Hepatocellular carcinoma (HCC) is the third

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1 Intention-to-Treat Analysis of Liver Transplantation for Hepatocellular Carcinoma: Living Versus Deceased Donor Transplantation Prashant Bhangui, 1 Eric Vibert, 1,2,4 Pietro Majno, 5 Chady Salloum, 1 Paola Andreani, 1 Joao Zocrato, 1 Philippe Ichai, 1,4 Faouzi Saliba, 2,4 Rene Adam, 1,2,4 Denis Castaing, 1,2,4 and Daniel Azoulay 1,2,3 For patients who have cirrhosis with hepatocellular carcinoma (HCC), living donor liver transplantation (LDLT) reduces waiting time and dropout rates. We performed a comparative intention-to-treat analysis of recurrence rates and survival outcomes after LDLT and deceased donor liver transplantation (DDLT) in HCC patients. Our study included 183 consecutive patients with HCC who were listed for liver transplantation over a 9-year period at our institution. Tumor recurrence was the primary endpoint. At listing, patient and tumor characteristics were comparable in the two groups (LDLT, n 5 36; DDLT, n 5 147). Twenty-seven (18.4%) patients dropped out, all from the DDLT waiting list, mainly due to tumor progression (19/27 [70%] patients). The mean waiting time was shorter in the LDLT group (2.6 months versus 7.9 months; P ). The recurrence rates in the two groups were similar (12.9% and 12.7%, P ), and there was a trend toward a longer time to recurrence after LDLT ( months versus months, P ). Tumors exceeding the University of California, San Francisco (UCSF) criteria, tumor grade, and microvascular invasion were independent predictive factors for recurrence. On an intention-to-treat basis, the overall survival (OS) in the two groups was comparable. Patients beyond the Milan and UCSF criteria showed a trend toward worse outcomes with LDLT compared with DDLT (P ). Conclusion: The recurrence and survival outcomes after LDLT and DDLT were comparable on an intent-to-treat analysis. Shorter waiting time preventing dropouts is an additional advantage with LDLT. LDLT for HCC patients beyond validated criteria should be proposed with caution. (HEPATOLOGY 2011;53: ) Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. 1 One million new cases of HCC are Abbreviations: AFP, alpha-fetoprotein; DDLT, deceased donor liver transplantation; DFS, disease-free survival; HCC, hepatocellular carcinoma; LDLT, living donor liver transplantation; LT, liver transplantation; OS, overall survival; UCSF, University of California, San Francisco; UNOS, United Network of Organ Sharing. From the 1 Centre Hépato-Biliaire, Hôpital Paul Brousse, Assistance Publique- Hôpitaux de Paris, Villejuif, France; 2 Université Paris-Sud, Villejuif, France; 3 INSERM, Unité 1004, Villejuif, France; 4 INSERM, Unité 785, Villejuif, France; and 5 Transplantation Unit, Department of Visceral Surgery, University Hospital of Geneva, Geneva, Switzerland. Received October 15, 2010; accepted January 27, Address reprint requests to: Daniel Azoulay, Centre Hépato-Biliaire, Hôpital Paul Brousse, Assistance Publique-Hôpitaux de Paris, 12 Avenue Paul Vaillant Couturier, Villejuif, France. daniel.azoulay@pbr.aphp.fr; fax: (33) Copyright VC 2011 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI /hep Potential conflict of interest: Nothing to report. Additional Supporting Information may be found in the online version of this article. diagnosed every year, resulting in 250,000 to 1 million deaths. 2,3 The incidence of HCC is also increasing in the Western world; in the United States, 8,500 to 11,500 new HCC cases are detected every year. 4 Because most cases of HCC in the western world occur in a cirrhotic liver, liver transplantation (LT) represents the treatment of choice, offering good oncological outcomes and a cure of cirrhosis. 5 The Milan criteria 6 (one nodule with a maximal diameter of 5 centimeters or up to 3 nodules with a maximal diameter of 3 centimeters), have been adopted by the United Network of Organ Sharing (UNOS) as standard criteria for selection of patients with HCC for LT. Provided these criteria are fulfilled, long term survival after LT for HCC is similar to that after transplantation for patients without HCC. 6-8 Additional models for end-stage liver disease points allotted in patients with HCC have also allowed improvement in disease-free survival (DFS) in these patients

2 HEPATOLOGY, Vol. 53, No. 5, 2011 BHANGUI ET AL After the first adult-to-adult living donor liver transplantation (LDLT) was performed in 1994, the possibility of increasing the donor pool for liver transplantation emerged. Studies supported the safe application of the same criteria (Milan criteria and the University of California, San Francisco [UCSF] criteria 10 ) to select patients with HCC for LDLT. 11 In their studies based on the Markov model, Cheng et al. 12 and Sarasin et al. 13 also showed that LDLT could confer a substantial survival advantage for patients with compensated cirrhosis and nonresectable early stage HCC, and may especially be warranted if the waiting time for a deceased donor liver graft was expected to exceed 7 months. This is indeed the case in most of the patients with HCC listed for LT today. In the United States, approximately 7,000 new patients with HCC are put on the waiting list for LT every year, 14 10% to 15% of whom die during the waiting period. 15 In Europe and the United States, the dropout rate at various centers ranges between 15% and 35%. 16,17 Although the use of adult-to-adult LDLT may shorten waiting time, decrease mortality on the waiting list, 13,18 and reduce cold ischemia time, thus improving the short-term results of LT via optimal graft function, questions regarding the implications of the type of graft on the disease process and outcome have been raised. 19,20 The potential risks of LDLT for HCC include fast-tracking to transplantation with the risk of more tumor recurrences post-transplantation, 21,22 the risk of a less optimal cancer surgery due to technical constraints, and the rapid regeneration that occurs in the immediate post LDLT period, which could provide an ideal milieu for cancer progression in these patients, which in turn could lead to early 23,24 or multiple-site recurrence. Some multicenter and few single-center studies have compared the results of LDLT with deceased donor liver transplantation (DDLT) for HCC. However, none of these studies was performed on an intentionto-treat strategy. The primary goal of our study was to analyze, on an intention-to-treat basis, whether LDLT performed as well as DDLT in patients with HCC with regard to long-term outcomes. We chose recurrence rate as the primary endpoint of our study, because recurrence is the most important factor determining long-term outcome and is responsible for late deaths after LT. Patients and Methods From March 2000 to November 2009, 183 adult patients with HCC with cirrhosis were listed for LT at our center (Centre Hepatobiliaire, Paul Brousse Hospital, Villejuif, France). During this period, a total of 95 LDLTs and 960 DDLTs were performed. Patient Selection, Evaluation, and Treatment During the Waiting Period. The cohort of 183 consecutive patients included only those who were diagnosed to have HCC preoperatively, either histologically proven or as defined by Barcelona criteria. 25 The evaluation of the tumor and extent of disease was performed using multidetector helical computed tomography of the abdomen and thorax and magnetic resonance imaging of the abdomen with gadolinium contrast (Gd-MRI). Bone scintigraphy was performed in all cases. During the waiting period, patients were reviewed every 6 weeks by way of liver function tests, alphafetoprotein levels (AFP), and abdominal ultrasound examination. Multidetector helical computed tomography of the thorax and abdomen and/or Gd-MRI were repeated every 3 months during the waiting period. Bone scintigraphy was repeated, and a site-specific MRI examination was performed according to bone symptoms, if any. Absolute contraindications for listing the patient for transplantation, as well as indications for removal of the patient from the waiting list, were presence of extrahepatic disease and presence of macroscopic vascular invasion, irrespective of the level of involvement (from main trunk to segmental). AFP values were not considered when making this decision. The detailed evaluation of living donors at our center has been reported. 26 During the waiting period, radiofrequency ablation and/or transarterial chemoembolization were used on a case-by-case basis according to tumor characteristics (location, number, and size) and liver function. None of the patients included in the study underwent resection during the waiting period before LT. Liver Transplantation and Pathological Examination. LT was performed using standard techniques; a cell-saver device was never used. On the day of transplantation, all potential recipients underwent an exploratory laparotomy to rule out extrahepatic disease. Frozen section examination of hilar lymph nodes was systematically performed. Operative mortality was defined as death occurring either in the perioperative period during hospitalization for LT or up to 90 days post-lt. The pathological analysis of the explanted liver was performed by a pathologist blinded to the type of transplantation (LDLT or DDLT). The following tumor characteristics were systematically noted on gross and microscopic examination: number of tumor nodules,

3 1572 BHANGUI ET AL. HEPATOLOGY, May 2011 Table 1. Characteristics of Patients with HCC Listed for Liver Transplantation At Listing Actually Received Transplant Candidates for CDLT (n 5 147) Candidates for LDLT (n 5 36) P Value Transplanted with CDLT (n 5 120) Transplanted with LDLT (n 5 36) P Value Sex, men/women 125/22 32/ /20 32/ Age, years Etiology of cirrhosis, n (%) Viral 99 (67) 28 (77) 88 () 28 (77) Alcoholic 38 (26) 6 (16) 26 (21) 6 (16) Other 10 (7) 2 (6) 6 (7) 2 (6) HIV coinfection, n (%) 20 (13) 2 (6) (12) 2 (5) 0.24 MELD score AFP, lg/l , No. of nodules Maximum tumor diameter, mm Beyond Milan criteria, n (%) 33 (22) 10 (27) (21) 10 (27) 0.44 Outside UCSF criteria, n (%) 20 (13) 5 (13) (13) 5 (13) 0.93 Pretransplant ablation therapy, n (%) 68 (40) 13 (36) (38) 12 (33) 0.73 Transarterial chemoembolization, n (%) 65 (96) 12 (92) (93) 11 (92) 0.87 Radiofrequency ablation, n (%) 3 (4) 1 (8) (7) 1 (8) 0.87 Abbreviations: AFP, alpha-fetoprotein; CDLT, cadaveric donor liver transplantation; HCC, hepatocellular carcinoma; HIV, human immunodeficiency virus; LDLT, living donor liver transplantation; MELD, model for end-stage liver disease; UCSF, University of California, San Francisco. tumor size, tumor location, vascular invasion (none, macroscopic, or microscopic), presence of satellite nodules, and histological tumor grade (Edmonson grading). Endpoints of the Study. The primary endpoint of the study was the rate of recurrence after transplantation. We chose this primary endpoint because it is the only factor that specifically affects mortality after LT for HCC, accounting for approximately 50% of late mortality. 23 The secondary endpoints were overall survival (OS) from the time of listing (intention-totreat analysis, including dropouts) and after transplantation (including only patients with HCC on the explanted specimen). Statistical Analysis. The two groups (LDLT and DDLT) were compared for patient and tumor characteristics, operative and postoperative outcomes, and long-term outcomes (recurrence and survival). A univariate analysis was performed in each group by excluding cases of postoperative deaths to identify risk factors for recurrence. Due to a limited number of recurrences in each group, a multivariate analysis could not be performed separately for the two groups. Because the pattern of recurrence in both groups was similar, multivariate analysis was performed on the whole patient cohort (combining the 2 groups) to identify independent risk factors for recurrence. A chi-square test was used to compare categorical data; a Student t test was used to compare contiguous variables. Recurrence and survival probabilities were calculated using the Kaplan-Meier method and were compared with a log-rank test. P < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS version 13.0 (SPSS Inc., Chicago, IL). Results Comparison of the Study Groups. Table 1 compares the characteristics of the 183 patients with HCC (according to histology or BCLC criteria) who were listed for LDLT (36 cases) and DDLT (147 cases) and those who were finally transplanted (36 LDLT and 120 DDLT, respectively). The two groups were similar for patient demographics and tumor characteristics. Dropout from Waiting List for Transplantation. The dropout rate for patients listed for LDLT was 0%, whereas 27 (18.4%) patients dropped out from the DDLT list (P ¼ 0.01). The median time from listing to dropout in these patients was 9 months. Tumor progression (i.e., tumoral vascular thrombosis and/or tumor metastases) was the main cause of dropout (19/27 [70%]) in our series. Proportion of Patients Undergoing Transplantation and Waiting Times. Thirty-six patients (100% of those listed) underwent LDLT, and 120 patients (81.6% of those listed) underwent DDLT. The waiting time for the LDLT group ( months) was significantly shorter compared with the DDLT group ( months; P ¼ 0.001). Three patients in the LDLT group and 4 patients in the DDLT group did not have any proof of HCC on the explanted liver. These patients were excluded when the recurrence rate and OS posttransplantation were calculated.

4 HEPATOLOGY, Vol. 53, No. 5, 2011 BHANGUI ET AL Fig. 1. Rate of recurrence of hepatocellular carcinoma after liver transplantation: living donor liver transplantation (LDLT) versus cadaveric donor liver transplantation (CDLT). Operative Mortality. Nine patients died during the postoperative period. There were three postoperative deaths in the LDLT group compared with 6 postoperative deaths in the DDLT group (8% versus 5%; P ¼ 0.45). None of the deaths were tumor-related. The median delay to postoperative death overall was 0.82 months (range, months); the delay was similar in the two groups (DDLT, 0.59 months; LDLT, 0.82 months). Tumor Recurrence. The mean follow-up was months for the LDLT group and months for the DDLT group (P ¼ 0.23). None of the patients in our study received immunosuppression with rapamicin post-lt. Eighteen patients out of 141 survivors after transplantation with a proven HCC on the explanted specimen developed tumor recurrence: 14 out of 110 (12.7%) patients in the DDLT group, 4 out of 31 (12.9%) patients in the LDLT group (P ¼ 0.78). The rate of recurrence of HCC post-lt in the two groups (LDLT versus DDLT) is shown in Fig. 1. A trend toward longer time to recurrence after LDLT ( months, range months) compared with DDLT ( months; range, 2-47 months) was observed. However, this difference did not reach statistical significance (P ¼ 0.06). At 5 years, the Table 2. Univariate Analysis of Prognostic Factors of Recurrence in Living Donor Liver Transplantation and Deceased Donor Liver Transplantation LDLT CDLT No Recurrence (n 5 27) Recurrence (n 5 4) P Value No Recurrence (n 5 96) Recurrence (n 5 14) P Value Sex: women Age, years Liver cirrhosis, no. of cases Viral Alcoholic Other MELD score at listing No. of nodules Diameter of largest nodule, mm AFP at listing, ng/l ,002 <0.01 Outside Milan criteria, n 4 4 < Outside UCSF criteria, n 1 3 < No preoperative treatment, n Time on waiting list, months Cold ischemia time, minutes No. of blood units transfused No. of nodules Diameter of largest nodule, mm Outside Milan criteria, n <0.01 Outside UCSF criteria (n ¼ 148),* no. of cases <0.01 Satellite nodules (n ¼ 147),* no. of cases Edmonson grade III/IV (n ¼ 114),* no. of cases <0.01 Macroscopic VI (n ¼ 120),* no. of cases <0.01 Microscopic VI (n ¼ 128),* no. of cases <0.01 Abbreviations: AFP, alpha-fetoprotein; CDLT, cadaveric donor liver transplantation; LDLT, living donor liver transplantation; MELD, model for end-stage liver disease; UCSF, University of California, San Francisco. *Some variables were not available for all patients. Indicated are the numbers of patients for whom values were available. The percentage was calculated according to available data.

5 1574 BHANGUI ET AL. HEPATOLOGY, May 2011 Table 3. Univariate and Multivariate Analysis of Prognostic Factors of Recurrence After Transplantation for HCC on Cirrhotic Liver Excluding Nine Cases of Postoperative Mortality and Seven Cases of Absent HCC on the Specimen Univariate Analysis Multivariate Analysis Variables Total (N 5 141) Risk Ratio (95% CI) P Value Risk Ratio (95% CI) P Value Preoperative variables Sex: women 23 (16%) 0.65 ( ) 0.56 Age, years ( ) 0.95 Liver cirrhosis n cases (%) Viral 104 (73.8) ( ) 0.69 Alcoholic 26 (18.4) 0.25 ( ) 0.17 Other 11 (7.8) 0.62 ( ) 0.65 Living related liver transplant, n (%) 31 (22.0) 0.96 ( ) 0.94 MELD score at listing ( ) 0.38 No. of nodules ( ) 0.03 Diameter of largest nodule, mm ( ) 0.42 AFP at listing, ng/l ( ) 0.11 Outside Milan criteria, n (%) 34 (24.1) 3.95 ( ) Outside UCSF criteria, n (%) 20 (14.2) 3.84 ( ) ( ) No preoperative treatment, n (%) 32 (22) 2.63 ( ) ( ) 0.07 Time on waiting list, months ( ) 0.92 Peri- and postoperative variables Cold ischemia time, minutes ( ) 0.49 No. of blood units transfused ( ) 0.94 No. of nodules ( ) 0.04 Diameter of largest nodule, mm ( ) Outside Milan criteria, n (%) 47 (33.3) 5.18 ( ) Outside UCSF criteria (n ¼ 140)* 34 (24.3) 4.40 ( ) ( ) 0.10 Satellite nodules (n ¼ 139),* n (%) 49 (35.3) 4.08 ( ) ( ) 0.20 Edmonson grade III/IV (n ¼ 106),* n (%) 60 (42.6) 6.89 ( ) ( ) 0.04 Macroscopic vascular invasion (n ¼ 113),* n (%) 13 (11.5) ( ) Microscopic vascular invasion (n ¼ 121),* n (%) 29 (24.0) 7.02 ( ) ( ) Abbreviations: AFP, alpha-fetoprotein; CI, confidence interval; HCC, hepatocellular carcinoma; MELD, model for end-stage liver disease; UCSF, University of California, San Francisco. *Some variables were not available for all patients. Indicated are the numbers of patients for whom values were available. The percentage was calculated according to available data. recurrence rate in both groups was similar (12% versus 14%; P ¼ 0.94). Risk Factors of Tumor Recurrence. Table 2 shows the results of univariate analysis for prognostic factors of recurrence in each group separately (LDLT and DDLT). The predictive factors of recurrence were similar in both groups, and were related to a more aggressive tumor (i.e., number of nodules, diameter of largest nodule, preoperative AFP levels, presence of satellite nodules and vascular invasion by the tumor) and to selecting patients beyond established and validated selection criteria (Milan and UCSF). The numbers of recurrences were small in both groups (LDLT, n ¼ 4; DDLT, n ¼ 27), hence a separate multivariate analysis could not be performed. However, because the pattern of recurrence in both groups was similar, multivariate analysis was performed combining the 2 groups (all 31 patients who had recurrence after LT). On multivariate analysis, among the preoperative variables, transplantation patients with tumors beyond UCSF criteria (P ¼ 0.007) emerged as an independent predictive factor for recurrence (Table 3). Edmonson grade III-IV (P ¼ 0.04) and presence of microscopic vascular invasion (P ¼ 0.009) on the specimen were the other independent poor predictive factors for recurrence. We tested only UCSF criteria in multivariate analysis and not Milan criteria, number, or diameter of nodules (all of which were significant on univariate analysis) to obviate colinearity. UCSF criteria essentially include the Milan criteria. Similarly, patients with macroscopic vascular invasion are already included in the larger group of patients with microscopic vascular invasion. Overall Survival on an Intention-to-Treat Basis. The OS in the two groups (LDLT versus DDLT) after listing (intention-to-treat) and after transplantation (only for those patients with HCC confirmed on the explanted liver) were similar (P ¼ 0.68 and P ¼ 0.36, respectively) (Figs. 2A,B).

6 HEPATOLOGY, Vol. 53, No. 5, 2011 BHANGUI ET AL had intrahepatic recurrence, and two patients had both intrahepatic and extrahepatic recurrence. In the overall patient cohort, after recurrence, 42%, 23%, and 0% of the patients survived at 1, 3, and 5 years, respectively. The survival at 3 years after recurrence in the DDLT group was 30%, whereas in the LDLT group it was 25%. This difference was not statistically significant (P ¼ 0.95). At last follow-up, 79% of recipients of DDLT were alive without disease compared with 72% of recipients of LDLT (P ¼ 0.43). Discussion Our study shows that LDLT and DDLT for patients who have liver cirrhosis with HCC result in similar recurrence rates (the primary endpoint of the present study) and similar survival outcomes on an intentionto-treat basis. The dropout rate and waiting period in the LDLT group were significantly lower compared Fig. 2. Overall survival of patients with hepatocellular carcinoma listed for liver transplantation: living donor liver transplantation (LDLT) versus cadaveric donor liver transplantation (CDLT). (A) After listing (intention-to-treat). (B) After transplantation (patients with no HCC on specimen excluded). On multivariate analysis, blood transfusion and microscopic vascular invasion emerged as independent poor prognostic factors for OS on an intention-to-treat basis (data not shown). There was a trend toward worse survival outcomes in those patients beyond Milan or UCSF criteria who underwent LDLT compared with those who underwent DDLT (P ¼ 0.06 in both cases) (Figs. 3 and 4). Sites of Recurrence and Survival Postrecurrence. There was no difference in the site of recurrence between the two groups (P ¼ 0.77). In the LDLT group, of the four recurrences, two patients had extrahepatic recurrences (one in the lungs and one in the bony skeleton), one patient had an intrahepatic recurrence, and one patient had a recurrence in the liver, lungs, and suprarenal glands. In the DDLT group, of the 14 recurrences, six patients had an extrahepatic recurrence (four pulmonary, one in the bony skeleton, and one in the adrenal glands), six patients Fig. 3. Overall survival of patients with hepatocellular carcinoma after listing (intention-to-treat): living donor liver transplantation (LDLT) versus cadaveric donor liver transplantation (CDLT) with respect to Milan criteria. (A) Within Milan criteria. (B) Beyond Milan criteria.

7 1576 BHANGUI ET AL. HEPATOLOGY, May 2011 Fig. 4. Overall survival of patients with hepatocellular carcinoma after listing (intention-to-treat): living donor liver transplantation (LDLT) versus cadaveric donor liver transplantation (CDLT) with respect to University of California, San Francisco (UCSF) criteria. (A) Within UCSF criteria. (B) Beyond UCSF criteria. with the DDLT group. There was also a trend toward longer time to recurrence in the LDLT group. Transplantation outside UCSF criteria, poorly differentiated tumors, and vascular invasion emerged as independent predictive factors for recurrence in our study. Previous studies have reported macroscopic vascular invasion, tumor differentiation and size, 11 presence of bilobar disease, 28 use of salvage transplantation and transplantation patients beyond UCSF criteria, 28 earlier period in transplant program, higher AFP levels, and older recipient age 22 as predictive factors of recurrence (Table 4). In our study, the OS in the LDLT and DDLT groups was similar, and higher blood transfusion requirements and vascular invasion by the tumor emerged as independent poor prognostic factors for OS (data not shown). None of the studies published to date comparing DDLT with LDLT investigated the outcomes on an intention-to-treat basis. Our intention-to-treat analysis considers patients who dropped out of the waiting list, studies post orthotopic LT recurrence, as well as progression to death for both groups as proposed by Brown. 29 When the Milan criteria, 6 which have now been adopted by the UNOS as the model selection criteria for LT in HCC patients, are used for patient selection, the results are good. 11,30,31 However, these criteria were considered too restrictive, and other expanded criteria were proposed. 10,32-38 It is noteworthy that most of these criteria were not initially designed for LDLT, and more importantly that there is not a single criterion common to all the selection criteria proposed to date. This demonstrates a wide variation in the use of selection criteria at various centers around the world. LDLT opened up a new source of organs, and the possibility of expansion of eligibility criteria for transplantation for HCC was explored. However, several additional issues were also raised; we address these issues in the subsequent sections, in view of the results of our study. Does Fast Track Transplantation Using LDLT Decrease the Dropout Rate at the Cost of an Increased Recurrence Rate? Placing patients with HCC on a fast track to transplantation using LDLT may neither provide adequate time to assess the tumors aggressiveness nor allow clinically undetectable micrometastases or vascular invasion to appear. 21,22 This may result in a lower dropout but higher recurrence rate in LDLT recipients compared with DDLT recipients. On the other hand, it can also be argued that placing patients with HCC on a fast track to transplant may reduce the chances of extrahepatic dissemination. In our study, the waiting period for LDLT was significantly lower than that for DDLT. However,, no difference was observed in the rate of recurrence in the two groups of patients. Furthermore, among the patients who recurred, patients who underwent LDLT developed their first recurrence later than those who underwent DDLT (Fig. 1). In addition, there was no difference in severity of recurrence at presentation in the two groups. Does Rapid Regeneration of the Living Donor Graft After LDLT Stimulate Tumor Growth? A rapidly regenerating liver post-ldlt could be a more favorable milieu for tumor progression in case of persistent occult tumor foci. 23,24 Some authors have suggested that this finding could explain the higher recurrence rate after LDLT compared with DDLT. 22,39 In our study, the recurrences in the LDLT group occurred later compared with the DDLT group (Fig. 1), and none of the patients who

8 HEPATOLOGY, Vol. 53, No. 5, 2011 BHANGUI ET AL Table 4. Reported Series in Literature Living Donor Versus Cadaveric Donor Liver Trasnplantation for HCC Author, Year Study Period No. of Patients Waiting Time (Days)* Operative Mortality Overall Survival Disease-Free Survival LDLT CDLT LDLT CDLT LDLT CDLT LDLT CDLT LDLT CDLT Predictive Factors of Recurrencey Gondolesi, NG 8/36 NG 60% (2 years) 70% (2 years) 74% (2 years) 83% (2 years) Bilobar disease (LDLT only) Hwang, NG NG 24/237 14/75 73% (3 years) 61.1% (3 years) 79.7% (2 years) 81.6% (2 years) Macroscopic vascular invasion, tumor differentiation, size Lo, % (5 years) 94% (5 years) NG NG Salvage transplantation, beyond UCSF criteria Fisher, NG NG 67% (3 years) 63% (3 years) 62% (3 years) Earlier period vs , # higher AFP level, # older recipient age # Vakili, ** 74 NG 168 0/28 9/74 81% (5 years) 58% (5 years) NG NG NG Di Sandro, NG NG 69% (5 years) 76.7% (5 years) 95.5% (5 years) 89.4% (5 years) NG Li, NG NG 45% (4 years) 38% (4 years) 38% (4 years) 37% (4 years) NG Present study /36 6/120 AL, 73% (5 years); AT, 73% (5 years) AL, 71% (5 years); AT, 82% (5 years) 75% (5 years) 88% (5 years) Beyond UCSF criteria preoperatively, tumor differentiation, microscopic vascular invasion Abbreviations: AFP, alpha-fetoprotein; AL, after listing; AT, after transplantation; CDLT, cadaveric donor liver transplantation; HCC, hepatocellular carcinoma; LDLT, living donor liver transplantation; NG, not given; UCSF, University of California, San Francisco. *Median. On multivariate analysis. Including 39 cases of incidental HCC on the specimen. Actual numbers in each group not specified. Due to significant difference in operative mortality. Without incidental HCC on specimen. Including three cases of incidental HCC on the specimen for LDLT versus five cases for CDLT (P ¼ 0.035). #Predictive factors of recurrence or death from time of transplantation. **Including six cases of incidental HCC on the specimen and one patient without cirrhosis; corresponding information not given for the 74 cases of cadaveric liver transplants. Median waiting time for HCC patients in the region.

9 1578 BHANGUI ET AL. HEPATOLOGY, May 2011 recurred had diffuse, multisite recurrence. In addition, at multivariate analysis, LDLT was not a prognostic factor for recurrence post-lt. Does the Technique of LDLT per se Forego the Principles of Oncological Surgery? During LDLT, the meticulous dissection, the possibility of tumor capsule violation, the preservation of the native vena cava, and conservation of long native vessel lengths in the liver hilum may increase the risk of not removing foci of residual tumor. Greater manipulation of the native liver may also lead to tumor embolization through the hepatic veins, thus promoting tumor dissemination. On the other hand, the liver hilum and retrohepatic area have never been shown to be the predominant site of recurrence in patients transplanted using a living donor graft. In our study, there was no difference in the proportion of patients who recurred after transplantation in the two groups (12.9% versus 12.7% in the LDLT and DDLT groups, respectively; P ¼ 0.78). In addition, none of the patients in the LDLT group had a recurrence in the hilum or in the area of the preserved native vena cava. Does the Possibility of LDLT Justify an Expansion of Eligibility Criteria for LT in HCC Patients? Various studies have reported conflicting results regarding the ideal selection criteria for LDLT in patients with HCC. The Milan criteria adopted by the UNOS as the standard criteria for selection of patients with HCC for DDLT have been considered safe and applicable to LDLT as well. 10,31 In the study by Gondolesi et al., 27 one-third of patients receiving a living donor graft were beyond the Milan criteria, yet the incidence rates of recurrence, OS, and DFS were similar to results after DDLT performed during the same period at their center. The patients with tumors 5 cm had received intraoperative and postoperative chemotherapy in their study. The Japanese Study Group on Organ Transplantation 40 showed that even when the Milan criteria were exceeded, a 3-year OS and DFS of 60% and 52.6% respectively, could be achieved in LDLT patients. On the other hand, Lo et al. 28 reported that transplanting patients beyond UCSF criteria was an independent predictive factor for recurrence. We found that transplanting patients beyond UCSF criteria was an independent predictive factor for recurrence of HCC (Tables 2 and 3, Figure 5). Transplanting patients beyond the Milan criteria also yielded worse survival outcomes with LDLT compared with DDLT (Table 2, Fig. 3). The results of our study indeed suggest that one must be cautious before expanding the indications for LDLT in patients with HCC beyond UCSF criteria. In our study, the survival outcomes on an intention-to-treat basis were better in the DDLT group compared with the LDLT group when patients were beyond Milan or UCSF criteria (Figs. 3 and 4). This finding can probably be explained by a natural selection process whereby patients with more severe disease dropout on the waiting list in the DDLT group, and patients with better prognosis finally undergo transplantation with a good long-term outcome. On the other hand, patients in the LDLT group undergo transplantation early, disallowing this natural selection. Nevertheless, the local availability of deceased donors and waiting time for a DDLT in a given region 39 must be taken into account. Of course, when taking the final decision of going ahead with LDLT in a patient beyond standard criteria (Milan or UCSF), due importance should be given to donor safety and morbidity, 26 among other issues. Our study does have some limitations. A randomized study would have been the best type of clinical study to resolve the debate regarding use of LDLT versus DDLT for HCC patients. This ideal study is indeed difficult to realize, if at all feasible, given the complex decision-making process involved in LDLT. In addition, the proportion of LDLT patients in our series is indeed low compared with the patients who underwent DDLT. In view of the few recurrences that occurred, the number of variables assessed in univariate analysis seem to be many. A larger multicenter study comparing an equal number of patients with HCC in both groups (LDLT and DDLT) would be ideal, and this is underway in France. In conclusion, the present study shows that, contrary to the hypothesis of possible oncological compromise by using LDLT for treatment of HCC, LDLT does as well as DDLT in terms of recurrence and survival outcomes. In addition, the significantly shorter waiting time (aiding to avoid dropouts from the waiting list), is a major advantage of using LDLT. However, one has to be cautious while expanding the criteria for LDLT in HCC patients as this may lead to worse long-term outcomes. Acknowledgment: We thank all the liver transplant coordination staff and nursing staff at Centre Hepatobiliaire, Hopital Paul Brousse, for their untiring efforts toward the liver transplant program at our institution.

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