Scandinavian Journal of Gastroenterology. 2014; 49: 373–380

ORIGINAL ARTICLE

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Predisposing factors for recurrence of HBV-related small hepatocellular carcinoma after percutaneous radiofrequency ablation

WON SOHN1, YONG-HAN PAIK1, MIN WOO LEE2, HYUNCHUL RHIM2, HYO KEUN LIM2, JU YEON CHO1, GEUM-YOUN GWAK1, MOON SEOK CHOI1, JOON HYEOK LEE1, KWANG CHEOL KOH1, SEUNG WOON PAIK1 & BYUNG CHUL YOO1 1

Department of Medicine, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea, and Department of Radiology, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea

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Abstract Background. Radiofrequency ablation (RFA) as a curative therapy for hepatocellular carcinoma (HCC) is widely used. The aim of this study was to investigate predisposing factors for HCC recurrence in patients with hepatitis B virus (HBV)-related small HCC after RFA. Methods. A total of 170 patients underwent percutaneous RFA for HBV-related small HCC (£3 cm in diameter) from January 2008 to December 2010 at Samsung Medical Center. We analyzed the risk factors for recurrence of HCC after RFA. Results. The median follow-up duration was 27.0 months. A total of 89 patients (52%) experienced recurrence after percutaneous RFA. Cumulative recurrence-free rates after RFA at 1-, 3-, and 5 years were 81.3%, 47.2% and 35.7%, respectively. Univariate analysis showed that predisposing factors for HCC recurrence were the multinodularity (hazard ratio (HR) 2.22, p = 0.005), pre-RFA HBV DNA levels ‡2000 IU/mL (HR 1.61, p = 0.025), and Barcelona Clinic Liver Cancer stage A (HR 1.54, p = 0.046). The independent risk factors for recurrence by multivariate analysis were the multinodularity (HR 1.94, p = 0.026) and pre-RFA HBV DNA levels ‡2000 IU/mL (HR 1.57, p = 0.039). Conclusion. Multinodularity and HBV DNA levels were associated with the recurrence of HBV-related small HCC after RFA.

Key Words: chronic hepatitis B, hepatocellular carcinoma, radiofrequency ablation, recurrence

Introduction Hepatocellular carcinoma (HCC) is one of the most common types of cancer worldwide [1]. The risk of HCC is greatly increased in chronic liver disease [2]. Hepatitis B or C is an important factor affecting the progression to HCC in patients with chronic liver disease [3]. Hepatitis B virus (HBV) infection is the most common etiology that can result in liver cirrhosis and HCC [4]. The risk of HCC in chronic hepatitis B is 100 times higher than that in noncarriers [5]. Surgical resection or local ablation treatment such as radiofrequency ablation (RFA) and percutaneous ethanol injection are preferentially recommended for HCC with a tumor diameter of 3 cm or less [6,7]. Surgical resection is considered to be the surest

modality for curative therapy. But it is performed in only a small portion of HCC patients because of unfavorable liver function. Therefore, RFA is widely used for curative therapy of early HCC in Western and Asian countries [8,9]. RFA is a curative therapy for HCC in terms of efficacy and safety. However, intrahepatic recurrence rate after RFA has been reported to be between 22% and 63% in small HCC (maximum tumor diameter £3 cm) [10]. The recurrence of HCC was associated with tumor characteristics (e.g., tumor size and number) as well as underlying liver disease such as etiology and the presence of cirrhosis. Risk factors for HCC recurrence after RFA were tumor size, tumor location and prothrombin time [11,12]. Tumor number and serum alpha-fetoprotein (AFP) level are independent

Correspondence: Yong-Han Paik, MD PhD, Department of Medicine, Sungkyunkwan University School of Medicine, Samsung Medical Center, 81 Irwon-Ro Gangnam-gu, Seoul 135-710, Korea. Tel: +82 2 3410 3878. Fax: +82 2 3410 6983. E-mail: [email protected]

(Received 22 October 2013; revised 27 November 2013; accepted 30 November 2013) ISSN 0036-5521 print/ISSN 1502-7708 online  2014 Informa Healthcare DOI: 10.3109/00365521.2013.871745

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prognostic factors for HCC recurrence after RFA in patients with cirrhosis [13]. Viral load is a significant risk factor for the occurrence as well as recurrence of HCC after curative therapy in patients with hepatitis B. A large cohort study showed that elevated HBV DNA level (‡10,000 copies/mL) was a predictive factor for HCC occurrence independent of other risk factors [14]. Several reports showed that high HBV viral load is associated with HCC recurrence after curative resection in chronic hepatitis B [15,16]. However, the effect of HBV viral load on HCC recurrence after RFA has not been well studied. The aim of this study was to identify the risk factors for HCC recurrence after curative RFA in HBVrelated small HCC (tumor size £3 cm). In particular, we investigated the effect of HBV viral load on HCC recurrence after RFA.

satisfying the following criteria underwent percutaneous RFA for initial curative therapy at Samsung Medical Center, Seoul, Korea: (i) maximal diameter of tumor £30 mm; (ii) number of tumor £3; (iii) no portal vein invasion; (iv) Child-Pugh class A or B; (v) no recurrence within 3 months after RFA. Among these 188 patients, we excluded the patients (i) with coinfection with hepatitis C or human immunodeficiency virus (n = 3); (ii) with any concurrent malignancy (n = 8); (iii) with local tumor progression after RFA (n = 5); and (iv) who received liver transplantation without recurrence after RFA (n = 2). Finally, 170 patients were evaluated on the basis of retrospective analysis (Figure 1). We made a diagnosis of HCC based on the American Association for the Study of Liver Diseases guidelines [6]. The study was approved by the institutional review board of Samsung Medical Center.

Materials and methods

Radiofrequency ablation

Study population

RFA was performed percutaneously under ultrasound guidance. Ultrasound was used to guide a target to the tumor and monitor the ablation process. Internally cooled electrodes with an exposed tip (Cool-tip RFA system, Valleylab, Boulder, CO,

From January 2008 to December 2010, 188 patients with HBV-related HCC (positive surface antigen of the hepatitis B virus (HBsAg) for at least 6 months) 188 patients with HBV-related HCC underwent RFA (January 2008 – December 2010) Tumor size ≤ 3cm Tumor number ≤ 3 No portal vein invasion Child-pugh class A or B No recurrence within 3 months after RFA

18 Patients were excluded HCV or HIV co-infection (n = 3) With other concurrent malignancies (n = 8) Local tumor progression after RFA (n = 5) Liver transplantation due to recurrence after RFA (n = 2)

170 Patients were included in the final analysis

Figure 1. Flow sheet of the patients in this study. HCC = hepatocellular carcinoma; RFA = radiofrequency ablation; HCV = hepatitis C virus; HIV = human immunodeficiency virus.

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Predisposing factors for recurrence after RFA in HBV-related HCC USA; or VIVA RF System, STARmed, Goyang, Korea) were used for RFA. To deliver the radiofrequency energy, impedance-based control of the generator was used according to the manufacturer’s instructions for each device. If an ultrasonic window for the target tumor was poor or the target was in the vicinity of the diaphragm or colon, artificial ascites were used [17]. Patients were managed to control RFA-related pain. They were treated with intravenous injection of 2% lidocaine hydrochloride and subsequent intravenous drip infusion of pethidine hydrochloride (50 mg) mixed with 50 mL of 5% dextrose in water. Infusion rate was controlled according to the intensity of pain. All tumors were ablated with complete necrosis of at least 5 mm of normal liver parenchyma encircling the tumor. In some cases, multiple overlapping ablations were performed to achieve an adequate ablation margin. Study measurements We reviewed pre-RFA patients’ clinical characteristics: age, gender, platelet count, prothrombin time, serum albumin, total bilirubin, aspartate transaminase, alanine transaminase, AFP, HBV DNA level, presence of HBV envelope antigen (HBeAg), history of antiviral therapy, Child-Pugh classification, presence of liver cirrhosis, and tumor size and number. Meaningful antiviral therapy was considered as medication use for at least 3 months before RFA. Cirrhosis was determined by imaging methods such as ultrasonography or computer tomography (CT). Positive findings of cirrhosis were defined as a coarse change of liver parenchyma plus surface nodularity with or without ascites, varices, and splenomegaly. Tumor stage was assessed by the Barcelona Clinic Liver Cancer (BCLC) staging system [18]. Tumor recurrence after RFA was monitored regularly. Dynamic CT and/or magnetic resonance imaging with serum AFP were performed for follow-up every 3 months during the first 2 years after RFA, and every 6 months thereafter. Recurrence pattern after RFA was classified into three types: local tumor progression, intrahepatic distant recurrence, and extrahepatic spread. Local tumor progression was defined as a newly enhancing lesion within or around the ablation site in dynamic CT [19]. To analyze the HCC recurrence and its related factors after RFA, we excluded local tumor progression because it may be associated with residual tumor cells with microscopic spread beyond the margin of the ablation site [20]. We focused on the risk factors for intrahepatic recurrence or extrahepatic spread of primary cancer rather than the progression of residual tumor cells after RFA in HBV-related HCC. The definition of tumor recurrence was applied

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to the same criteria diagnosed with the primary HCC. The follow-up duration of recurrence was defined as the interval from the RFA procedure to identification of tumor recurrence or the last follow-up without recurrence. The follow-up of recurrence was performed on the basis of our institution’s data, while overall survival was monitored based on data from our institution as well as that from the National Statistical Office. This study was conducted using data up to March 31, 2013. Statistical analysis Cumulative overall and recurrence-free survival rate was calculated by the Kaplan–Meier method. Log-rank test was used to compare the recurrence-free survival by significant risk factor. Predisposing factors for recurrence of HCC after RFA were assessed using the univariate and multivariate Cox proportional hazards models. The variables for the multivariate analysis were determined considering the statistical significance in the univariate analysis or clinical correlation. Multivariate analysis with forward conditional stepwise method was applied to avoid the multicollinearity. When the p Value was less than 0.05, the result was considered as statistically significant. All statistical analyses were performed using SPSS for Window release 18.0 (SPSS Inc, Chicago, IL, USA). Results Patient characteristics The baseline characteristics of 170 enrolled patients with HCC are shown in Table I. The mean age of the patients was 56.1 years. One hundred and thirty-two men (78%) and 38 women (22%) were enrolled in the study. They had mostly cirrhotic liver (144 patients, 84%), but relatively good liver function (Child-Pugh class A, 89%). HBeAg positivity was observed in 75 patients (45%). Eighty-eight patients (52%) had HBV DNA level below 2000 IU/mL and 82 patients (48%) received antiviral therapy at diagnosis: lamivudine in 25, adefovir in 9, lamivudine plus adefovir in 12, clevudine in 5, and entecavir in 31 patients. The average maximal tumor size was 19.3 mm. One hundred and forty-seven patients (86%) had a single HCC nodule. BCLC stage of enrolled patients was very early stage in 79 and early stage in 91 patients. Overall survival and recurrence in patients with HCC after RFA A total of 10 out of 170 patients (6%) died. The median follow-up duration of overall survival after

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Table I. Basic characteristics of the patients (n = 170).

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Number/mean ± SD Age Gender Women Men Platelet (103/mm2) Prothrombin time (INR) Albumin (g/dL) Total bilirubin (mg/dL) AST (U/L) ALT (U/L) ALP (U/L) AFP (ng/mL)

Predisposing factors for recurrence of HBV-related small hepatocellular carcinoma after percutaneous radiofrequency ablation.

BACKGROUND. Radiofrequency ablation (RFA) as a curative therapy for hepatocellular carcinoma (HCC) is widely used. The aim of this study was to invest...
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