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DOI:10.2214/AJR.04.1573
AJR 2006; 186:S275-S283
© American Roentgen Ray Society


Original Research

Radiofrequency Ablation of Recurrent Hepatocellular Carcinoma After Hepatectomy: Therapeutic Efficacy on Early- and Late-Phase Recurrence

Wei Yang1, Min Hua Chen1, Shan Shan Yin1, Kun Yan1, Wen Gao1, Yan Bin Wang1, Ling Huo1, Xiao Peng Zhang2 and Bao Cai Xing3

1 Department of Ultrasound, Peking University School of Oncology, 52 Fu-cheng Rd., Hai-dian District, Beijing 100036, People's Republic of China.
2 Department of Radiology, Peking University School of Oncology, Beijing 100036, People's Republic of China.
3 Department of Surgery, Peking University School of Oncology, Beijing 100036, People's Republic of China.

Received October 8, 2004; accepted after revision February 25, 2005.

 
Address correspondence to M. H. Chen (minhuachen{at}vip.sina.com).


Abstract
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
 
OBJECTIVE. Our objective was to assess the efficacy and safety of radiofrequency ablation of recurrent hepatocellular carcinoma (HCC) after hepatectomy and to compare the effects on early- and late-phase recurrence.

SUBJECTS AND METHODS. We studied 41 patients with 76 recurrent HCC tumors (diameter range, 2.0–6.6 cm; mean, 3.8 ± 1.3 [SD] cm) after hepatectomy who underwent sonography-guided percutaneous radiofrequency ablation in our hospital (recurrent-HCC group). The interval between surgery and recurrence ranged from 1 to 96 months (mean, 24.5 months). These patients were divided into an early-recurrence group (20 patients with 41 recurrent HCC tumors) and a late-recurrence group (21 patients with 35 recurrent HCC tumors). Early recurrence was defined as that occurring within 1 year after surgery, and late recurrence was defined as that occurring after 1 year. Another 116 patients with 172 primary HCC tumors (diameter range, 1.2–7.0 cm; mean, 3.9 ± 1.1 cm) treated by radiofrequency ablation were regarded as a control group. No other therapies were given before radiofrequency ablation in any group. Regular follow-up with enhanced CT was performed to evaluate the treatment results. Ablation was considered successful if no contrast enhancement was detected in the treated area on 1-month CT scans. Indexes including ablation success rate, local recurrence rate, distant recurrence rate, and survival were obtained for analysis and comparison.

RESULTS. The ablation success rate, local recurrence rate, distant recurrence rate, and mean overall survival time of the recurrent-HCC group were 93.4% (71/76 tumors), 9.2% (7/76 tumors), 36.6% (15/41 patients), and 30.9 ± 3.7 months, respectively. The incidence of distant recurrence in the early-recurrence group was significantly higher than that in the late-recurrence group (55.0% vs 19.0%, p = 0.017). The early-recurrence group had a shorter overall survival than did the late-recurrence group (mean overall survival, 16.4 ± 2.4 vs 42.9 ± 4.4 months, p < 0.001) or the control group (16.4 ± 2.4 vs 45.9 ± 2.5 months, p < 0.001). The survival time of the late-recurrence group was similar to that of the control group (42.9 ± 4.4 vs 45.9 ± 2.5 months, p > 0.05). Serious hemorrhage after radiofrequency ablation occurred in one patient in the late-recurrence group and was controlled with conservative treatment.

CONCLUSION. Radiofrequency ablation is generally effective and safe in treating recurrent HCC after hepatectomy and is more effective in late recurrence than in early recurrence.

Keywords: cancer • CT • liver • radiofrequency ablation • sonography


Introduction
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
 
Hepatocellular carcinoma (HCC) is one of the most widespread solid cancers worldwide, with an estimated incidence of at least one million new cases per year [1]. Hepatectomy has been regarded as the gold standard treatment for HCC; however, an intrahepatic recurrence rate of as high as about 70% was seen within 5 years after surgery despite postoperative histologic findings of no residual tumor in the resected tumor margin [24]. Intrahepatic recurrence has two origins: intrahepatic metastasis and multicentric occurrence. Intrahepatic metastasis refers to metastatic lesion spread from the primary main tumor and occurs quickly in the remnant liver; multicentric occurrence refers to newly developed lesions in the cirrhotic background long after hepatectomy. Generally, the two kinds of recurrence can roughly be distinguished according to the time of appearance [58].

To achieve longer survival of HCC patients, one of the most important issues is the choice of an appropriate technique to treat recurrent HCC after surgery. Repeated hepatectomy has been effective in treating recurrent HCC, but a second resection is contraindicated in most patients [2, 3, 9]. In the past few years, adoption of radiofrequency ablation to treat primary and secondary hepatic tumors has been increasing because of its high efficacy and minimal invasiveness [1012]. However, studies on the use of radiofrequency ablation to treat recurrent HCC after hepatectomy are rare [1315]. Despite the fact that intrahepatic metastasis and multicentric occurrence are of different origins and that, therefore, survival rates after treatment are different, little effort has been made to distinguish the two patterns, with both being regarded simply as "recurrent tumors." Thus, we studied the effects of radiofrequency ablation on 41 patients with 76 recurrent HCC tumors after hepatectomy and compared the effects on early recurrence (intrahepatic metastasis) and late recurrence (multicentric occurrence), setting 1 year as the cutoff between the early and late phases.


Subjects and Methods
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
 
Patients
This study was approved by the institutional review board of the Peking University School of Oncology, and written informed consent was obtained from all patients before their treatment.

Between January 2000 and August 2004, 52 consecutive patients who had recurrent HCC after hepatectomy underwent percutaneous radiofrequency ablation with sonographic guidance in our hospital. Eleven of the 52 patients were excluded because they had received other therapies for recurrent HCC, such as transcatheter arterial chemoembolization (TACE) or percutaneous ethanol injection (PEI), before radiofrequency ablation. The remaining 41 patients with 76 recurrent HCC tumors after hepatectomy formed the study population. During the same period, 116 patients with 172 primary HCC tumors underwent radiofrequency ablation in our hospital and received no other therapy before radiofrequency ablation; they formed the control group. All patients met the following criteria for treatment with percutaneous radiofrequency ablation: percutaneously accessible tumors, no more than five tumors, absence of thrombosis in the portal vein, resected or controlled extrahepatic metastasis, a prothrombin time ratio greater than 60%, and a platelet count greater than 60,000/µL.

The hepatectomy procedures performed on the recurrent-HCC group before radiofrequency ablation consisted of lobectomy or segmentectomy in 20 patients and subsegmentectomy or partial resection in 21 patients. No tumor cells were found at histologic analysis of tissue from the margins of resected tumors in any patient.

After surgery, the patients were monitored regularly in the outpatient clinic for intrahepatic recurrence, using a follow-up protocol. Every 2–3 months for the first year, the serum {alpha}-fetoprotein level was measured and abdominal sonography and enhanced CT were performed. After the first year, the {alpha}-fetoprotein level was measured every 2–3 months and abdominal sonography and enhanced CT were performed every 4–6 months. Routine sonography, color Doppler sonography, and {alpha}-fetoprotein level during the follow-up period provided additional information for diagnosis. Patients who had a CT contrast allergy underwent MRI or enhanced sonography. Suspected intrahepatic recurrence was confirmed by percutaneous fine-needle biopsy.

The interval between surgery and diagnosis of recurrence ranged from 1 to 96 months (mean, 24.5 months). All patients underwent radiofrequency ablation within 1–2 months after diagnosis of recurrence. In this study, all malignant lesions in the remnant liver were regarded as intrahepatic recurrences. The 41 recurrent-HCC patients were categorized according to the recurrence interval into an early (recurrence) group, including 20 patients with 41 recurrent HCC tumors, or a late (recurrence) group, including 21 patients with 35 recurrent HCC tumors. Early recurrences and late recurrences were defined as those occurring within 1 year or after 1 year, respectively, from the date of hepatectomy. Despite the different recurrence intervals before radiofrequency ablation, the two groups did not significantly differ in clinical characteristics (Table 1).


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TABLE 1: Clinical Characteristics of 41 Patients with 76 Recurrent HCC Tumors

 

Of the 116 primary HCC patients in the control group, 88 were men and 28 were women (age range, 24–80 years; mean, 60.1 ± 1.2 [SD] years). The tumors ranged from 1.2 to 7.0 cm in diameter (mean, 3.9 ± 1.1 cm). Sixty-five of the 116 recurrent HCC patients had Child-Pugh class A cirrhosis, 46 had class B, and five had class C. Seventy-six patients (65.5%) had stage III or IV tumors (TNM system [16]).

Techniques and Equipment
All radiofrequency ablation was performed percutaneously under real-time sonographic guidance by two radiologists, each of whom had more than 10 years of experience in sonography-guided interventional procedures such as PEI. The treatments were performed with conscious sedation or general anesthesia. Conscious sedation was induced with IV administration of 2.5–5.0 mg of midazolam and 50–100 µg of fentanyl (Fentaini, Renfu). Local infiltration anesthesia was induced with 5–15 mL of 1% lidocaine (Liduokayin, Yimin). When the tumor was adjacent to the diaphragm or the liver surface, an IV bolus of propofol (Diprivan, Zeneca) (1–2 mg/kg) and fentanyl (50–100 µg) was given to induce general anesthesia in combination with local anesthesia.

The patients were conscious when the electrode was placed. Their vital signs, such as blood pressure, heart rate, respiratory rate, and oxygen saturation, were continuously monitored during the procedure. Generally, patients were discharged 2–4 hr after treatment if no evidence of active bleeding was seen on the sonograms. Patients with heart or respiration disease or a slight coagulation function disorder were hospitalized for 1–3 days after the procedure.

The radiofrequency ablation system used in this study was a 460-kHz generator unit (model 1500, RITA Medical Systems), which was capable of delivering a maximum power of 150 W through a 14-gauge electrode. The electrode contained nine hook-shaped prongs that could be deployed from the central needle cannula. Five of the nine prongs contained a thermocouple at the tip, and this array electrode (Starburst XL, RITA Medical Systems) enabled ablation of a 5.0-cm region. A spherelike coagulation area 3–5 cm in diameter could be produced when the electrode was inserted into the tumor and nine prongs were deployed from the cannula. The time to produce a 5-cm ablation sphere was about 20 min. Tumors larger than 3.5 cm needed multiple overlapping ablations [17]. The safe margin in the ablation procedure enveloped the entire tumor and a 0.5- to 1.0-cm margin of surrounding normal tissue.

Real-time sonography (SSD-2000 and SSD-4000, Aloka) was performed using 3.5- to 5.0-MHz small-sector and board-view convex probes equipped with attachments for biopsy and radiofrequency electrode insertion.

Assessment of Therapeutic Efficacy and Follow-Up
To evaluate the tumor response to radiofrequency ablation, we performed contrast-enhanced CT 1 month after the treatment. For the comparatively large tumors, additional CT scans were obtained within 24 hr after the treatment to determine whether there was any residual malignant tissue that might need additional ablation. The ablation was considered successful if all of the following were found on the initial images: no enhancement within or around the tumor, clear and smooth margins around the ablation zone, and extension of the ablation zone beyond the tumor borders compared with images obtained before radiofrequency ablation [18, 19]. All recurrent HCC tumors after hepatectomy were ablated in the initial radiofrequency ablation. Ablation in a patient was regarded as successful if all of that patient's recurrent HCC tumors had been ablated successfully.

Subsequently, patients were monitored with the follow-up protocol. Enhancement in or around the ablation zone on follow-up images was considered local recurrence. New nodules at other sites of the liver were considered distant recurrences. The period of follow-up ranged from 3 to 58 months (mean, 14.5 months) after radiofrequency ablation.

All CT examinations were performed using a helical scanner (Plus 4, Siemens Medical Solutions) with 5-mm collimation and a 7.5 mm/sec table speed. A total of 100 mL of nonionic contrast material (iohexol, 300 mg of iodine per milliliter [Omnipaque], Nycomed Amersham) was administered at a rate of 3 mL/sec with a power injector (OP 100, Medrad). The CT images were acquired before the injection and 25 sec (hepatic arterial phase) and 60 sec (portal venous phase) after the beginning of injection.

Two radiologists with more than 10 years of experience in liver studies interpreted the CT images without knowledge of the patients' group information. In all cases, the therapeutic result of the ablation was decided by consensus. When disagreement occurred, a third radiologist was invited to interpret the CT scans, and his judgment would prevail.

Residual tumor, local recurrence, and distant recurrence were retreated if the patient was physically strong enough to tolerate another radiofrequency ablation session. In this study, 15 recurrent-HCC patients received 2–4 sessions because of tumor residue or intrahepatic recurrence. The number of repeated radiofrequency ablations is summarized in Table 2.


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TABLE 2: Repeated Radiofrequency Ablations in Recurrent-HCC Patients

 

Statistical Analysis
The ablation success rate and local recurrence rate were determined by counting numbers of tumors and patients. The distant recurrence rate was determined by counting numbers of patients. The chi-square test and independent-sample t test were used to analyze differences in clinical features and therapeutic efficacy among the three groups. The survival rate was the fraction of patients who survived on a particular day and was calculated using the Kaplan-Meier method, even though most patients did not die during the study. Survival time was calculated starting from the time of the first radiofrequency ablation. The log-rank test was used to compare survival differences. If a patient died of causes other than tumor progression at the time of writing, that patient was censored. The Kaplan-Meier method automatically accounted for censored patients because both the numerator and the denominator were reduced on the day a patient was censored [20]. The level of significance was set at 0.05 for all tests. SPSS statistical analysis software (SPSS Inc.) was used.


Results
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
 
Therapeutic Efficacy
In the recurrent-HCC group, ablation (evaluated by CT 1 month after the initial procedure) was successful in 71 (93.4%) of 76 tumors and in 36 (87.8%) of 41 patients. One of the five patients with residual nonablated tumor declined an additional radiofrequency ablation session because tumor was adherent to the diaphragm; the remaining four tumors in four patients were ablated successfully after the second or third session. During the followup period, local recurrence developed in another seven tumors (9.2%) in seven patients (17.1%). Distant recurrence was observed in 15 (36.6%) of 41 patients, and a total of 21 distant recurrences were ablated. The mean overall survival time and disease-free survival time were 30.9 ± 3.7 months and 17.2 ± 2.5 months, respectively. Of the 21 patients with an elevated {alpha}-fetoprotein level before radiofrequency ablation, 15 showed a decrease in {alpha}-fetoprotein level 1–2 months after treatment, and in 12 of the 15 the level returned to normal.

Of the 20 patients (41 recurrent HCC tumors) in the early group, four experienced local recurrence of four recurrent HCC tumors 3–8 months after radiofrequency ablation, as well as distant recurrence. Two of the four underwent second and third sessions: Ablation was successful in one, and additional distant recurrences were found in the other. The final two declined another session because of multiple distant recurrences but underwent TACE. Of the remaining 16 patients, seven experienced distant recurrence 1–12 months after radiofrequency ablation. Of the seven, four underwent a second session and two a third, and ablation in these six patients was successful. The remaining patient declined another session because of multiple distant recurrences and died without receiving any more treatment. At the time of writing, 14 of the 20 patients had died, and six patients were still alive, four of whom were disease-free.

Of the 21 patients (35 recurrent HCC tumors) in the late group, three experienced local recurrence of three recurrent HCC tumors 3–18 months after radiofrequency ablation. One of the three patients declined another session because of poor liver function, one underwent a second session, and the remaining one underwent three more sessions to treat local recurrence and distant recurrence. All recurrent tumors were successfully ablated in the last two patients. Of the remaining 18 patients, three experienced distant recurrence 6–18 months after the initial radiofrequency ablation. One of the three underwent a second session, and the tumor was confirmed to be completely necrotic by follow-up. One patient declined another session because of multiple distant recurrences but underwent TACE. The remaining patient, whose tumor was too close to the inferior vena cava, received no further therapy. At the time of writing, four of the 21 patients had died, and 17 patients were still alive, 12 of whom were disease-free.

In the control group, ablation was successful in 94.8% (163/172) of tumors and in 92.2% (107/116) of patients. During the follow-up period, local recurrence developed in 9.9% (17/172) of tumors and in 13.8% (16/116) of patients. Distant recurrence was observed in 37.9% (44/116) of patients. The mean overall survival time was 45.9 ± 2.5 months, and the disease-free survival time was 20.9 ± 2.2 months.

Comparison of Therapeutic Efficacy
The results of radiofrequency ablation for the early group, late group, and control group are shown in Table 3 and Figures 1A, 1B, 1C, 1D, 2A, 2B, 2C, 2D, 3A, 3B, 3C, 3D, and 3E. The incidence of distant recurrence in the early group was significantly higher than that in the late group (p = 0.017). No significant differences in other variables were found among these three groups.


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TABLE 3: Comparison of Radiofrequency Results of Early-Recurrence Group, Late-Recurrence Group, and Control Group

 

Figure 1
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Fig. 1A —54-year-old man in whom intrahepatic hepatocellular carcinoma (HCC) recurred 3 months after partial resection of right hepatic lobe (early-recurrence group). Before radiofrequency ablation, {alpha}-fetoprotein level rose to 788.9 ng/mL. Transverse contrast-enhanced CT scan shows spherical recurrent tumor in segment VII (arrow).

 

Figure 2
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Fig. 1B —54-year-old man in whom intrahepatic hepatocellular carcinoma (HCC) recurred 3 months after partial resection of right hepatic lobe (early-recurrence group). Before radiofrequency ablation, {alpha}-fetoprotein level rose to 788.9 ng/mL. Intercostal sonogram shows this tumor being treated by sonography-guided radiofrequency ablation.

 

Figure 3
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Fig. 1C —54-year-old man in whom intrahepatic hepatocellular carcinoma (HCC) recurred 3 months after partial resection of right hepatic lobe (early-recurrence group). Before radiofrequency ablation, {alpha}-fetoprotein level rose to 788.9 ng/mL. Contrast-enhanced CT scans obtained 1 month after radiofrequency ablation show unenhanced area of coagulation extending beyond original tumor (arrowhead) but distant recurrence (arrow) in segment II. {alpha}-Fetoprotein level was 24 ng/mL. Patient subsequently underwent another radiofrequency ablation for recurrent HCC.

 

Figure 4
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Fig. 1D —54-year-old man in whom intrahepatic hepatocellular carcinoma (HCC) recurred 3 months after partial resection of right hepatic lobe (early-recurrence group). Before radiofrequency ablation, {alpha}-fetoprotein level rose to 788.9 ng/mL. CT scan obtained 5 months after repeated radiofrequency ablation shows nodular enhanced area in outer part of ablated area (arrow), indicating local recurrence. Multiple distant recurrences and portal vein thrombosis (arrowhead) developed at same time. This patient survived 13 months before dying of tumor spread and metastasis.

 

Figure 5
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Fig. 2A —64-year-old man in whom intrahepatic hepatocellular carcinoma recurred 69 months after partial resection of left hepatic lobe (late-recurrence group). Transverse contrast-enhanced CT scan shows spherical recurrent tumor (arrow) in right lobe of liver.

 

Figure 6
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Fig. 2B —64-year-old man in whom intrahepatic hepatocellular carcinoma recurred 69 months after partial resection of left hepatic lobe (late-recurrence group). Intercostal sonogram shows tumor being treated by sonography-guided radiofrequency ablation.

 

Figure 7
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Fig. 2C —64-year-old man in whom intrahepatic hepatocellular carcinoma recurred 69 months after partial resection of left hepatic lobe (late-recurrence group). CT scan obtained 1 month after radiofrequency ablation shows low-attenuation area of coagulation (arrow) with sharp margin and no enhancement.

 

Figure 8
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Fig. 2D —64-year-old man in whom intrahepatic hepatocellular carcinoma recurred 69 months after partial resection of left hepatic lobe (late-recurrence group). CT scan obtained 17 months after radiofrequency ablation shows obvious decrease in size of unenhanced area of ablation (arrow). This patient was still alive after more than 2 years, with completely necrotic tumor.

 

Figure 9
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Fig. 3A —67-year-old man in whom intrahepatic hepatocellular carcinoma recurred 55 months after partial resection of right hepatic lobe (late-recurrence group). Before radiofrequency ablation, level of {alpha}-fetoprotein reached 180 ng/mL. Transverse contrast-enhanced CT scans show no nodular enhancement in arterial phase but low-attenuation nodule (arrow) in portal phase. Nodule was verified to be malignant by needle biopsy.

 

Figure 10
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Fig. 3B —67-year-old man in whom intrahepatic hepatocellular carcinoma recurred 55 months after partial resection of right hepatic lobe (late-recurrence group). Before radiofrequency ablation, level of {alpha}-fetoprotein reached 180 ng/mL. Intercostal sonograms show 2.8-cm tumor being treated by sonography-guided radiofrequency ablation.

 

Figure 11
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Fig. 3C —67-year-old man in whom intrahepatic hepatocellular carcinoma recurred 55 months after partial resection of right hepatic lobe (late-recurrence group). Before radiofrequency ablation, level of {alpha}-fetoprotein reached 180 ng/mL. CT scan obtained 6 months after radiofrequency ablation shows low-attenuation area of coagulation in segment V, with sharp margin and no enhancement. At same time, level of {alpha}-fetoprotein decreased to 5 ng/mL.

 

Figure 12
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Fig. 3D —67-year-old man in whom intrahepatic hepatocellular carcinoma recurred 55 months after partial resection of right hepatic lobe (late-recurrence group). Before radiofrequency ablation, level of {alpha}-fetoprotein reached 180 ng/mL. CT scan obtained 18 months after radiofrequency ablation shows nodular enhanced area (arrow) in right exterior part of ablated area, indicating local recurrence. This recurrence was treated by repeated radiofrequency ablation.

 

Figure 13
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Fig. 3E —67-year-old man in whom intrahepatic hepatocellular carcinoma recurred 55 months after partial resection of right hepatic lobe (late-recurrence group). Before radiofrequency ablation, level of {alpha}-fetoprotein reached 180 ng/mL. CT scan obtained 1 month after repeated radiofrequency ablation shows that ablated lesion had clear margin and no enhancement. This patient was still alive after more than 2 years, with complete tumor necrosis.

 

Overall survival curves and survival rates for the three groups are shown in Table 4 and Figure 4. The overall survival of the early group was significantly shorter than that of the late group (mean, 16.4 ± 2.4 vs 42.9 ± 4.4 months, p < 0.001) and that of the control group (16.4 ± 2.4 vs 45.9 ± 2.5 months, p < 0.001). The overall survival of the late group was similar to that of the control group (42.9 ± 4.4 vs 45.9 ± 2.5 months, p > 0.05).


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TABLE 4: Overall Survival Rates of Early-Recurrence Group, Late-Recurrence Group, and Control Group

 

Figure 14
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Fig. 4 —Overall survival curves after radiofrequency ablation of early-recurrence group (n = 20), late-recurrence group (n = 21), and control group (n = 116). Gray line = late recurrence group; black line = early recurrence group; dashed line = control group.

 

Disease-free survival curves and survival rates for the three groups are shown in Table 5 and Figure 5. The disease-free survival of the early group was significantly shorter than that of the late group (mean, 10.8 ± 2.5 vs 23.8 ± 3.7 months, p = 0.006) and that of the control group (10.8 ± 2.5 vs 20.9 ± 2.2 months, p = 0.002). The disease-free survival of the late group was similar to that of the control group (23.8 ± 3.7 vs 20.9 ± 2.2 months, p > 0.05).


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TABLE 5: Disease-Free Survival Rates of Early-Recurrence Group, Late-Recurrence Group, and Control Group

 

Figure 15
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Fig. 5 —Disease-free survival curves after radiofrequency ablation of early-recurrence group (n = 20), late-recurrence group (n = 21), and control group (n = 116). Gray line = late recurrence group; black line = early recurrence group; dashed line = control group.

 

Complications
No procedure-related deaths occurred. One severe intraperitoneal hemorrhage occurred in the late group, but no surgery was necessary. This patient, who had a recurrent tumor 4.6 cm in diameter protruding from the left liver surface, received one radiofrequency ablation session, and a great deal of blood was observed in the peritoneal cavity within 24 hr afterward. The bleeding was controlled with an 800-mL blood transfusion and conservative treatment, and the tumor was seen to be completely necrotic on follow-up CT.


Discussion
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
 
Although remarkable advances in surgical and imaging techniques have improved the prognosis of HCC patients, the high incidence of intrahepatic recurrence remains a major challenge in HCC therapy [21, 22]. The commonly used methods of treating recurrent HCC have included repeated hepatectomy, TACE, radiofrequency ablation, and PEI. Investigation of a treatment for recurrence, and of the efficacy of that treatment, is important in prolonging survival after resection of HCC.

Repeated hepatectomy is still regarded as an ideal technique to treat recurrent HCC after initial resection. However, severe pain and injury accompany repeated hepatectomy, and the related morbidity rate is more than 10% and the mortality rate more than 2% [21, 23]. In addition, because of the presence of severe adhesions, progressive liver dysfunction, or multiple tumors, repeated hepatectomy is more difficult technically than initial hepatectomy [9, 24]. Thus, only 10–40% of patients with recurrent HCC can undergo repeated hepatectomy safely [2, 3, 9].

TACE and PEI are important and widely used treatments for recurrent HCC after resection [3, 4, 23, 25]. However, long-term survival after TACE or PEI is not satisfactory [21, 2527]. In recent decades, the high efficacy of radiofrequency ablation as a local treatment for hepatic tumors has been confirmed by many clinical studies [28, 29]. Radiofrequency ablation has obtained a higher rate of necrosis than PEI in small tumors and in infiltrating lesions of any size and has avoided the side effects that result when a large amount of ethanol is required [30]. In multiple recurrent HCC tumors, radiofrequency ablation has obtained greater local efficacy than TACE, with fewer side effects and less impairment of liver function [31].

Analysis of Radiofrequency Ablation Efficacy
This study showed no significant differences in the rates of ablation success and local recurrence between the early and late groups, but the incidence of distant recurrence in the early group was significantly higher than that in the late group, suggesting that recurrent tumors arising from intrahepatic metastasis grew more rapidly than did those arising from multicentric occurrence. Local recurrence occurred in only seven patients, whereas distant recurrence occurred in 15 patients, and 11 of the 15 were from the early group. Local recurrence was uncommon after radiofrequency ablation, but distant recurrence was much more frequent. Local destruction of tumor might benefit overall and disease-free survival in a subset of patients but could not overcome the tumor biology for patients in whom micrometastatic development had started at the time of radiofrequency ablation. Eleven of 20 patients in the early group (55%) had distant recurrence after radiofrequency ablation, whereas four of 21 patients in the late group (19%) had distant recurrence; multiple recurrences developed in four of the 11 patients in the early group and one of the four in the late group, making them unable to tolerate further sessions. Therefore, late recurrence is thought to be preferable to early recurrence in terms of indications for radiofrequency ablation. This information should be beneficial for assessing outcomes and choosing the optimal treatment for recurrent HCC.

Few studies have been published on radiofrequency ablation in recurrent HCC after hepatectomy. Choi et al. [13] reported overall 1-, 2-, and 3-year survival rates of 82%, 72%, and 54%, respectively. They considered radiofrequency ablation for recurrent HCC after surgery to be beneficial. Our study went further by distinguishing early recurrence from late recurrence with regard to the efficacy of radiofrequency ablation, demonstrating a significant difference in survival between the recurrent-HCC groups with early and late recurrence. Our overall 1-, 2-, and 3-year survival rates were 88.9%, 81.5%, and 72.4%, respectively, in the late group and 55.9%, 20.4%, and 10.2%, respectively, in the early group.

Differences in the biologic origin and behavior of early- and late-phase recurrences might account for the differences in prognosis [7]. Recurrence in the remnant liver after hepatectomy could originate from either intrahepatic metastasis of the primary tumor or multicentric occurrence in cirrhotic background. The fact that venous invasion is the most significant risk factor for early recurrence suggests that intrahepatic metastasis is an important mechanism of early intrahepatic recurrence after resection of HCC. In contrast, the risk of late recurrence varies according to the grade of hepatitis and is thought to be related to the elevated carcinogenicity of the background liver. Multicentric occurrence is a main mechanism of late recurrence [32]. Preliminary studies found that the interval after hepatectomy that best discriminated intrahepatic metastasis from multicentric occurrence was 1 year, compared with other intervals such as 0.5, 1.5, and 2 years [7, 24]. Hence, early and late recurrences were defined in our study as recurrences before or after 1 year from the date of hepatectomy.

According to the hypothesis above, we analyzed the effects of radiofrequency ablation on early and late recurrence and compared the results with the result for primary HCC (control group). We found that the overall survival and disease-free survival of the late group were similar to those of the control group but that survival results were less favorable for the early group than for the other two groups, despite similar treatment. This finding, in turn, strongly supports the hypothesis that recurrence after 1 year was attributable mainly to a second primary lesion [7, 24], whereas early recurrence might be due to intrahepatic metastasis and spread. The comparable survival times after radiofrequency ablation between the late group and the primary-HCC group renews the idea that once liver cancer recurs after surgery, it is at an advanced stage and not amenable to curative therapy again.

Comparison of Therapeutic Efficacy Between Radiofrequency Ablation and Other Techniques
Some other authors also have analyzed the outcome of intrahepatic recurrence after other treatments in relation to recurrence patterns of HCC. Matsuda et al. [8] reported that the 1- and 3-year survival rates were 100% and 69.7%, respectively, for patients with multicentric occurrence after repeated operation and 57.1% and 14.3%, respectively, for patients with intrahepatic metastasis. Poon et al. [7] reported that patients with early recurrence had a worse median survival after recurrence than did patients with late recurrence, regardless of whether they were treated by repeated resection (38 vs 47 months, p = 0.032), TACE (17 vs 32 months, p < 0.001), or PEI (14 vs 25 months, p = 0.003). The median survival after conservative management was similar between the two groups (4.0 vs 5.6 months, p = 0.235). Our study also showed that early recurrence had a worse prognosis than late recurrence after radiofrequency ablation (mean survival, 16.4 ± 2.4 vs 42.9 ± 4.4 months, p < 0.001). It seemed that, compared with conservative management, radiofrequency ablation could be beneficial to both patterns of recurrence after hepatectomy. Also, compared with TACE and PEI, radiofrequency ablation is likely to achieve better results for late recurrence and equal results for early recurrence.

Compared with overall survival after repeated hepatectomy, overall survival after radiofrequency ablation was similar in the late group but worse in the early group. The social and economic impact would be obvious if survival for the late group after radiofrequency ablation were comparable to that after repeated hepatectomy. The current study showed that survival in the early group was not as good after radiofrequency ablation as after repeated hepatectomy. This finding might be due to too small a sample size. Further studies on larger populations of patients and with longer follow-up periods are needed to compare survival after radiofrequency ablation with survival after repeated surgery. However, the therapeutic threshold for operation on recurrent HCC is considerably higher than that for radiofrequency ablation. In other words, the indications are broader for radiofrequency ablation than for surgery.

Complications of Radiofrequency Ablation
Of the 41 recurrent-HCC patients, one experienced a comparatively serious hemorrhage. This patient had a history of local resection of the left liver lobe for HCC. Two years later, a 4.6-cm recurrent tumor was found partly protruding from the left surface of segment IV. CT before radiofrequency ablation showed bleeding and necrotic tissue inside the tumor. The intraperitoneal hemorrhage was caused by increased abdominal pressure when the patient coughed at the fourth hour after the radiofrequency ablation. After blood transfusion and conservative treatment, the bleeding was controlled. This complication suggests that patients with protruding and large recurrent tumors after surgical resection are not candidates for percutaneous radiofrequency ablation, especially if insufficient liver parenchyma surrounds the tumor.

Advantages and Disadvantages of Radiofrequency Ablation
Low cost, low risk, and the simplicity of the technique make radiofrequency ablation possible to perform at most hospitals. Patients with small HCC tumors generally are treated as outpatients, and most can lead a normal daily life thereafter. Furthermore, improvements in the technique and optimization of the multiple-ablations protocol has achieved better efficacy for treatment of large tumors [10, 17]. Another advantage of radiofrequency ablation is that it can be repeated many times easily and safely to treat residual tumor or intrahepatic recurrence. Our study showed that six patients who underwent three or four sessions of radiofrequency ablation survived 14–54 months with no major complications. However, in patients with a highly carcinogenic liver in which new nodules frequently appear, liver transplantation may be a better choice.

Percutaneous radiofrequency ablation has intrinsic drawbacks. First, tumors near the major hepatic vessels are not easy to destroy completely. Second, the risk of incomplete tumor destruction is higher for radiofrequency ablation than for surgical resection [13]. Furthermore, radiofrequency ablation can cause adherence between tumor and diaphragm or adjacent structures, making repeated hepatectomy more difficult.

Study Limitations
This study was limited by a possible selection bias resulting from the comparison of these nonrandomized groups. Furthermore, recurrence interval is not always of value in differentiating the mode of intrahepatic recurrence. When recurrent tumors occur soon after hepatectomy, they are interpreted as intrahepatic metastasis, although the possibility of multicentric occurrence cannot be completely ruled out. In contrast, recurrent tumors that develop more than 1 year after hepatectomy rarely originate from intrahepatic metastasis.

In summary, aggressive radiofrequency ablation might lengthen survival in recurrent-HCC patients after hepatectomy, especially in patients with recurrence more than 1 year after surgery.


References
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
 

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