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A case-control study comparing percutaneous radiofrequency ablation alone or combined with transcatheter arterial chemoembolization for hepatocellular carcinoma
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EJSO 36 (2010) 257e263
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A case-control study comparing percutaneous radiofrequency ablation alone or combined with transcatheter arterial chemoembolization for hepatocellular carcinoma Z.-W. Peng a,b, M.-S. Chen a,b,*, H.-H. Liang a,b, H.-J. Gao a,b, Y.-J. Zhang a,b, J.-Q. Li a,b, Y.-Q. Zhang a,b, W.Y. Lau c a
Department of Hepatobiliary Surgery, Cancer Centre of Sun Yat-Sen University, 651 Dongfeng Road East, Guangzhou 510060, China b State Key Laboratory of Oncology in Southern China, Guangzhou 510060, China c Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China Accepted 6 July 2009 Available online 29 July 2009
Abstract Aims: To assess whether combining percutaneous radiofrequency ablation (PRFA) with transcatheter arterial chemoembolization (TACE) was better than PRFA alone for hepatocellular carcinoma (HCC). Materials and methods: One hundered twenty patients (with a solitary HCC 7.0 cm in diameter or multiple HCC (3), each 3.0 cm in diameter) treated with PRFA combined with TACE were compared with 120 well-matched controls selected from a pool of 652 patients who received PRFA alone during the study period. Results: The 1-, 2-, 3-, 5-year overall survival rates for the TACE-PRFA and PRFA groups were 93%, 83%, 75%, 50%, and 89%, 76%, 64%, 42%, respectively ( p ¼ .045). Subgroup analyses showed the survival for the TACE-PRFA group was better than the PRFA group for tumors >5.0 cm ( p ¼ .031) and for multiple tumors ( p ¼ .032), but not for tumors 5.0 cm ( p ¼ .319) and for solitary tumor ( p ¼ .128). The 1-, 2-, 3-, 5-year progression free survival (PFS) for the TACE-PRFA and PRFA groups was 90%, 76%, 63%, 42%, and 76%, 60%, 47%, 30%, respectively ( p ¼ .002). Child-pugh class, Diameter of tumor and hepatitis B surface antigen (HBsAg) were significant prognostic factors. Conclusion: Patients treated with TACE-PRFA had better overall survivals than PRFA alone, but only in a subgroup of patients with tumor >5 cm or multiple tumors. Ó 2009 Elsevier Ltd. All rights reserved. Keywords: Percutaneous radiofrequency ablation; Transcatheter arterial chemoembolization; Hepatocellular carcinoma; Progression free survival; Overall survival
Introduction Hepatocellular carcinoma (HCC) is the 6th most common cancer worldwide and the third most frequent cause of death of cancer.1 Although the majority of cases are still found in Asia and Africa, recent evidence has shown that the incidence and mortality rate of HCC are rising in North America and Europe.2,3 The 2005 guidelines of the American Association * Corresponding author at: Department of Hepatobiliary Surgery, Cancer Centre of Sun Yat-Sen University, 651 Dongfeng Road East, Guangzhou 510060, PR China. Tel./fax: þ86 20 8734 3117, þ86 1390 224 1061 (mobile). E-mail address: [email protected] (M.-S. Chen). 0748-7983/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2009.07.007
for the Study of Liver Diseases (AASLD) for HCC4 state that surgical resection can be offered to patients with a solitary lesion if they are non-cirrhotic, or have cirrhosis but still have well-preserved liver function. Liver transplantation is an effective option for patients with a solitary lesion 5 cm or up to 3 lesions, each 3 cm in diameter. However, surgical resection can be used only in around 5% of western patients and around 40% of Asian patients,5,6 and liver transplantation is limited due to donor shortage and long waiting lists.4,7 Percutaneous radiofrequency ablation (PRFA) has emerged as a new treatment modality because of its effectiveness and safety for small HCC (5.0 cm), with a 3-year survival rate of 62e77%,8,9 a low treatment complication rate of 8e9%, and a low treatment mortality rate of 0e0.5%.10e13
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Unfortunately, the complete tumor necrosis rate for tumors larger than 5 cm is less favorable.14 To improve the results of PRFA, the zone of ablation needs to be extended to allow larger tumors to be ablated. The efficacy of PRFA is based on heat delivery and blood circulation inside the tumor may prevent proper heating.4 The combination of PRFA with other procedures which occlude the circulation may improve the results of PRFA.15,16 Transcatheter arterial chemoembolization (TACE) is an effective treatment, which has been widely used in HCC.17 It may slow tumor progression and improves survival by combining the effect of targeted chemotherapy with that of ischemic necrosis induced by arterial embolization. The purpose of our study was to evaluate whether PRFA combined with TACE (TACE-PRFA) could result in better survival outcomes than PRFA alone in patients with HCC. Materials and methods Patients Between August 1999 and September 2007, 120 patients (total 178 tumors) received TACE-PRFA for HCC (TACEPRFA group). The PRFA group of 120 patients (total 163 tumors) came from a pool of 652 patients who received PRFA for HCC during the study period and who met all the selection criteria for TACE-PRFA. The cases were matched with a 1:1 ratio between the TACE-PRFA group and the PRFA group as far as possible in the following order of matching: (a) age, (b) gender, (c) size of lesion, (d) number of lesions, (e) baseline serum albumin, (f) baseline serum bilirubin, (g) same period of enrollment (August 1999eSeptember 2007), (h) baseline serum AFP. The selection was stopped once the first 120 controls were identified. The survival outcomes of the PRFA group were not known at the time of the matching. The demographic data of these two groups of patients are shown in Table 1. Diagnosis The diagnosis of HCC was confirmed by needle biopsy in 105 patients; and by noninvasive criteria for HCC as used by the American Association for the Study of the Liver guidelines4 in 135 cases. All the patients were diagnosed HCC accompanied with cirrhosis in our study. All the patients were unsuitable or refused to receive surgical resection. Selection criteria The selection criteria for TACE-PRFA for HCC were: 1. A solitary HCC 7.0 cm in diameter, or multiple HCC (3), each 3.0 cm in diameter 2. No radiologic evidence of invasion into major portal/ hepatic vein branches 3. HCC that was visible on ultrasound (US), with an acceptable/safe path between skin and tumor.
Table 1 Demographic data. TACE-PRFA
PRFA
No. of patients Age (years)a Male (M/F) HBsAg ()b
120 54.31 11.62 110/10 100/20
120 56.72 11.52 110/10 95/25
Previous treatment None Recurrence after liver resection
74 46
81 39
Serum AFP (ng/mL)c 400 >400
81 39
80 40
Serum ALB (g/L)d <35 35
28 92
33 87
Serum bilirubin (umol/L) <20 20
62 58
64 56
Child-pugh class A B
102 18
98 22
Number of tumors 1 >1
81 39
91 29
Diameter of tumor (cm) 5 >5
85 35
88 32
Ablative margin (cm) 0.5 >0.5
56 64
50 70
There was no significant difference between these 2 groups of patients in the demographic data. a Mean S.D. b hepatitis B surface antigen. c Alpha fetoprotein. d Albumin.
4. No extrahepatic metastases, severe liver dysfunction (Child-Pugh class C), or significant coagulopathy (prothrombin activity < 40%, platelet count < 40 109/mm3). 5. No history of encephalopathy, ascites refractory to diuretics or history of variceal bleeding 6. No history of previous treatment Treatment TACE-PRFA or PRFA was performed by a single experienced interventional radiologist (M-S C) who had 12 years of experience in interventional radiology at the start of the study in August 1999. Technique of TACE TACE was performed after diagnostic hepatic angiography. The catheter was inserted selectively into the target artery. An angiographic introducer (5 F in diameter and 10 cm in length) was used (Radiofocus Guide Wire M,
Z.-W. Peng et al. / EJSO 36 (2010) 257e263
Terumo Corporation, Tokyo, Japan). The selective catheterization was performed with hydrophilic angiographic catheters, 5 F in caliber, 70 cm in length with Cobra 2 curve, and moved forward by a hydrophilic guide, curved, 150 cm in length, 0.035 in. in caliber (Radiofocus Guide Wire M, Terumo Corporation, Tokyo, Japan). The first 5e10 ml iodized oil (Lipiodol, Laboratorie Guerbet, Aulnay-sous-Bois, France) was mixed with anticancer drugs: Epirubicin (50 mg/m2) and Mitomycin (8 mg/m2), to form an emulsion which was slowly injected under fluoroscopic control. According to residual susceptibility of the lesion, enhancement of the TACE mixture and hepatic function,16 treatment was completed with further injection of pure Lipiodol (2e10 ml). Gelatin sponge impregnated with contrast medium was injected into the tumor to slow down the blood flow to the tumor after the lipiodol injection.18 Technique of PRFA The patients were placed in the supine position. Local anesthetic with 1% lidocaine was injected from the insertion point on the skin down to the peritoneum along the planned puncture track. Conscious analgesic sedation by intravenous fentanyl citrate and droperidol was applied before the procedure. PRFA was performed under real-time US guidance (EUB-2000, HITACHI Medical Systems). In the TACE-PRFA group, PRFA was performed 3 days to 4 weeks after TACE. Mutiple electrodes PRFA From August 1999 to September 2004, we used a commercially available system (RF 2000; Radio-Therapeutics Mountain View, CA), and a needle electrode with a 15-gauge insulated cannula with 10 hook-shape expandable electrode tines with a diameter of 3.5 cm at expansion (LeVeen; RadioTherapeutics). Monopolar electrode PRFA Since September 2004, we used a commercially available system with a 375-kHz computer-assisted radiofrequency generator (Elektrotom HiTT 106, Berchtold, Medizinelektronik, Germany) and an open-perfused electrode (Berchtold, Tuttlingen, Germany) of 15 cm, 14 gauge, and a 15 mm active electrode tip with microbores. The procedures of PRFA were same to that in our previous report.19 For tumors smaller than 3.0 cm a single ablation was performed. For tumors larger than 3.0 cm, multiple overlapping ablations as described by Chen et al.20 were performed. The first ablation started at the location farthest away from the skin puncture site. After the ablation was completed, the electrode tines were retracted; the needle was withdrawn to the second predetermined location. Then the electrode tines were re-expanded and the RF generator was reactivated. This process was repeated until the entire lesion was adequately covered. During RFA,
259
a hyperechoic area was observed around the electrode tip on ultrasonic monitoring. The aim of the treatment was to have this hyperechoic area covering an area larger than 1 cm around the HCC. At the end of the procedure, the generator was reactivated to ablate the needle tract to prevent bleeding. Follow-up Dual-phase contrast-enhanced spiral computed tomography (CT) was done four weeks after treatment and thereafter every two months in the first two years. At each follow-up visit, blood tests, including liver function tests and serum alpha fetoprotein, were done. The follow-up visits were spaced out to once every three months after two years. Assessment of response was based on the modified European Association for the Study of the Liver (EASL) criteria.21 Residual viable tumor tissue was considered to be present on the first CT assessment at four weeks after treatment if uptake of contrast agent in the arterial phase of dynamic CT. Residual viable tumor was treated with a second PRFA and reassessed with CT four weeks later for both groups. If residual viable tumor was still present, the treatment was considered as failure and the patient was treated with TACE. Local recurrence was considered to be present when new lesions were seen at, or adjacent to, the completely ablated lesion after PRFA. Intrahepatic metastasis was present when new lesions were seen in the other parts of the liver, and extrahepatic metastasis was defined as a metastatic lesion outside the liver. Magnetic resonance imaging (MRI) was carried out if CT was uncertain about the residual, or recurrent metastatic lesions. From August 1999 to December 2004 all CT examinations were performed with a multi-detector row CT scanner (CTTWIN, Philips, the Netherlands) by using a sequential acquisition of 8 mm-thick sections, 120 kV, and 250 mA. Since January 2005 CT examinations were performed with a spiral CT scanner (Brilliance 16, Philips, the Netherlands) using the same technical parameters. CT scanner was performed 45 s after 80e100 ml contrast agents(Ultravist, Schering AG, Germany) was injected into cubital vein in a rate of 3e4 ml/s by a high-pressure injection syringe. MRI was performed with a 1.5T scanner (CVi, GE medical systems, USA), using a sequential acquisition of 5e8 mm section thickness. Pulse sequences included a nonenhanced breath-hold T1-weighted gradientecho sequence (120/1.5 [repetition time msec/echo time msec], 80 flip angle, 320 224 matrix, and 1e2-mm intersection gap) and a respiratory-triggered fat-saturated T2weighted fast spin-echo sequence (4000e6000/102e108, four signals acquired, 384 224 matrix, and 1e2 mm intersection gap). Contrast-enhanced T1-weighted breath-hold gradient-echo images were acquired in the transverse plane with and without fat saturation by using the same technical parameters described for the nonenhanced sequence. For MR imaging, an intravenous contrast agent (gadodiamide, Omniscan; Nycomed Amersham, Priceton, NJ, USA) was used during dynamic postcontrast imaging.
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For local recurrence and intrahepatic metastases, PRFA or TACE was given as long as the tumor, the liver function, and the general condition of the patient allowed. Otherwise, supportive treatment was given. For extrahepatic metastasis, supportive care was given. Definition Definition of Progression Free Survival (PFS) was same to that of FDA Briefing Document in 2006.22 The ablative margin was defined as the minimal margin of normal liver parenchyma incorporated into the zone of ablation.23 Major complications were defined as complications which resulted in an admission to the hospital for therapy, an unplanned increase in the level of medical care, prolonged hospitalization, permanent adverse sequelae, or death. Statistical analysis Demographic data for the two groups were compared using Student’s t-test for continuous data and the c2 test for categorical data. The overall survival and PFS were calculated using the life-table method. The survival curves were constructed by the KaplaneMeier method and compared by the log-rank test. The relative prognostic significance of the variables in predicting overall survival was assessed by multivariate Cox proportional hazards regression analysis. The statistical analyses were performed using the SPSS 10.0 statistical software (SPSS Company, Chicago, Illinois, USA,). Results were given as mean S.D. All statistical tests were two-sided, and a significant difference was considered when p < 0.05. Results Patient groups (Table 1) For the 120 patients in the TACE-PRFA group and the 120 patients in the PRFA group, there was no significant difference between these 2 groups of patients in the demographic data. The numbers of patients that had 1, 2, 3, 4, and 5-year follow-up were 92, 71, 45, 31, 17 and 98, 68, 40, 27, 16 for TACE-PRFA group and PRFA group respectively, and the mean standard deviation of the follow-up period were 36.5 12.1 (range 3.2e90.0) months and 34.8 11.7 (range 3.0e88.5) months for each group ( p ¼ .542).
There were no procedure-related mortalities or major complications. Pain and fever were the most commonly seen complications. Forty-five patients suffered from moderate/severe pain in the TACE-PRFA group compared with 39 in the PRFA group. Slightly more patients experienced fever in the TACE-PRFA group (n ¼ 36) than in the PRFA group (n ¼ 20) ( p ¼ .037). Survival Overall survival (Fig. 1) The 1-, 2-, 3-, 5-year overall survival for the groups TACE-PRFA and PRFA was 93%, 83%, 75%, 50%, and 89%, 76%, 64%, 42%, respectively. The overall survival was significantly better for the TACE-PRFA group than the PRFA group ( p ¼ .045) (Fig. 1). On subgroup analyses, the survival for the TACE-PRFA group was significantly better than the PRFA group for tumors >5.0 cm ( p ¼ .031), but not for tumors 5.0 cm ( p ¼ .32). The survival for the TACE-PRFA group was also significantly better than the PRFA group in patients with 2 or 3 tumors ( p ¼ .032), but not for patients with a solitary tumor ( p ¼ .13). PFS The 1-, 2-, 3-, 5-year PFS for the groups TACE-PRFA and PRFA was 90%, 76%, 63%, 42%, and 76%, 60%, 47%, 30%, respectively. The TACE-PRFA group was significantly better than the PRFA group ( p ¼ .002) (Fig. 2). Multivariate analysis All variants list in Table 1 were included in multivariate analysis. Multivariate Cox proportional hazards regression analyses showed Child-pugh class, Diameter of tumor and hepatitis B surface antigen (HBsAg) were significant
1.0
0.8
Cum Survival
260
0.6
0.4
Complete ablation and complications
0.2
The demographic data are shown in Table 1. In 213 of 240 patients (89%), complete ablation was depicted at the spiral CT 4 weeks after treatment. In 27 patients with residual viable tumor: 9 patients in the TACE-PRFA group and 18 in the PRFA group, a second PRFA was performed. After the second treatment, viable tumor was still present in 7 patients (2 in the TACE-PRFA group, 5 in the PRFA group). These patients were considered as treatment failure and they underwent TACE.
0.0
PRFA (n=120) TACE-PRFA (n=120)
0
1
2
3
4
5
Overall Survival (years)
TACE -PRFA: 120
92
71
45
31
10
PRFA: 120
98
68
41
28
17
Number of patients were at risk during follow-up time Figure 1. Overall survival curves for patients treated with TACE - PRFA or PRFA.
Z.-W. Peng et al. / EJSO 36 (2010) 257e263
Some factors may influence on the efficacy of PRFA
1.0
0.8
Cum Survival
261
0.6
0.4
PRFA
0.2
(n=120)
TACE-PRFA (n=120) 0.0 0
1
2
3
4
5
Progression Free Survival (years) TACEPRFA: 120
67
47
32
19
6
PRFA: 120
67
29
21
14
7
Number of patients were at risk during follow-up time Figure 2. Progression free survival for patients treated with TACE - PRFA or PRFA.
prognostic factors for overall survival for patients treated with TACE-PRFA or PRFA. Patients with good function (Child-pugh A), Diameter of tumor 5 cm and HBsAg negative had significantly better survival. Recurrence (Table 2) At the time of sensor, 38 and 63 patients developed tumor recurrence in the groups TACE-PRFA and PRFA, respectively. The overall recurrence was lower in the TACEPRFA group than that for PRFA group. On subgroup analyses, intrahepatic recurrence for the TACE-PRFA group was significantly lower than that for the RFA group. For local recurrence and for extrahepatic metastases, there was no significant difference between the 2 groups (Table 2). Discussion PRFA has been widely utilized for the treatment of small HCC (2e3 cm) with encouraging results.24,25
But the therapeutic effect of PRFA decreases as the tumor increases in size. Livraghi and his associates26 reported complete tumor necrosis rates by PRFA were 90%, 71%, 45% for tumors <3.0 cm, 3.0e5.0 cm and >5.0 cm, respectively. The currently available PRFA systems produce an ablation zone of 3.0e5.0 cm in diameter. As it is generally accepted that the ‘ablative margin’ of ablation for small HCC is at least 1.0 cm,5,27 it is not surprising that the results for tumors >3.0 cm treated with PRFA are still unsatisfactory. Goldberg et al. demonstrated that blood flow exerted a strong negative influence on the volume of thermal coagulation achieved by radiofrequency ablation, and that occlusion of blood vessels reduced the undesirable cooling (heat loss) of the area treated with thermal coagulation.28 Reason for using of TACE-PRFA TACE prior to PRFA reduces the cooling effect of hepatic blood flow on thermal coagulation by decreasing hepatic arterial flow, and induces tumor destruction. Furthermore, iodized oil and gelatin sponge particles used in TACE reduce the portal flow around the tumor by filling the peripheral portal vein around the tumor with iodized oil through multiple arterioportal communications.29 The area of complete tissue necrosis induced by TACE-PRFA may be larger than PRFA alone, thus reducing the chance of tumor recurrence. Veltri and his associates16 demonstrated that TACE-PRFA for medium and large HCC (3.0e8.0 cm, mean 4.9 cm) resulted in a relatively high complete local response rate, especially for HCC <5 cm, with promising mid-term clinical results. In their study, for the 46 patients treated with TACE-PRFA, the 1-, 2year survival rates were 89.7% and 67.1%, respectively. Our result confirmed this point: although there was no difference between two groups for incomplete necrosis rates, more patients in PRFA group (18 patients) showed residual viable tumor than that in TACE-PRFA group (9 patients). Our results showed that TACE-PRFA significantly increased the overall survival rate, and recurrence in TACEPRFA group were lower than that in PRFA group. The major reason for the results may be due to the higher intrahepatic recurrence rate in PRFA group. Intrahepatic recurrence
Table 2 Tumor recurrence after treatment.a Treatment group
Total no. of patients
Total no. of patients with recurrence
Overall recurrence Local recurrence
Intrahepatic recurrence
Extrahepatic metastasis
TACE-PRFA PRFA P value
120 120
38 63 .036
4 5 .999
33 55 .044
1 3 .317
The overall recurrence was lower in the TACE-PRFA group than that for PRFA group. On subgroup analyses, intrahepatic recurrence for the TACE-PRFA group was significantly lower than that for the RFA group. a In the group TACE-PRFA, both intrahepatic recurrence and extrahepatic metastases were present in 1 patients. In the group PRFA, both intrahepatic recurrence and extrahepatic metastasis were present in 3 patients.
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decreased in TACE-PRFA group may be due to two factors. First, TACE can find and deal with some small HCC nodules, which cannot be found by CT or MRI before treatment. Second, micro-metastasis, if existed, can be treated by TACE. These small nodules if could not control and micro-metastasis may induce intrahepatic recurrence. It is well-known that recurrence is the major factor for death of patients with HCC. This result may be also the major reason for PFS was better in TACE-PRFA group than that in PRFA group. Performing TACE-PRFA for larger and multiple HCC Although previous studies showed that TACE-PRFA achieved higher complete local response rate than PRFA alone for tumor less than 5 cm,16 we believed that TACEPRFA may be more suitable for tumor >5 cm. Others and our previous studies had showed that small HCC (<5 cm) could often be successfully treated by local therapy only. Our previous study had showed that the efficacy of local therapy for HCC < 5 cm was almost the same to that of surgical resection.13 So it is hard to improve results by combination therapy. But for the tumor larger than 5 cm, it was difficult to completely destroy the tumor by local therapy alone despite of application of multiple overlapping ablation. The combination therapy of TACE and PRFA may induce a larger necrosis area than PRFA alone because of the decreasing of cooling effect by TACE. On the other side, micro-metastasis was common beyond macroscopic metastasis, especially for the larger tumor with more chance to have micro-metastasis,30 which may due to the recurrence after PRFA. So TACE-PRFA may be more suitable to treat large HCC > 5 cm. Multiple HCC may be also easier to show micro-metastasis than solitary HCC. TACE before PRFA can control or eliminate micro-metastasis, which may be reduce the recurrence after treatment. Conclusion This study showed that patients treated with TACE-PRFA had better overall survivals than PRFA alone, but only in a subgroup of patients with tumor >5 cm or multiple tumors. Conflict of interest There is no conflict of interest in our study. Acknowledgement Supported by a grant of Sciences and Technology Committee of Guangdong Province, 2006 China. References 1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74–108.
2. Taylor-Robinson SD, Foster GR, Arora S, Hargreaves S, Thomas HC. Increase in primary liver cancer in the UK, 1979e94. Lancet 1997; 350:1142–3. 3. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 1999;340:745–50. 4. Bruix J, Sherman M. Practice guidelines committee, American association for the study of liver diseases. Management of hepatocellular carcinoma. Hepatology 2005;42:1208–36. 5. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003;362:1907–17. 6. Lai EC, Fan ST, Lo CM, Chu KM, Liu CL, Wong J. Hepatic resection for hepatocellular carcinoma. An audit of 343 patients. Ann Surg 1995;221:291–8. 7. Schwartz M. Liver transplantation for hepatocellular carcinoma. Gastroenterology 2004;127:S268–76. 8. Lencioni R, Cioni D, Crocetti L, et al. Early-stage hepatocellular carcinoma in patients with cirrhosis: long-term results of percutaneous image-guided radiofrequency ablation. Radiology 2005;234: 961–7. 9. Tateishi R, Shiina S, Teratani T, et al. Percutaneous radiofrequency ablation for hepatocellular carcinoma. An analysis of 1,000 cases. Cancer 2005;103:1201–9. 10. Lau WY, Leung TW, Yu SC, Ho SK. Percutaneous local ablative therapy for hepatocellular carcinoma: a review and look into the future. Ann Surg 2003;237:171–9. 11. Curley SA. Radiofrequency ablation of malignant liver tumors. Oncologist 2001;6:14–23. 12. Mulier S, Mulier P, Ni Y, et al. Complications of radiofrequency coagulation of liver tumors. Br J Surg 2002;89:1206–22. 13. Chen MS, Li JQ, Zheng Y, et al. A prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma. Ann Surg 2006;243:321–8. 14. Livraghi T, Goldberg SN, Lazzaroni S, et al. Hepatocellular carcinoma: radiofrequency ablation of medium and large lesions. Radiology 2000;214:761–8. 15. Zhang YJ, Liang HH, Chen MS, et al. Hepatocellular carcinoma treated with radiofrequency ablation with or without ethanol injection: a prospective randomized trial. Radiology 2007;244: 599–607. 16. Veltri A, Moretto P, Doriguzzi A, Pagano E, Carrara G, Gandini G. Radiofrequency thermal ablation (RFA) after transarterial chemoembolization (TACE) as a combined therapy for unresectable non-early hepatocellular carcinoma (HCC). Eur Radiol 2006;16:661–9. 17. Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 2003;37:429–42. 18. Kwok PC, Lam TW, Chan SC, et al. A randomized clinical trial comparing autologous blood clot and gelfoam in transarterial chemoembolization for inoperable hepatocellular carcinoma. J Hepatol 2000;32:955–64. 19. Peng ZW, Liang HH, Chen MS, et al. Percutaneous radiofrequency ablation for the treatment of hepatocellular carcinoma in the cardate lobe. Eur J Surg Oncol 2008;34:166–72. 20. Chen MH, Yang W, Yan K, et al. Large liver tumors: protocol for radiofrequency ablation and its clinical application in 110 patientsmathematic model, overlapping mode, and electrode placement process. Radiology 2004;232:260–71. 21. Bruix J, Sherman M, Llovet JM, et al. Clinical management of hepatocellular carcinoma: conclusions of the Barcelona 2000 EASL Conference. European Association for the Study of the Liver. J Hepatol 2001;35:421–30. 22. Development of ThermoDoxTM plus radiofrequency ablation (RFA) in patients with hepatocellular carcinoma (HCC). Celsion Corporation FDA Briefing Document 2006, IND number: 66,827, serial number: 027. 23. Mulier S, Ni Y, Jamart J, Ruers T, Marchal G, Michel L. Local recurrence after hepatic radiofrequency coagulation: multivariate meta-analysis and review of contributing factors. Ann Surg 2005;242:158–71.
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28. Goldberg SN, Hahn PF, Tanabe KK, et al. Percutaneous radiofrequency tissue ablation: does perfusion-mediated tissue cooling limit coagulation necrosis? J Vasc Interv Radiol 1998;9: 101–11. 29. Seki T, Tamai T, Nakagawa T, et al. Combination therapy with transcatheter arterial chemoembolization and percutaneous microwave coagulation therapy for hepatocellular carcinoma. Cancer 2000;89: 1245–51. 30. Shi M, Zhang CQ, Zhang YQ, Liang XM, Li JQ. Micrometastasis of solitary hepatocellular carcinoma and appropriate resection margin. World J Surg 2004;28:376–81.
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A case-control study comparing percutaneous radiofrequency ablation alone or combined with transcatheter arterial chemoembolization for hepatocellular carcinoma Z.-W. Peng a,b, M.-S. Chen a,b,*, H.-H. Liang a,b, H.-J. Gao a,b, Y.-J. Zhang a,b, J.-Q. Li a,b, Y.-Q. Zhang a,b, W.Y. Lau c a
Department of Hepatobiliary Surgery, Cancer Centre of Sun Yat-Sen University, 651 Dongfeng Road East, Guangzhou 510060, China b State Key Laboratory of Oncology in Southern China, Guangzhou 510060, China c Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China Accepted 6 July 2009 Available online 29 July 2009
Abstract Aims: To assess whether combining percutaneous radiofrequency ablation (PRFA) with transcatheter arterial chemoembolization (TACE) was better than PRFA alone for hepatocellular carcinoma (HCC). Materials and methods: One hundered twenty patients (with a solitary HCC 7.0 cm in diameter or multiple HCC (3), each 3.0 cm in diameter) treated with PRFA combined with TACE were compared with 120 well-matched controls selected from a pool of 652 patients who received PRFA alone during the study period. Results: The 1-, 2-, 3-, 5-year overall survival rates for the TACE-PRFA and PRFA groups were 93%, 83%, 75%, 50%, and 89%, 76%, 64%, 42%, respectively ( p ¼ .045). Subgroup analyses showed the survival for the TACE-PRFA group was better than the PRFA group for tumors >5.0 cm ( p ¼ .031) and for multiple tumors ( p ¼ .032), but not for tumors 5.0 cm ( p ¼ .319) and for solitary tumor ( p ¼ .128). The 1-, 2-, 3-, 5-year progression free survival (PFS) for the TACE-PRFA and PRFA groups was 90%, 76%, 63%, 42%, and 76%, 60%, 47%, 30%, respectively ( p ¼ .002). Child-pugh class, Diameter of tumor and hepatitis B surface antigen (HBsAg) were significant prognostic factors. Conclusion: Patients treated with TACE-PRFA had better overall survivals than PRFA alone, but only in a subgroup of patients with tumor >5 cm or multiple tumors. Ó 2009 Elsevier Ltd. All rights reserved. Keywords: Percutaneous radiofrequency ablation; Transcatheter arterial chemoembolization; Hepatocellular carcinoma; Progression free survival; Overall survival
Introduction Hepatocellular carcinoma (HCC) is the 6th most common cancer worldwide and the third most frequent cause of death of cancer.1 Although the majority of cases are still found in Asia and Africa, recent evidence has shown that the incidence and mortality rate of HCC are rising in North America and Europe.2,3 The 2005 guidelines of the American Association * Corresponding author at: Department of Hepatobiliary Surgery, Cancer Centre of Sun Yat-Sen University, 651 Dongfeng Road East, Guangzhou 510060, PR China. Tel./fax: þ86 20 8734 3117, þ86 1390 224 1061 (mobile). E-mail address: [email protected] (M.-S. Chen). 0748-7983/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2009.07.007
for the Study of Liver Diseases (AASLD) for HCC4 state that surgical resection can be offered to patients with a solitary lesion if they are non-cirrhotic, or have cirrhosis but still have well-preserved liver function. Liver transplantation is an effective option for patients with a solitary lesion 5 cm or up to 3 lesions, each 3 cm in diameter. However, surgical resection can be used only in around 5% of western patients and around 40% of Asian patients,5,6 and liver transplantation is limited due to donor shortage and long waiting lists.4,7 Percutaneous radiofrequency ablation (PRFA) has emerged as a new treatment modality because of its effectiveness and safety for small HCC (5.0 cm), with a 3-year survival rate of 62e77%,8,9 a low treatment complication rate of 8e9%, and a low treatment mortality rate of 0e0.5%.10e13
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Unfortunately, the complete tumor necrosis rate for tumors larger than 5 cm is less favorable.14 To improve the results of PRFA, the zone of ablation needs to be extended to allow larger tumors to be ablated. The efficacy of PRFA is based on heat delivery and blood circulation inside the tumor may prevent proper heating.4 The combination of PRFA with other procedures which occlude the circulation may improve the results of PRFA.15,16 Transcatheter arterial chemoembolization (TACE) is an effective treatment, which has been widely used in HCC.17 It may slow tumor progression and improves survival by combining the effect of targeted chemotherapy with that of ischemic necrosis induced by arterial embolization. The purpose of our study was to evaluate whether PRFA combined with TACE (TACE-PRFA) could result in better survival outcomes than PRFA alone in patients with HCC. Materials and methods Patients Between August 1999 and September 2007, 120 patients (total 178 tumors) received TACE-PRFA for HCC (TACEPRFA group). The PRFA group of 120 patients (total 163 tumors) came from a pool of 652 patients who received PRFA for HCC during the study period and who met all the selection criteria for TACE-PRFA. The cases were matched with a 1:1 ratio between the TACE-PRFA group and the PRFA group as far as possible in the following order of matching: (a) age, (b) gender, (c) size of lesion, (d) number of lesions, (e) baseline serum albumin, (f) baseline serum bilirubin, (g) same period of enrollment (August 1999eSeptember 2007), (h) baseline serum AFP. The selection was stopped once the first 120 controls were identified. The survival outcomes of the PRFA group were not known at the time of the matching. The demographic data of these two groups of patients are shown in Table 1. Diagnosis The diagnosis of HCC was confirmed by needle biopsy in 105 patients; and by noninvasive criteria for HCC as used by the American Association for the Study of the Liver guidelines4 in 135 cases. All the patients were diagnosed HCC accompanied with cirrhosis in our study. All the patients were unsuitable or refused to receive surgical resection. Selection criteria The selection criteria for TACE-PRFA for HCC were: 1. A solitary HCC 7.0 cm in diameter, or multiple HCC (3), each 3.0 cm in diameter 2. No radiologic evidence of invasion into major portal/ hepatic vein branches 3. HCC that was visible on ultrasound (US), with an acceptable/safe path between skin and tumor.
Table 1 Demographic data. TACE-PRFA
PRFA
No. of patients Age (years)a Male (M/F) HBsAg ()b
120 54.31 11.62 110/10 100/20
120 56.72 11.52 110/10 95/25
Previous treatment None Recurrence after liver resection
74 46
81 39
Serum AFP (ng/mL)c 400 >400
81 39
80 40
Serum ALB (g/L)d <35 35
28 92
33 87
Serum bilirubin (umol/L) <20 20
62 58
64 56
Child-pugh class A B
102 18
98 22
Number of tumors 1 >1
81 39
91 29
Diameter of tumor (cm) 5 >5
85 35
88 32
Ablative margin (cm) 0.5 >0.5
56 64
50 70
There was no significant difference between these 2 groups of patients in the demographic data. a Mean S.D. b hepatitis B surface antigen. c Alpha fetoprotein. d Albumin.
4. No extrahepatic metastases, severe liver dysfunction (Child-Pugh class C), or significant coagulopathy (prothrombin activity < 40%, platelet count < 40 109/mm3). 5. No history of encephalopathy, ascites refractory to diuretics or history of variceal bleeding 6. No history of previous treatment Treatment TACE-PRFA or PRFA was performed by a single experienced interventional radiologist (M-S C) who had 12 years of experience in interventional radiology at the start of the study in August 1999. Technique of TACE TACE was performed after diagnostic hepatic angiography. The catheter was inserted selectively into the target artery. An angiographic introducer (5 F in diameter and 10 cm in length) was used (Radiofocus Guide Wire M,
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Terumo Corporation, Tokyo, Japan). The selective catheterization was performed with hydrophilic angiographic catheters, 5 F in caliber, 70 cm in length with Cobra 2 curve, and moved forward by a hydrophilic guide, curved, 150 cm in length, 0.035 in. in caliber (Radiofocus Guide Wire M, Terumo Corporation, Tokyo, Japan). The first 5e10 ml iodized oil (Lipiodol, Laboratorie Guerbet, Aulnay-sous-Bois, France) was mixed with anticancer drugs: Epirubicin (50 mg/m2) and Mitomycin (8 mg/m2), to form an emulsion which was slowly injected under fluoroscopic control. According to residual susceptibility of the lesion, enhancement of the TACE mixture and hepatic function,16 treatment was completed with further injection of pure Lipiodol (2e10 ml). Gelatin sponge impregnated with contrast medium was injected into the tumor to slow down the blood flow to the tumor after the lipiodol injection.18 Technique of PRFA The patients were placed in the supine position. Local anesthetic with 1% lidocaine was injected from the insertion point on the skin down to the peritoneum along the planned puncture track. Conscious analgesic sedation by intravenous fentanyl citrate and droperidol was applied before the procedure. PRFA was performed under real-time US guidance (EUB-2000, HITACHI Medical Systems). In the TACE-PRFA group, PRFA was performed 3 days to 4 weeks after TACE. Mutiple electrodes PRFA From August 1999 to September 2004, we used a commercially available system (RF 2000; Radio-Therapeutics Mountain View, CA), and a needle electrode with a 15-gauge insulated cannula with 10 hook-shape expandable electrode tines with a diameter of 3.5 cm at expansion (LeVeen; RadioTherapeutics). Monopolar electrode PRFA Since September 2004, we used a commercially available system with a 375-kHz computer-assisted radiofrequency generator (Elektrotom HiTT 106, Berchtold, Medizinelektronik, Germany) and an open-perfused electrode (Berchtold, Tuttlingen, Germany) of 15 cm, 14 gauge, and a 15 mm active electrode tip with microbores. The procedures of PRFA were same to that in our previous report.19 For tumors smaller than 3.0 cm a single ablation was performed. For tumors larger than 3.0 cm, multiple overlapping ablations as described by Chen et al.20 were performed. The first ablation started at the location farthest away from the skin puncture site. After the ablation was completed, the electrode tines were retracted; the needle was withdrawn to the second predetermined location. Then the electrode tines were re-expanded and the RF generator was reactivated. This process was repeated until the entire lesion was adequately covered. During RFA,
259
a hyperechoic area was observed around the electrode tip on ultrasonic monitoring. The aim of the treatment was to have this hyperechoic area covering an area larger than 1 cm around the HCC. At the end of the procedure, the generator was reactivated to ablate the needle tract to prevent bleeding. Follow-up Dual-phase contrast-enhanced spiral computed tomography (CT) was done four weeks after treatment and thereafter every two months in the first two years. At each follow-up visit, blood tests, including liver function tests and serum alpha fetoprotein, were done. The follow-up visits were spaced out to once every three months after two years. Assessment of response was based on the modified European Association for the Study of the Liver (EASL) criteria.21 Residual viable tumor tissue was considered to be present on the first CT assessment at four weeks after treatment if uptake of contrast agent in the arterial phase of dynamic CT. Residual viable tumor was treated with a second PRFA and reassessed with CT four weeks later for both groups. If residual viable tumor was still present, the treatment was considered as failure and the patient was treated with TACE. Local recurrence was considered to be present when new lesions were seen at, or adjacent to, the completely ablated lesion after PRFA. Intrahepatic metastasis was present when new lesions were seen in the other parts of the liver, and extrahepatic metastasis was defined as a metastatic lesion outside the liver. Magnetic resonance imaging (MRI) was carried out if CT was uncertain about the residual, or recurrent metastatic lesions. From August 1999 to December 2004 all CT examinations were performed with a multi-detector row CT scanner (CTTWIN, Philips, the Netherlands) by using a sequential acquisition of 8 mm-thick sections, 120 kV, and 250 mA. Since January 2005 CT examinations were performed with a spiral CT scanner (Brilliance 16, Philips, the Netherlands) using the same technical parameters. CT scanner was performed 45 s after 80e100 ml contrast agents(Ultravist, Schering AG, Germany) was injected into cubital vein in a rate of 3e4 ml/s by a high-pressure injection syringe. MRI was performed with a 1.5T scanner (CVi, GE medical systems, USA), using a sequential acquisition of 5e8 mm section thickness. Pulse sequences included a nonenhanced breath-hold T1-weighted gradientecho sequence (120/1.5 [repetition time msec/echo time msec], 80 flip angle, 320 224 matrix, and 1e2-mm intersection gap) and a respiratory-triggered fat-saturated T2weighted fast spin-echo sequence (4000e6000/102e108, four signals acquired, 384 224 matrix, and 1e2 mm intersection gap). Contrast-enhanced T1-weighted breath-hold gradient-echo images were acquired in the transverse plane with and without fat saturation by using the same technical parameters described for the nonenhanced sequence. For MR imaging, an intravenous contrast agent (gadodiamide, Omniscan; Nycomed Amersham, Priceton, NJ, USA) was used during dynamic postcontrast imaging.
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For local recurrence and intrahepatic metastases, PRFA or TACE was given as long as the tumor, the liver function, and the general condition of the patient allowed. Otherwise, supportive treatment was given. For extrahepatic metastasis, supportive care was given. Definition Definition of Progression Free Survival (PFS) was same to that of FDA Briefing Document in 2006.22 The ablative margin was defined as the minimal margin of normal liver parenchyma incorporated into the zone of ablation.23 Major complications were defined as complications which resulted in an admission to the hospital for therapy, an unplanned increase in the level of medical care, prolonged hospitalization, permanent adverse sequelae, or death. Statistical analysis Demographic data for the two groups were compared using Student’s t-test for continuous data and the c2 test for categorical data. The overall survival and PFS were calculated using the life-table method. The survival curves were constructed by the KaplaneMeier method and compared by the log-rank test. The relative prognostic significance of the variables in predicting overall survival was assessed by multivariate Cox proportional hazards regression analysis. The statistical analyses were performed using the SPSS 10.0 statistical software (SPSS Company, Chicago, Illinois, USA,). Results were given as mean S.D. All statistical tests were two-sided, and a significant difference was considered when p < 0.05. Results Patient groups (Table 1) For the 120 patients in the TACE-PRFA group and the 120 patients in the PRFA group, there was no significant difference between these 2 groups of patients in the demographic data. The numbers of patients that had 1, 2, 3, 4, and 5-year follow-up were 92, 71, 45, 31, 17 and 98, 68, 40, 27, 16 for TACE-PRFA group and PRFA group respectively, and the mean standard deviation of the follow-up period were 36.5 12.1 (range 3.2e90.0) months and 34.8 11.7 (range 3.0e88.5) months for each group ( p ¼ .542).
There were no procedure-related mortalities or major complications. Pain and fever were the most commonly seen complications. Forty-five patients suffered from moderate/severe pain in the TACE-PRFA group compared with 39 in the PRFA group. Slightly more patients experienced fever in the TACE-PRFA group (n ¼ 36) than in the PRFA group (n ¼ 20) ( p ¼ .037). Survival Overall survival (Fig. 1) The 1-, 2-, 3-, 5-year overall survival for the groups TACE-PRFA and PRFA was 93%, 83%, 75%, 50%, and 89%, 76%, 64%, 42%, respectively. The overall survival was significantly better for the TACE-PRFA group than the PRFA group ( p ¼ .045) (Fig. 1). On subgroup analyses, the survival for the TACE-PRFA group was significantly better than the PRFA group for tumors >5.0 cm ( p ¼ .031), but not for tumors 5.0 cm ( p ¼ .32). The survival for the TACE-PRFA group was also significantly better than the PRFA group in patients with 2 or 3 tumors ( p ¼ .032), but not for patients with a solitary tumor ( p ¼ .13). PFS The 1-, 2-, 3-, 5-year PFS for the groups TACE-PRFA and PRFA was 90%, 76%, 63%, 42%, and 76%, 60%, 47%, 30%, respectively. The TACE-PRFA group was significantly better than the PRFA group ( p ¼ .002) (Fig. 2). Multivariate analysis All variants list in Table 1 were included in multivariate analysis. Multivariate Cox proportional hazards regression analyses showed Child-pugh class, Diameter of tumor and hepatitis B surface antigen (HBsAg) were significant
1.0
0.8
Cum Survival
260
0.6
0.4
Complete ablation and complications
0.2
The demographic data are shown in Table 1. In 213 of 240 patients (89%), complete ablation was depicted at the spiral CT 4 weeks after treatment. In 27 patients with residual viable tumor: 9 patients in the TACE-PRFA group and 18 in the PRFA group, a second PRFA was performed. After the second treatment, viable tumor was still present in 7 patients (2 in the TACE-PRFA group, 5 in the PRFA group). These patients were considered as treatment failure and they underwent TACE.
0.0
PRFA (n=120) TACE-PRFA (n=120)
0
1
2
3
4
5
Overall Survival (years)
TACE -PRFA: 120
92
71
45
31
10
PRFA: 120
98
68
41
28
17
Number of patients were at risk during follow-up time Figure 1. Overall survival curves for patients treated with TACE - PRFA or PRFA.
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Some factors may influence on the efficacy of PRFA
1.0
0.8
Cum Survival
261
0.6
0.4
PRFA
0.2
(n=120)
TACE-PRFA (n=120) 0.0 0
1
2
3
4
5
Progression Free Survival (years) TACEPRFA: 120
67
47
32
19
6
PRFA: 120
67
29
21
14
7
Number of patients were at risk during follow-up time Figure 2. Progression free survival for patients treated with TACE - PRFA or PRFA.
prognostic factors for overall survival for patients treated with TACE-PRFA or PRFA. Patients with good function (Child-pugh A), Diameter of tumor 5 cm and HBsAg negative had significantly better survival. Recurrence (Table 2) At the time of sensor, 38 and 63 patients developed tumor recurrence in the groups TACE-PRFA and PRFA, respectively. The overall recurrence was lower in the TACEPRFA group than that for PRFA group. On subgroup analyses, intrahepatic recurrence for the TACE-PRFA group was significantly lower than that for the RFA group. For local recurrence and for extrahepatic metastases, there was no significant difference between the 2 groups (Table 2). Discussion PRFA has been widely utilized for the treatment of small HCC (2e3 cm) with encouraging results.24,25
But the therapeutic effect of PRFA decreases as the tumor increases in size. Livraghi and his associates26 reported complete tumor necrosis rates by PRFA were 90%, 71%, 45% for tumors <3.0 cm, 3.0e5.0 cm and >5.0 cm, respectively. The currently available PRFA systems produce an ablation zone of 3.0e5.0 cm in diameter. As it is generally accepted that the ‘ablative margin’ of ablation for small HCC is at least 1.0 cm,5,27 it is not surprising that the results for tumors >3.0 cm treated with PRFA are still unsatisfactory. Goldberg et al. demonstrated that blood flow exerted a strong negative influence on the volume of thermal coagulation achieved by radiofrequency ablation, and that occlusion of blood vessels reduced the undesirable cooling (heat loss) of the area treated with thermal coagulation.28 Reason for using of TACE-PRFA TACE prior to PRFA reduces the cooling effect of hepatic blood flow on thermal coagulation by decreasing hepatic arterial flow, and induces tumor destruction. Furthermore, iodized oil and gelatin sponge particles used in TACE reduce the portal flow around the tumor by filling the peripheral portal vein around the tumor with iodized oil through multiple arterioportal communications.29 The area of complete tissue necrosis induced by TACE-PRFA may be larger than PRFA alone, thus reducing the chance of tumor recurrence. Veltri and his associates16 demonstrated that TACE-PRFA for medium and large HCC (3.0e8.0 cm, mean 4.9 cm) resulted in a relatively high complete local response rate, especially for HCC <5 cm, with promising mid-term clinical results. In their study, for the 46 patients treated with TACE-PRFA, the 1-, 2year survival rates were 89.7% and 67.1%, respectively. Our result confirmed this point: although there was no difference between two groups for incomplete necrosis rates, more patients in PRFA group (18 patients) showed residual viable tumor than that in TACE-PRFA group (9 patients). Our results showed that TACE-PRFA significantly increased the overall survival rate, and recurrence in TACEPRFA group were lower than that in PRFA group. The major reason for the results may be due to the higher intrahepatic recurrence rate in PRFA group. Intrahepatic recurrence
Table 2 Tumor recurrence after treatment.a Treatment group
Total no. of patients
Total no. of patients with recurrence
Overall recurrence Local recurrence
Intrahepatic recurrence
Extrahepatic metastasis
TACE-PRFA PRFA P value
120 120
38 63 .036
4 5 .999
33 55 .044
1 3 .317
The overall recurrence was lower in the TACE-PRFA group than that for PRFA group. On subgroup analyses, intrahepatic recurrence for the TACE-PRFA group was significantly lower than that for the RFA group. a In the group TACE-PRFA, both intrahepatic recurrence and extrahepatic metastases were present in 1 patients. In the group PRFA, both intrahepatic recurrence and extrahepatic metastasis were present in 3 patients.
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decreased in TACE-PRFA group may be due to two factors. First, TACE can find and deal with some small HCC nodules, which cannot be found by CT or MRI before treatment. Second, micro-metastasis, if existed, can be treated by TACE. These small nodules if could not control and micro-metastasis may induce intrahepatic recurrence. It is well-known that recurrence is the major factor for death of patients with HCC. This result may be also the major reason for PFS was better in TACE-PRFA group than that in PRFA group. Performing TACE-PRFA for larger and multiple HCC Although previous studies showed that TACE-PRFA achieved higher complete local response rate than PRFA alone for tumor less than 5 cm,16 we believed that TACEPRFA may be more suitable for tumor >5 cm. Others and our previous studies had showed that small HCC (<5 cm) could often be successfully treated by local therapy only. Our previous study had showed that the efficacy of local therapy for HCC < 5 cm was almost the same to that of surgical resection.13 So it is hard to improve results by combination therapy. But for the tumor larger than 5 cm, it was difficult to completely destroy the tumor by local therapy alone despite of application of multiple overlapping ablation. The combination therapy of TACE and PRFA may induce a larger necrosis area than PRFA alone because of the decreasing of cooling effect by TACE. On the other side, micro-metastasis was common beyond macroscopic metastasis, especially for the larger tumor with more chance to have micro-metastasis,30 which may due to the recurrence after PRFA. So TACE-PRFA may be more suitable to treat large HCC > 5 cm. Multiple HCC may be also easier to show micro-metastasis than solitary HCC. TACE before PRFA can control or eliminate micro-metastasis, which may be reduce the recurrence after treatment. Conclusion This study showed that patients treated with TACE-PRFA had better overall survivals than PRFA alone, but only in a subgroup of patients with tumor >5 cm or multiple tumors. Conflict of interest There is no conflict of interest in our study. Acknowledgement Supported by a grant of Sciences and Technology Committee of Guangdong Province, 2006 China. References 1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74–108.
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