14 Liver Transplant for Hepatocellular Carcinoma 225 Systemic Chemotherapy Traditionally, there have been few effective systemic chemotherapy options for patients with HCC, regardless of stage [58, 59]. More recently, the oral multi- kinase inhibitor of the vascular endothelial growth factor receptor, sorafenib, was shown to have a small but measurable survival benefit in patients with Stage IV HCC [60, 61]. The trial that established this effect focused mainly on CTP class A patients. Subsequently, off-label use of this drug has entered the liver transplant arena. Some patients with unsuspected advanced pathologic stage HCC have been treated with sorafenib post-transplant. There is a limited but growing experience with the drug in the pre-transplant setting. Few objective reports on this experience are avail- able, but multiple trials have been initiated to determine its impact on patients with HCC [62], either as a routine neoadjuvant therapy in early-stage patients or as a modality to downstage UNOS T3-4 patients to transplantable criteria, usually in combination with other interventional neoadjuvant approaches such as TACE. The impact that sorafenib delivered immediately prior to liver transplant has (as seen sometimes in the neoadjuvant setting) on wound healing, liver regeneration, and/or hepatic artery thrombosis is unknown. Experience with Liver Transplantation in the Post “Milan Criteria” Era As clinical staging and pathological staging are discordant in as many as 30% of HCC liver transplant recipients, it has been noted that selected patients with pathologic staging that unexpectedly exceeded the CMC have achieved favorable oncologic outcomes post-transplant. These data have encouraged several programs to implement and investigate expanded HCC criteria. The goal of these expanded criteria systems has been to identify a subset of patients outside of the CMC who would share equivalent survival rates, thereby increasing the pool of patients who may benefit from transplantation. The most frequently used set of extended HCC criteria are the UCSF criteria [10]. These criteria modestly expand the tumor size criteria beyond CMC to include those patients with solitary HCC lesions up to 6.5 cm and patients with 2–3 tumors to have an individual upper size limit of 4.5 cm and an aggregate upper size limit of 8 cm. In large studies, these expanded criteria capture an additional 10–20% of patients beyond CMC alone [32, 63, 64]. In limited application, the UCSF group and others have found equivalent survival rates for patients in CMC and those between CMC and UCSF (Table 14.2)[22, 32, 63, 64]. Patients with final pathologic staging in excess of UCSF criteria do consis- tently have higher recurrence rates and poorer survival post-transplant (Fig. 14.1) Further pathological analysis indicates that tumor size and number that exceed 226 T.A. Aloia et al. Table 14.2 Comparison of post-liver transplant survivals for patients with pathological staging within conventional Milan criteria, within UCSF criteria, and beyond UCSF criteria Milan UCSF Beyond UCSF UCLA [22] N = 126 86% N = 208 81% N = 133 32% French Multicenter [32] N = 184 70% N = 39 64% N = 238 34% UCSF [10]––N = 60 75% N = 10 <30% Spain [63] N = 33 68% N = 26 67% N = 6 48% Fig. 14.1 [Post-transplant] survival estimate by preoperative imaging assessment [22] UCSF criteria serve as surrogates for microvascular invasion and poor tumor dif- ferentiation, which may biologically explain the relationship between the advanced staging and the poor outcomes [65]. These data are compelling and have supported the development of Regional “T3” MELD exception criteria. Typically, these criteria do not advantage waitlisted patients to the degree that UNOS T2 (CMC) patients are advantaged, but depending on median MELD scores in the region, these MELD exception points may facilitate transplantation for this subset of patients. As with any staging system there are certain patients who, from a prognostic standpoint, are not appropriately accounted for. In the case of HCC both the CMC and the UCSF criteria are fairly rigid. In response to this rigidity, the Milan group has recently reported on a multicenter experience with liver transplantation for HCC tumors outside of CMC and has developed more flexible criteria that combine tumor number with maximal tumor diameter in centimeters. This analysis has found that post-transplant survivals for patients with a score of 7 or less (e.g., two tumors with maximal diameter of 5 cm or five tumors with maximal diameter of 2 cm) are similar and oncologically acceptable (Fig. 14.2)[66]. This rule of seven trans- plant eligibility criteria requires validation in other settings but is appealing in its flexibility, allowing a more clinically applicable system that would be fair to HCC patients. 14 Liver Transplant for Hepatocellular Carcinoma 227 Fig. 14.2 Contour plot of the 5-year overall-survival probability according to size of the largest tumor, number of tumors, and presence or absence of microvascular invasion [66] While UNOS, regional liver transplant committees, and individual liver trans- plant programs struggle with the equitable application of these various staging systems, what is apparent is that there is no currently used component to account for tumor biology. For example, patients with T3 lesions who remain stable over long waitlist times or achieve downstaging via dramatic responses to neoadjuvant treat- ments have no mechanism to advance on the liver transplant waitlist. Recent studies have shown that patients downstaged to T2 criteria may share similar post-transplant outcomes with those who started in T2 criteria [29, 38, 67, 68]. If confirmed in 228 T.A. Aloia et al. controlled trials, downstaging criteria may need to be accounted for in future clinical staging systems and MELD exception criteria proposals [69]. Current practice Current regional practice regarding the management of HCC patients in the pre- transplant setting has been dictated by the median MELD score for transplantation and the regional MELD exception point criteria, which vary across regions. In gen- eral, patients with HCC within CMC (UNOS T2 stage) receive MELD exception to 22 points. Variable upgrades to 25 or more points are granted on an every 3-month basis provided that the disease remains stable on serial radiographic imaging. For a program with a median laboratory MELD score of 20, this point allocation schema yields short waitlist times. In contrast, urban programs in competitive markets that transplant at median MELD scores above 26 may have HCC patients routinely waiting over 6 months for allograft offer. In the setting of long waitlist times, several programmatic strategies have been developed. First, programs with extended waitlist times typically develop a broad array of neoadjuvant treatment modalities to prevent disease progression and, therefore, limit waitlist dropout. These modalities include repetitive transarterial chemoembolization, intraarterial radiotherapy, and systemic chemotherapy. Second, several programs have shifted their practice to living-related liver transplants. This serves to shorten the wait times and to convert the procedure into an elective oper- ation. Of course, this requires additional resources and assumes the medical risk for a living donor. Third, programs have sought to use extended criteria cadaveric allografts. These organs so-called orphan livers have unique risk profiles and should be considered on a case-by-case basis. In the setting of advanced malignancy in the liver, they offer a viable option despite higher risks of early allograft dysfunction. The role of liver resection in the pre-transplant setting remains controversial. Although liver resection has been proposed as a bridge therapy to transplantation [70], this strategy is associated with high recurrence rates [20, 71, 72] and has not been embraced within the USA. In general, the US experience suggests that CTP class A patients without portal hypertension rarely present with HCC at a resectable stage of disease. For patients with more advanced liver disease, the US medico-legal environment tends to dissuade surgeons from assuming the morbidity and mortality risk associated with liver resection. In addition, there remains concern that the pre- vious procedure may unacceptably increase the complication rate associated with repeat laparotomy for transplantation [73]. Living Donor Liver Transplantation for HCC The role of living donor liver transplantation in HCC treatment developed in response to the wide gap between the number of patients with transplantable HCC and the lack of available cadaveric donor allografts. In Asia, multiple centers have 14 Liver Transplant for Hepatocellular Carcinoma 229 published large series of HCC patients receiving living donor liver allografts. In the USA, early living donor liver transplant programmatic development was stunted in 2002 by a highly publicized donor death. In addition, several data sources sug- gested that HCC recipient outcomes may be inferior to those of deceased donor transplantation. This may be related to rapid transplantation of patients with aggres- sive tumor biology that would have been “declared” during an interval of time on the waitlist. In addition, US living donor liver transplantation has been character- ized by the tendency to reserve the procedure for recipients with HCC beyond CMC [20, 74, 75]. In addition, initial OPTN/UNOS data suggested that living donor allografts had worse survival rates, although this may have been related to a learning curve effect [76]. In 2007, the nine member A2ALL consortium also reported a learning curve effect on mortality risk with living donor liver transplantation [75]. Although their comparison to deceased donor transplantation found an association between living liver donor transplantation and higher HCC recurrence rates independent of disease stage, overall 3-year mortality rates were similar. In contrast to these data, the world experience would suggest that living donor liver transplantation performed in experienced centers with low donor complication rates offers an acceptable option for patients with both CMC and extended (T3) stage HCC [39, 77, 78]. It can serve to expand the donor pool and offers the advan- tages of an elective operation performed earlier in the course of disease, thereby limiting the possibility of disease progression during prolonged waitlist intervals [78, 79]. In the USA, clinical studies aimed at defining the HCC stage that most benefits from the technique are ongoing. Outcomes and Determinants for Recurrence Following Liver Transplantation for HCC Multiple patient, tumor, and transplant-related variables have been investigated for their ability to predict recurrence of HCC following liver t ransplantation. As is true for the prognosis of all patients under treatment for HCC, the presence of vascular invasion, typically into portal venous and/or hepatic venous structures, consistently ranks as the highest risk factor for tumor recurrence [12, 13, 22, 80–85]. Three decades of experience with liver transplantation have reinforced this concept to the point that pre-transplant radiographic evidence of gross vascular invasion is considered an absolute contraindication to liver transplantation. For patients with unsuspected microvascular invasion in the explanted liver, the recurrence rate may be as high as 60% at 1-year, mandating vigilant follow-up and consideration of adjuvant chemotherapy aimed at forestalling recurrence. The dominant influence of microvascular invasion on post-transplant outcomes also emphasizes the need for improvements in pre-transplant staging modalities. For each clinical HCC staging system currently in use, there continues to be a consistent degree of prognostic inaccuracy based on the absence of information regarding vas- cular invasion. Even the Modified Milan Rule of 7 system shows a significant shift 230 T.A. Aloia et al. of the isograms depending on the presence of vascular invasion in the explant spec- imens (Fig. 14.2)[66]. For the field to progress more precise imaging modalities, perhaps with functional correlates to vascular invasion, are required. Secondary, but still significant, risk factors for HCC recurrence following trans- plant include elevated pre-transplant AFP levels, multifocality/satellitosis, and poor tumor differentiation. Although increased tumor number and particularly maximal tumor size are associated with higher HCC recurrence rates, these factors have not consistently been found to be prognostic independent of their relationship with microvascular invasion and tumor differentiation [12, 22, 80–82, 86, 87]. Based on these data, in the absence of radiologic or biopsy evidence for vascular invasion, there are few objective criteria that reliably predict recurrence following transplant for HCC. For patients with “high-risk” HCC (i.e., size >5 cm, >3 tumors, poor differentiation) further development of measures that identify favorable individual tumor biology are needed to optimize liver transplant candidacy. The suspected relationship between hepatitis C virus infection on poor post- transplant oncologic outcomes in HCC patients has also been investigated. Although hepatitis C patients tend to have worse patient and allograft survival rates compared to non-hepatitis C patients, analyses show that this effect is independent of HCC and oncologic outcomes [83, 84]. In summary, patients with UNOS T2 HCC and no evidence for microvascular invasion in the explanted tumor site are frequently cured of HCC and have recur- rence rates less than 20% at 5 years. Although the all-stage patient survival curve Fig. 14.3 Kaplan-Meier patient survival estimates for different etiologies of end-stage liver disease [88] 14 Liver Transplant for Hepatocellular Carcinoma 231 for patients transplanted for HCC is poorer than for other indications (5 yr 60%), this rate is far superior to the historical survival rate of similar stage patients who do not undergo transplant (Fig. 14.3)[88]. In addition, this general survival curve represents a mixture of clinical and pathologic disease stages. As stated above, for patients with favorable pathologic staging in the absence of vascular invasion, liver transplant can achieve excellent patient, allograft, and oncologic outcomes. In the absence of reliable indicators for favorable vs. unfavorable tumor biology, the indications for transplant in patients with “high-risk” HCC remain controversial. Immunosuppression Following Liver Transplantation for HCC From the beginning of liver transplantation, transplant physicians have feared that immunosuppression given to induce tolerance of the foreign allograft in the recipient collaterally reduces the ability of the immune system to fight malignant cancer. Liver transplant recipients with a history of HCC are not only at high risk for HCC tumor recurrence but also have elevated rates of skin and colorectal cancer. With regard to specific immunosuppression medications, limited data suggest that cyclosporine may be associated with a more aggressive pattern of HCC recurrence in preclinical and patient studies [89–91]. In this setting, novel immunosuppression protocols have been tested in patients transplanted with HCC indications [92]. The most commonly advocated regimen calls for a transition from calcineurin inhibitors (e.g., cyclosporine or tacrolimus) to the bacterial macrolide, sirolimus. Despite serving as an effective immuno- suppressant to prevent allograft rejection, there is preclinical data to support the simultaneous tumoricidal effect of this agent, which may help to prevent recurrence [93, 94]. The drug has been used in a compassionate setting post-liver transplant with a good safety profile [95]. The US Food and Drug Administration has warned that patients given sirolimus immediately after transplant may have an elevated r isk of hepatic artery thrombosis and those taking the combination of sirolimus and cal- cineurin inhibitor may be at higher risk for post-transplant infections. With these caveats in mind, the use of sirolimus and other allograft immunosuppressive agents with tumoricidal properties remain under investigation in patients transplanted for HCC. Future Perspectives The history of liver transplantation for HCC has been characterized by constant clinical and scientific investigation. Transplant clinicians continue to try to appro- priately allocate the scarce resource of donor liver allografts to the most deserving patients, in many cases relying on imperfect staging information to make these difficult decisions. This environment naturally leads to controversy (Table 14.3). 232 T.A. Aloia et al. Table 14.3 Major controversial areas in liver transplantation for HCC Improving the accuracy of pre-transplant staging (i.e., tumor size, tumor number, microvascular invasion, prognostic molecular signature) Integration of tumor biology in candidate selection (i.e., response to neoadjuvant therapy and downstaging) Establishing criteria for organ allocation to patients exceeding Conventional Milan Criteria who may have similar survivals (i.e., UCSF criteria) Optimal application of neoadjuvant therapies Refining criteria for allocation of living donor liver transplants Integration of new technologies (i.e., systemic sorafenib and radioembolization) pre- and post- transplant Immunosuppression modulation in HCC recipients Independent of liver transplantation, the HCC field is moving toward molecular staging. There is promising data that certain proteomic and molecular profiles cor- relate with survival in patients with HCC [96]. 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