thrombi in the adjacent liver.4 Our study also showed that the overall and disease-free survival rates at 1, 2, and 3 years were the same for small HCC patients treated with either RFA or surgical resection (P > 0.05). In contrast, another large retrospective study for HCC patients with tumor less than 5 cm in diameter enrolled in the Liver Cancer Study Group of Japan.41 The results showed that HCC patients who received liver resection (n = 8010) had better survival than RFA (n = 4037) or TACE (n = 841). In the Japan study, the lesions of HCCs measuring > 3 cm were included in this study resulting incomplete Journal of Gastroenterology and Hepatology 29 (2014) 193–200
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Figure 1 Early-phase computed tomography (CT) scans of hepatocellular carcinoma nodule in the diaphragmatic dome area in a 54-year-old man. The hepatic nodule with a 10 mm enhancing tumor (arrows) in the diaphragmatic dome area (a) nodules were diagnosed after transcatheter arterial embolization with iodized oil and biopsy under the CT scan guidance, following treated with RF ablation under the CT guidance. Scan of venous phase obtained 1 month after RF ablation showed no enhancement in the tumor area (arrowshead). As (b) showed that iodized oil injected at the site of previous transcatheter arterial embolization before radiofrequency ablation (RFA) was accumulated in an HCC nodule. Early-phase transverse CT scans of an intrahepatic metastatic nodule located the right hepatic lobes 3 months after the surgical hepatectomy in an 18-year-old man. As (c) showed that the nodule obtained before RF ablation showed a 1.4-cm enhancing tumor (arrows) in the right hepatic lobes. Scan obtained 14 months after RFA of (d) showed no enhancement in the tumor area (arrows). The technique effectiveness was considered complete.
ablation and the proportion of patients with associated cirrhosis was lower in the surgical resection group than in the nonsurgically treated group. The beneficial effect of hepatectomy was due to the removal of venous tumor thrombi and complete eradication of the primary tumor with clean resection margins.35,42 Another similar study from the Hong Kong, China,19 compared the survival outcome and disease-free survival of a total of 228 patients who underwent RFA of small (< 3 cm; n = 155) and medium (3.1– 5 cm; n = 73) HCC by percutaneous or surgical approach. Percutaneous RFA approach achieved similar tumor control with lower morbidity compared with the surgical approach for patients with small HCC. In our study, during a follow-up of 40 months, there was a trend toward a higher intrahepatic recurrence in the percutaneous RFA group as well as extrahepatic metastases in the surgical hepatectomy group, but the difference was not of statistical significance (P = 0.502 and P = 0.611, respectively). Local recurrences after percutaneous RFA might be attributable to insufficient ablation of the primary tumor, and/or the presence of portal or hepatic venous tumor thrombi in the adjacent liver.43 The predominant trend of extrahepatic recurrence in the hepatectomy group was associated with the following factors: compression, separating of the primary tumor, intraoperative blood transfusion, hematogenous dissemination, and/or devascularization.23,44
However, RFA had significant advantages over surgical resection in causing only one major and one minor complications, less severe pain, a shorter intensive care unit stay and hospital stays (P < 0.01). These data were similar to the first large clinical experience with RFA as reported by Rossi et al.45 and other researchers.36,46 Two patients underwent liver transplantation further after re-recurrence, and salvage liver transplantation is an efficacious treatment for patients with recurrent HCC and should be considered when repeated hepatic resection is not feasible.47 There are still a few outstanding issues that are worth pursuing in future studies. First of all, the sample size of 120 patients in this study was relatively small. However, with the strong belief by oncologists and surgeons as well as patients that RFA has become a more commonly used treatment modality for HCC, we believe that a larger sample size will likely be collected for future comparison with surgical resection. Second, in this study, intrahepatic recurrences were treated further with either TACE or repeated hepatectomy or RFA when indicated. Local effective control of intrahepatic recurrence might increase and affect the overall survival time and the progression-free survival time. Nevertheless, we do think that a longer period of follow-up in the future might be beneficial for the comparison of the disease-free and overall survival rates between RFA and hepatectomy group.
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Figure 2 Magnetic resonance imaging (MRI) with hepatobiliary contrast agent of a “typical” small hepatocellular carcinoma. On the blank T1-weighted MRI, the new lesion was visible in the right liver lobe in a male patient, 44 years old, with 25 years of infection of hepatitis B (a). In the contrast artery (b) and portal venous phase (c), the lesion showed markedly enhancement. 1 month later after the RFA treatment of this lesion, the lesion was visible with a central scar in the T1-weighted MRI (d). After contrast the lesion showed no enhancement during the artery phase (e) and portal venous phase (f).
Figure 3 Magnetic resonance imaging (MRI) with hepatobiliary contrast agent of a “typical” hepatocellular carcinoma. On the blank T1-weighted MRI, the new lesion was visible in the right liver lobe in a female patient, 34 years old, 5 months later of hepatectomy (a). In the contrast artery phase, the lesion showed strong enhancement (b). In the portal venous phase, the lesion was slightly hyperintense compared to the normal liver tissue (c). 1 month later after the radiofrequency ablation (RFA) treatment of right liver lobe, on the blank T1-weighted MRI, the lesion was visible with a central scar (d). After contrast the lesion showed no enhancement with exception of the central scar in the artery phase (e) and portal venous phase (f).
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Figure 4 No significant difference of the rates of disease-free survival between the radiofrequency ablation (RFA) group and the surgical hepatectomy group. The rates of disease-free survival in the RFA group versus the surgical hepatectomy group at 1, 2, and 3 years were 91.6% versus 90.4%, 87.4% versus 85.2%, and 55.4% versus 41.3% (a). No significant difference was noted between the two groups (P = 0.443, log–rank test). And as (b) showed, the overall survival rates at 1, 2, and 3 years were 97.5%, 91.2% and 82.5%, respectively, in the RFA group and, 93.7%, 86.2% and , 77.5%, respectively, in the surgical hepatectomy group. No significant difference was noted between the two groups (P = 0.207, log–rank test). RFA group; , Hepatectomy group.
In conclusion, RFA give similar long-time effectiveness compared with hepatectomy resection for patients with small HCC, including complete tumor treatment rate, and disease-free and overall survival rate. Importantly, other than being less invasive, RFA offers additional advantages over surgical resection in giving better short-term postoperative results such as lower complication rates, and shorter intensive care unit and hospital stays. Further studies such as enlarged multicenter randomized trials are required to validate the results of the current study.
Acknowledgments The authors acknowledge Dr. Gerry Ellis working in Sir Run Run Shaw hospital for the writing assistance and critical revision of the manuscript for important intellectual content. This work was fully supported by grants from Zhejiang Science and Technology Agency funding 2010C13025-1 (H.M. Pan), National Natural Science Foundation of China 81272593 (H.M. Pan), Zhejiang Provincial Natural Science Foundation of China LY13H160013 (Y. Fang) and Zhejiang Provincial Natural Science Foundation of China LQ13H160009 (W. Chen).
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