Liver transplantation for hepatocellular carcinoma (HCC) is restricted by the scarcity of cadaver grafts. Living donor liver transplantation (LDLT) may potentially increase the applicability but its role and limitation are not clear. We studied the outcome of a cohort of 51 patients with unresectable HCC who were accepted on list for both options of deceased donor liver transplantation (DDLT) and LDLT. Twenty-five of 51 (49%) patients had voluntary living donors (group 1) and 26 did not (group 2). Patients in group 1 were younger, and more often had a MELD score more than 20 or blood group other than O. Twenty-one patients of group 1 underwent LDLT after a median waiting time of 24 days (range, 2–126 days), but 4 did not because the donors were not suitable (HBsAg-positive, 2; ABO-incompatible, 1; liver dysfunction, 1). Of the 30 patients who remained on list, only 6 underwent DDLT after a median waiting time of 344 days (range, 22–1359 days, P < .005). Nineteen died before transplantation and 2 were alive but taken off the list because of disease progression (drop-out rate, 70%). One patient was alive on list and 2 had undergone transplantation outside Hong Kong. The 1-, 2-, 3-, and 4-year intention-to-treat survival rates were 88%, 76%, 66%, and 66%, respectively, for group 1 and 72%, 46%, 38%, and 31%, respectively, for group 2 (relative risk of death for group 1, 0.35; 95% CI, 0.14 to 0.90; P = .029). In conclusion, although complicated factors such as donor voluntarism and selection criteria limit the role of LDLT for HCC, LDLT allows more patients to undergo early transplantation and results in a better outcome. (Liver Transpl 2004;10:440–447.)
Liver transplantation offers the best chance of cure for unresectable hepatocellular carcinoma (HCC),1–3 but the scarcity of cadaver liver grafts has seriously limited its role. To justify organ allocation, candidacy is restricted only to patients with early tumors who fulfill strict selection criteria1, 4 so that the survival is comparable to that with non-neoplastic disease. Unfortunately, the prolonged waiting time results in drop-outs because of tumor progression and adversely affects the outcome of these patients.5, 6 In addition, the unpredictable timing of a deceased donor graft makes it difficult if not impossible to accurately stage the disease and to plan any study for neoadjuvant therapy before transplantation.
With the recent advances in adult living donor liver transplantation (LDLT),7–9 there is potentially a drastic change in the role of liver transplantation. Studies on hypothetical decision analytic models10, 11 have demonstrated the theoretical survival benefit of LDLT over deceased donor liver transplantation (DDLT) which depends largely on the waiting time and drop-out rate. In parts of Asia including Hong Kong where there is a high incidence of HCC and a low deceased donor rate, LDLT is likely to generate a great benefit. Nonetheless, although LDLT is not restricted by the system of deceased donor organ allocation and waiting time, many other factors such as donor voluntarism or selection may limit its application in practice.12, 13 There are no clinical studies on the applicability and role of LDLT in this setting. In this article, we studied the role and limitation of LDLT for HCC in a liver transplant program in Asia where deceased donors are scarce. For the first time, we evaluated the survival benefit of LDLT over DDLT on the basis of intention-to-treat from the perspective of the donor/recipient.
HCC, hepatocellular carcinoma; LDLT, living donor liver transplantation; DDLT, deceased donor liver transplantation; MELD, model for end-stage liver disease; HBV, hepatitis B virus.
Patients and Methods
We retrospectively studied the computer database of the liver transplant waiting list and identified 51 consecutive patients with a diagnosis of HCC who were accepted on list from January 1997 to March 2002. These patients constituted 3.5 % of the 1,438 patients with a diagnosis of HCC who were managed at the Department of Surgery of the University of Hong Kong Medical Center, Queen Mary Hospital during the same period. In our strategy for the management of HCC, partial hepatectomy with a curative intent, whenever possible was considered the treatment of first choice.14 The criteria for partial hepatectomy included anatomically resectable disease, absence of distant metastasis or tumor thrombus in main portal vein or inferior vena cava, and adequate liver function reserve. Cirrhosis alone was not considered a contraindication for hepatic resection. Selected patients with unresectable tumors ≤5 cm underwent local tumor ablation using cryotherapy or radiofrequency ablation. Only patients 65 years of age or younger with disease not amenable to partial hepatectomy or local ablation were considered for liver transplantation. The Milan criteria1 and more recently, the UCSF criteria4 were used for the selection of patients for listing. The remaining patients were treated by palliative therapies such as transarterial lipiodol chemoembolization or symptomatic treatment.
These 51 patients with HCC who were listed for transplantation were the subjects of the present study. There were 44 men and 7 women with a mean age of 51.4 years (range, 11–65 years) and all were ethnic Chinese. The causes of the underlying liver disease were chronic hepatitis B infection in 47 patients (HBsAg-positive, 47; HBeAg-positive, 23; HBV DNA-positive by bDNA assay, 16), cryptogenic in 2, Budd-Chiari syndrome in 1, and combined hepatitis B and C infection in 1 patient (positive for HBeAg and HBV DNA). Twenty-one patients had decompensated liver cirrhosis and had HCC detected during evaluation for transplantation (n = 11) or while waiting on list (n = 10; median interval, 11.6 months; range 2.3–45.7 months). In the remaining 30 patients, the primary indication for liver transplantation was unresectable HCC. Seventeen of these 30 patients had received previous treatments for HCC including transarterial chemoembolization (n = 15), partial hepatectomy (n = 10), intralesional alcohol injection (n = 2), and systemic chemotherapy (n = 1). Patients who had previous partial hepatectomy for HCC but subsequently required liver transplantation for hepatic decompensation in the absence of recurrent disease, and patients with an incidental finding of HCC in the explanted liver after transplantation were not included.
Upon acceptance on list, these patients were offered the options of both DDLT and LDLT. As a result of the relative shortage of deceased donor grafts and the prevalence of HCC in Hong Kong, there was no prioritization based on the diagnosis of HCC, and cadaver organ allocation was based on the severity of liver failure only. The option of LDLT was available at any time after listing and the primary decision depended on the family member's voluntary intent together with the patient's acceptance. Our protocol for evaluation of the living donor has been described previously.13 We emphasized the importance of confirming the donor's voluntary intent before proceeding to evaluating medical or surgical suitability. The family members were not solicited for donation and the potential donor was identified by himself or herself, and not by the medical staff. The psychological status of the volunteer donor was assessed by a clinical psychologist and a separate interview was conducted in the absence of the patient and other family members. The donor was given the opportunity to withdraw at any time, with the assurance that an excuse on medical ground would be provided by the transplant team. The donor needed to have compatible ABO-blood group, negative serology for hepatitis B surface antigen and hepatitis C antibody, and no evidence of any acute or chronic illness that would increase the operative risk. Computed tomography with volumetry was performed to determine the size of the donor's liver and a left lobe or right lobe graft was selected to provide a graft larger than 40% of the recipient's standard liver weight15 as estimated according to the Urata formula.16
For the recipients, computed tomography of the abdomen and thorax, and radionucleotide bone scan were performed at initial diagnosis and then every 3 to 6 months. If no living donor was available, transarterial lipiodol chemoembolization was given to those with adequate hepatic reserve during the waiting period. Patients whose tumor progressed on serial imaging to beyond the acceptance criteria would be removed from the list after discussion at a multidisciplinary liver transplant meeting.
We studied the outcome of this cohort of 51 patients with death as the main end-point and patient survival as the primary outcome measure. No patient was lost to follow-up, which was censored at the end of May 2003. The cumulative probability of survival was estimated by life-table method and compared using the log rank test. For intention-to-treat analysis of patient survival, the zero time point was set as the time of acceptance for transplantation with a known diagnosis of HCC (i.e.. time of acceptance on list or time of diagnosis of HCC whichever was the later). From the perspective of the patient and donor, the availability and initiation of evaluation of a voluntary living donor was taken as their decision for intention-to-treat with LDLT while the remaining patients were assumed to have opted for DDLT. To identity factors that might affect this decision, the characteristics of the patients with or without voluntary donors were compared. Patients who eventually underwent DDLT were also compared to those who received LDLT. Continuous variables were expressed as median (range) and comparisons between subgroups were done by using the Mann-Whitney U test. Categorical variables were compared by using chi-squared test or Fisher's exact test and a P value of < .05 was considered statistically significant.
During the study period, 2 additional patients with HCC exceeding the acceptance criteria underwent LDLT. One patient had a solitary tumor nodule of 9.4 cm in diameter and the other had a solitary tumor of 3 cm with radiologic evidence of invasion of a segmental branch of portal vein detected during evaluation for transplantation. At the multidisciplinary liver transplant meeting, these 2 patients were not accepted on the waiting list. Nonetheless, the patients appealed and requested strongly for the option of LDLT despite detailed explanation of the risk of recurrence and a worse outcome. Eventually, approval was obtained for both patients to be accepted for LDLT under the condition that should graft failure occurred, retransplantation using cadaver graft would not be available. These 2 patients with extended indications were described separately and were not included in the analysis of the cohort of 51 patients.
Decision for LDLT
In 25 of the 51 (49 %) patients, 1 or more family members volunteered as living donors and underwent evaluation (group 1). The remaining 26 patients (group 2) had no voluntary living donor or the patient refused to accept living donation. Table 1 shows a comparison of the baseline characteristics of the 2 groups. The decision for LDLT was associated with a younger age of the patients (median, 50 years vs. 56 years; P = .025), a MELD score > 20 (5 of 25 vs. 0 of 26; P = .023) and a blood group other than O (19 of 25 vs. 12 of 26; P = .045). There was no significant relationship between the primary indication for transplantation and any of the tumor factors such as α fetoprotein level, size and number of tumors, and previous treatment. However, there tended to be more patients with recurrent HCC after previous partial hepatectomy in group 1 (7 of 25 vs. 3 of 26; P = .173).
Table 1. Comparison of Baseline Characteristics of the 2 Groups of Patients
Group 1 (n = 25)
Group 2 (n = 26)
Abbreviations: MELD, model for end-stage liver disease; αFP, alpha fetoprotein.
Twenty-one (84 %) of the 25 patients in group 1 eventually underwent LDLT after a median waiting time of 24 days (range, 2–126 days) using 19 right lobe grafts with middle hepatic vein, 1 right lobe graft without middle hepatic vein, and 1 left lobe graft with middle hepatic vein. The donors included spouse (n = 7), son/daughter (n = 8), sister (n = 2), son-in-law (n = 2), mother (n = 1), and nephew (n = 1). The median operation blood loss for the donor was 400 ml (range, 230–1200 ml) and none required any homologous blood product transfusion. The median hospital stay was 7 days (range, 6–19 days). Two donors had major postoperative complications. One developed intrahepatic cholestasis, which was resolved spontaneously, and the other had bile duct stricture, which was treated with endoscopic balloon dilatation. Both donors were well with normal liver function after a follow-up of 20 months and 26 months, respectively.
Waiting on List for Deceased Donor Grafts
The remaining 4 patients of group 1 did not receive LDLT because the voluntary donors were not suitable as a result of positive serology for hepatitis B surface antigen (n = 2), ABO-blood group incompatibility (n = 1), and liver dysfunction (n = 1). Together with the 26 patients who did not have any voluntary living donor, 30 patients remained on the waiting list for DDLT. Fifteen patients underwent transarterial chemoembolization to reduce tumor growth during the waiting period. Our selection criteria for transarterial chemoembolization included absence of hepatic encephalopathy, gross acites, or a recent history of variceal bleeding and a serum total bilirubin level ≤50 μmol/L. As of May 30, 2003, only 6 (20 %) patients have received DDLT at Queen Mary Hospital after a median waiting time of 344 days (range, 22–1359 days). Nineteen patients had died without receiving transplantation after a median of 10 months (range, <1–57 months) (Table 2). Two were alive but had been taken off the waiting list after 8 months and 14 months, respectively, because of tumor progression (drop-out rate, 70%) and 1 was still on the waiting list after waiting for 17 months. The remaining 2 patients have received liver transplantation outside Hong Kong. These 2 patients were treated as censored observations in the intention-to-treat survival analysis. Hence, the option of LDLT increased the applicability of liver transplantation from 12% (6 of 51) to 53% (27 of 51) (Fig. 1).
Table 2. Cause of Death in 19 Patients Before Liver Transplantation
Cause of Death
No. of Patients
Esophageal variceal bleeding
The characteristics of the recipients and tumors at the time of transplantation are shown in Table 3. Seven of the 21 LDLT recipients and none of the 6 DDLT recipients had previous partial hepatectomy before acceptance on list (P = .155). On the other hand, after acceptance on list, none of the 21 recipients of LDLT and 5 of the 6 recipients of DDLT had received treatment with transarterial chemoembolization during the waiting period (P < .001). Otherwise, there was no significant difference in the tumor characteristics. The waiting time was significantly shorter for LDLT (median, 24 days; range, 2–126 days) than for DDLT (median, 344 days; range, 22–1359 days; P < .005).
Table 3. Characteristics of Tumors at Time of Transplantation
The actuarial survival of this cohort of 51 patients at 1, 2, 3, and 4 years was 80%, 64%, 56%, and 50%, respectively. As of the end of May 2003, 24 of the 51 patients had died including 6 of the 25 (24%) patients in group 1 and 18 of 26 (69%) patients in group 2. Three patients in the former group and 16 patients in the latter group died before transplantation. There was no transplant-related mortality but 5 patients died after transplantation. In group 1, 1 patient died disease-free at 12 months from empyema thoracis and 2 died from recurrent HCC at 19 and 22 months after LDLT. In group 2, 2 patients died from graft failure due to recurrent hepatitis B after DDLT in Hong Kong and outside Hong Kong, respectively. The intention-to-treat survival at 1, 2, 3, and 4 years was 88%, 76%, 66%, and 66%, respectively, for group 1 as compared to 72%, 46%, 38%, and 31%, respectively, for group 2 (relative risk of death for group 1, 0.35; 95% CI, 0.14 to 0.90; P = .029) (Fig. 2). The recipient actuarial survival at 1, 2, and 3 years was 95%, 81%, and 81%, respectively, after LDLT and 80% for all after DDLT (P = .507) (Fig. 3). Further analysis to compare the survival of patients who underwent LDLT to those who underwent DDLT was not performed because of the small number of patients. As for the 2 other patients who underwent LDLT for extended indications, both were alive, 1 disease-free at 32 months and the other with recurrence at 29 months after transplantation.
The present study defined the role and limitation of LDLT in patients with unresectable HCC in Hong Kong. LDLT significantly increased the applicability of liver transplantation and there was a definite survival advantage of LDLT as compared to DDLT on an intention-to-treat basis in a cohort of 51 patients. Nonetheless, the role of LDLT is limited by the lack of donor voluntarism and donor selection criteria and its overall impact on the survival of patients with early unresectable HCC waiting for transplantation is less than that predicted by hypothetical studies based on decision analytic models.10, 11
The results of DDLT for HCC depend on the time waiting for an organ donor. Recent studies from Spain and the United States5, 6 have shown an increasing waiting time and a growing incidence of drop-outs, which resulted in a significant adverse effect on the intention-to-treat survival. In the study from Barcelona,5 where the mean waiting time was 162 days, 23% of patients dropped out because of tumor progression and the 2-year intention-to-treat survival rate was 54%. The dropout rate and intention-to-treat survival rate at 2 years were 43.6% and 72.6%, respectively in the study by Yao et al. from San Francisco.6 In Hong Kong where the deceased donor liver donation rate was low17 and the incidence of HCC was high,18 the mean waiting time for DDLT (344 days) and drop-out rate (70%) were much higher and the 2-year intention-to-treat survival for DDLT was 46% only. Such a dismal outcome of patients waiting on list for DDLT supports our policy to restrict transplantation only for highly selected patients with early tumors not amenable to partial hepatectomy or local ablative therapy. It also provides justification for us to initiate the alternative option of LDLT which increased the overall applicability of liver transplantation from 12% to more than 50%.
The critical factor that limits an even greater role of LDLT is the availability of a suitable voluntary donor. There were no voluntary living donors in more than 50% of the patients and the donor selection criteria further limited its use in 4 out of 25 cases. Incidentally, our previous study on the applicability of LDLT in high-urgency patients showed the impact of a lack of donor voluntarism in a similar proportion of patients.13 The decision for voluntary liver donation is a complicated psychological process for the potential donor that involves various social, cultural, interpersonal, and family factors. Our analysis showed that younger patients with a higher liver disease severity score and possibly those who recur after failure of previous radical treatment by partial hepatectomy were more likely to have a voluntary living donor. These factors may be easily recognized by the living donor to indicate a perceivably greater need for early transplantation and a greater benefit for the recipient. The higher rate of previous hepatectomy in those with voluntary living donors also suggests that LDLT may be regarded by many as a last resort only when other treatments fail. The family members may have more opportunities to consider the future possibility of LDLT in the process of the previous treatments and follow-up. Conversely, the importance of other tumor-related characteristics such as number and size which have been shown to predict drop-out6 were less apparent for the living donor. It is interesting to understand why patients of blood group O are less likely to have voluntary donors. In our experience, many family members are aware of or would check their own blood group before deciding to volunteer for donation and hence, this donor selection factor appears prematurely to create an apparent effect on donor voluntarism.
Intention-to-treat analysis is particularly important in determining the role of liver transplantation because the operation is frequently restricted by graft availability. It provides a realistic estimation of the outcome of all those who intend to receive a treatment and allows a proper comparison with alternative treatment options. Intention-to-treat analysis for DDLT has been reported,5, 6 but there has never been any intention-to-treat analysis for LDLT. A few case series reported the outcome of patients after LDLT for HCC.19–21 In hypothetical studies using decision analytic model,10, 11 assumption was taken that a living donor was readily available and immediate LDLT was always possible except for a short waiting time for the process of donor evaluation.11 With this assumption, the survival advantage of LDLT was obvious when compared to the intention-to-treat survival for DDLT. While such a comparison may be useful for an individual donor to consider the benefit of LDLT, it does not provide any useful information for the transplant community to evaluate the role of LDLT in improving the survival of a cohort of patients waiting for transplantation. To evaluate properly the impact of LDLT on the outcome of patients with early unresectable HCC and the value of a LDLT program, the survival of both LDLT and DDLT should be calculated according to intention-to-treat basis.
For analysis of survival according to intention-to-treat principle, it is necessary to define the cohort of patients to be treated and the zero time point for the decision. This is clear for DDLT as all patients on the waiting list should be included and the zero time point is the time of listing. Analysis of intention-to-treat survival after LDLT is more difficult because the precise cohort of patients and the zero time point of intention-to-treat are arguable. Theoretically, from the perspective of the transplant team, the alternatives of both DDLT and LDLT are available to all the patients accepted on list. The process of waiting for a living donor is comparable to that of waiting for a cadaver graft. While the availability of a deceased donor graft depends on the system of organ allocation, the availability of a living donor depends on the family members' voluntarism and the donor selection criteria. Nevertheless, as the decision to pursue LDLT rests primarily on the living donor, analysis of the intention-to-treat survival for LDLT may include only those patients with a voluntary donor who starts to undergo medical evaluation and the remaining patients are considered to opt for DDLT. Analysis from this donor/recipient perspective takes into account the effect of the donor selection criteria, which has not been taken into consideration in hypothetical studies,10, 11 in limiting the survival advantage of LDLT. It allows a proper estimation of the expected outcome at a stage when the option of LDLT is actively pursued and a fairer comparison with DDLT in terms of its impact on survival. Despite the limitation of donor selection criteria, LDLT reduced the risk of death by ⅔ as compared to the alternative option of DDLT, and the survival rate at 4 years was increased from 31% for DDLT to 66% for LDLT.
In contrast to a deceased donor graft, which is a scarce public resource subject to a system of equitable allocation, a living donor liver graft is a gift to a dedicated recipient. The decision for LDLT is not based on a comparison of the outcome of 2 recipients, but on the balance of the risks and benefits for the donor and recipient. As a result, extended indications for LDLT in patients with HCC more advanced than the recommended criteria have been proposed. The Kyoto group adopted a selection criteria to include patients with HCC of any number and size and to exclude only those with extrahepatic metastasis or vascular invasion.21 Twenty-five of 56 patients who underwent LDLT did not meet the Milan criteria and the overall 3-year survival after transplantation was 55% only. Gondolesi et al.19 reported a 1-year survival of 82% in a series of 27 patients undergoing LDLT using a similar extended criteria. The follow-up, however, was short and was less than 1 year in 21 patients. Previous experience with liver transplantation in patients with advanced HCC indicates that the recurrence rate with extended indications will be high22–24 and the controversy is whether the recipient's compromised outcome justifies the risk of the living donor. At present, we regard LDLT for HCC with extended indications as an experimental procedure with unknown cost effectiveness and we do not recommend its routine practice. Only exceptional cases will be considered on an individual basis, and we have accepted only 2 patients in our experience with the management of 1,438 HCCs during the study period. In addition, since these patients are not eligible for deceased donor graft allocation in the first place, retransplantation using deceased donor graft should not be allowed if graft failure occurred.
In conclusion, although hypothetical studies suggested that LDLT should be the dominant strategy for patients with early unresectable HCC because of its survival advantage, the role of LDLT in clinical practice may be limited by complicated factors such as donor voluntarism and selection criteria. This issue is further complicated by the controversial extended indications of LDLT for patients with more advanced disease. The role and limitation of LDLT may vary in different transplant programs and are evolving with time. More clinical studies, preferably with an intention-to-treat basis, are needed before the impact of the strategy of LDLT in the management of patients with HCC can be defined.