LIVER TRANSPLANTATION 21:961–968, 2015

ORIGINAL ARTICLE

Surgical Results for Recurrent Hepatocellular Carcinoma After Curative Hepatectomy: Repeat Hepatectomy Versus Salvage Living Donor Liver Transplantation Yo-Ichi Yamashita, Yoshihiro Yoshida, Takeshi Kurihara, Shinji Itoh, Norifumi Harimoto, Toru Ikegami, Tomoharu Yoshizumi, Hideaki Uchiyama, Ken Shirabe, and Yoshihiko Maehara Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

The aims of this study were to evaluate the efficacy of repeat hepatectomy (Hx) and salvage living donor liver transplantation (LDLT) for recurrent hepatocellular carcinoma (HCC). A retrospective cohort study was performed to analyze the surgical results of repeat Hx and salvage LDLT for patients with recurrent HCC within the Milan criteria from 1989 to 2012. A total of 159 patients were divided into 2 groups: a repeat Hx group (n 5 146) and a salvage LDLT group (n 5 13). Operative results and patient prognoses were compared between the 2 groups. The operative invasiveness, including the operation time (229.1 6 97.7 versus 862.9 6 194.4 minutes; P < 0.0001) and blood loss (596.3 6 764.9 versus 24,690 6 59,014.4 g; P < 0.0001), were significantly higher in the salvage LDLT group. The early surgical results, such as morbidity (31% versus 62%; P 5 0.0111) and the duration of hospital stay (20 6 22 versus 35 6 21 days; P 5 0.0180), were significantly worse in the salvage LDLT group. There was no significant difference in the overall survival (OS) rate, but the disease-free survival rate of the salvage LDLT group was significantly better (P 5 0.0002). The OS rate of patients with grade B liver damage in the repeat Hx group was significantly worse (P < 0.0001), and the 5-year OS rate was quite low, that is, 20% (liver damage A, 77% for the repeat Hx group and 75% for the salvage LDLT group). The prognosis of patients with grade B liver damage after repeat Hx for recurrent HCC is poor, and salvage LDLT would be a potent option for such patients. Liver Transpl C 2015 AASLD. 21:961-968, 2015. V Received February 2, 2015; accepted March 3, 2015. Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide.1 This disease burden is expected to increase in the future in conjunction with the high prevalence of hepatitis B virus (HBV) in Asia and sub-Saharan Africa and with the rising incidence of hepatitis C virus infections, alcoholic liver disease, and steatohepatitis in devel-

oped countries.2 The mainstay of curative treatment for HCC is hepatectomy (Hx). With advances in surgical techniques and perioperative care,3,4 the results of Hx for HCC have greatly improved. Nonetheless, longterm survival after Hx remains unsatisfactory because of the high incidence of intrahepatic recurrence (up to 68%-98% of patients).5 Thus, effective therapeutic

Abbreviations: AFP, alpha-fetoprotein; BMI, body mass index; CT, computed tomography; DCP, des-gamma-carboxyprothrombin; DFS, disease-free survival; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCVAb, hepatitis C virus antibody; HR, hazard ratio; Hx, hepatectomy; ICGR15, indocyanine green retention rate at 15 minutes; im, pathological intrahepatic metastasis; KU, Kyushu University; lc, histological cirrhosis; LD, liver damage; LDLT, living donor liver transplantation; LDT, liver-directed therapy; LPD, lipiodolization; LT, liver transplantation; OS, overall survival; RFA, radiofrequency ablation; SD, standard deviation; TACE, transarterial chemoembolization; vp, pathological portal venous infiltration. Potential conflict of interest: Nothing to report. This study was partly funded by a Grant-in-Aid (no. 25462093) from the Ministry of Education, Science, and Culture of Japan. Address reprint requests to Yo-Ichi Yamashita, M.D., Ph.D., Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan. Telephone: 81-92-642-5469; FAX: 81-92-642-5482; E-mail: [email protected] DOI 10.1002/lt.24111 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases

C 2015 American Association for the Study of Liver Diseases. V

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strategies for intrahepatic recurrence are critical to prolong survival after Hx for HCC. In the past 2 decades, repeat Hx has been reported to be safe and to prolong survival after intrahepatic recurrence.5-12 Our department has aggressively adopted repeat Hx as the main curative option for treating recurrent HCC and has reported good surgical results with repeat Hx for recurrent HCC.13 Recently, salvage liver transplantation (LT) was proposed as a curative option for the intrahepatic recurrence of HCC, but it is still not widely used because of the insufficient number of cadaveric donors and the limited availability of appropriate living donors.14-16 Salvage LT may offer a good strategy for relieving patients with a good prognosis after HCC recurrence, but concerns remain over the potential for increased difficulty with LT after prior Hx to negate the benefit of salvage LT.5 A treatment strategy for patients with recurrent HCC within the Milan criteria17 should be established; however, there have been few reports comparing the results of different treatments for recurrent HCC, such as repeat Hx and salvage LT.18,19 In order to clarify the efficacy of salvage living donor liver transplantation (LDLT) for patients with recurrent HCC, we performed a retrospective review of patients undergoing repeat Hx or salvage LDLT for recurrent HCC within the Milan criteria at our institution.

PATIENTS AND METHODS A total of 1354 Hx procedures for HCC were performed at the Department of Surgery and Sciences of Kyushu University Hospital between January 1989 and March 2012. Repeat Hx was performed in 146 patients with recurrent HCC within the Milan criteria. All 146 patients had disease-free survival (DFS) of more than 1 year after the initial Hx for primary HCC. For patients with end-stage liver cirrhosis who had no modality except LDLT available to cure HCC, 13 LDLTs for recurrent HCC after curative Hx against primary HCC (salvage LDLT) were performed. Although all patients with repeat Hx met the Milan criteria in this series, there were no restrictions on the tumor size or number of nodules in candidates for salvage LDLT for recurrent HCC within the Kyushu University (KU) criteria20,21; therefore, 5 patients (38.5%) did not meet the Milan criteria. Since our proposal of the KU criteria,21 we have not performed salvage LDLT for patients with recurrent HCC who have both a tumor size >5 cm and a des-gammacarboxyprothrombin (DCP) level > 300 mAU/mL. All our patients with repeat Hx also satisfied the KU criteria. The medical records of patients in this series were followed until March 2014, and the median follow-up periods were 72 months for the repeat Hx group and 63 months for the salvage LDLT group.

Surgical Techniques and Follow-up Methods The details of our surgical techniques and patient selection criteria for repeat Hx have been reported

LIVER TRANSPLANTATION, July 2015

previously and are almost identical to those of the initial Hx for primary HCC.13,22 Our transplantation procedures for both the donors and the recipients have been described previously.21,23,24 Donors were selected from candidates who hoped to be living donors. Donors were required to be within the third degree of consanguinity with recipients or spouses and to be between 20 and 65 years of age. Our criteria for choosing a graft type for recipients have been reported previously.25 In this series, 8 left lobe plus caudate grafts, 4 right lobe grafts, and 1 posterior segment graft were transplanted. Immunosuppression consisted of the combination of tacrolimus (Prograf; Astellas Pharma, Inc., Tokyo, Japan) or cyclosporine (Neoral; Novartis Pharma K.K., Tokyo, Japan) with a steroid and/or mycophenolate mofetil (MMF; Chugai Pharmaceutical Co., Ltd., Tokyo, Japan).25,26 We mainly examined 5 surgical outcomes between the 2 groups: postoperative mortality, morbidity, duration of the hospital stay, overall survival (OS), and DFS. Any death that occurred in the hospital after Hx was recorded as mortality. Complications were evaluated with Clavien’s classification,27 and those with a score of grade II or more were defined as positive. After discharge, all patients were examined for HCC recurrence by ultrasonography and tumor markers such as alpha-fetoprotein (AFP) and DCP every month and by dynamic computed tomography (CT) every 3 or 4 months.4 No patients received adjuvant chemotherapy or adjuvant lipiodolization (LPD) in our series. We treated recurrent HCC by repeat Hx,13 ablation therapy,28 and LPD29 according to the previously described strategy.7

Statistical Analysis Continuous variables were expressed as means and standard deviations (SDs) and were compared with the Student t test. Categorical variables were compared with either the chi-square test or Fisher’s exact test as appropriate. The OS and DFS curves were generated with the Kaplan-Meier method and were compared with the log-rank test. All analyses were performed with JMP Pro 9.0.2 (SAS Institute, Inc., Cary, NC). P values < 0.05 were considered to indicate statistical significance.

RESULTS Comparison of the Patient Background Characteristics The results of the comparison of patient background characteristics between the 2 groups are summarized in Table 1. There were significant differences in the age of patients between the groups (repeat Hx, 68.2 6 9.6 years; salvage LDLT, 56.2 6 5.6 years; P < 0.0001). The mean body mass indices (BMIs) of both groups were less than 25 kg/m2 (repeat Hx, 22.9 6 3.1 kg/m2; salvage LDLT, 24.5 6 3.1 kg/m2;

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TABLE 1. Comparisons of Patient Background Characteristics Variables Age, mean 6 SD, years Male/female BMI, kg/m2 Diabetes mellitus, n (%) Esophageal varices, n (%) HBsAg(1), n (%) HCVAb(1), n (%) Platelet count, mean 6 SD, 3104/mL Total bilirubin, mean 6 SD, mg/dL Albumin, mean 6 SD, g/dL ALT, mean 6 SD, IU/L PT, mean 6 SD, % Child A, n (%) Liver damage A, n (%)

Repeat Hx (n 5 146)

Salvage LDLT (n 5 13)

P Value

68.2 6 9.6 99/47 22.9 6 3.1 36 (25) 35 (24) 27 (18) 100 (68) 12.6 6 4.7 0.7 6 0.3 4.0 6 0.4 37.0 6 27.7 90.1 6 13.7 140 (96) 118 (81)

56.2 6 5.6 10/3 24.5 6 3.1 2 (15) 12 (92) 4 (31) 9 (69) 8.2 6 3.7 2.4 6 0.1 2.9 6 0.6 49.1 6 26.2 58.8 6 14.9 1 (8) 1 (8)