The use of orthotopic liver transplant for hepatocellular carcinoma was a major advance, pioneered by Thomas E. Starzl as a way to circumvent the limitations imposed on the liver surgeon by the presence of cirrhosis and liver failure. Patients with a few small tumors, whatever their degree of liver damage, may expect prolonged survival (70% at 5 years). Patients with more advanced tumors have high recurrence rates and more limited survival, possibly due to immune suppression or pretransplant understaging of their tumors. Another possibility is that patients with micrometastases have a longer survival time, during which the metastases eventually become evident. Recent advances include the identification of patients using levels of tumor markers to allow more careful patient selection with better outcomes. The con­tributions of molecular signatures and the new, effective antiviral agents are possibly significant.

Key words : Prognosis, Recurrence

Introduction

We review herein the aims and achievements of orthotopic liver transplant (OLTx) performed for hepatocellular carcinoma (HCC), the limitations of the results, possible reasons for these limitations, and attempts to expand the indications for OLTx. We also discuss HCC phenotyping and patient selection, pretransplant medical tumor downstaging, the contribution of the new antiviral therapies, and possible new directions in treatment.

Aims of liver transplant for hepatocellular carcinoma: how did we do?
The first human OLTx was performed by Thomas E. Starzl in 1963.¹ Many of the patients in the early years of this procedure had a diagnosis of HCC. The attraction of OLTx as a treatmeint for patients with HCC was that it was the only treatment with the potential to simultaneously treat 2 diseases: HCC and the underlying liver cirrhosis.

At the time of its introduction, the expectations for OLTx were 2-fold. First, the procedure was expected to avoid the limitations imposed on the surgeon by liver damage when resecting HCC arising in a cirrhotic liver. In this expectation, OLTx proved to be incredibly successful. Second, it was hoped that this same limitation avoidance would permit removal of increasingly large or multifocal HCCs. In the second expectation, the results were quite mixed,^2-5 as shown in Table 1 (a composite of outcomes from 5 centers).

Expanding limits on tumor size
It became clear that the best outcomes were seen in single HCC lesions, up to 5 cm in diameter, and in patients with up to 3 tumors, none greater than 3 cm in diameter. These are now known as the Milan criteria, and they have been the predominant basis for HCC patient selection since their establishment.⁶ Recent attempts have been made to cautiously increase the size of the HCC lesion allowed for transplant (the “expanded criteria”) without compromising the 70% five-year survival seen with the Milan criteria.^7-9 However, these expanded criteria are still in the process of validation and limit identification.

Why do recurrences occur?
During the process of OLTx for HCC, both the tumor and the diseased liver are removed, and the liver is replaced. It was expected that this would be curative for both diseases, but this was not the case for HCCs beyond the Milan criteria. Why not?

An easy explanation was that, similar to surgery for breast or colon cancer, there are factors that predispose to HCC recurrence, including tumor invasion of local blood and lymphatic vessels and the presence of preexisting micrometastases (Figure 1). Identification of macroscopic portal vein thrombosis, as identified by computed tomography or magnetic resonance imaging, has been shown in multiple studies to be associated with high rates of HCC recurrence after transplant. Presumably, the presence of a tumor burden in the portal vein leads directly to systemic venous dissemination.

However, an interesting and unexplored question is why does an HCC beyond 5 cm predispose to increased recurrence rates? Pretransplant under­diagnosis of multifocal HCC or the presence of microscopic portal vein thrombosis are possible explanations. There is something interesting about the 5-cm size limit, beyond which the incidence of both portal vein thrombosis and extrahepatic metas­tasis increases.^10,11 We hypothesize that increasing lesion size is associated with a change in biology or aggressiveness, and this has indeed been recently demonstrated.¹² However, other possible contributors to HCC recurrence after OLTx include immune suppression with increased tumor growth,^13,14 circulating tumor cells,^15-18 enhanced carcinogenesis in the presence of recurrent hepatitis, and patients living longer after transplant, thus having more time for preexisting micrometastases to grow.

Patterns of recurrence
Almost 50% of recurrences occur outside the liver,^10,19-21 suggesting the presence of micrometastases at the time of OLTx. However, immune suppression may also alter the biology of HCC.

Has the pendulum swung too far toward orthotopic liver transplant for small hepatocellular carcinomas?
With advances in surgical resection technique and lower perioperative mortality, survival after liver resection is increasing at many centers.^22-26 This could be particularly important in countries that experience difficulties in obtaining donor livers for transplant. Perhaps the expanded use of resection for HCC and the decreased use of transplant for smaller HCCs could release livers for other transplant indications, such as the presence of a more advanced tumor.

Orthotopic liver transplant for advanced hepatocellular carcinoma?
What is wrong with 50% three-year survival for patients who would otherwise be dead? The 70% survival at 5 years of patients within the Milan criteria is similar to that seen in patients without HCC; these data were persuasive in formulating the Milan criteria to allow inclusion of HCC patients as recipients for of OLTx.

However, the survival of patients with unre­sectable HCC is typically much more limited. In the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) trial, the median overall survival was 10.7 months.²⁷ If fewer patients with small HCCs underwent transplant, some donor livers would be released for patents with more advanced tumors. Although the survival of patients with more advanced HCC is predicted to be less than for those within the Milan criteria, it is still likely to be much longer than in patients with severe cirrhosis and beyond-Milan, unresectable HCC.

Smarter recipient selection: identifying hepato­cellular carcinoma subtypes using alpha-fetoprotein levels and molecular profiling
It has recently been shown that high and low levels of alpha-fetoprotein and the use of histologic phenotyping help identify subsets of HCC patients who do worse or better after OLTx.^28-31 As molecular-signature assessments improve, these are also likely to contribute to better HCC patient selection.³²

Is there a role yet for neoadjuvant (downsizing) or adjuvant treatment?
Using medical therapy, such as intrahepatic arterial chemoembolization or radioembolization, as a bridge to transplant has become common in many centers during the waiting period, which is often several months before a donor liver becomes available. The intention is to prevent growth of the HCC to beyond the Milan criteria and thus to prevent patient dropout from the OLTx wait list. However, the idea for using these therapies to downstage patients from extra-Milan to within-Milan criteria is beginning to gain traction, although the results for long-term survival and tumor-free survival are not yet clear.^33-37 The recent, large Adjuvant Sorafenib for Hepatocellular Carcinoma After Resection or Ablation (STORM) trial, however, failed to meet its hoped-for endpoints³⁸ and showed no benefit to survival for adjuvant sorafenib after resection. More effective anti-HCC agents are awaited.

Effective new antiviral therapies: are they now part of hepatocellular carcinoma therapy?
The recent advent of effective therapies against both chronic hepatitis B and C, associated with high complete virologic responses, is likely to transform not only the incidence of virus-associated HCC, but also our management of the tumors. Preliminary evidence has shown reduced HCC recurrence rates after resection and reduced death from all causes in HCC patients.^39-44 As the new therapies become incorporated into many aspects of HCC treatment, it is likely that they will enhance survival rates for HCC ablation, resection, and transplant.

Where are we heading?
Transplant is, in a way, a victim of its own success: everywhere in the world, we have fewer organs available than patients who need a transplant. Therefore, a primary purpose of our actions today should be the best use of our resources, combining the improved biologic knowledge of HCC that we have achieved (ie, molecular signatures for HCC subgeno- and phenotyping) with different strategies, such as more effective hepatitis prevention and treatment, and clinical trials of newer anti-HCC agents in the adjuvant setting. Finally, we should consider more aggressive pretransplant downstaging, to increase the success of OLTx in recipients with larger HCC lesions.

Molecular signatures for hepatocellular carcinoma subgeno- and phenotyping
In recent years, it has been shown that therapies targeted to tumor characteristics are effective. Furthermore, the field of transcriptomics is providing molecular signatures for prognostication. In this regard, the underlying non-HCC liver disease seems to be particularly relevant.

We are also entering a new era of molecular HCC classification. The increasing evidence that patterns of gene expression can predict HCC biology is extremely important in selecting the best treatment for an individual patient. The HCC biology is relevant to the recurrence rate after surgical treatment, the general prognosis, and the sensitivity to specific targeted therapies. Currently, all of these concepts are still in the research phase but are soon likely to become useful tools for clinicians.

This brings us to reconsider the value of liver biopsy. In solid-tumor oncology, a biopsy is considered essential for diagnosis and treatment. Lately, however, liver biopsy has not been used routinely for the diagnosis of HCC, as physicians are relying on the high probability of HCC when a cirrhotic patient with a vascular lesion has an elevated blood level of alpha-fetoprotein. Therefore, we believe that the role of liver biopsy and tumor biopsy in a patient with HCC should be reconsidered as we study the molecular signatures for both HCC and the underlying liver disease.

Hepatitis treatment
Most causes of HCC are known, and in recent years, new strategies have become available for treating hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. Three phases of prevention now exist for HBV: primary, secondary, and tertiary. Primary prevention is achieved using the HBV vaccine, usually administered in the neonatal period. Secondary prevention is accomplished by treating chronic carriers of HBV with the new suppressive and curative drugs to avoid disease progression to either cirrhosis, HCC, or both. Tertiary prevention seems achievable using the new suppressive and curative HBV drugs in carriers who undergo liver resection for HCC and are at risk for recurrence. New evidence suggests that such treatments can lower the recurrence rate. Therefore, we should think of these therapies as part of cancer treatment.

Even though a vaccine is not yet available for primary prevention of HCV infection, the new curative drugs seem to be effective in secondary and possibly tertiary prevention.

Clinical trials of newer agents in the adjuvant setting
The high recurrence rate of HCC after liver resection has not been significantly affected by the use of adjuvant chemotherapy. Recent data, however, suggest that more potent anti-HBV (and likely anti-HCV) treatments may be important in decreasing HCC recurrence after surgical treatment. However, transarterial chemoembolization and the use of yttrium 90 have not thus far been successful in the adjuvant setting. The recent STORM trial failed to enhance survival after OLTx; it is possible that the use of sorafenib has been overhyped.

Major recent advances in curative therapy for HCV (eg, sofosbuvir) and HBV, with complete virologic responses, have led to trials of these therapies as adjuvants to resection, with greatly decreased recurrence seen. These therapies should be piloted for posttransplant treatment. If successful in decreasing hepatitis recurrence, they will be attractive as potential treatments for increasing the survival of patients with HCC, with or without transplant. In fact, we have recently learned that the tumor micro­environment (eg, hepatitides in the case of HCC) is hugely important in promoting tumor growth.

Downstaging to increase the use of orthotopic liver transplant in recipients with larger hepatocellular carcinoma lesions
What about patients with HCC lesions measuring 6 to 7 cm without macrovascular invasion? Should we deny a potentially curative operation based on size alone? We have worked for years with the Milan criteria, but a number of studies push us beyond them, and we need to consider new criteria in our clinical practice (eg, the University of California, San Francisco criteria).

There is definitely a benefit for patients under­going neoadjuvant treatment in downstaging larger HCCs. Transarterial chemoembolization, radio­frequency ablation, and the use of yttrium 90 could downstage patients who are outside the Milan criteria, allowing them to meet the criteria and thereby qualify for OLTx. Several reports show that patients who are downstaged into the Milan criteria and subsequently transplanted have the same survival and recurrence rate as patients who present with disease originally within the Milan criteria.

Finally, locoregional therapy may act as a biologic test of disease, allowing patients to remain on the waiting list longer. This then allows for identification of patients who will progress and who will not benefit from OLTx.

Conclusions

The use of OLTx for treatment of patients with liver tumors permits the simultaneous therapy of 2 different but related diseases: cirrhosis and HCC. The development of OLTx was a major step forward, as it eliminated the constraints imposed on the cancer surgeon by cirrhosis and liver failure. However, experience showed that only small HCCs could be successfully cured. The reasons for this are still unclear, but the likely explanations are listed in Figure 1. Perhaps more HCC patients with more advanced tumors will benefit in the future from OLTx with changes in immunosuppressive strategies, more effective neoadjuvant or adjuvant therapies, and the use of more effective antiviral therapies. Current efforts to more clearly identify subsets of HCC patients are already yielding results in patient selection, with better outcomes after OLTx. The scientific and clinical understanding of HCC biology is an area of great investigational interest and activity.

We are beginning to enter the phase of genomics and proteomics as applied to HCC. It is also becoming evident that HCC does not grow in isolation, but rather in relation to growth- and inflammatory factors from the underlying parenchyma. This raises the possibility of categorizing patients into pro­gnostic subsets prior to any therapy. We are entering the exciting era of personalized medicine, with the selection of suitable treatments for an individual patient. This seems to be the way of the future.

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