To evaluate the response to neoadjuvant therapy, EASL guidelines suggest that the treatment effect should be assessed based on the amount of viable tumor load, not just a reduction in overall tumor size, and suggested using dynamic CT or MRI to differentiate between viable tumor and necrosis [51]. Overall assessment should include the combined results of target lesions, non-target lesions, and new lesions based on modified Response Evaluation Criteria in Solid Tumors (mRECIST) [52]. Methodologically, a 3-month interval reassessment of radiological image along with AFP sampling is widely accepted in clinical practice [53].

In terms of morphological criteria after the down-stage of intermediate HCC, Milan criteria are the worldwide accepted LT criteria. The UCSF criteria are also being used in some regions in the USA. However, in combination with tumor markers or other surrogate markers, transplant criteria after down-stage may not necessarily be Milan or UCSF criteria as long as tumors respond well to LRT [7, 22]. This area is still a controversial topic in many high volume LT centers.

There is the need to identify surrogate markers for tumor biology in addition to morphological tumor size and number to explore optimal criteria. Because of its association with pathological feature and tumor biology, tumor markers such as AFP and PIVKA-II (protein induced by vitamin K absence) have gained attention. Several studies from Japan suggested that PIVKA-II correlate well with microvascular invasion [54, 55]. AFP is widely recognized as predictive factor for post-transplant recurrence and is proposed to be included for the LT criteria after the down-stage of advanced HCC [1]. Because several studies showed a preoperative AFP level >1000 ng/mL to be a strong independent predictor of post-transplant tumor recurrence, US national conference on liver allocation recommend that for patients who had an initial AFP >1000 ng/mL, successful down-staging should include a decrease to AFP levels <500 ng/mL, and all subsequent AFP levels must also be <500 ng/mL prior to LT [1]. Since there is no biomarker that can predict or prognosticate HCC patients prior to LT, tumor behavior during the waiting time has been considered as a surrogate marker for tumor biology. During period of waiting time after down-stage, the tumor biology is allowed to become apparent by radiological study. This concept “ablate and wait” has recently gained popularity among transplant community [56].

Adjuvant systemic chemotherapy for HCC is given after LT in attempt to treat the micro-metastases that might be present at the time of LT. Table 13.2 summarized selected studies of adjuvant chemotherapy after LT for HCC. Doxorubicin is the most commonly used agent for adjuvant chemotherapy to HCC but newer agents are currently being tested [57, 58].

In 1990s, several uncontrolled trials were conducted to look for outcomes after LT for HCC beyond Milan criteria using doxorubicin-based adjuvant chemotherapy; disease-free survival ranged 46–54 % at 5 years that were considered to be better compared to historical controls [23, 59]. However, the results of these uncontrolled studies are in contrast to recent studies. Pokorny et al. conducted the first prospective RCT to evaluate the efficacy of perioperative doxorubicin chemotherapy for patients with advanced HCC who underwent LT [60]. Thirty-four HCC patients received biweekly doxorubicin pre-, intra-, and postoperatively and were compared with 28 control patients. 5-years OS were 38 and 40 % in the chemotherapy group and in the control group, and 5-years DFS rates were 43 and 53 % without significant difference. Another prospective, randomized, multicenter study was reported from Sweden comparing 17 patients with chemotherapy and 25 control HCC patients. The study showed no significant advantage of adjuvant therapy with weekly systemic doxorubicin administered perioperatively [61].

More recently, some investigators investigated the efficacy of adjuvant FOLFOX in patients who underwent LT for HCC [62]. FOLFOX (5-FU, leucovorin, and oxaliplatin) is a commonly used chemotherapy regimen that has shown clinical activity in metastatic colorectal cancer [63, 64] and was recently reported to be active against HCC [65, 66]. The first RCT from China showed somewhat promising result as there was improvement in OS but not in DFS. More studies are needed to investigate the efficacy of FOLFOX as adjuvant therapy for HCC.

With the efficacy of sorafenib in advanced HCC [40, 41], its use in the transplantation field has been tested [67]. Several small series reported data on the safety and efficacy of sorafenib in patients with HCC recurrence after LT [68–72]. These studies showed the safety and preliminary efficacy profile of sorafenib for recurrent HCC after LT. No deterioration of liver graft function was reported, and adverse events were easily manageable with dose reduction of sorafenib. However, dose reduction was needed in 20–73 % of patients in these reports in the post-LT setting, indicating full dose of sorafenib (400 mg twice daily) may not be feasible. In regard to efficacy, the studies showed median time to progression of 2.9–6.8 months and a median OS after the initiation of sorafenib of 5.4–20.1 months [68–70, 72].

Better outcomes with response to sorafenib in the transplanted patients compared to non-transplant patients can be explained by smaller metastatic lesions, and preserved liver function of transplanted patients. In addition, mammalian target of rapamycin (mTOR) inhibitors were used with sorafenib in the majority of reported cases and thus a potential synergistic anticancer activity of these two drugs could be postulated.

The data of the good safety profile and efficacy in recurrent HCC after LT suggest potential role of sorafenib as adjuvant treatment in high-risk patients after LT. To date, the data on sorafenib regarding adjuvant therapy are limited with only one small retrospective case-control match study [73]. Currently, a phase II randomized multicenter prospective study to investigate the efficacy of adjuvant sorafenib for high-risk patients is underway (ONC-2010-31). However, with the recent data demonstrating that sorafenib did not improve recurrence-free survival compared with placebo after curative resection or ablation of hepatocellular carcinoma (HCC), it dampens the enthusiasm of the usage of sorafenib after LT [74].

m-TOR inhibitors have gained a high degree of attention in regard to suppression of tumor activity. These drugs have a potential anticancer effect which has been demonstrated in the experimental setting. The anticancer effect is related to the prevention of angiogenesis by blocking vascular endothelial growth factor-mediated pathways in endothelial cells as well as blockade of downstream for P-I-3-kinase and akt pathways [75].

Kneteman et al. reported the first successful series of 40 HCC patients (19 within Milan criteria, 21 beyond) using sirolimus-based immunosuppressive protocol designed to minimize exposure to calcineurin inhibitor (CNI) and steroids [76]. Only five patients experienced HCC recurrence at 44 months follow-up. Four-years DFS were 81 % and 77 % in patients within Milan criteria and beyond Milan criteria, respectively. Since this satisfactory result, several centers have employed m-TOR inhibitors for immunosuppressive protocol in HCC patients [77, 78].

Recently, a matched case-control study from Bologna showed significant benefits from sirolimus-based immunosuppression compared with CNI-treated patients [79]. Tumor stage and unfavorable HCC pathological features were matched between two cohorts of 31 patients. Three-year DFS was significantly higher in sirolimus group with 86 % vs. CNI group with 56 %.