Living-donor LT (LDLT) has the most significant impact in Asia, where the issue of organ shortage is most extreme. The availability of LDLT has provided the driving force for a drastic increase in cases of LT in recent years. The number of LDLTs performed in Asia each year has increased tremendously. In 2005, LDLT accounted for 90% of the 1497 LTs performed in Asia (excluding mainland China)[20]. In Hong Kong, about half of the LTs are LDLTs, and more than half are for HCC.

To justify LDLT for HCC, it should have a survival outcome comparable to that of deceased-donor LT (DDLT). Roayaie et al[21] reported a tendency for early tumor recurrence after LDLT (mean: 8.7 mo) when compared with DDLT (mean: 19.6 mo) in a cohort of 311 patients with histologically confirmed HCC after LT. Another multicenter LDLT cohort study (A2ALL) of 106 HCC patients reported a significantly higher 3-year tumor recurrence rate after LDLT (29%) compared with that after DDLT (0%)[22]. In Hong Kong, a retrospective study has been conducted to compare LDLT and DDLT in terms of treatment outcomes in 60 HCC patients[23]. Given the standard patient selection criteria based on radiological tumor size and number according to the UCSF criteria, there was an obvious selection bias for some important clinical characteristics in the LDLT group. Patients having LDLT for HCC had fewer incidental tumors, a lower rate of preoperative transarterial chemoembolization (TACE), a lower rate of salvage transplantation (with pretransplant resection or ablation), shorter waiting time on list, and a lower graft-weight-to-standard-liver-weight ratio. The inferior oncological outcomes in the LDLT group were possibly caused by more aggressive tumor behavior and small-for-size graft injury and regeneration[24]. Although the overall survival rates were comparable between the LDLT and DDLT groups, the cumulative 5-year HCC recurrence rate was significantly higher in LDLT group (29% vs 0%). Thus, selection of patients with early HCC based on standard tumor size and number for LDLT and DDLT may eventually result in different clinical outcomes. When considering a patient for an LDLT, besides a certain set of patient selection criteria, there are more factors to be taken into account, which include the unique nature of a living-donor graft as a dedicated gift to the recipient and potential donor risks, and additional clinical characteristics should also be considered and good preoperative counseling should be given to the donor and patient. In Hong Kong, the policy of “6-mo-wait” before salvage transplantation does not apply to LDLT, since both donors and recipients willingly accept the relatively higher recurrence rate with the realization that LDLT is their only option.

Catalano et al[25] reported the initial results of graft liver resection for graft ischemic damage in 12 patients. The perioperative mortality rate was high at 66.6%, manifesting the difficulty of graft liver resection in the presence of sepsis. On the other hand, Sommacale et al[26] reported that graft liver resection for intrahepatic recurrence achieved a low mortality rate and satisfactory long-term survival with a median follow-up of 92 mo. Nonetheless, there were only 3 patients in the series. According to unpublished data from the only LT center in Hong Kong, in 252 patients who underwent LT for HCC, 35 had disease recurrence. Three patients had only intrahepatic recurrence and underwent aggressive resection. This very small series had a 66.7% 3-year survival and 0% mortality. Actually, all reported series were small and the studies had a retrospective nature with significant selection biases. Hence, more evidence is needed to support graft liver resection as a good treatment for HCC recurrence.

Radiofrequency ablation (RFA), a local ablative treatment, is the established treatment option for resectable and unresectable HCCs. Its efficacy has been shown to be comparable to that of partial liver resection in treating small HCCs[27]. It would be reasonable to extrapolate that RFA can be an option for treating post-LT intrahepatic recurrence of HCC too. A case report showed that percutaneous RFA achieved 2-year disease-free survival in a 65-year-old patient who had a solitary recurrent HCC inside the graft liver[28].

Numerous advances in external-beam radiation therapy have allowed more accurate targeting and made aggressive dose-fractionation strategies possible with techniques such as stereotactic body radiation therapy (SBRT). As a kind of radiosurgery, SBRT was originally developed to treat intracranial malignancies. It has since been adopted to treat extracranial diseases. The use of SBRT as treatment of HCC has yet to be established, but it is tested by a number of clinical trials for its efficacy in treating unresectable and unablatable HCCs. Initial results showed that it achieved a local control rate of 87%-100%[17,29-31].

Intra-arterial infusion of yttrium-90 microspheres (Y-90 SIR) is an established treatment for unresectable HCCs[32] and has gained popularity in recent years. It is often used to treat advanced HCC, especially in patients with a large tumor burden, suboptimal performance status, or lobar portal vein thrombosis[33]. Chan et al[34] reported that in the treatment of primary HCC, it achieved a 38%-65% partial response rate and a median survival duration of 23 mo, which is 2.6-4.7 times the duration seen in historic controls. In a recent study of 20 patients with unresectable HCCs, it achieved an overall survival rate of 90% at a median follow-up period of 275 d (range: 32-677 d)[33]. However, the data on the use of SBRT and intra-arterial infusion of Y-90 SIR for recurrent HCC after LT are extremely scarce. In the only two case reports, complete tumor necrosis was observed in a 52-year-old and a 42-year-old patient with solitary intrahepatic recurrence of HCC after a course of SBRT and intra-arterial infusion of Y-90 SIR respectively[35,36].

TACE is often used as a bridging therapy for waitlisted patients and its results are satisfactory. Lo et al[37] reported that it resulted in marked tumor response, and the actuarial survival was significantly better in the TACE group (1 year: 57%, 2 years: 31%, 3 years: 26%) compared with the control group (1 year: 32%, 2 years: 11%, 3 years: 3%, P = 0.002). When adjustments for baseline variables that were prognostic on univariate analysis were made with a multivariate Cox model, the survival benefit of TACE remained significant (relative risk of death: 0.49; 95%CI: 0.29-0.81; P = 0.006).

Chok et al[38] compared TACE and RFA for unresectable HCCs and found that they were comparable in terms of time to disease progression (P = 0.95) and overall survival (P = 0.02).

Successful outcomes of TACE therapy (with and without the use of iodized oil) for the treatment of recurrent intrahepatic HCC after LT have been reported[39,40] although the studies were small and retrospective in nature. As said before, the transcatheter procedure can be technically demanding in the presence of distorted vasculature in a post-LT setting.

High-intensity focused ultrasound (HIFU) ablation is a relatively new totally extracorporeal treatment for unresectable HCCs. Ng et al[41] in their initial research reported that it achieved a primary effective treatment rate of 79.5% and 1-year and 3-year overall survival rates of 87.7% and 62.4% respectively.

Cheung et al[42] compared HIFU ablation with TACE and reported that HIFU ablation achieved rates of complete tumor response, partial tumor response, stable disease and progressive disease (in accordance with the modified Response Evaluation Criteria in Solid Tumors) of 50%, 7.7%, 25.6% and 7.7% respectively. As with TACE, the corresponding rates were 0%, 21.2%, 63.5% and 15.4% respectively (P < 0.0001). The 1-year, 3-year and 5-year survival rates achieved by HIFU ablation were 84.6%, 49.2% and 32.3% respectively, and those by TACE were 69.2%, 29.8% and 2.3% respectively (P = 0.001).

Chan et al[43] compared HIFU ablation with RFA in terms of survival. The two kinds of ablative treatment produced similar results. The 1-year, 2-year, and 3-year disease-free survival rates were 37.0%, 25.9% and 18.5% respectively in the HIFU group, and 48.6%, 32.1% and 26.5% respectively in the RFA group (P = 0.61). The 1-year, 2-year, and 3-year overall survival rates were 96.3%, 81.5% and 69.8% respectively in the former, and 92.1%, 76.1% and 64.2% respectively in the latter (P = 0.19).

In the pilot study on HIFU ablation as a bridging therapy for HCC patients waitlisted for LT conducted at the only LT center in Hong Kong, it was found that with the availability of HIFU ablation, the rate of receiving bridging therapy increased dramatically from 39.2% to 80.4%. HIFU ablation and TACE achieved similar percentages of tumor necrosis as seen in excised livers (P = 0.353), and both treatments resulted in significantly higher necrosis rates than that in the best medical treatment group (P = 0.010 and 0.020)[44]. As HIFU ablation has been shown to be a useful bridging therapy, it should have great potential in the management of recurrent HCC after LT.

Mammalian target of rapamycin (mTOR) inhibitors have been shown to have a direct antitumorigenic effect and to be able to inhibit cell growth[45-47]. In experimental models of HCC, the mTOR pathway was aberrantly activated in up to half of the cases. Although the currently available data came from retrospective studies and are premature, there is the hope that mTOR-based immunosuppressive therapy after LT will one day come into use[48]. The use of sorafenib, an inhibitor of multiple tyrosine kinases (including c-Raf and b-Raf), has been approved as a first-line treatment for advanced HCC[49]. Activation of the Ras/mitogen-activated protein kinase pathway is a common finding in neoplastic processes (including in HCC) and is a determinant for promoting cell proliferation and the survival of tumor cells. This makes sorafenib an interesting drug; its use as a treatment for unresectable HCCs and as an adjuvant treatment before and after HCC recurrence is being investigated[50]. A study from Spain demonstrated that combination therapy resulted in an overall response (in accordance with the Response Evaluation Criteria in Solid Tumors) rate of 3.8% (1/26), and there was sustained stabilization of disease in 13 additional cases (50.0%)[42]. The median overall survival was 19.3 mo (95%CI: 13.4-25.1 mo), and the median time to progression was 6.77 mo (95%CI: 2.3-11.1 mo). Although a few studies have shown that there is some evidence of synergistic anticancer activity, early-phase clinical studies of mTOR inhibitors plus sorafenib for advanced HCC reported ambivalent findings, which were the results of increased toxicity (e.g., hand-foot syndrome) in combination therapy[51,52]. In a recent study from Italy, the outcomes of sorafenib treatment for post-LT HCC recurrence were significantly better than those of best medical care [median patient survival from recurrence: 21.3 mo vs 11.8 mo, hazard ratio (HR) = 5.2, P = 0.0009; median patient survival from untreatable presentation or progression: 10.6 mo vs 2.2 mo, HR = 21.1, P < 0.0001]. The only factor associated with survival found by multivariate analysis was treatment with sorafenib (HR = 4.0, P = 0.0325). No severe adverse event was registered[53]. Individualized treatment should be tailor-made for individual recipients, and input from oncologists would be of great value. However, drug toxicity is a major concern as shown in many studies, and their recommendations should not be overlooked.

It has been suggested that immunosuppressive therapy should switch from using non-mTOR inhibitors to using mTOR inhibitors. Another suggestion is that mTOR inhibitors can be used as an add-on. Monaco[54] found that the use of mTOR inhibitors might decrease the incidence of new malignancy after transplantation, mainly skin cancer.

A clinical trial by Alamo et al[55] comparing calcineurin inhibitors with everolimus and sirolimus for patients who received LT for oncological disease reported that the HCC recurrence rate was significantly lower and survival significantly prolonged in patients receiving either everolimus or sirolimus. A meta-analysis by Liang et al[56] endorsed the safety and efficacy of sirolimus-based immunosuppression for patients who received LT for HCC. Pooled results of the five studies eligible for evaluation showed that sirolimus-based regimens prolonged overall survival (OR = 2.47; 95%CI: 1.72-3.55) and decreased tumor recurrence (OR = 0.42; 95%CI: 0.21-0.83), with no significant differences in acute rejection and hepatic artery thrombosis.

A United States study compared sirolimus-based maintenance therapy with calcineurin inhibitor treatment for recipients of LT for HCC and found that overall survival was better in the sirolimus arm[57]. Clinical trials examining the anticancer effects of mTOR inhibitors in recipients of LT for HCC have shown encouraging results[58]. On multivariate analysis in a large Canadian trial, sirolimus-based maintenance therapy was one of the factors associated with improved survival after LT for HCC (HR = 0.53, 95%CI: 0.31-0.92, P≤ 0.05)[59].

The reported results of using these relatively new agents has suggested that they may prevent or reduce the incidence of HCC recurrence after LT, but a definite answer from large randomized controlled trials is still lacking.