The use of targeted therapies heralded a new era in the management of hepatocellular carcinoma. As mentioned above, cytotoxic chemotherapies have rarely yielded response rates of greater than 20 % and no trial has demonstrated a survival benefit for chemotherapy (Nowak et al. 2004). Sorafenib, an oral inhibitor of VEGFR and Raf, is the only systemic treatment that confers a statistical survival advantage, and has dramatically changed the management of HCC (Hollebecque et al. 2015). To date, it is the only targeted therapy approved by the FDA for HCC, despite multiple phase III trials targeting different pathways including VEGF, PDGFR, FGFR, EGFR, and mTOR (Table 2) (Abou-Alfa and Venook 2013; Harding and Abou-Alfa 2014). There are other targeted therapies currently under clinical trials exploring a host of cellular targets, including MET, MEK, arginine, and immune checkpoint inhibitors target (Table 3) (Hollebecque et al. 2015).

Sorafenib was studied in the SHARP trial in patients with advanced HCC (Llovet et al. 2008b). In this phase III study, 602 patients were treated with sorafenib plus placebo or placebo alone. The use of sorafenib improved survival by 30 %, translating to an overall survival of nearly 3 months. This survival was most pronounced in patients with HCV-related cirrhosis. The trial excluded patients with Child-Pugh B and C, raising questions about its efficacy and tolerability in patients with poor liver function. However, The Gideon registry showed that sorafenib could be used safely is subsets of patients with Child-Pugh B cirrhosis (Lencioni et al. 2014). In 2007, Sorafenib was approved by the FDA for systemic therapy for unresectable HCC. The benefit of sorafenib was replicated in the Asia-Pacific study although the magnitude of difference was smaller (Cheng et al. 2009). Several reasons have been postulated including ethnicity, population, etiology of HCC, and underlying liver function (Di Marco et al. 2013). Common side effects of sorafenib include anorexia, diarrhea, weight loss, hand foot skin reaction, hoarse voice and hypertension (Llovet et al. 2008b; Cheng et al. 2009).

The use of sorafenib in the setting of OLT for HCC has not been studied at length. Given its efficacy in unresectable HCC, a number of studies have been conducted exploring the role of sorafenib prior to OLT as a “bridging therapy,” postoperatively as an adjuvant therapy to decrease recurrence rates and in the salvage setting of recurrent HCC after OLT.

Though sorafenib clearly improves survival in transplant-ineligible patients with HCC, as shown in two large randomized phase III studies, it does not have dramatic response rates in the form of tumor shrinkage. The SHARP and Pan-Asia study had response rate by RECIST to be less than 5 %. Using standard RECIST may not be ideal, in part because of its cytostatic properties, as well as due to necrosis causing tumors to appear larger (Abou-Alfa et al. 2006). In fact, modifications to conventional RECIST have been developed, resulting in the modified RECIST (mRECIST), for a more appropriate assessment of response in HCC trials. mRECIST has been accepted and endorsed by the European Association for Study of the Liver and by the American Association for the Study of Liver Diseases. Using mRECIST in assessing response increases the amplitude of the observed tumor shrinkage and thus a better assessment of a therapeutic effect (Lencioni and Llovet 2010; Edeline et al. 2012). However, response rates with sorafenib are still low despite using mRECIST, and thus sorafenib is not an ideal candidate for neoadjuvant therapy as a monotherapy to downstage tumors prior to OLT. There have been case reports of transplant-ineligible patients initially treated with sorafenib who achieved a rare reduction in tumor burden, allowing them to be listed (Vagefi and Hirose 2010; Adair and Wigmore 2013). However, this is an uncommon outcome. Its most promising use is expected to be seen when used in combination with locoregional therapy, such as TACE, and TARE, and external beam radiation. In patients treated with conventional bridging therapies to the tumor locally, dropout rates from the transplant list can be as high as 50 % (Maddala et al. 2004). The combination is likely to have synergistic effects and is currently being actively studied (Fujiki et al. 2014). There is an ongoing prospective, phase III study entitled HeiLivCa, evaluating this hypothesis. Over 200 patients on the transplant list for HCC are randomized to receive TACE plus sorafenib or TACE alone prior to OLT, with the primary outcome as time-to-progression (Hoffmann et al. 2008). The results of this study are not yet available.

Generally, the goal of neoadjuvant therapy is to achieve tumor shrinkage prior to surgical resection, so as to improve surgical outcomes and limit residual disease. Tumors beyond Milan Criteria, exceeding 5 cm, do benefit from down-staging with TACE or TARE followed by OLT (Huang et al. 2013). As mentioned above, sorafenib does not generally shrink tumors, but it may improve outcomes by lowering the rate of dropout from the transplant list due to progression. An explorative, cost-benefit analysis was performed looking at the potential for improvement in rates of OLT for eligible patients should they receive sorafenib as a bridge to transplant. The authors determined that sorafenib has the potential to increase probability of receiving OLT by 5 % (Vitale et al. 2010). However, the safety of sorafenib prior to OLT has not fully been studied. The criticism of the analysis was that it did not take into consideration the potential for poor surgical outcomes for patients taking sorafenib, which has the potential to complicate wound healing during and after surgery (Finn 2012). A cohort study was performed comparing posttransplant outcomes in ten patients who received sorafenib prior to OLT. Death rates were similar to control patients, but a significantly higher incidence of acute graft rejection and biliary complications were noted in the treatment group (Truesdale et al. 2011). Conflicting results were reported in a later study that compared 15 patients treated with sorafenib prior to OLT to 64 controls. This study demonstrated no increase in the rate of surgical complications or overall survival (Frenette et al. 2013). At this time there is no convincing data that sorafenib is an effective “bridging therapy” for patients with HCC prior to OLT. There is evidence that it may be safe to transplant patients after having received sorafenib, but data is conflicting. Results from the HeiLivCa study are certainly anticipated.

Limited attention has been given to using targeted therapies after OLT as adjuvant therapy to lower the risk of recurrence in high risk patients. The first study to analyze sorafenib in the adjuvant setting was a retrospective case–control analysis of eight patients who were treated with sorafenib after OLT (Saab et al. 2010). Only one of the eight patients developed recurrent HCC, while four out of eight matched controls recurred. There was a non-statistical 1-year survival advantage for the sorafenib group compared to the control group of 87.5 % and 62.5 % respectively. A subsequent retrospective study in Taiwan found similar positive results (Teng et al. 2012). In this case–control study, five of 17 patients received adjuvant sorafenib within 6 weeks after OLT. The disease-free survival for patients with or without adjuvant sorafenib were 100 % versus 37.5 % at 6 months, 66.7 % versus 9.4 % at 12 months, and 66.7 % versus zero percent at 18 months. Though these studies were small, they did suggest a potential role for sorafenib in the adjuvant setting. A prospective study enrolled seven patients to receive sorafenib after OLT for HCC if their explanted livers revealed tumor burden exceeding the Milan criteria. These patients were compared to 12 similar historical controls who received no adjuvant therapy. Two of seven patients who received sorafenib developed HCC recurrence, as compared to nine of 12 patients in the control group. Sorafenib was determined to be safe as well (Shetty et al. 2014). Larger prospective trials will be necessary to determine whether sorafenib is safe and effective as an adjuvant therapy after OLT for HCC. A large randomized phase II trial is ongoing for high risk patients following liver transplantation (Busuttil 2015).

Another area of concern is the use of sorafenib for recurrent HCC after OLT. As mentioned above, there is an unmet need for therapy these patients. The universal requirement for immunosuppression in this population raises questions about the applicability of the SHARP trial in this setting. A considerable amount of data exists on the safety and of sorafenib while patients are receiving immunosuppressive medicines, with mixed results. The first such study, conducted in Japan, retrospectively analyzed 13 patients who were treated with sorafenib for recurrent HCC (Yoon et al. 2010). Only ten patients were included in the final evaluation. Six of these ten patients achieved stable disease. The median time-to-progression was 2.9 months and OS was 5.4 months. These results are comparable to those found in the SHARP study. Subsequently there have been multiple small studies that have yielded similar results (Teng et al. 2012; Sposito et al. 2013; Pfeiffenberger et al. 2013; Waghray et al. 2013). The first of these studies was a case–control study in China, wherein sorafenib was used to treat six patients with recurrent HCC after OLT. OS rates for patients in the palliative and control groups were 66.7 % versus 40 % (p = 0.248) at 6 months, 66.7 % versus 40 % (p = 0.248) at 12 months, and 50 % versus 20 % (p = 0.17) at 18 months, respectively. Another study from Italy compared a cohort 15 patients treated with sorafenib and 24 patients who received the best supportive care. There was a significant difference in median survival after HCC recurrence in the group that received sorafenib with respect to historic controls (21.3 vs.11.8 months: p = 0.0009). In a separate retrospective study, 18 patients from Italy and Germany with HCC recurrence were analyzed, eight of whom received sorafenib. There was a slight survival advantage in the sorafenib group. Lastly, a study in America prospectively compared 17 patients who received sorafenib for HCC relapse against 17 patients who were not treated. Survival at 3 and 12 months from recurrence was 100 % and 63 %, respectively, in patients on sorafenib group, and 73 % and 23 %, respectively, in the control group.