Living Donor Liver Transplantation Versus Deceased Donor Liver Transplantation for Hepatocellular Carcinoma: Comparable Survival and Recurrence

LIVER TRANSPLANTATION 18:315-322, 2012 ORIGINAL ARTICLE Living Donor Liver Transplantation Versus Deceased Donor Liver Transplantation for Hepatocellular Carcinoma: Comparable Survival and Recurrence Lakhbir Sandhu, Charbel Sandroussi, Markus Guba, Markus Selzner, Anand Ghanekar, Mark S. Cattral, Ian D. McGilvray, Gary Levy, Paul D. Greig, Eberhard L. Renner, and David R. Grant Multi-Organ Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada Several studies have reported higher rates of recurrent hepatocellular carcinoma (HCC) after living donor liver transplantation (LDLT) versus deceased donor liver transplantation (DDLT). It is unclear whether this difference is due to a specific biological effect unique to the LDLT procedure or to other factors such as patient selection. We compared the overall survival (OS) rates and the rates of HCC recurrence after LDLT and DDLT at our center. Between January 1996 and September 2009, 345 patients with HCC were identified: 287 (83%) had DDLT and 58 (17%) had LDLT. The OS rates were calculated with the Kaplan-Meier method, whereas competing risks methods were used to determine the HCC recurrence rates. The LDLT and DDLT groups were similar with respect to most clinical parameters, but they had different median waiting times (3.1 versus 5.3 months, P ¼ 0.003) and median follow-up times (30 versus 38.1 months, P ¼ 0.02). The type of transplant did not affect any of the measured cancer outcomes. The OS rates at 1, 3, and 5 years were equivalent: 91.3%, 75.2%, and 75.2%, respectively, for the LDLT group and 90.5%, 79.7%, and 74.6%, respectively, for DDLT (P ¼ 0.62). The 1-, 3-, and 5-year HCC recurrence rates were also similar: 8.8%, 10.7%, and 15.4%, respectively, for the LDLT group and 7.5%, 14.8%, and 17.0%, respectively, for the DDLT group (P ¼ 0.54). A regression analysis identified microvascular invasion (but not the graft type) as a predictor of HCC recurrence. In conclusion, in well-matched cohorts of LDLT and DDLT recipients, LDLT and DDLT provide similarly low recurrence rates and high survival rates for the treatment of HCC. Liver Transpl 18:315-322, 2012. VC 2012 AASLD. Received November 18, 2010; accepted November 7, 2011. Hepatocellular carcinoma (HCC) ranks third among the leading causes of cancer death. It is the fifth most prevalent cancer worldwide. 1 Most cases of HCC (80%-90%) arise against a background of cirrhosis. 2 Liver transplantation (LT) offers the best chance of curing HCC that is confined to the liver because it provides a complete oncological resection, removes the fertile field for further cancer development, and corrects the underlying liver dysfunction. 3,4 In most jurisdictions, however, the demand for deceased donors exceeds the supply of deceased donor organs. 5 In these regions, living donor liver transplantation Additional Supporting Information may be found in the online version of this article. Abbreviations: AFP, alpha-fetoprotein; CNI, calcineurin inhibitor; d, standardized difference; DDLT, deceased donor liver transplantation; DFS, disease-free survival; HCC, hepatocellular carcinoma; HR, hazard ratio; LDLT, living donor liver transplantation; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; OS, overall survival; PEI, percutaneous ethanol injection; RFA, radiofrequency ablation; TACE, transarterial chemoembolization. This study was partially funded by a post-m.d. fellowship award (20019) from the Canadian Cancer Society (to Lakhbir Sandhu). Address reprint requests to David R. Grant, M.D., Multi-Organ Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, 585 University Avenue, NCSB 11C-1248, Toronto, Ontario, Canada M5G 2N2. Telephone: 416-340-5230; FAX: 416-340-5242. E-mail: david.grant@uhn.on.ca DOI 10.1002/lt.22477 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 VC 2012 American Association for the Study of Liver Diseases.

316 SANDHU ET AL. LIVER TRANSPLANTATION, March 2012 (LDLT) for HCC offers several advantages: shorter wait times, the possibility of optimizing the pretransplant treatment of the tumor, and a consistently highquality graft. Some centers remain reluctant to offer LDLT for HCC because of early reports of higher rates of cancer recurrence and inferior patient survival after LDLT versus deceased donor liver transplantation (DDLT). 6-9 Many have speculated that the higher rates of recurrence found after LDLT might be due to the following factors: (1) the growth factors that mediate the regeneration of the hemiliver after LDLT may potentiate HCC recurrence, 10 (2) an aggressive or rapidly progressive HCC biology may not be recognized during the decreased waiting time for transplantation, 11 and (3) the technical challenges of performing a complete, inferior vena cava sparing hepatectomy for LDLT may lead to a suboptimal oncological resection. 12 However, there is another possibility: the high rates of HCC recurrence after LDLT are due to the preferential use of LDLT for patients with aggressively growing or advanced tumors or other factors. The present study was, therefore, undertaken so that we could compare the outcomes of LDLT and DDLT for HCC at our center. Our relatively high clinical volume of LT procedures for HCC and an allocation system that allowed us to offer both forms of LT to patients within or beyond the Milan criteria distinguish this report from previous studies. PATIENTS AND METHODS All patients with preoperatively diagnosed HCC (n ¼ 345) between January 1996 and September 2009 were identified from a prospectively maintained clinical database (Organ Transplant Tracking Record, HKS Medical Information Systems, Omaha, NE). The data were supplemented by reviews of the patient charts. Information about patient demographics, tumor characteristics, preoperative and postoperative courses, tumor recurrence, and deaths were collected in a standardized manner. Institutional review board approval (08.1013-AE) was obtained. The diagnosis of HCC was made according to the practice guidelines of the American Association for the Study of Liver Diseases. 13 All patients with suspected HCC were reviewed at a multidisciplinary tumor board. Although radiofrequency ablation (RFA) was employed in patients with single lesions that were <2 cm, more extensive disease resulted in resection if the liver reserve was adequate. Patients who were not candidates for resection were considered for LT. Patients with HCC were listed according to the following criteria: HCC was confined to the liver (with no restrictions on the tumor size or number), there were no constitutional symptoms, there was no radiological evidence of vascular invasion, and there was biopsy confirmation that the dominant lesion was not poorly differentiated if the staging was beyond the Milan criteria; (the Toronto criteria 14 ). LDLT was offered to all patients for whom cancer clearance could be obtained despite the vena cava being left in situ. Patients with tumors abutting the inferior vena cava, hepatic veins, or porta hepatis were offered only DDLT to prevent the compromising of oncological margins during the course of LDLT. Living donor candidates were evaluated according to previously published protocols. 15 While patients with HCC were on the waiting list, they underwent triphasic computed tomography or magnetic resonance imaging as well as routine blood work every 3 months. Recommendations for bridging therapy were made by a multidisciplinary tumor board. Those with fewer than 3 tumors and with no tumor nodule measuring more than 3 cm were candidates for RFA and/or percutaneous ethanol injection (PEI). Patients with a Child-Pugh score of A and nonablatable tumors were treated with transarterial chemoembolization (TACE). A small proportion of the patients received conformal external beam radiotherapy. 16 Patients with interval disease progression remained candidates for LT if they continued to meet the Toronto criteria. Intraoperative details for living donor hepatectomy and recipient implantation have been previously described. 17 The tumor stage was determined during the explant pathology examination. The total tumor diameter (including areas of necrosis) was used for calculating the explant tumor size. Macrovascular invasion was defined as gross invasion of the lobar or segmental branches of the portal or hepatic veins. Microscopic invasion was defined as the presence of tumor emboli within the portal vein, central hepatic vein, or capsular vessels. The degree of differentiation was based on the modified Edmondson and Steiner criteria. 18 The posttransplant immunosuppression was calcineurin inhibitor (CNI) based in all patients. Patients undergoing LDLT received induction therapy with anti-thymocyte globulin or basiliximab. Induction therapy was used only in DDLT recipients with renal insufficiency or when CNI neurotoxicity was identified during the early postoperative period. Steroids were tapered over the first 3 months after transplantation. For patients with renal insufficiency, low-dose CNI regimens were supplemented with antimetabolites. Mammalian target of rapamycin inhibitors (mtor) were not used in the early posttransplant period unless there was CNI neurotoxicity. They were also rarely used in the late postoperative period; at 1, 3, and 5 years, less than 10% of the patients in the LDLT group or the DDLT group were receiving a mtor. Posttransplant surveillance consisted of imaging studies and measurements of alpha-fetoprotein (AFP) levels every 3 to 6 months. The time to HCC recurrence was defined as the time between the date of transplantation and the date of the first imaging study identifying recurrent disease. All analyses were censored as of March 31, 2010, so the minimum follow-up was at least 6 months. No patients were lost to follow-up.

LIVER TRANSPLANTATION, Vol. 18, No. 3, 2012 SANDHU ET AL. 317 Statistical Analysis All analyses were conducted with SAS 9.2 (SAS, Cary, NC) and R 2.5 for competing risks analyses. The survival analysis was based on clinical staging derived from the tumor characteristics at the time of the last axial imaging before LT. Continuous variables were compared with the parametric Student s t test or the nonparametric Mann-Whitney U test (whichever was appropriate). Categorical variables were analyzed with the chi-square test or Fisher s exact test. The Kaplan- Meier method was used to determine overall survival (OS) and disease-free survival (DFS) from the time of transplantation. 19 Recurrence rates were calculated with competing risks methods and represent the cumulative probabilities of recurrence. The delta method was employed to estimate the confidence intervals for recurrence. Unadjusted survival or recurrence rates across different groups were compared with the log-rank test. To identify predictors of survival, we undertook univariable and multivariable Cox proportional hazards regressions. 20 For the identification of predictors of recurrence, a Fine and Gray competing risks model, which considers death to be a competing risk to recurrence, was employed to estimate subdistribution hazard ratios (HRs). 21 AFP levels were categorized to be either 400 IU/mL or <400 IU/mL at the time of transplantation in agreement with previous literature. 22,23 Predictors with an associated P value of 0.15 or less in the univariable analysis were included in the multivariable model. Covariates are reported as HRs with 95% confidence intervals. A P value < 0.05 was considered statistically significant. Cohort effects could not be analyzed because of the low number of LDLT procedures at the beginning of our accrual period. A sensitivity analysis was undertaken to compare OS and disease recurrence rates in a matched subgroup of patients. LDLT patients were directly and exactly matched to DDLT patients according to 6 characteristics: the underlying etiology of cirrhosis; the AFP level at the time of HCC diagnosis (<400 IU/mL or 400 IU/mL); meeting the Milan criteria; and the presence of microvascular invasion, macrovascular invasion, and poorly differentiated tumors. The comparability of the matched LDLT and DDLT subgroups was evaluated through the calculation of the standardized difference (d) of baseline characteristics. For the calculation of the OS, DFS, and HCC recurrence rates, the matched nature of the subgroups was taken into account. Unadjusted survival or recurrence rates across different groups were compared with the chisquare test. The sensitivity analysis was undertaken to identify potential differences that were not detected in the initial analysis because of potential confounding by the indication. RESULTS Patient and Tumor Characteristics During the 14-year study period, 345 patients with a preoperative diagnosis of HCC underwent LT: 287 (83%) underwent DDLT, and 58 (17%) underwent LDLT (Table 1). There were no significant differences between the 2 groups with respect to age, sex, AFP level at HCC diagnosis, or medical Model for End- Stage Liver Disease (MELD) score. More LDLT patients had cirrhosis due to hepatitis C (65.5% versus 47.7%), whereas cirrhosis secondary to hepatitis B (28.2% versus 13.8%) or alcohol (13.9% versus 8.6%) was more common among DDLT recipients versus LDLT recipients (P ¼ 0.04). The median waiting time from listing to transplantation was shorter for LDLT recipients (median ¼ 3.1 months, range ¼ 0.2-25.1 months) versus patients receiving cadaveric donor grafts (median ¼ 5.3 months, range ¼ 0-35.7 months, P ¼ 0.003). The tumor characteristics, which were determined by pretransplant imaging and explant pathology examinations, were similar between the 2 groups; the patients did not differ in terms of the tumor number, the size of the largest tumor nodule, or the total tumor diameter (Table 1). Overall, 50% of the LDLT recipients underwent bridging therapy while awaiting transplantation compared with 55.4% of the patients in the DDLT group (P ¼ 0.45); the proportions of patients treated with RFA, TACE, PEI, or other modalities as bridging therapy were not significantly different between the LDLT group and the DDLT group. Pathology specimens demonstrated that the proportions of patients meeting the Milan criteria were similar in the 2 groups (57.9% in the LDLT group and 50.9% in the DDLT group, P ¼ 0.33). The follow-up in the LDLT group was slightly shorter (median ¼ 30 months, range ¼ 2.5-87.1 months) than the follow-up in the DDLT group (median ¼ 38.1 months, range ¼ 0-160.3 months, P ¼ 0.02). OS The overall median survival time of the cohort was 9.7 years (or 116 months). The overall 1-, 3-, and 5-year survival probabilities were 91.3%, 75.2%, and 75.2%, respectively, for the LDLT group and 90.5%, 79.7%, and 74.6%, respectively, for the DDLT recipients (P ¼ 0.62; Table 2 and Fig. 1). The survival rates were also similar when the LDLT and DDLT cases were compared stage for stage: the OS rates was comparable for those patients meeting the Milan criteria and those patients exceeding the Milan criteria for each graft type (Fig. 2). Notably, the type of donor graft (living versus cadaveric) was not predictive of OS. In a univariable analysis, a number of variables had an associated P value 0.15, and they were included in a multivariable model (Supporting Table 1). In a multivariable analysis, the graft type was not predictive of worse survival after LT for HCC. HCC Recurrence and DFS For patients who experienced recurrence, the median time to recurrence was 12 months (or 1.0 year). The HCC recurrence rates at 1, 3, and 5 years for the

318 SANDHU ET AL. LIVER TRANSPLANTATION, March 2012 TABLE 1. Patient and Tumor Characteristics LDLT (n ¼ 58) DDLT (n ¼ 287) P Value Patient characteristics Age (years)* 54.5 6 8.8 55.8 6 7.1 0.30 Male [n (%)] 46 (79.3) 246 (85.7) 0.23 Underlying diagnosis [n (%)] 0.04 Hepatitis C virus 38 (65.5) 137 (47.7) Hepatitis B virus 8 (13.8) 81 (28.2) Alcohol 5 (8.6) 40 (13.9) Other 7 (12.1) 29 (10.1) MELD score 12.5 (6-32) 11.0 (6-47) 0.23 AFP (IU/mL) 11.5 (5-900) 11.0 (5-59,870) 0.81 Wait-list time (months) 3.1 (0.2-25.1) 5.3 (0.0-35.7) 0.003 Status at transplant (based on pretransplant imaging) Number of tumor nodules 1 (0-11) 1 (0-12) 0.58 Diameter of largest nodule (cm) 2.7 (0.5-17) 2.7 (0.5-10.4) 0.74 Total tumor diameter (cm) 3.9 (0.5-22) 3.8 (0.5-15.4) 0.91 Bridging therapy [n/n (%)] 29/58 (50.0) 159/287 (55.4) 0.45 RFA 19/29 (65.5) 105/159 (66.0) TACE 4/29 (13.8) 31/159 (19.5) PEI 6/29 (20.7) 17/159 (10.7) Other 0/29 (0.0) 6/159 (3.8) Beyond the Milan criteria [n/n (%)] 16/58 (27.6) 91/280 (32.5) 0.46 Tumor morphology according to explant pathology Number of tumor nodules 2.0 (1.0-11.0) 2.0 (1.0-12.0) 0.33 Diameter of largest nodule (cm), 3.3 (0.6-23.0) 3.0 (0.4-11.0) 0.21 Total tumor diameter (cm), 5.4 (0.6-40.0) 4.5 (0.4-35.0) 0.23 Vascular invasion Microvascular invasion 15/53 (28.3) 70/244 (28.7) 0.96 Macrovascular invasion 9/53 (17.0) 41/246 (16.7) 0.96 Poor differentiation 3/52 (5.8) 33/232 (14.2) 0.10 Beyond the Milan criteria 33/57 (57.9) 145/285 (50.9) 0.33 *The data are presented as means and standard deviations. The data are presented as medians and ranges. Calculated when tumors were present. TABLE 2. Primary Outcomes LDLT DDLT OS Recurrence Rate DFS OS Recurrence Rate DFS 1 year 91.3 (80.3-96.3) 8.8 (1.4-16.2) 87.7 (76.0-94.0) 90.5 (86.4-93.4) 7.5 (4.4-10.5) 85.5 (80.8-89.1) 3 years 75.2 (58.4-85.9) 10.7 (2.6-18.9) 75.1 (59.3-85.5) 79.7 (74.2-84.2) 14.8 (10.4-19.3) 75.2 (69.4-80.0) 5 years 75.2 (58.4-85.9) 15.4 (3.6-27.2) 70.4 (52.5-82.7) 74.6 (68.3-79.9) 17.0 (12.1-22.0) 69.8 (63.2-75.5) NOTE: The data are presented as percentages and 95% confidence intervals. LDLT group were 8.8%, 10.7%, and 15.4%, respectively (Table 2); they were 7.5%, 14.8%, and 17.0%, respectively, for the DDLT recipients (P ¼ 0.54). The DFS probability at 1, 3, and 5 years were 87.7%, 75.1%, and 70.4%, respectively, for the LDLT recipients and 85.5%, 75.2%, and 69.8%, respectively, for the DDLT patients (P ¼ 0.82; Table 2). Although multiple predictors of DFS were identified in the univariable analysis, only microvascular invasion remained significant after a multivariable analysis (HR ¼ 3.26, 95% confidence interval ¼ 1.16-9.19; Supporting Table 2). Microvascular invasion (but not the graft type) was also the lone predictor of recurrence in the multivariable model (Table 3). Further analysis via the stratification of the LDLT and DDLT groups by the Milan criteria revealed no significant differences in the recurrence rates or DFS (Supporting Table 3). Sensitivity Analysis Thirty-nine LDLT recipients were matched to 39 DDLT patients. The patients were comparable (d < 0.10) with

LIVER TRANSPLANTATION, Vol. 18, No. 3, 2012 SANDHU ET AL. 319 respect to age, MELD score, mean number of tumor nodules, and mean diameter of the largest nodule. There were notable differences in the time on the waiting list (d ¼ 0.75), the percentage of male patients (d ¼ 0.33), the proportion of patients with bridging therapy (d ¼ 0.21), and the total tumor diameter (d ¼ 0.22; Table 4). However, the patients were matched for those characteristics most likely to affect HCC recurrence [the underlying etiology of cirrhosis, the AFP level at the time of transplantation (400 IU/mL or <400 IU/ ml); exceeding the Milan criteria; and the presence or absence of microvascular invasion, macrovascular invasion, and poorly differentiated tumors]. There were no significant differences between the LDLT and DDLT recipients in terms of HCC recurrence (P ¼ 0.55), DFS (P ¼ 1.00), or OS (P ¼ 0.64; Table 5). Figure 1. OS of patients after LDLT versus DDLT (P ¼ 0.62). DISCUSSION This is the largest single-institution study to date comparing the results of LDLT and DDLT for patients with HCC. In contrast to some previous reports, 6-9 we found no evidence of a higher rate of cancer recurrence after LDLT versus DDLT in either our primary analysis or our sensitivity analysis. Similarly to previously published reports, 8,9,12,24-27 using both a conventional analysis and a matched-cohort sensitivity analysis, we found similar OS rates with the 2 Figure 2. (A) OS of patients meeting the Milan criteria: LDLT versus DDLT (P ¼ 0.68). (B) OS of patients exceeding the Milan criteria: LDLT versus DDLT (P ¼ 0.42).

320 SANDHU ET AL. LIVER TRANSPLANTATION, March 2012 TABLE 3. Predictors of Recurrence Univariable Analysis Multivariable Analysis Variable Subdistribution HR P Value Subdistribution HR P Value Age (years) 0.98 (0.95-1.02) 0.32 Sex 0.88 (0.43-1.81) 0.63 LDLT versus DDLT* 0.90 (0.41-2.02) 0.81 0.66 (0.24-1.84) 0.43 MELD score 0.98 (0.93-1.03) 0.39 Underlying diagnosis 1.00 Hepatitis B virus 1.00 Hepatitis C virus 0.64 (0.33-1.23) 0.18 Alcohol 0.95 (0.41-2.22) 0.91 Other 1.06 (0.45-2.48) 0.90 Wait-list time (months) 0.98 (0.94-1.03) 0.44 AFP 400 IU/mL 2.60 (1.20-5.64) 0.02 2.39 (0.95-5.99) 0.06 Number of tumor nodules 1.15 (1.05-1.25) 0.003 1.12 (0.68-1.84) 0.65 Diameter of largest nodule (cm) 1.17 (1.07-1.27) 0.001 1.15 (0.80-1.66) 0.45 Total tumor diameter (cm) 1.11 (1.04-1.18) 0.001 0.93 (0.66-1.31) 0.68 Beyond the Milan criteria 2.86 (1.64-5.00) <0.001 0.82 (0.30-2.27) 0.70 Microvascular invasion 3.47 (1.92-6.25) <0.001 3.06 (1.09-8.54) 0.03 Macrovascular invasion 3.17 (1.75-5.72) <0.001 1.43 (0.50-4.10) 0.51 Poor differentiation 1.24 (0.55-2.80) 0.61 NOTE: Ninety-five percent confidence intervals are presented in parentheses. *The donor status was kept in the multivariable model because it was the variable of primary interest. TABLE 4. Comparison of Baseline Factors in Matched Patients (Sensitivity Analysis) LDLT (n ¼ 39) DDLT (n ¼ 39) d* Patient characteristics Age (years) 55.7 6 7.6 55.3 6 6.9 0.06 Male [n (%)] 29 (74.4) 34 (87.2) 0.33 Underlying diagnosis [n (%)] 0 Hepatitis C virus 29 (74.4) 29 (74.4) Hepatitis B virus 6 (15.4) 6 (15.4) Alcohol 2 (5.1) 2 (5.1) Other 2 (5.1) 2 (5.1) MELD score 14.8 6 5.6 15.0 6 8.7 0.03 AFP 400 IU/mL [n (%)] 2 (5.1) 2 (5.1) 0 Wait-list time (months) 4.0 6 4.6 8.8 6 7.8 0.75 Status at transplant (based on pretransplant imaging) Number of tumor nodules 1.3 6 1.1 1.3 6 1.1 0 Diameter of largest nodule (cm) 2.8 6 2.0 2.7 6 1.4 0.06 Total tumor diameter (cm) 3.9 6 2.4 3.4 6 2.2 0.22 Bridging therapy [n (%)] 17 (43.6) 21 (53.8) 0.21 Tumor morphology according to explant pathology Vascular invasion Microvascular invasion [n (%)] 10 (25.6) 10 (25.6) 0 Macrovascular invasion [n (%)] 7 (17.9) 7 (17.9) 0 Poor differentiation [n (%)] 2 (5.1) 2 (5.1) 0 Beyond the Milan criteria [n (%)] 29 (74.4) 29 (74.4) 0 *d values less than 0.1 indicate very small differences, d values between 0.1 and 0.3 indicate small differences, d values between 0.3 and 0.5 indicate moderate differences, and d values greater than 0.5 indicate large differences. The data are presented as means and standard deviations. d is 0 because the groups are matched for this factor. procedures. Finally, the type of graft was not predictive of OS or DFS in a Cox regression analysis. In the present study, the HCC recurrence rates at 1, 3, and 5 years were 8.8%, 10.7%, and 15.4%, respectively, for the LDLT group and 7.5%, 14.8%, and 17.0% for the DDLT recipients (P ¼ 0.54; Table 2). However, because of the small number of LDLT recipients, our results are also consistent with recurrence

LIVER TRANSPLANTATION, Vol. 18, No. 3, 2012 SANDHU ET AL. 321 TABLE 5. Primary Outcomes of Matched Patients (Sensitivity Analysis) LDLT DDLT OS DFS Recurrence Rate OS DFS Recurrence Rate 1 year 92.2 (77.8-97.4) 89.6 (74.6-96.0) 5.3 (0.0-12.4) 89.7 (74.9-96.0) 87.2 (71.9-94.4) 7.7 (0.0-16.1) 3 years 79.3 (60.7-89.8) 79.6 (61.1-89.9) 5.3 (0.0-12.4) 86.5 (70.5-94.2) 82.1 (62.8-91.9) 12.8 (0.3-25.4) 5 years 79.3 (60.7-89.8) 72.3 (48.9-86.4) 12.5 (0.0-27.6) 86.5 (70.5-94.2) 74.6 (50.0-88.3) 20.3 (2.2-38.3) NOTE: The data are presented as percentages and 95% confidence intervals. rates as high as 16.2%, 18.9%, and 27.2% at 1, 3, and 5 years, respectively, because these numbers represent the upper limits of the 95% confidence intervals of our recurrence estimates. In contrast to our findings, reports from other centers have suggested that the rate of HCC recurrence is higher after LDLT versus DDLT. 6-9 For example, Fisher et al., 8 reporting on behalf of the Adult-to-Adult Living Donor Liver Transplantation Cohort Study in the United States, found that the 3-year HCC recurrence rate was 29% for LDLT and 0% for DDLT (P ¼ 0.002). Similarly, Lo et al. 7 reported a higher rate of recurrence at 5 years in an LDLT group (29%) versus a DDLT group (0%, P ¼ 0.03). In a more recent study, Vakili et al. 9 likewise found that LDLT recipients experienced HCC recurrence more often than DDLT recipients (29% versus 12%, P < 0.05). The inferior outcomes with LDLT versus DDLT for HCC that were identified in the latter comparative cohort studies and in other case series 28 may be attributable to differences in the population case mixes. For instance, in the Fisher et al. study, 15% of the patients in the LDLT group had poorly differentiated tumors, 8 compared with 5.8% of the LDLT recipients in our center s experience. The study by Lo et al. 7 likewise had a higher proportion of LDLT patients with poorly differentiated tumors (19%). Another poor prognostic indicator was prevalent in the study by Vakili et al. 9 :46%of the tumors in the LDLT group had microvascular invasion, whereas only 28.3% of the tumors in our LDLT group. Some of the observed differences in the case mixes may also be explained in part by regional variations in deceased donor organ availability and the subsequent use of living donors for patients with more advanced tumors. Invariably, these patients will experience higher rates of HCC recurrence. Notably, our patients had equal access to DDLT and LDLT even when their tumors exceeded the Milan criteria. Studies with patient case mixes comparable to the case mix in this study have equally found lower and more acceptable rates of HCC recurrence among LDLT recipients. 12,24-27,29-31 Furthermore, patients at our center with tumors beyond the Milan criteria might also have had more favorable tumor biology than patients beyond the Milan criteria at other centers because of our practice of biopsying and excluding patients with poorly differentiated lesions. In this analysis, an AFP level 400 IU/mL at the time of transplantation was predictive of worse OS, as reported by many others. 22,23 Thus, the present data are consistent with the view that the cancer biology (not the graft type) is the most important determinant of recurrence and survival after LT. This study has several strengths, including a relatively large sample size with a moderately large proportion of tumors beyond the Milan criteria, the uniform treatment of patients with established protocols, the complete follow-up of all patients; and a rigorous statistical analysis using both a conventional survival analysis and a matched sensitivity analysis to reduce the risk of confounding by indication. Its limitations include the retrospective analysis of data, the relatively small number of LDLT recipients, and possibly limited generalizability due to our unique tumor selection criteria. As with previous reports, it is worth noting that the sample size of our cohort is too small to conclusively disprove the possibility of a truly higher recurrence rate of HCC or diminished OS with LDLT versus DDLT. In conclusion, a careful analysis of LT for HCC at our center found that LDLT and DDLT provide similar chances of a cure for HCC, and this suggests that it is appropriate to offer either procedure to HCC patients with anatomically suitable lesions. ACKNOWLEDGMENT The authors thank J. C. Victor for his assistance with the statistical analyses and Robert Grant for his valuable input during the preparation of this article. REFERENCES 1. World Health Organization. Mortality data. http://www. who.int/healthinfo/statistics/mortality/en/index.html. Accessed November 2011. 2. Zaman SN, Melia WM, Johnson RD, Portmann BC, Johnson PJ, Williams R. Risk factors in development of hepatocellular carcinoma in cirrhosis: prospective study of 613 patients. Lancet 1985;1:1357-1360. 3. Mazzaferro V, Llovet JM, Miceli R, Bhoori S, Schiavo M, Mariani L, et al.; for Metroticket Investigator Study Group. 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