 less-aggressive tumor biology [75]. In addition, for patients with oligometastatic disease, the resection of isolated extrahepatic recurrent HCC in regional lymph nodes, adrenal glands and lungs has shown favorable results [145][146][147].

Locoregional Therapies
Data on liver-directed locoregional therapies for the management of HCC recurrence after LT are largely lacking, with only some small case series currently available. In a retrospective study, Huang et al. compared 15 patients with post-LT HCC recurrence treated surgically with 11 patients treated with radiofrequency ablation (RFA), showing no differences in the 5-year OS (35% vs. 28%, p = 0.88) and a worse disease-free survival, although not statistically significant, in the RFA group (16% vs. 0%; p = 0.75) [148]. Microwave ablation (MWA) also may be useful in treating HCC recurrence after LT [149]. Zhai et al. evaluated safety and efficacy of MWA in a series of 11 LT recipients with intrahepatic recurrent HCC, finding the procedure was well tolerated and only three cases had tumor progression after treatment (1-7 months) [150]. However, survival rate at 2 years was 15.3% and the mean survival time was 17.3 months.
The efficacy of conventional transarterial chemoembolization (TACE) in 28 patients with recurrent HCC after living donor LT was evaluated by Ko et al. [151]. A reduction in tumor size ≥25% was observed in 19/28 patients (67.9%), but intrahepatic or extrahepatic metastasis was observed in 92.9% of patients in the first 6 months of follow-up after TACE. Moreover, prognosis was very poor, with 1-, 3-and 5-year survival rates resulting 47.9%, 6.0% and 0%, respectively, and a mean survival of 9 months [151]. Similar results were obtained by Zhou et al. who demonstrated a significantly improvement in post-recurrence survival in TACE group, despite the prognosis remaining far from being satisfactory (286 days vs. 85 days, p = 0.03) [152].

Systemic Therapies
Since its approval following the positive results of the SHARP and the Asia-Pacific trial [153,154], systemic therapy with sorafenib became the standard of care for advanced stage HCC, and it has also been studied in the management of non-resectable recurrent HCC after LT. However, its safety and effectiveness in this setting has not been evaluated in randomized clinical trials, and available data are limited and restricted to small studies and case series. A single-center retrospective investigation form Italy compared 15 patients treated with sorafenib and 24 receiving best supportive care (BSC) after HCC recurrence, demonstrating a significantly improved recurrence-free survival in the former group (21.3 vs. 11.8 months, HR = 5.2, p = 0.0009) [155]. In their metanalysis, Mancuso et al. demonstrated that patients with recurrence receiving sorafenib after LT had a pooled 1-year survival of 63% (ranging from 18% to 90%) [156]. Overall, a median survival of 12 months (range 1. 45-21.3) was demonstrated for sorafenib treatment in this setting [155,[157][158][159][160][161][162].
Sorafenib use in the after-LT period may be limited by side effects and its safety is a point of concern. More than half of patients with recurrent HCC treated with sorafenib require dose reduction [137,155]. In a recent analysis of the United States cohort of the GIDEON registry, the safety and tolerability of this drug was evaluated in patients with HCC recurrence after LT and after surgical resection [163]. This study demonstrated that most adverse events occurred in the first 4 weeks of treatment and the incidence of toxicities requiring sorafenib discontinuation was similar between the two groups. Therefore, the authors were not able to conclude that sorafenib in post-transplant setting was associated with an increased toxicity compared to patients treated for their primary HCC. However, close monitoring is mandatory, not only during the first weeks of treatment, but also in the case of immunosuppression with mTOR inhibitors since this association demonstrated an increase in the rate of dose reduction and discontinuation due to severe adverse events [162,[164][165][166][167].
In patients progressing while on treatment with sorafenib, regorafenib in second-line setting may be an option [168]. It proved to be a safe and tolerable treatment in a preliminary evaluation [169], and very recently a multicenter retrospective cohort study including 81 patients (36 treated with regorafenib and 45 undergoing BSC at sorafenib discontinuation) confirmed these findings [170]. From sorafenib discontinuation, regorafenib was able to provide a significantly longer OS compared to BSC (13.1 vs. 5.5 months, p = 0.002) and was independently associated with lower mortality (HR = 0.37, 95% CI 0.16-0.89) [170]. The median OS of the sorafenib/regorafenib sequence (considered from the beginning of sorafenib) was 28.8 months. All regorafenib-treated patients experienced side effects, but adverse events (grade ≥ 3) were severe in 14 patients (38.9%) [170]. Currently, no data except for case reports [171] are available for other recently approved tyrosine kinase inhibitors (lenvatinib [172] and cabozantinib [173]) and monoclonal antibodies (ramucirumab [174]). Although transplanted patients have been excluded from all registration trials, these drugs will likely be adopted soon in real-life series in post-LT settings, as previously done with sorafenib and regorafenib, thus allowing the collection of data on new treatment sequences to adopt in this special population [175].
The use of other systemic chemotherapy agents has been evaluated for the treatment of HCC recurrence after LT, but data are again very limited. Metronomic capecitabine (administered in low doses without breaks) proved to be safe and effective in advanced HCC [176][177][178], and it was evaluated also in 38 patients with post-LT HCC recurrence [179]. The safety profile was similar to that of sorafenib and a significantly increased survival after tumor recurrence was reported compared to patients undergoing BSC (median 22 vs. 7 months; p < 0.01).
Very recently, several studies evaluating the role of immunotherapy in HCC have been conducted and more are currently ongoing. ICIs are designed to target programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) or cytotoxic T-lymphocyteassociated antigen 4 (CTLA-4), all fundamental negative regulators of T cell function [180]. These drugs act through the stimulation of an effective antitumor immune response, allowing immune system to recognize and destroy cancer cells. However, the reactivation of the immune system is not only directed against the tumor and can also lead to immune mediated adverse events, similar to autoimmune diseases, as a consequence to the loss of the ability to recognize self from non-self. Following positive results of phase II clinical trials (Checkmate 040 [181] and Keynote 224 [182]), the Food and Drug Administration granted conditional approval the PD-1 inhibitors nivolumab and pembrolizumab in secondline after sorafenib. Unfortunately, recent phase III studies failed to confirm a statistically significant advantage in progression-free and OS for pembrolizumab [183]. No phase III data on nivolumab in second-line are available at this time, but the OS of nivolumab treated patients in first-line was not significantly longer compared to those receiving sorafenib in the Checkmate 459 phase III trial [184]. A significant step forward in the management of advanced HCC and a robust proof of the effectiveness of immunotherapy has been achieved very recently following the positive results of the IMbrave150 trial [185]. More than 10 years after sorafenib approval, the combination of atezolizumab (an anti-PD-L1) and bevacizumab (anti-vascular endothelial growth factor (VEGF) monoclonal antibody) proved to be superior over sorafenib in first line.
Despite the very promising results with immunotherapy, the possibility to safely use ICIs in post-transplant setting remains a relevant issue. In solid organ transplant recipients, PD-1/PD-L1 pathway is fundamental in regulating alloimmunity and transplant tolerance [186]. Therefore, the use of ICIs after transplantation may expose these patients to the risk of allograft rejection and graft loss, with more severe cases that may progress even to death [175,187,188]. Several case reports have been published on the use of drugs targeting CTLA-4 and PD-1/PD-L1 in patients with HCC, melanoma and non-small cell lung cancer after liver, kidney, heart and corneal transplants [188][189][190][191][192][193]. Safety and efficacy of PD-1 inhibitors was reported in a retrospective pilot evaluation of the Mayo Clinic experience in seven patients (five with recurrent HCC and two with melanoma) after LT [190]. In this study, three out of seven patients discontinued the treatment early (two because of graft rejection and one because of multiorgan failure unrelated to therapy). Among the four patients evaluable for response assessment, three patients with HCC recurrence progressed and a complete response without graft rejection was observed in one patient with metastatic melanoma. Literature reports 25-54% graft rejection rates, occurring rapidly after the start of immunotherapy (8-19 days) [190][191][192]. In the case of graft rejection, some effective treatments are available (steroids, mycophenolate mofetil and antith