Hepatol Int (2012) 6:505–510 DOI 10.1007/s12072-011-9290-y
ORIGINAL ARTICLE
Recurrence rates and factors for recurrence after radiofrequency ablation combined with transarterial chemoembolization for hepatocellular carcinoma: a retrospective cohort study Jeong Han Kim • Hyung Joon Yim • Kwang Gyun Lee • Seung Young Kim • Eun Suk Jung • Young Kul Jung • Ji Hoon Kim • Yeon Seok Seo • Jong Eun Yeon Hong Sik Lee • Soon Ho Um • Kwan Soo Byun • Ho Sang Ryu
•
Received: 8 November 2010 / Accepted: 16 June 2011 / Published online: 5 July 2011 Ó Asian Pacific Association for the Study of the Liver 2011
Abstract Purpose There have been reports that radiofrequency ablation (RFA) combined with transarterial chemoembolization (TACE) is as equally effective as surgical resection for the treatment of hepatocellular carcinoma (HCC). This study aimed to evaluate recurrence rate and risk factor of recurrence after RFA combined with TACE for early stage HCC. Methods We reviewed the medical records of the patients who were diagnosed with early stage HCC between March 2006 and August 2008 at Korea University Medical Center and treated with RFA combined with TACE for curative intent (n = 65). Results Recurrence rate was 40% (26 cases) and the time to recurrence was 14.9 months. Cumulative recurrence rate at 1 year was 20% (13 cases) and at 2 years was 33.8% (22 cases). Significant variables for recurrence were: (1) RFA repeated more than one session at initial therapy (P \ 0.001) and (2) size of main lesion C2 cm (P = 0.047). Jeong Han Kim H. J. Yim (&) S. Y. Kim Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine, Gojan-dong, Danwon-gu, Ansan-si, Gyeonggi-do 425-707, Korea e-mail:
[email protected] K. G. Lee Y. S. Seo H. S. Lee S. H. Um H. S. Ryu Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Anam-dong, Seongbuk-gu, Seoul 425-707, Korea E. S. Jung Y. K. Jung Ji Hoon Kim J. E. Yeon K. S. Byun Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Gurodong-gil, Guro-gu, Seoul 425-707, Korea
Conclusions The recurrence rate of combination therapy was considerably high. Regardless of the therapy used, careful post-RFA follow-up is needed, especially if additional treatment is required after the first session or if the main lesion is C2 cm at the time of RFA. Keywords Hepatocellular carcinoma Radiofrequency ablation Transarterial chemoembolization
Introduction Hepatocellular carcinoma (HCC) is one of the most serious complications of chronic liver disease and the most frequent cause of death in patients with compensated liver cirrhosis [1]. The prognosis of HCC is determined not only by tumor stage, but also by hepatic reserve [2]. HCC staging systems that take into account tumor stage and underlying liver function include the Okuda stage [2, 3], the Cancer of the Liver Italian Program (CLIP) [4], Chinese University Prognostic Index for HCC (CUPI) [5], Japan integrated staging [6, 7], and Barcelona Clinic Liver Cancer (BCLC) [8]. Among these, the BCLC staging system has been adopted by the American Association for the Study of Liver Disease (AASLD) and is being widely used. The main advantage of this staging system is that it links staging with treatment modalities and with an estimation of life expectancy that is based on the published response rates to the various treatments [2]. In this system, early stage denotes preserved liver function (Child–Pugh A and B) with a solitary tumor B5 cm or up to three nodules B3 cm. The patients in an early stage can be effectively treated by curative therapies, such as hepatic resection, liver transplantation and local ablation therapies [2, 9].
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Recently, there have been reports that radiofrequency ablation (RFA) combined with transarterial chemoembolization (TACE) is as effective as surgical resection [10]. This could be attributed to the synergy between TACE and RFA, as described previously [11]. Sequential application of TACE and RFA is, therefore, increasingly being used in the treatment of HCC patients with well-compensated liver disease [12]. However, the recurrence rate and the risk factors of recurrence after RFA combined with TACE are not well known. This study aimed to evaluate the recurrence rate and risk factors after RFA combined with TACE for the treatment of early stage HCC.
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recurrence. For univariate analysis, we used the student’s t test for continuous variables and Chi-square test or Fisher’s exact test for categorical variables. For multivariate analysis, logistic regression analysis was done. A P value of \0.05 was considered to be significant.
Results Baseline characteristics A total of 65 patients were enrolled. The patients’ baseline characteristics are summarized in Table 1. The patient group included 48 males (73.8%) with a mean age of
Materials and methods Table 1 Baseline characteristics
Patients In this study, we retrospectively reviewed the medical records of patients in an early HCC cohort. The cohort consists of patients who were diagnosed with early stage HCC by BCLC between March 2006 and August 2008 at Korea University Medical Center (Anam, Guro, and Ansan Hospital) and who were treated with RFA combined with TACE for curative intent. The patients were followed up under surveillance of recurrence by abdominal computed tomography or magnetic resonance image.
Variables
TACE ± RFA (n = 65)
Male (%)
48 (73.8)
Agea
59.9 ± 10.1
Etiology
Diagnosis of HCC
Unknown (%)
5 (7.7)
HBV (%)
31 (47.7)
HCV (%)
13 (20)
Alcohol (%)
8 (12.3)
HBV ? Alcohol (%)
7 (10.8)
HBV ? HCV ? Alcohol (%)
1 (1.5)
Cirrhosis (%)
52 (80)
Child–Pugh scorea
Diagnosis of HCC was performed using the AASLD guidelines: (1) in the case of a nodule[2 cm with a typical pattern of HCC in one imaging study or alpha-fetoprotein (AFP) [200 ng/mL; (2) in the case of a nodule between 1 and 2 cm with a coincidental typical vascular pattern in two imaging studies; otherwise, (3) biopsy was performed. Treatment of HCC RFA was performed when the HCC lesions met the Milan criteria; single HCC B5 cm in diameter or up to three HCCs, none larger than 3 cm and, with no metastasis or vascular invasion [13]. The reasons why liver transplantation was not performed included patient’s reluctance to major operation, economic issues, cardiopulmonary dysfunction, or lack of liver donor. Initial treatments were RFA combined with TACE. In the case of multiple nodules, all the nodules were treated by the same method.
A (%)
123
50 (76.9)
B (%)
15 (23.1) a
AFP (ng/mL) PIVKA-II (mAU/mL)a
101.2 ± 353.4 164.2 ± 398.9
Follow-up duration (month)a
18.9 ± 9.4
Number of lesiona
1.3 ± 0.5
Multiple lesion (%)
14 (21.5)
Size of largest lesion (cm)a
2.2 ± 0.9
Modified UICC I (%)
31 (47.7)
II (%)
22 (33.8)
III (%)
12 (18.5)
Recurrence (%) Time to recurrence (month)
26 (40) a
14.9 ± 8.1
Recurred site Single, same segment (%)
Statistical analysis We compared the recurrence rate and time to recurrence between the groups and analyzed risk factors for
5.9 ± 1.1
Child–Pugh class
a
4 (16)
Single, same lobe but different segment (%)
6 (24)
Single, different lobe (%) Multiple (%)
6 (24) 9 (36)
Mean ± standard deviation
HBV hepatitis B virus, HCV hepatitis C virus
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507
Child–Pugh class A cases (76.9%) and 15 class B (23.1%). The mean AFP was 101.2 ± 353.4 ng/mL, and the mean protein induced by vitamin K absence or antagonist II (PIVKA-II) was 164.2 ± 398.9 mAU/mL. The mean follow-up duration was 18.9 ± 9.4 months. The mean number of tumor was 1.3 ± 0.5 and 14 patients (21.5%) had multiple lesions. The mean maximal diameter of tumor was 2.2 ± 0.9 cm. With respect to the Modified Union Internationale Contre le Cancer (Modified UICC) stage, 31 patients were stage I (47.7%), 22 were stage II (33.8%) and 12 were stage III (18.5%) [6]. Recurrence after RFA combined with TACE Overall recurrence rate was 40% (26 cases) and the time to recurrence was 14.9 ± 8.1 months. The cumulative recurrence rate at 1 year was 20% (13 cases) and at 2 years was 33.8% (22 cases). The cumulative recurrence rates after the combined treatment are depicted in Fig. 1. Fig. 1 Cumulative recurrence rates after the combined treatment with TACE and RFA
Risk factors of recurrence
59.9 ± 10.1 years. The most common etiology was hepatitis B virus infection, followed by hepatitis C virus infection. There were 52 cirrhotic patients (80.0%), and the mean Child–Pugh score was 5.9 ± 1.1. There were 50
To evaluate the risk factors of recurrence, patients were divided into the recurred group and non recurred group (Table 2). The proportion of males, mean age, etiology, the proportion of cirrhosis, Child–Pugh class, mean AFP, mean
Table 2 Comparison between recurred group and non recurred group
Variables
Recurred (n = 26)
Non recurred (n = 39)
Male (%)
21 (80.8)
27 (69.2)
0.392
Agea
60.5 ± 12.0
59.4 ± 8.8
0.689
Etiology Unknown (%)
1 (6.7)
4 (10.3)
0.761
HBV (%)
12 (46.2)
19 (48.7)
HCV (%)
7 (26.9)
6 (15.4)
Alcohol (%)
3 (11.5)
5 (12.8)
HBV ? Alcohol (%)
3 (11.5)
4 (10.3)
HBV ? HCV ? Alcohol (%)
0 (0)
1 (2.6)
Cirrhosis (%)
23 (88.5)
29 (74.4)
Child–Pugh class A (%)
22 (84.6)
28 (71.8)
B (%)
4 (15.4)
11 (28.2)
AFP (ng/mL)a
148.3 ± 526.1
69.9 ± 160.4
0.385
PIVKA-II (mAU/mL)a
224.9 ± 493.5
117.6 ± 309.0
0.337
Multiple lesions (%)
4 (15.4)
10 (25.6)
0.373
2.5 ± 1.0
2.0 ± 0.8
Size of largest lesion (cm)
Mean ± standard deviation
HBV hepatitis B virus, HCV hepatitis C virus
0.214 0.368
a
Modified UICC
a
P value
I (%) II (%)
12 (46.2) 10 (38.5)
19 (48.7) 12 (30.8)
III (%)
4 (15.4)
8 (20.5)
1.4 ± 0.6
1.0 ± 0.0
Initial RFA frequency
0.029 0.772
\0.001
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PIVKA-II, the proportion of multiple tumors, and the proportion of modified UICC stage did not differ between the groups. There were two significantly different variables between the recurred group and non recurred group: (1) diameter of largest lesion (2.5 ± 1.0 vs. 2.0 ± 0.8 cm, respectively, P = 0.029) and (2) initial RFA frequency (1.4 ± 0.5 vs. 1.0 ± 0.0, respectively, P \ 0.001). For a more detailed analysis, patients were divided according to diameter of the largest lesion (C2, 3, or 4 cm) (Table 3). The groups based on diameter of largest lesion were all significantly different between the recurred group and non recurred group. If the diameter of the tumor was \2 cm, there was no recurrence. So, the minimal diameter indicative of recurrence could be set at 2 cm (100 vs. 84.6%, P = 0.047). Patients were also divided according to frequency of RFA (number of sessions for the completion of ablation) by ‘‘two times or more’’ or ‘‘three times or more’’ (Table 4). But there was only one patient treated ‘‘three times or more,’’ and there were no significant differences between the recurred group and non recurred group. So, an initial RFA ‘‘two times or more’’ itself could be considered a risk factor as ‘‘two times or more’’ group showed higher recurrence rate as compared to single session group (30.8 vs. 0%, P \ 0.001). Logistic regression analysis of these two factors was performed as a multivariate analysis (Table 5). The diameter of the largest tumor (P = 0.045, odds ratio 1.931) and initial RFA frequency (P = 0.006, odds ratio 10.008) were all significant variables.
Table 3 Comparison of largest lesion size between recurred group and non recurred group Variables
Recurred No. (%) (n = 26)
Non recurred No. (%) (n = 39)
P value
Largest lesion C2 cm
26 (100)
33 (84.6)
0.047
Largest lesion C3 cm
9 (34.6)
7 (17.9)
0.042
Largest lesion C4 cm
4 (15.4)
1 (2.6)
0.018
Discussion HCC is the fifth leading cause of cancer death worldwide, accounting for more than 500,000 deaths annually, showing an increasing incidence throughout the world [14, 15]. HCC usually develops in patients with advanced liver fibrosis due to chronic liver diseases, such as chronic hepatitis B, chronic hepatitis C and alcoholic liver disease [15, 16]. Early detection and prompt implementation of treatment result in longer survival [9]. Several associations and authors have endorsed the staging and treatment algorithm from the BCLC group as the best tool for management [2, 17, 18]. Curative therapy exists for HCC if diagnosed early [2]. Surgical resection, liver transplantation and local ablation by radiofrequency or by ethanol injection are now standard therapies at early stages. With these options, survival at 5 years ranges between 40 and 70% [9]. However, HCC is characterized by extremely frequent intrahepatic recurrences, even after successful curative treatments, and it cannot be prevented by adjuvant therapies [19, 20]. Therefore, evaluation of risk factors for recurrence is important. Both RFA and TACE have limitations and drawbacks when used alone. As tumor size increases, the effectiveness of RFA is generally reduced. This is due to the incomplete ablation, which can be explained by increased blood flow in larger lesions leading to heat loss. It has been hypothesized that, by administering TACE prior to RFA, reducing or eliminating the heat loss that is mediated by tissue perfusion would be possible [21–24]. As a result, the ablation volume of coagulation necrosis could be increased, enabling more effective treatment of larger HCCs than with RFA alone [25]. Furthermore, TACE, being a regional treatment, can target undetected satellite lesions outside of the zone of RFA-induced necrosis [12]. Cheng et al. [26] reported a randomized controlled trial and suggested that combination therapy with RFA and chemoembolization is superior to chemoembolization alone or RFA alone in improving survival for patients with HCCs [3 cm. But this report has since been retracted [27]. Therefore, a need to further evaluate the efficacy and recurrence rate of this combination therapy persists. We performed this study for this purpose. Although it would be difficult to conclude if Table 5 Logistic regression analysis for risk factor of recurrence
Table 4 Comparison of initial RFA frequency between recurred group and non recurred group Variables
Recurred No. (%) (n = 30)
Non recurred No. (%) (n = 56)
P value
Initial RFA C2 times
8 (30.8)
0 (0)
\0.001
Initial RFA C3 times
1 (3.8)
0 (0)
0.400
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Variables
Size of largest lesion Initial RFA frequency
Coefficient
P value
Odds ratio
95% confidential interval
0.660
0.045
1.935
1.014–3.693
21.548
0.006
10.008
1.948–51.401
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combination therapy is superior or inferior to RFA alone at this time, there were considerable recurrences. So, it is conceivable that a large number of patients are needed to demonstrate the superiority of combination therapy. Our data could be used as a fundamental reference when designing a proper randomized controlled trial. Despite its technical simplicity and safety, local recurrence at a RFA treatment site is common, varying from 2 to 36% in reported studies [28–32]. Risk factors for local recurrence include large tumor size, multiple tumor nodules, subcapsular tumors, and perivascular tumors [30, 32–39]. In the present study, significant variables for recurrence were as follows: initial RFA performed more than once (30.8 vs. 0%, P \ 0.001) and a main lesion C2 cm (100 vs. 84.6%, P = 0.047). This result is consistent with those of previous studies, i.e., large tumor size and character of tumor making RFA difficult. In conclusion, the recurrence rate of combination therapy was considerably high. Careful post-RFA follow-up should be involved considering the risk of recurrence if additional treatment is required after the first session or if the main lesion is [2 cm at the time of RFA. In addition, a well-designed randomized controlled trial is needed to further elucidate the effectiveness of combination of TACE and RFA in near future. Acknowledgements This study was supported by a grant from Ministry for Health, Welfare and Family Affairs, Republic of Korea (No. A050021).
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