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Original Research  n  Vascular

Kyoung Doo Song, MD Hyo Keun Lim, MD, PhD Hyunchul Rhim, MD, PhD Min Woo Lee, MD, PhD Young-sun Kim, MD, PhD Won Jae Lee, MD, PhD Yong Han Paik, MD, PhD Geum-Youn Gwak, MD, PhD Jong Man Kim, MD, PhD Choon Hyuck David Kwon, MD, PhD Jae-Won Joh, MD, PhD

Purpose:

To compare the long-term outcomes of repeated hepatic resection and radiofrequency (RF) ablation for recurrent hepatocellular carcinoma (HCC) by using propensity score matching.

Materials and Methods:

This retrospective study was approved by the institutional review board, and the requirement to obtain informed consent was waived. Thirty-nine patients who underwent repeated hepatic resection and 178 who underwent RF ablation for recurrent HCC (mean tumor size 6 standard deviation, 1.8 cm 6 0.7) between November 1994 and December 2012 were included in the study. Patients ranged in age from 24 to 85 years (mean, 54.9 years). Men ranged in age from 25 to 85 years (mean, 54.8 years), and women ranged in age from 24 to 76 years (mean, 55.4 years). A 1:2 repeated hepatic resection group–RF ablation group matching was done by using propensity score matching. The overall survival (OS) and disease-free survival (DFS) were compared before and after propensity score matching. Complications were assessed.

Results:

Before matching, OS rates at 1, 3, 5, and 8 years were 88.8%, 88.8%, 83.9%, and 56.3%, respectively, with repeated hepatic resection and 98.9%, 82.5%, 71.0%, and 58.3% for RF ablation. DFS rates at 1, 3, and 5 years were 66.1%, 48.5%, and 43.1% for repeated hepatic resection and 70.1%, 40.8%, and 30.0% for RF ablation. After matching, the OS rates at 1, 3, 5, and 8 years were 98.7%, 85.7%, 72.1%, and 68.6%, respectively, and the DFS rates at 1, 3, and 5 years were 71.8%, 45.1%, and 39.4% in the RF ablation group (n = 78). Neither the OS nor DFS rate was significantly different between the two groups before matching (P = .686 and P = .461) and after matching (P = .834 and P = .960). The postoperative mortality rate was 2.6% in the repeated hepatic resection group and 0% in the RF ablation group.

Conclusion:

The long-term OS and DFS were not significantly different between repeated hepatic resection and RF ablation for patients with recurrent HCC after hepatic resection.

1

 From the Department of Radiology and Center for Imaging Science (K.D.S., H.K.L., H.R., M.W.L., Y.S.K., W.J.L.), Department of Medicine (Y.H.P., G.Y.G.), and Department of Surgery (J.M.K., C.H.D.K., J.W.J.), Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro, Gangnam-gu, Seoul 135-710, Republic of Korea. Received July 5, 2014; revision requested August 22; revision received September 18; accepted September 22; final version accepted October 10. Supported by Samsung Medical Center (grant GFO1130071). Address correspondence to H.K.L. (e-mail: [email protected]).

and Interventional Radiology

Repeated Hepatic Resection versus Radiofrequency Ablation for Recurrent Hepatocellular Carcinoma after Hepatic Resection: A Propensity Score Matching Study1

 RSNA, 2015

q

 RSNA, 2015

q

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1

VASCULAR AND INTERVENTIONAL RADIOLOGY: Repeated Hepatic Resection vs Radiofrequency Ablation for Recurrent HCC

F

or very early or early stage hepatocellular carcinoma (HCC), hepatic resection, liver transplantation, and local ablation therapy are considered to be curative modalities (1). In clinical practice, because of the shortage of organs for transplantation and the nonnegligible postoperative mortality and morbidity of liver transplantation, hepatic resection and percutaneous ablation therapy are chosen most commonly as first-line treatments. Currently, local ablation therapy, especially radiofrequency (RF) ablation, is considered comparable to hepatic resection in terms of long-term survival for patients with early stage HCC, as evidenced by numerous studies (2–5). Although the cumulative 5-year recurrence rate after hepatic resection ranges from 70% to 80% (6), guidelines for the management of recurrent HCC after hepatic resection have not yet been established. Available treatment options for recurrent HCC after hepatic resection are not particularly different from initial treatment options. Compared with initial treatment, more limited liver

function reserve and technical difficulties in repeated hepatic resection owing to postoperative adhesion are expected in the treatment of recurrent HCC after hepatic resection. In addition, the size of recurrent HCC may be smaller than that of the initial HCC because of increased surveillance. These additional factors may affect treatment outcomes. Several studies have independently reported that both repeated hepatic resection and RF ablation were effective for managing recurrent tumors after hepatic resection for HCC (6–10). In addition, two studies compared the outcomes of repeated hepatic resection and RF ablation for recurrent HCC after hepatic resection (11,12). However, these comparative studies were limited by their relatively small study populations. Furthermore, comparison of therapeutic outcomes was performed without correction for potential confounding factors that might affect the outcomes of repeated hepatic resection and RF ablation. Our aim was to compare long-term outcomes of repeated hepatic resection and RF ablation for recurrent HCCs by using propensity score matching.

Advances in Knowledge nn After propensity score matching, the overall survival rates were not significantly different between repeated hepatic resection and radiofrequency (RF) ablation for recurrent hepatocellular carcinoma (HCC) after hepatic resection (88.8%, 88.8%, 83.9%, and 56.3% at 1, 3, 5, and 8 years, respectively, for repeated hepatic resection vs 98.7%, 85.7%, 72.1%, and 68.6% for RF ablation; P = .834). nn After propensity score matching, the disease-free survival rates were not significantly different between repeated hepatic resection and RF ablation for recurrent HCC after hepatic resection (66.1%, 48.5%, and 43.1% at 1, 3, and 5 years, respectively, for repeated hepatic resection vs 71.8%, 45.1%, and 39.4% for RF ablation; P = .960). 2

Materials and Methods Our study was conducted as a retrospective analysis of a prospective database in a single center. Our study was approved by the institutional review board of our hospital, and the requirement to obtain informed consent was waived because this was a retrospective clinical study.

Patients Between November 1994 and December 2012, 2387 patients underwent hepatic resection for HCC as a first-line treatment. Among them, patients who underwent repeated hepatic resection (n = 39) or RF ablation (n = 178) for intrahepatic recurrent HCC were included in our study. Patients ranged in age Implication for Patient Care nn RF ablation can be considered as a viable alternative for the treatment of recurrent HCC after hepatic resection.

Lim et al

from 24 to 85 years (mean, 54.9 years). Men ranged in age from 25 to 85 years (mean, 54.8 years), and women ranged in age from 24 to 76 years (mean, 55.4 years) (Fig 1). The mean size of recurrent HCCs (6standard deviation) was 1.8 cm 6 0.7. HCC diagnosis was based on histologic examination by means of ultrasonographically (US) guided core biopsy in six of the 178 patients (3.4%) in the RF ablation group. In the remainder, HCC was diagnosed on the basis of one of two clinical criteria from the American Association for the Study of Liver Diseases at the time of RF ablation (1,13).

Treatment of HCC and Follow-up In our institution, repeated hepatic resection was considered if a patient had a single tumor or oligonodular tumor within a monosegment of liver with good liver function reserve. Repeated hepatic resection was generally avoided if patients had gross ascites, an indocyanine green retention rate of more than 20% at 15 minutes and/or a serum total bilirubin level of more than 1.5 mg/dL, or the presence of moderate esophageal varix, which signifies severe portal hypertension. For RF ablation, our inclusion criteria were as Published online before print 10.1148/radiol.14141568  Content codes: Radiology 2015; 000:1–10 Abbreviations: ALT = alanine aminotransferase CI = confidence interval DFS = disease-free survival HCC = hepatocellular carcinoma OS = overall survival RF = radiofrequency Author contributions: Guarantors of integrity of entire study, H.K.L., J.M.K.; study concepts/study design or data acquisition or data analysis/ interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval; agrees to ensure any questions related to the work are appropriately resolved, all authors; literature research, K.D.S., H.K.L., M.W.L., G.Y.G.; clinical studies, K.D.S., H.K.L., H.R., M.W.L., Y.S.K., W.J.L., Y.H.P., J.M.K., C.H.D.K., J.W.J.; statistical analysis, K.D.S.; and manuscript editing, K.D.S., H.K.L., H.R., M.W.L., Y.S.K., W.J.L., Y.H.P., G.Y.G. Conflicts of interest are listed at the end of this article.

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Percutaneous US-guided RF ablation was performed in 170 patients, and intraoperative RF ablation was performed in eight. Procedures were performed by one of five radiologists (H.K.L., W.J.L., H.R., Y.S.K., and M.W.L., with 14, 12, 14, 8, and 8 years of experience with this procedure by the end of the study, respectively). If the index tumor was treated according to the protocol and was completely covered by RF ablation zones as determined with the immediate imaging study (ie, technical success) (14), a follow-up study was performed 1 month later. If incomplete ablation was confirmed on the immediate imaging study, the second session of RF ablation was performed on the same day. If a tumor was completely ablated without residual enhancing tumor on contrast-enhanced CT scans at 1 month after RF ablation (technique effectiveness), a subsequent follow-up examination was repeated every 3–6 months with contrast-enhanced CT or magnetic resonance (MR) imaging.

Figure 1

Figure 1:  Flowchart summarizes patient inclusion. PEI = percutaneous ethanol injection, RFA = radiofrequency ablation, rHR = repeated hepatic resection, TACE = transcatheter arterial chemoembolization.

follows: a single tumor (5 cm in the greatest dimension), multiple nodular tumors (three or fewer, each 3 cm in longest dimension), Child-Pugh class A or B disease, no portal vein thrombosis or extrahepatic metastasis, prothrombin time ratio of more than 50%, and platelet count of more than 50 000/mm3 (50 3 109/L). Open repeated hepatic resection was performed in 36 patients, and laparoscopic repeated hepatic resection was performed in three. Tumorectomy was performed in 14 patients, single segmentectomy in 10, left lateral

Lim et al

segmentectomy in eight, left hemihepatectomy in three, and right hemihepatectomy in four. Resection was performed by one of three surgeons (J.M.K., C.H.D.K., and J.W.J., with 6, 10, and 21 years of experience with hepatic resection by the end of the study, respectively). If there were no complications immediately after repeated hepatic resection, contrast material– enhanced computed tomography (CT) was performed 1 month after surgery and then a follow-up examination was performed every 3–6 months according to the risk of recurrence.

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Data Acquisition Baseline patient characteristics, the size of initial tumors, the presence of microvascular invasion, and the histologic grade of the initial tumor were obtained. The size and number of recurrent HCCs and the interval between initial hepatic resection and repeated hepatic resection or RF ablation were also obtained. Complications were stratified according to the Clavien classification of postoperative complications (15). Major complications were defined as those classified as grade II or higher. Overall survival (OS), diseasefree survival (DFS), and subsequent treatment methods for recurrent tumors were recorded. Local tumor progression (tumor recurrence along the margin of the ablation zone) was also evaluated in the RF ablation group. Statistical Analysis Because patients were not randomized to undergo repeated hepatic resection versus RF ablation, we matched patients on the basis of their propensity to receive repeated hepatic resection at randomization. The propensity score is 3

VASCULAR AND INTERVENTIONAL RADIOLOGY: Repeated Hepatic Resection vs Radiofrequency Ablation for Recurrent HCC

Lim et al

Table 1 Baseline Patient Characteristics before and after Propensity Score Matching Parameter Median follow-up (mo)† Mean age (y) Male sex Diabetes mellitus Hypertension HBsAg positive Anti-HCV positive Liver cirrhosis Child-Pugh score  5  6  7 BCLC stage A ALT level .40 IU/L Platelet count .15 3 104/mm3 AFP level .200 ng/mL Recurrent tumor size .2 cm At least two recurrent tumors Histologic grade of initial tumor‡  I  II  III  IV Microvessel invasion of initial tumor Initial hepatic resection type   One segment   Two segments   At least three segments

M

Before Matching

Surgical Resection (n = 39)*

RF Ablation (n = 178)*

36.3 (0.8–126.6) 52.5 6 9.8 31 (79) 4 (10) 11 (28) 36 (92) 1 (2.6) 23 (59)

44.7 (5.6–139.8) 55.4 6 10.6 145 (81.5) 36 (20.2) 53 (29.8) 149 (83.7) 12 (6.7) 130 (73.0)

35 (90) 4 (10) 0 (0) 23 (59) 5 (13) 12 (31) 6 (15) 17 (44) 7 (18)

145 (81.5) 27 (15.2) 6 (3.3) 73 (41.0) 61 (34.3) 58 (32.6) 14 (7.9) 50 (28.1) 22 (12.4)

4 (10) 32 (82) 2 (5.1) 1 (2.6) 15 (38)

21 (11.8) 146 (82.0) 10 (5.6) 1 (0.5) 85 (47.8)

20 (51) 14 (36) 5 (13)

67 (37.6) 49 (27.5) 62 (34.8)

ASD 30.1 4.8 32.4 3.4 31.9 26.1 28.2 ,36.0

32.7 63.3 3.9 20.6 30.9 14.4 ,12.5

18.9 ,65.0

After Matching P Value

RF Ablation (n = 78)*

.151 .105 .776 .146 .846 .170 .319 .081

43.6 (9.2–139.8) 53.6 6 10.9 58 (74) 8 (10) 22 (28) 70 (90) 3 (3.8) 46 (59)

.028 .063 .826 .141 .058 .434 .689

.375 .026

66 (85) 12 (15) 0 (0) 40 (51) 12 (15) 25 (32) 9 (12) 31 (40) 13 (17) 11 (14) 63 (81) 3 (3.8) 1 (1.3) 27 (35)

ASD

P Value

10.7 12.5 0.0 0.0 9.5 8.0 0.0 ,16.7

.236 .622 .547 .999 .999 .670 .724 .999 .371

14.0 7.6 2.7 10.5 7.7 3.3 ,11.7

.319 .732 .892 .540 .694 .455 .908

7.8 ,15.1

.683 .733

37 (47) 27 (35) 14 (18)

Note.—AFP = a-fetoprotein, anti-HCV = antibody to hepatitis C virus, ASD = absolute standardized difference, BCLC = Barcelona Clinic Liver Cancer, HBsAg = hepatitis B surface antigen. * Except where indicated, data are numbers of patients, with percentages in parentheses. †

Numbers in parentheses are the range.

‡

Edmondson-Steiner grade.

the conditional probability of receiving an exposure given a vector of measured covariates (16). We used multivariable logistic regression models to estimate propensity scores, using the following baseline characteristics as covariates in the model: age, sex, presence of diabetes mellitus, presence of hypertension, presence of liver cirrhosis, hepatitis B surface antigen status, antibody to hepatitis C virus status, presence of microvascular invasion of initial tumors, Edmondson-Steiner grade of initial tumors, type of initial hepatic resection (group I = tumorectomy or segmentectomy; group II = left lateral segmentectomy, right posterior segmentectomy, 4

right inferior segmentectomy, or central hepatectomy; group III = right hemihepatectomy, left hemihepatectomy, or extended hemihepatectomy), size and number of recurrent tumors, liver function reserve (Child-Pugh classification), Barcelona Clinic Liver Cancer stage, afetoprotein level, alanine aminotransferase (ALT) level, and platelet count. Before matching, the mean propensity score for receiving hepatic resection was 0.270 for patients in the repeated hepatic resection group (n = 39) and 0.160 for patients in the RF ablation group (n = 178), with a standardized difference of 69.4% (t test, P , .001). We matched all 39 patients in the repeated

hepatic resection group with 78 patients in the RF ablation group using the nearest neighbor method (caliber = 0.02). After matching, the mean propensity score for receiving hepatic resection was 0.270 for patients in the repeated hepatic resection group (n = 39) and 0.226 for patients of the RF ablation group (n = 78), with a standardized difference of 27.7% (two-way analysis of variance test, P = .111). We assessed the balance of all baseline covariates in Table 1 between the two groups before and after propensity score matching using the standardized difference (percentage of the pooled standard deviation). Our propensity score model

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M

was well calibrated and discriminated effectively between patients who underwent repeated hepatic resection and RF ablation at baseline (C statistic = 0.719). A 20% standardized difference corresponds to a small difference between groups (17), and a 10% standardized difference might indicate the smallest potentially meaningful difference (18). Before matching, continuous variables were compared by using the Student t test or Mann-Whitney U test between the two groups. Categoric variables were compared with the x2 test or Fisher exact test. After 1:2 matching, two-way analysis of variance was used for comparison of continuous variables and the Cochran-Mantel-Haenszel test was used for categoric variables. OS and DFS were estimated from the date of treatment for recurrent HCC with the Kaplan-Meier method before and after matching and were compared with the log-rank test before matching and the stratified log-rank test after matching. The cumulative rate of local tumor progression after RF ablation was also calculated with the Kaplan-Meier method. Prognostic factors for OS and DFS were assessed by using Cox proportional hazard models in univariate and multivariate analyses for all patients, not just the propensity score–matched patients. Potential prognostic factors included all baseline covariates used in propensity score matching and treatment modality. All analyses were performed by using the R software package (version 3.0.2; R Foundation for Statistical Computing, Vienna, Austria) and PASW statistical software (version 18.0; SPSS, Chicago, Ill). For all statistical tests, P , .05 was considered indicative of a statistically significant difference.

Results The mean tumor size at initial HCC diagnosis was 3.6 cm 6 2.5 for the repeated hepatic resection group and 4.3 cm 6 2.9 for the RF ablation group (P = .110). The proportion of single HCC was 92.5% for the repeated hepatic resection group and 84.3% for the RF

ablation group (P = .531) at the time of initial treatment. The median time between initial hepatic resection and repeated hepatic resection or RF ablation was 20.9 months (range, 3.1–136.3 months) and 18.0 months (range, 3.1– 118.4 months), respectively (P = .272). Before matching, the median follow-up period was 36.3 months (range, 0.8–126.6 months) for the repeated hepatic resection group and 44.7 months (range, 5.6–139.8 months) for the RF ablation group. Baseline patient characteristics are summarized in Table 1. A larger proportion of patients in the RF ablation group had very early stage disease with the Barcelona Clinic Liver Cancer classification. The proportion of patients who underwent hemihepatectomy or extended hemihepatectomy was larger in the RF ablation group than in the repeated hepatic resection group. The mean size of recurrent HCCs was 1.8 cm 6 0.7. The mean size of recurrent tumors was 2.2 cm 6 1.1 for the repeated hepatic resection group and 1.7 cm 6 0.6 for the RF ablation group (P = .001). Seven of the 39 patients in the repeated hepatic resection group (18%) and five of the 178 patients in the RF ablation group (2.8%) had HCC larger than 3 cm (P = .001).

Comparison of Survival Results between the Groups before Propensity Score Matching The estimated OS rates at 1, 3, 5, and 8 years were 88.8%, 88.8%, 83.9%, and 56.3%, respectively, for the 39 patients in the repeated hepatic resection group and 98.9%, 82.5%, 71.0%, and 58.3 for the 178 patients in the RF ablation group. The cumulative DFS rates at 1, 3, and 5 years were 66.1%, 48.5%, and 43.1%, respectively, for the repeated hepatic resection group and 70.1%, 40.8%, and 30.0% for the RF ablation group. Neither the OS nor DFS rate was significantly different between the two groups (P = .686 and P = .461, respectively) (Fig 2). With regard to DFS, the presence of diabetes mellitus (P = .015; hazard ratio = 1.642; 95% confidence interval [CI] = 1.102, 2.448), ALT level greater than 40 IU/L (P = .026; hazard ratio

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= 1.486; 95% CI = 1.048, 2.107), and at least two recurrent tumors (P = .001; hazard ratio = 2.156; 95% CI = 1.347, 3.453) were significant factors at univariate analysis. At multivariate analysis, diabetes mellitus (P = .026; hazard ratio = 1.681; 95% CI = 1.064, 2.656), ALT level greater than 40 IU/L (P = .034; hazard ratio = 1.519; 95% CI = 1.033, 2.235), at least two recurrent tumors (P = .001; hazard ratio = 2.783; 95% CI = 1.538, 5.034), and microvascular invasion (P = .019; hazard ratio = 1.641; 95% CI = 1.086, 2.482) were significant factors (Table 2). In terms of OS, diabetes mellitus was the only significant factor found at univariate analysis (P = .004; hazard ratio = 2.203; 95% CI = 1.295, 3.750) and multivariate analysis (P = .028; hazard ratio = 2.168; 95% CI = 1.085, 4.334) with use of Cox proportional hazard models in the combined repeated hepatic resection and RF ablation groups (Table 3).

Comparison of Survival Results between the Groups after Propensity Score Matching After propensity score matching, patients in the repeated hepatic resection and RF ablation groups were not significantly different with regard to any baseline covariates (Table 1). Propensity score matching reduced standardized differences for all observed covariates to less than 20% in absolute value, which represents a substantial improvement in covariate balance between the two groups. The estimated OS rates at 1, 3, 5, and 8 years were 98.7%, 85.7%, 72.1%, and 68.6%, respectively, in the 78 matched patients in the RF ablation group. The cumulative DFS rates at 1, 3, and 5 years were 71.8%, 45.1%, and 39.4%, respectively. After matching, the OS and DFS rates were still not significantly different between the two groups (P = .834 and P = .960, respectively) (Fig 2). Complications and Treatment for Subsequent Recurrent HCC There was intra-abdominal adhesion in 25 of the 39 patients in the repeated hepatic resection group (64%). Eleven 5

VASCULAR AND INTERVENTIONAL RADIOLOGY: Repeated Hepatic Resection vs Radiofrequency Ablation for Recurrent HCC

Lim et al

Figure 2

Figure 2:  Kaplan-Meier survival curves of patients who underwent repeated hepatic resection (rHR ) or RF ablation (RFA) for recurrent HCC after hepatic resection. (a) Cumulative OS curves and (b) cumulative DFS curves before propensity score matching. (c) Cumulative OS curves and (d) cumulative DFS curves after propensity score matching. There were no significant differences in survival outcomes either before or after propensity score matching.

of the 39 patients (28%) had severe adhesion. During adhesiolysis, laceration of liver parenchyma and bile leakage (n = 1) and diaphragmatic tear (n = 1) occurred. In one patient, there was a substantial prolongation of procedure time because of severe adhesion. In the repeated hepatic resection group, one of the 39 patients (2.6%) experienced a major complication (grade V): death due to hepatic failure 10 days after the procedure. The patient 6

had undergone central hepatectomy for initial HCC 23 months earlier and underwent segment 7 segmentectomy for a recurrent HCC. The preoperative laboratory findings were as follows: indocyanine green retention rate at 15 minutes, 12.7%; total bilirubin level, 1.7 mg/dL; international normalized ratio, 1.01; and albumin level, 4.6 g/dL. In the RF ablation group, four of the 178 patients (2.2%) experienced a major complication: Three patients experienced a

grade II complication, requiring antibiotic therapy for abscess in the ablation zones, and one patient experienced a grade III complication, requiring antibiotic therapy and percutaneous drainage for abscess in the ablation zone. There was no procedure-related mortality in the RF ablation group. During the follow-up period after the treatment for recurrent tumors, HCC recurred in 18 of the remaining 38 patients in the repeated hepatic

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Table 2 Univariate and Multivariate Analyses of Prognostic Factors for DFS Univariate Analysis Variable Repeated hepatic resection Age Male sex Diabetes mellitus Hypertension HBsAg positive Anti-HCV positive Liver cirrhosis Child-Pugh score   5 vs 6   5 vs 7 BCLC stage A ALT level .40 IU/L Platelet count .15 3 104/mm3 AFP .200 ng/mL Recurrent tumor size .2 cm At least two recurrent tumors Histologic grade of initial tumor*   I vs II   I vs III and IV Microvessel invasion of initial  tumor Initial hepatic resection   One segment vs two segments   One segment vs at least three  segments

Multivariate Analysis

HR

95% CI

P Value

HR

95% CI

P Value

0.830 0.999 1.427 1.642 1.190 0.619 0.377 0.821

0.504, 1.365 0.982, 1.016 0.885, 2.301 1.102, 2.448 0.827, 1.713 0.402, 0.954 0.701, 2.555 0.565, 1.195

1.046 0.988 1.137 1.681 1.130 0.585 0.744 0.798

0.616, 1.776 0.969, 1.008 0.671, 1.926 1.064, 2.656 0.734, 1.740 0.327, 1.045 0.322, 1.720 0.527, 1.210

1.367 0.881 1.357 1.486 0.887 0.778 1.281 2.156

0.876, 2.133 0.323, 2.404 0.964, 1.910 1.048, 2.107 0.608, 1.292 0.395, 1.533 0.893, 1.837 1.347, 3.453

1.217 0.575 0.710 1.519 0.705 0.855 1.755 2.783

0.760, 1.951 0.195, 1.698 0.373, 1.349 1.033, 2.235 0.460, 1.081 0.410, 1.781 0.918, 3.352 1.538, 5.034

1.328 0.691 1.338

0.761, 2.316 0.265, 1.800 0.949, 1.887

.462 .999 .145 .015 .349 .030 .999 .303 .362 .169 .805 .080 .026 .531 .469 .179 .001 .202 .318 .449 .096

1.005 0.504 1.641

0.599, 2.039 0.172, 1.478 1.086, 2.482

.868 .229 .634 .026 .578 .070 .489 .288 .373 .414 .317 .296 .034 .109 .675 .089 .001 .206 .750 .212 .019

0.855 1.033

0.557 0.693, 1.541

.683 .999 .872

0.476 0.843

0.582, 1.451 0.533, 1.333

.763 .715 .465

Note.—AFP = a-fetoprotein, anti-HCV = antibody to hepatitis C virus, BCLC = Barcelona Clinic Liver Cancer, HBsAg = hepatitis B surface antigen, HR = hazard ratio. * Edmondson-Steiner grade.

resection group (47%) and 117 of the 178 patients in the RF ablation group (65.7%). The diagnosis of HCC recurrence was based on histologic specimens obtained at surgery in three patients in the RF ablation group. In the remainder of the RF ablation group and all patients in the repeated hepatic resection group, recurrence was diagnosed on the basis of clinical criteria from the American Association for the Study of Liver Diseases. Treatment for subsequent recurrent HCCs is summarized in Figure 3.

Discussion In our study, we demonstrated that patients who underwent RF ablation had

OS and DFS rates similar to those who underwent repeated hepatic resection for recurrent HCC after hepatic resection. Although there have been two studies that compared OS and DFS outcomes between repeated hepatic resection and RF ablation for recurrent HCC after hepatic resection, to our knowledge, our study was performed in the largest study population and presents the longest follow-up data ever reported (11,12). In addition, as a result of propensity score matching, the absolute standardized difference of almost all potential confounding factors became less than 15%. This means that potential confounding factors were adjusted effectively. In the determination of the first-line treatment option for recurrent

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HCC after hepatic resection, prospective randomized trials can provide reliable evidence. However, these are difficult to perform because treatment courses are determined in consideration of various clinical factors. Therefore, the results of our study, which were obtained after balancing patient demographics, liver function reserves, and tumor characteristics between the repeated hepatic resection and RF ablation groups, can provide important data with which to establish guidelines for the management of recurrent HCC after hepatic resection. We observed a tendency toward a longer DFS in the repeated hepatic resection group than in the RF ablation group before propensity score matching, but the difference was not statistically significant. In addition, this tendency disappeared after propensity score matching, and the DFS rate became almost the same between two groups. This result is in line with that of a previous study (11) in which DFS for recurrent HCC after hepatic resection tended to be better in the repeated hepatic resection group than in the RF ablation group but without a statistically significant difference. Our finding can be explained by the relatively small tumor size in our study. In general, as the tumor size decreases, the rate of complete tumor ablation with RF ablation increases and the possibility of the presence of satellite nodules decreases (19). In the analysis of prognostic factors of DFS, treatment modality was not a significant factor. Instead, diabetes mellitus, ALT level, tumor number, and microvascular invasion were significant prognostic factors. Our finding might suggest that the status of background liver parenchyma or tumor biology is more important for tumor recurrence than treatment modality. Previous studies have indicated that positive Ki-67 staining of tumor cells was an independent predictor of local tumor progression (20,21). Similar to our findings, these results also suggested that tumor characteristics are important for HCC recurrence. In our study, the OS outcomes with repeated hepatic resection and RF 7

VASCULAR AND INTERVENTIONAL RADIOLOGY: Repeated Hepatic Resection vs Radiofrequency Ablation for Recurrent HCC

Table 3 Univariate and Multivariate Analyses of Prognostic Factors for Overall Survival Univariate Analysis Variable Repeated hepatic resection Age Male sex Diabetes mellitus Hypertension HBsAg positive Anti-HCV positive Liver cirrhosis Child-Pugh score   5 vs 6   5 vs 7 BCLC stage A ALT .40 IU/L Platelet count .15 3 104/mm3 AFP .200 ng/mL Recurrent tumor size .2 cm At least two recurrent tumors Histologic grade of initial tumor*   I vs II   I vs III and IV Microvessel invasion of initial  tumor Initial hepatic resection   One segment vs two segments   One segment vs at least three  segments

Multivariate Analysis

HR

95% CI

P Value

HR

95% CI

P Value

0.864 1.006 1.643 2.203 1.514 0.662 1.589 0.683

0.426, 1.754 0.982, 1.031 0.810, 3.334 1.295, 3.750 0.915, 2.506 0.370, 1.184 0.633, 3.989 0.405, 1.153

0.890 0.992 1.504 2.228 1.479 0.849 1.244 0.723

0.393, 2.015 0.962, 1.022 0.661, 3.424 1.115, 4.453 0.788, 2.775 0.386, 1.869 0.383, 4.042 0.398, 1.312

1.847 1.442 1.230 1.047 1.502 1.142 1.136 1.496

1.033, 3.301 0.505, 4.115 0.743, 2.038 0.626, 1.751 0.889, 2.538 0.516, 2.527 0.677, 1.908 0.759, 2.949

1.786 0.998 0.744 0.935 1.241 1.146 1.503 1.703

0.954, 3.344 0.281, 3.536 0.248, 2.233 0.511, 1.711 0.689, 2.236 0.431, 3.043 0.506, 4.464 0.634, 4.578

1.439 1.719 1.521

0.574, 3.608 0.516, 5.731 0.922, 2.511

.686 .631 .169 .004 .107 .164 .324 .154 .108 .039 .494 .420 .860 .013 .743 .629 .245 .662 .438 .378 .101

1.243 1.690 1.459

0.445, 3.470 0.386, 7.400 0.777, 2.741

.780 .581 .331 .023 .223 .685 .716 .286 .183 .070 .997 .598 .827 .472 .785 .463 .291 .776 .678 .486 .240

1.081 1.358

0.566, 2.063 0.759, 2.431

.558 .813 .303

1.055 1.273

0.492, 2.261 0.631, 2.570

.784 .891 .500

Note.—AFP = a-fetoprotein, anti-HCV = antibody to hepatitis C virus, BCLC = Barcelona Clinic Liver Cancer, HBsAg = hepatitis B surface antigen, HR = hazard ratio. * Edmondson-Steiner grade.

ablation for recurrent HCC after hepatic resection were not significantly different before and after matching. Two studies compared the OS between repeated hepatic resection and RF ablation for recurrent HCC after hepatic resection. Liang et al (12) reported that the 1-, 3-, and 5-year OS rates were 78.6%, 44.5%, and 27.6%, respectively, for repeated hepatic resection and 76.6%, 48.6%, and 39.9% for RF ablation. Chan et al (11) reported that the 1-, 3-, and 5-year OS rates were 89.7%, 56.5%, and 35.2%, respectively, for repeated hepatic resection and 83.7%, 43.1%, and 29.1% for RF ablation. The OS was not different between repeated hepatic resection and RF ablation, as was shown in our study. For treatment-naïve HCC, it is 8

generally accepted that OS outcomes after RF ablation are comparable to those of hepatic resection for HCCs of 2 cm or smaller (3,22,23), and several studies have reported nonsignificant differences in OS outcomes between hepatic resection and RF ablation for HCCs of 3 cm or smaller (24–26). As expected, the HCCs in our study were relatively small: 69.1% of HCCs (150 of 217) were smaller than 2 cm and 94.9% (206 of 217) were smaller than 3 cm. This can be explained by the fact that recurrent HCCs were detected earlier on imaging studies such as CT or MR images owing to scheduled follow-ups after hepatic resection. In addition to the high repeatability of RF ablation, the relatively small size of included tumors may result in the comparable OS

Lim et al

outcomes between repeated hepatic resection and RF ablation obtained in our study. There are expected differences to be considered in determining treatment options between initial tumors and recurrent tumors after hepatic resection. First, the more often hepatectomy is performed, the more technically difficult resection becomes because of intra-abdominal adhesions caused by previous hepatic resections as well as new growth of intrahepatic vascular structures after previous hepatic resection (7). In our study, severe adhesion was found in 11 of the 39 patients in the repeated hepatic resection group (28%), and liver laceration and diaphragmatic tear occurred during adhesiolysis. In terms of the type of repeated hepatic resection, open hepatic resection is favored over laparoscopic hepatic resection because of the risk of postoperative intra-abdominal adhesion occurring as a consequence of previous hepatic resection, although open hepatic resection is known to be associated with an increased overall complication rate relative to laparoscopic hepatic resection (27). In our study, unsurprisingly, only three of the 39 patients in the repeated hepatic resection group (7.7%) underwent laparoscopic repeated hepatic resection. RF ablation, conversely, has the advantage of easy repeatability. Second, limited hepatic function reserve remains in patients who have already undergone hepatic resection. Repeated hepatic resection is generally accepted as a safe treatment modality for recurrent HCC, with mortality rates ranging from 0% to 1.22% in recent studies (6–8). However, there is a potential risk of postoperative hepatic failure after repeated hepatic resection in patients with limited hepatic function reserve, as evidenced by the one patient who died of hepatic failure in the repeated hepatic resection group of our study. Therefore, treatment methods that can minimize further loss of nontumorous liver parenchyma should be considered. In general, RF ablation is superior to hepatic resection in preserving nontumorous liver parenchyma. Third, the size of the recurrent tumor is expected to be

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VASCULAR AND INTERVENTIONAL RADIOLOGY: Repeated Hepatic Resection vs Radiofrequency Ablation for Recurrent HCC

Lim et al

Figure 3

Figure 3:  Recurrences and management after repeated hepatic resection (rHR ) or RF ablation (RFA). ER = extrahepatic recurrence, IR = intrahepatic recurrence, RT = radiation therapy, TACE = transcatheter arterial chemoembolization.

smaller than that of the primary tumor because follow-up imaging studies are more thoroughly performed in patients with previous hepatic resection. It is well known that smaller tumor size is closely related to a higher rate of complete tumor ablation after RF ablation. If we consider these differences between initial HCCs and recurrent HCCs and the similar OS between repeated hepatic resection and RF ablation, the use of RF ablation to treat recurrent tumors after hepatic resection for HCC can be justified. However, not all recurrent tumors are good candidates for RF ablation because there may be challenging cases for performing RF ablation, such as tumors that are inconspicuous with guiding

imaging modalities or tumors that abut large vessels or critical organs. Therefore, it would be better to recognize repeated hepatic resection and RF ablation as complementary treatment modalities rather than totally competitive modalities. We believe that the complementary use of both modalities can overcome the limitations of each when used alone. Our study had several limitations. First, it was a single-center study. In general, the outcomes of both hepatic resection and RF ablation depend on the expertise and experience of the operators. In addition, more than 80% of the included patients were hepatitis B surface antigen carriers. Therefore, it may be difficult to generalize our results to those of

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other institutions where the main cause of HCC is not hepatitis B viral infection. Second, relatively few patients were included in the repeated hepatic resection group, although our study had the largest study population ever reported. Third, we failed to consider the effects of antiviral therapy and hepatitis B virus DNA level. These two parameters were quite variable from patient to patient during the follow-up periods. Therefore, it was difficult to categorize and adjust them between the two groups in this retrospective study. In conclusion, the long-term OS and DFS were not significantly different between repeated hepatic resection and RF ablation for patients with recurrent 9

VASCULAR AND INTERVENTIONAL RADIOLOGY: Repeated Hepatic Resection vs Radiofrequency Ablation for Recurrent HCC

HCC after hepatic resection. The use of RF ablation for the treatment of recurrent tumors after hepatic resection for HCC can be justified considering the relatively small size of recurrent tumors, limited hepatic function reserve, technical difficulty of repeated hepatic resection, and lower complication rate and higher repeatability of RF ablation. Disclosures of Conflicts of Interest: K.D.S. disclosed no relevant relationships. H.K.L. disclosed no relevant relationships. H.R. disclosed no relevant relationships. M.W.L. disclosed no relevant relationships. Y.S.K. disclosed no relevant relationships. W.J.L. disclosed no relevant relationships. Y.H.P. disclosed no relevant relationships. G.Y.G. disclosed no relevant relationships. J.M.K. disclosed no relevant relationships. C.H.D.K. disclosed no relevant relationships. J.W.J. disclosed no relevant relationships.

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