Living-donor vs deceased-donor liver transplantation for patients with hepatocellular carcinoma

Abstract

With the increasing prevalence of living-donor liver transplantation (LDLT) for patients with hepatocellular carcinoma (HCC), some authors have reported a potential increase in the HCC recurrence rates among LDLT recipients compared to deceased-donor liver transplantation (DDLT) recipients. The aim of this review is to encompass current opinions and clinical reports regarding differences in the outcome, especially the recurrence of HCC, between LDLT and DDLT. While some studies report impaired recurrence - free survival and increased recurrence rates among LDLT recipients, others, including large database studies, report comparable recurrence - free survival and recurrence rates between LDLT and DDLT. Studies supporting the increased recurrence in LDLT have linked graft regeneration to tumor progression, but we found no association between graft regeneration/initial graft volume and tumor recurrence among our 125 consecutive LDLTs for HCC cases. In the absence of a prospective study regarding the use of LDLT vs DDLT for HCC patients, there is no evidence to support the higher HCC recurrence after LDLT than DDLT, and LDLT remains a reasonable treatment option for HCC patients with cirrhosis.

Key Words: Deceased donor liver transplantation, Hepatocellular carcinoma, Living donors, Living-donor liver transplantation, Recurrence

Core tip: The current opinions and clinical reports regarding differences in the recurrence of hepatocellular carcinoma (HCC) between living donor liver transplantation (LDLT) and deceased donor liver transplantation (DDLT) were reviewed. In the absence of a prospective study regarding the use of LDLT vs DDLT for HCC patients, only with some retrospective studies with conflicting results, there is no evidence to support the higher HCC recurrence after LDLT than DDLT, and LDLT remains a reasonable treatment option for HCC patients with cirrhosis.

INTRODUCTION

Hepatocellular carcinoma (HCC) is the 7^th most common cancer overall and the 3^rd most common cause of cancer-related death worldwide[1,2]. Since the landmark report of the Milan criteria by Mazzaferro et al[3], which demonstrated comparable outcomes of patients with HCC having a single tumor smaller than 5 cm in diameter or up to 3 tumors smaller than 3 cm in diameter with no vascular invasion or extra-hepatic disease determined by preoperative imaging studies, deceased - donor liver transplantation (DDLT) has become an established treatment for cirrhotic patients with HCC[4,5]. Similarly, in Asian countries where living-donor liver transplantation (LDLT) comprises the majority of liver transplantation procedures, LDLT has become an established treatment for HCC patients with end-stage liver disease[6,7]. LDLT is now considered a promising treatment for HCC patients in Western countries, not only to compensate for the shortage of donor organs but also to reduce the dropout rate on the waiting list[8].

With the accumulation of LDLTs for HCC patients, the impact of LDLT on recipient outcome compared with DDLT, especially the recurrence of HCC after liver transplantation, has become an important topic of debate[9]. The aim of this review was to encompass the current opinions and clinical reports regarding the differences in outcome, especially the recurrence of HCC, between LDLT and whole liver DDLT.

STUDIES COMPARING LDLT AND DDLT FOR HCC PATIENTS

Studies comparing LDLT and DDLT for HCC patients are summarized in Table 1. All DDLTs reviewed here were done with the whole liver graft.

Table 1 Studies comparing living - donor liver transplantation and deceased - donor liver transplantation for hepatocellular carcinoma.

Ref.	Country	Year	Study period	Type of LT	Case number	Recurrence - free survival			P	% Recur-rence rate	P	Criteria used	% Outside Milan	Differencein tumorcharact-eristics	Median follow-up period (mo)
						1-yr	3-yr	5-yr
Impaired results in LDLT
Park et al[10]	South Korea	2014	1999-2010	LDLT	166	89		81	0.045	19	0.045	UCSF	NA	none	35
				DDLT	50	96		94		6
Vakili et al[13]	United States	2009	1999-2007	LDLT	28					29	0.05	UNOS	25	none	41
				DDLT	65					12
Kulik et al[12]	United States	2012	1998-2010	LDLT	100	80	66	56	0.05	38	0.0004	UNOS	59	More aggressive in LDLT	60
	Multi-center			DDLT	97	90	81	73		11			30
Lo et al[14]	Hong Kong	2007	1995-2004	LDLT	43	93	71	71	0.029	29	0.029	UCSF	26	More aggressive in LDLT	33
				DDLT	17	100	100	100		0			29
Comparable results
Sandhu et al[15]	Canada	2013	1996-2009	LDLT	58	88	75	70	NS	17	NS	Toronto criteria	28	none	38
				DDLT	287	86	75	70		15			32		31
Bhangui et al[16]	France	2011	2000-2009	LDLT	36	100	89	88	NS	13	NS	UCSF	27	none	58
				DDLT	120	93	89	86		13			21		50
Li et al[36]	China	2010	2005-2009	LDLT	38	71	42		NS	50	NS	UCSF	79	none	25
				DDLT	101	76	41			55			68
Di Sandro et al[35]	Italy	2009	2000-2007	LDLT	25		96	96	NS	4	NS	Milan	20	none	NA
				DDLT	154		91	89		11			31
Sotiropoulos et al[20]	Germany	2007	1998-2006	LDLT	45	88	75		NS	12	NS	UCSF	44	none	NA
				DDLT	55		81			14
Hwang et al[8]	South Korea	2005	1992-2002	LDLT	237	83	80		NS	18	NS		27	none	26
	Multi-center			DDLT	75	88	82			16			29		45
Gondolesi et al[17]	United States	2004	1988-2002	LDLT	36	82	74		NS	19	NS	UNOS	53	none	15
				DDLT	165	90	83			19

DDLT: Deceased - donor liver transplantation; HCC: Hepatocellular carcinoma; LDLT: Living - donor liver transplantation; LT: Liver transplantation; UCSF: University of California, San Francisco; UNOS: United Network for Organ Sharing; NA: Not applicable; NS: Not significant.

Studies reporting a poorer outcome in the LDLT setting

Park et al[10] recently reported poorer recurrence-free survival among 166 LDLT recipients (81% at 5 years) compared to 50 DDLT recipients (94% at 5 years; P = 0.045). The noteworthy finding of this study was that the smaller the LDLT graft, the poorer the recurrence - free survival. Based on this finding, Park et al[10] suggested that the physiology of the small graft may stimulate tumor recurrence.

The results of the A2ALL cohort in United States also demonstrated an impaired outcome in LDLT recipients. In their initial report[11], they found a higher rate of recurrence within 3 years in LDLT than in DDLT (29% vs 0%, P = 0.002), but there was a clear tendency toward more aggressive tumor characteristics in the LDLT group. The same group recently published an updated report[12], in which HCC recurrence remained significantly different between LDLT and DDLT after adjustment for tumor characteristics. They concluded that the higher recurrence observed after LDLT was likely due to differences in the tumor characteristics, pretransplant HCC management, and waiting time.

Vakili et al[13] reporting the Lahey Clinic experience, demonstrated that the HCC recurrence rate of LDLT (29%) was significantly higher than that of DDLT (12%) (P < 0.05), but survival after LDLT was significantly better than that following DDLT for HCC during the same period (P = 0.02).

Lo et al[14] from Hong Kong also reported a significantly higher incidence of HCC recurrence, 29% in LDLT and 0% in DDLT (P = 0.029). While the tumor characteristics were comparable between groups, the authors speculated that LDLT as a salvage transplantation, microscopic vascular invasion, and liver regeneration led to the difference in the recurrence rate.

Studies reporting a comparable outcome

Sandhu and colleagues of the Toronto group[15] reported that LDLT and DDLT both provide similarly low recurrence rates and high survival rates. They compared the results of 58 LDLT cases with those of 287 DDLT cases having comparable tumor characteristics, in which the 1-, 3-, and 5-year recurrence-free survival rates were 88%, 75%, and 70%, and 86%, 75%, and 70%, respectively.

In a well-designed study by Bhangui et al[16], an intention-to-treat analysis was conducted with recurrence rate representing the primary endpoint, comparing 36 LDLT cases and 147 DDLT cases. The authors demonstrated that both LDLT and DDLT provided similar recurrence - free survival rates (88% vs 86% at 5 years) for patients with HCC. The dropout rate and waiting time were significantly lower in the LDLT group than in the DDLT group, and there was also a trend toward a longer time to recurrence in the LDLT group, which may guarantee additional advantages with LDLT.

The Mount Sinai group[17,18] reported comparable recurrence - free survival between LDLT (n = 36) and DDLT (n = 165; 74% vs 83% at 2 years, P = 0.3). When stratified by tumor size (5 cm diameter) and the existence of microvascular invasion, there was still no difference between groups.

Sotiropoulos and colleagues of Essen, Germany[19,20], also supported the comparable recurrence - free survival rates between LDLT and DDLT for HCC (75% vs 81% at 3 years).

Hwang et al[21] of South Korea performed a nationwide survey regarding this issue. Among 237 LDLTs and 75 DDLTs for HCC, the 1 - and 3 - year recurrence - free survival rates were 83% and 80%, and 88% and 82%, respectively, with no significant difference between them.

A comparison of outcomes after liver transplantation obtained from database studies revealed comparable patient survival rates between LDLT and DDLT. According to a report from the Japanese Liver Transplantation Society Registry[22], a total of 6097 LDLTs were performed in Japan by the end of 2010, and 1225 (32%) were indicated for HCC, which was the most common indication in adult patients. The 1-, 3-, 5-, and 10-year cumulative survival rates of LDLT for HCC were 85%, 74%, 69%, and 60%, respectively. Todo and colleagues[23] performed a detailed survey using the same database (up to the end of 2005), comprising 653 patients who had undergone LDLT for HCC in Japan. At 1, 3, and 5 years, overall patient survival was 83%, 73%, and 69%, and disease-free survival was 77%, 65%, and 61%, respectively. Based on preoperative imaging studies, 62% were within the Milan criteria and 38% were beyond the Milan criteria, with 5-year recurrence-free survival rates of 90% and 61%, respectively (P < 0.001). These findings do not differ much from those obtained in the DDLT database of the United States and Europe[24-27], and may validate the use of LDLT for HCC patients.

CURRENT OPINIONS REGARDING THE DIFFERENCE BETWEEN LDLT AND DDLT

A randomized clinical study would be best to settle the controversy regarding the use of LDLT vs DDLT for HCC patients, but this is indeed difficult, if not impossible, to realize given the complicated decision-making process involved in LDLT. No prospective study has been conducted to date.

The Toronto group[28] recently performed a meta-analysis on 12 retrospective studies comparing the recurrence rates and recurrence - free survival between LDLT and DDLT recipients. A total of 633 LDLTs and 1232 DDLTs were enrolled, and the study provided evidence of lower disease - free survival after LDLT compared with DDLT for HCC (HR = 1.59, 95%CI: 1.02-2.49; P = 0.041). In contrast, there was no difference in overall survival between LDLT and DDLT (HR = 0.97, 95%CI: 0.73-1.27; P = 0.808). As mentioned by the authors of the paper, however, all involved studies were retrospective, had a low data quality score with poor reporting of baseline patient characteristics and an inadequate statistical approach, and were heterogeneous in critical aspects such as indication criteria and basal tumor characteristics, which warrant further well-designed studies to determine whether differences in HCC recurrence are due to study biases or biologic differences.

A recent review article by experts[29] concluded as follows: Although there is no strong evidence to support the higher HCC recurrence rates in LDLT than DDLT, the higher recurrence rates in LDLT recipients reported by several authors cannot be ignored. Actually, there are critical differences among societies such as: (1) differences in the allocation system for DDLT and LDLT; (2) differences in the availability of deceased donors; (3) differences in the potential waiting time; and (4) the differences in regional and national organ transplant law. In addition to taking into account these differences, liver transplant candidates with HCC and their potential live donors should be informed following risks and benefits; the waiting time for DDLT may lead to the dropout due to HCC progression which could be avoided by the prompt LDLT, however, the prompt LDLT may mask the aggressive tumor characteristics which may lead to a higher HCC recurrence rates. Although the currently available literatures can provide a low evidence for the difference of HCC recurrence between DDLT and LDLT, the tumor characteristics and biology seem to significantly influence on the recurrence, while the graft type and waiting time are less likely important as a possible risk factor.

POSTULATED THEORIES FOR DIFFERENCES BETWEEN LDLT AND DDLT

LDLT provides several advantages compared with DDLT, such as a shorter waiting time, good quality graft with normal liver function and shorter ischemic time, and pretransplant treatment optimization, which might contribute to improved survival in LDLT recipients. Some of these characteristics, on the other hand, may lead to a favorable milieu for tumor progression[9].

There are several hypotheses other than tumor characteristics to explain the inferior outcome of LDLT. One explanation for the higher recurrence rates in LDLT is fast-tracking patients into liver transplantation, the so - called fast-track effect[11,30]. Some patients with more biologically aggressive HCC might drop off the waiting list due to tumor progression beyond the criteria during the wait-time in the DDLT setting. In contrast, due to the shortened wait time for LDLT candidates, progression of HCC with an aggressive tumor biology might not be recognized during such a short wait-time. This scenario might account for the higher HCC recurrence in the LDLT setting.

Another hypothesized mechanism for the higher recurrence rates in LDLT is that growth factors and cytokines released during rapid regeneration of the partial grafts from living donors might contribute to tumor progression and recurrence[31-34]. A rapidly regenerating liver parenchyma and ischemic-reperfusion injury facilitated by a small-for-size graft in LDLT setting might be a more favorable environment for tumor progression and HCC recurrence.

Additionally, some authors[11,35,36] insist that the technique of LDLT per se foregoes the principles of oncologic surgery. During LDLT, the meticulous dissection and mobilization of the liver might increase the possibility of tumor capsule violation or tumor embolization through the hepatic veins, thus promoting tumor dissemination. Preserving the native vena cava and the bile duct/hepatic artery/portal vein in the hepatic hilum might increase the risk of leaving the residual tumors.

As opposed with the above-mentioned anecdotal explanations, the advanced tumor characteristics of LDLT recipients can reasonably explain the higher recurrence rate in the LDLT setting. Grafts from living donors are not limited by restrictions imposed by the organ allocation system, meaning that the relation of the graft and recipient is usually one-on-one. Consequently, selection criteria based on the tumor burden, such as the tumor size and number, can be considered relative on a case-by-case basis, taking into account the presence of risk factors for recurrence and the chance of survival, as well as the wishes of the donor[37]. Consequently, the majority of Asian transplant centers have adopted extended criteria beyond those of Milan or the University of California, San Francisco (UCSF)[38]. Based on some studies, differences in patient tumor characteristics between LDLT and DDLT remain a main reason for the higher recurrence rate in LDLT. Additionally, in the majority of the aforementioned studies comparing LDLT and DDLT for HCC patients, tumor burdens such as the size, number, vascular invasion, and poor differentiation have proved to be independent risk factors for HCC recurrence after liver transplantation, all of which may lead to a rational explanation for the impaired recurrence - free survival of LDLT compared to DDLT.

OUR EXPERIENCE

At our institution, the University of Tokyo Hospital, a total of 423 adult recipients underwent LDLT by the end of 2012. Among them, 125 (30%) patients had HCC. The principle criterion for LDLT for HCC at our center is “up to 5 nodules with a maximum tumor diameter within 5 cm”, which we call the “5-5 rule”[39]. Of the 125 patients, 118 (94%) were within the 5-5 rule criteria and 109 (87%) were within the Milan criteria. Overall survival of the 125 recipients at 1, 3, and 5 years was 88%, 82%, and 76%, respectively, with a median follow-up period of 8 years. A total of 11 (9%) patients developed HCC recurrence with a cumulative recurrence rate at 1, 3, and 5 years of 6%, 9%, and 11%, respectively.

We compared the graft regeneration rate between patients with HCC recurrence (n = 11) and those without recurrence (n = 114) to confirm the association of liver regeneration with HCC recurrence. The regeneration rate was calculated as follows: (graft volume at 3 mo after LDLT- initial graft volume)/initial graft volume × 100 (%). As shown in Table 2, there was no difference in the regeneration rate between those with HCC recurrence and those without recurrence. At the same time, the graft type (right vs left) and the initial graft volume ratio to the recipient’s standard liver volume were also compared between groups, revealing no difference. A similar result was reported by the Asan group of South Korea[40], in which the graft-recipient weight ratio had no impact on HCC recurrence after LDLT among 181 LDLT recipients with HCC. Our result as well as the report of the Asan group clearly demonstrated that graft regeneration of the partial liver graft has no impact on HCC recurrence, at least in a clinical setting. The independent predictors for HCC recurrence in our series were tumors not within the 5-5 rule (Tokyo criteria), AFP level over 400 ng/mL, and des-gamma-carboxy prothrombin levels over 200 mAU/mL.

Table 2 Graft characteristics and hepatocellular carcinoma recurrence.

	Patients with recurrence(n = 11)	Patients without recurrence(n = 114)	P
Regeneration rate at 3 mo (%)	90 ± 24	93 ± 34	0.732
Graft type: right/left	4/7	36/78	0.702
Initial graft volume ratio to standard liver volume (%)	46 ± 9	47 ± 9	0.842

CONCLUSION

In conclusion, there is no strong evidence to support higher HCC recurrence after LDLT than DDLT, and it may be reasonable to use different indication criteria for LDLT and DDLT, while there could be a potential bias in choosing the articles in the present study. LDLT should always be considered as a treatment option for HCC patients with advanced cirrhosis in areas where deceased donors are scarce or for patients whose tumor status interrupts access to DDLT.