Keywords

1 Introduction

From the time of its initial developments in the early 60s, liver transplantation (LT) appeared as the ideal cure for hepatocellular carcinoma (HCC) in liver cirrhosis because it provided the prospect of curing at the same time both the tumor and the underlying liver disease. However, the first experiences were disappointing, with many authors reporting a 5-year survival of less than 40% mainly because of recurrences of the primary tumor. A retrospective review of these discouraging results progressively led to the observation that patient survival was directly related to the stage of HCC at the time of LT. In several studies from the early 90s it was found that the survival of patients with incidental and small size nodules of HCC was increased compared to those who underwent liver resection. Recurrence in incidental/small tumors occurred in less than 15% of cases [1].

2 Liver Transplantation for Hepatocellular Carcinoma: The Milan Criteria

These were the basis on which a prospective study was conducted in Milan applying a priori restrictive criteria for the selection of HCC candidates for LT (namely a single nodule ≤5 cm or ≤3 nodules ≤3 cm, each with no macrovascular invasion at pre-transplant imaging). The seminal paper published in 1996 demonstrated that by applying such criteria it was possible to obtain long-term results that were better than for any other therapy applied for HCC [2], and similar to the outcomes of LT for non-oncologic indications. These so-called Milan criteria (MC) incorporated both single and multiple presentation of HCC and were subsequently validated by many other groups reporting 5-year survival rates of 70% or better, with recurrence rates below 15%, and became the benchmark for selecting patients with HCC for LT. After their implementation, the favorable post-transplant outcomes that were observed in cohort series were so convincing that further validation by randomized controlled trials (RCTs) was prevented. HCC, declared in 1989 a relative contraindication to LT by the US Department of Health, is today the second indication for LT in Europe (26.9% of indications) and it has therefore become one of the major fields of interest in hepatology and liver surgery.

3 Expanding Indications and Improving Results of Liver Transplantation for Hepatocellular Carcinoma

HCCs meeting the MC have been confirmed to be a separate prognostic category associated with good outcomes after LT and incorporated into major guidelines. However, in the absence of surveillance programs, only a minority of HCC are diagnosed at an early stage (namely within the MC), and excellent results have been observed in patients who underwent LT with an HCC exceeding the MC. These patients constitute the focus of debate about what is known as “expansion HCC criteria” for LT, either because they are selected as beyond the MC before transplantation or because they are selected as a result of being downstaged to meet the MC after neoadjuvant treatments (Fig. 19.1).

Fig. 19.1
A diagram of tumor-related strategies. It starts with extended criteria, to an arrow labeled downstaging treatments, and to Milan criteria. Extended criteria extend to treatment response for tumors beyond Milan criteria, Milan criteria extend to bridging treatment. This leads to liver transplantation, to adjuvant therapies. An arrow leads away from liver transplantation with the text labels reading modulation of immunosuppression and 5-year survival is greater than 70 percent.

Tumor-related strategies affecting the prognosis of patients undergoing liver transplantation for hepatocellular carcinoma

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3.1 Role of Neoadjuvant Therapies: Bridging to Liver Transplantation, Salvage, and Pre-emptive Liver Transplantation

The application of conventional therapies for HCC to candidates within MC as a bridge to LT has the primary objective of preventing tumor progression beyond conventional criteria during waiting list time, and consequently preventing dropout. Dropout rates increase with waiting list time, and the risk of dropout for HCC candidates is higher than the risk for candidates with non-malignant diseases after the first three months [3]. The rates of dropout depend on many variables linked to the individual tumor biology and to each transplantation center. For tumors with expected waiting times to LT <6 months, there is no evidence that neoadjuvant treatments are beneficial. For T2 tumors and for longer waiting times, neoadjuvant treatments are usually performed with transarterial chemoembolization, ablation techniques and liver resection in selected cases. Tumor stage and volume, alpha-fetoprotein (AFP) levels, response to treatments, and liver function affect the risk of dropout from the waiting list. These factors, together with vascular invasion and poor tumor differentiation, are major determinants of poor post-LT outcomes [4].

Because of the organ shortage, hepatic resection might serve as primary therapy for HCC, with LT as a salvage procedure in the case of recurrence. Initial experiences reported unfavorable outcomes for primary resection and salvage LT compared to primary LT [5]. Remarkably, secondary LT was associated with significantly higher operative mortality. Further studies, however, reported comparable intention-to-treat outcomes of HCC patients treated with primary LT or primary resection followed by salvage LT in the case of recurrence. In particular, when liver resection is performed with a minimally invasive approach, the risk of delisting, post-transplant patient death and tumor recurrence seem reduced when compared to open surgery [6].

Liver resection with pathological analysis of the specimen allows clinicians to identify those patients at high risk for recurrence (e.g., microvascular invasion, satellite lesions, high grade of differentiation) who might benefit from being listed for LT immediately after resection. The strategy of pre-emptive (or de principe) LT was introduced by the Barcelona group [7], and the authors demonstrated excellent long-term outcomes for patients who underwent LT after resection for a high-risk HCC. The feasibility of the pre-emptive LT strategy implies a high availability of liver grafts and a policy of transplanting patients with a high probability of recurrence even though still tumorless: the benefit of preventing an HCC recurrence by means of LT should be carefully balanced with the potential harm caused by the LT itself.

3.2 Beyond the Milan Criteria

Several experiences suggested that the restrictive MC may exclude from LT those patients with a more extensive disease but still in the range of a possible cure. The key aspect of selection criteria is that the definitions used should identify those patients who, despite exceeding the MC, might still do well without an increase in recurrence. At the same time, the definitions should also identify those patients within the MC that will be at high risk of recurrence. This two-end goal is paramount for the equitable use of the available organs.

The proposals for expansion of the MC were initially developed using tumor morphology, namely size and number. These factors have in fact been shown to be surrogate markers of microvascular invasion (MVI) and/or poor tumor differentiation, which are the principal determinants of tumor aggressiveness and consequent risk of post-LT recurrence [8]. Expanded morphological criteria increased the acceptable size and number of HCC nodules with respect to the MC, but the great heterogeneity and different accuracies of liver imaging techniques probably represent the greatest limitation of criteria based only on morphology.

In order to overcome these limits, criteria incorporating serum markers, such as AFP, that surrogate biological tumor characteristics have been proposed (Table 19.1). In particular, by combining the morphological characteristics of the tumor and the AFP values, it was possible to develop selection criteria for LT that definitively exceeded those of Milan without significantly increasing the risk of post-LT recurrence [9, 10]. The calculation of both the size and number of nodules and the AFP serum levels appears simple and available in every context, making these models applicable “dynamically”, in addition to the assessment of the HCC response to neoadjuvant treatments. Through multiple predictions made at each interval after tumor treatment, variations of prognosis during the course of disease can be determined.

Table 19.1 Examples of selection criteria for liver transplantation in patients with hepatocellular carcinoma (only externally validated selection criteria are reported)
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Finally, tumor differentiation, MVI, presence of circulating cancer cells and genomic markers have also been suggested as selection criteria for LT, but this assessment requires taking a biopsy that might induce tumor seeding. Furthermore, it is well known that tumors are heterogeneous and show areas of varying degrees of differentiation and genomic features. Hence, such an assessment is not 100% robust and no molecular signature has been properly validated. Nevertheless, it is clear that other parameters beyond tumor size and number will play an increasingly important role in the selection for LT of HCC patients beyond MC.

3.3 Downstaging of Hepatocellular Carcinoma Before Liver Transplantation

Downstaging is defined as a treatment given to HCC patients that are not eligible for LT because of tumors beyond conventional criteria, with the objective of reducing tumor burden (in terms of number, size or tumor vitality) to meet pre-established conventional limits (generally Milan or UCSF Criteria) that are considered acceptable for LT. HCC is rarely technically “non-transplantable”, and in this case downstaging treatments are performed with the aim of a migration to a stage with better prognosis (the MC). This strategy is treated separately in the following chapter. However, it is worth emphasizing that its effectiveness recently emerged in a RCT (XXL trial) demonstrating with a high level of evidence that, after sustained and successful downstaging of HCC beyond the MC, LT achieves a significant survival benefit with respect to any other non-transplant therapy [11].

3.4 Role of Adjuvant Treatments

Despite strict selection criteria, tumor recurrence after LT for HCC occurs in up to 20% of the cases [12] and is associated with a poor prognosis. The main strategies to prevent HCC recurrence involve adjuvant treatments and modulation of immunosuppression. Systemic therapy with several drugs (e.g., cisplatin or 5-fluorouracil) have failed to provide any benefit. Sorafenib, an oral multikinase inhibitor that improves survival of patients with advanced HCC, has been tested in some studies to prevent or treat HCC recurrence after liver transplantation. No solid evidence emerged from these studies and, even though its safety was confirmed, the potential for effective HCC treatment using sorafenib after transplant is doubtful [13].

Immunosuppression is a risk factor for tumor growth: the calcineurin inhibitors (CNI) cyclosporin and tacrolimus currently form the main components of immunosuppression after LT, although their potential tumor-promoting action is well known [14]. Several studies reported a higher risk of tumor recurrence for patients treated with high doses of CNIs, especially in the first month after LT [15]. Thus, an adequate balance between low immunosuppression and the risk of rejection should be encouraged. Because of their immunosuppressive and antiproliferative effects, the mTOR inhibitors sirolimus and everolimus have been suggested for immunosuppression of HCC patients. Several retrospective analyses and meta-analyses have reported a protective effect of sirolimus on the risk of post-LT HCC recurrence. All these data have been challenged by the negative results of a prospective phase III, international multicenter RCT that randomized patients to sirolimus and sirolimus-free immunosuppression regimens, reporting no difference in 5-year disease-free survival [16]. Thus, the use of mTOR inhibitors to reduce tumor recurrence cannot currently be recommended.

4 Organ Allocation in Patients with Hepatocellular Carcinoma

In most Western countries, liver allocation follows the principle of urgency, allocating the available organ to the sickest first. The MELD score, originally developed by the United Network for Organ Sharing Priority (UNOS), is used to prioritize patients with the highest short-term mortality risk. As it solely consists of biochemical variables (i.e., bilirubin, creatinine, INR), it would fail to assess the risk of disease progression and dropout in patients with malignant disease and compensated liver function. Thus, most allocation systems will give exception points to patients with HCC, with pre-fixed increases over time, in order to equalize the risk of death or dropout in both populations. However, a system that guarantees fixed points at baseline and fixed increases does not allow an equitable graft allocation between patients with and without cancer or a correct prioritization amongst patients with HCC at different stages and risk of dropout. To solve this issue, it has been recently suggested that priority be stratified for patients with HCC according to stage, response to therapy and evolution after therapy [17]. This kind of model does not require pre-determined entry criteria, and eligibility to transplant and priority is defined at the end of the therapeutic neoadjuvant process, namely after the best available therapy has been completed. Thus, preliminary tumor response to treatments could become the most flexible and defined criteria for expanding the indication to LT in HCC beyond the MC, without compromising the post-transplant outcome and therefore fully justifying the use of donated organs for cancer patients. This concept, which is a blend between urgency and utility principles also considering other variables related to local scenarios and resource distributions, has been adopted in Italy since 2016 and may improve the transparency and the efficacy of the allocation systems in place for HCC patients [18].

5 Future of Liver Transplantation for Hepatocellular Carcinoma

The number of patients diagnosed with HCC in several areas around the world is increasing. At the same time, the introduction of direct-acting antiviral agents has dramatically improved the outcome of patients infected with hepatitis C virus and will result in a reduced number of patients in need of LT because of end-stage liver disease. As a consequence, in the near future, it is expected that more organs will be available for patients with liver cancer, potentially justifying a careful expansion of the selection criteria.

The increase of non-alcoholic steatohepatitis (NASH) in the Western world has increased the rate of this disease as an indication for LT as well as an etiopathological factor for HCC. To date, conflicting evidence exists on the outcomes after LT for patients with NASH-related HCC compared to patients with HCC of different etiologies. Some studies have suggested a better oncological outcome when treating patients with HCC and NASH but, on the other hand, the post-LT outcomes of patients with NASH might be significantly affected by the associated comorbidities (obesity, diabetes, hypertension).

Current research targets clinical and molecular predictors of the risk of post-transplant recurrence, with the objective of overcoming the limits of current selection criteria based on morphology and serum tumor markers. Overall, this will hopefully result in a wider and more individualized access to the waiting lists. Identifying adjuvant strategies to reduce the risk of recurrence represents an unmet need, as does defining the most cost-effective approach for detecting and treating tumor recurrence after transplantation.