Correspondence *Mount Sinai School of Medicine, 1 Gustave Levy Place, Box 1104, New York, NY 10029, USA

Email myron.schwartz@mssm.edu

Introduction

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, and is the most rapidly increasing type of cancer in the US.¹ In the vast majority of cases, HCC arises as a consequence of underlying liver disease, usually viral hepatitis, the nature of which varies according to geographical region. Consequently, the mechanisms of hepatocarcinogenesis and the tumor characteristics vary from one part of the world to another. In Africa and Southern Asia, the role of hepatitis B virus (HBV) infection—which is acquired at birth or early in life—is highly predominant, and may be compounded by aflatoxin exposure, causing HCC to develop at a young age.² By contrast, in Japan and Western countries, the hepatitis C virus (HCV) is the predominant cause of HCC. The rapid rise of HCC in the West is related to an epidemic of HCV infection due to contamination of the blood supply and, more recently, spread via intravenous drug use. Recent estimates suggest that 4 million people in the US are infected with HCV.³ Coinfection with HIV is increasingly seen in patients with HCC, and while this may complicate management, there is thus far no clear evidence that coinfection increases the risk of developing HCC.⁴

Cirrhosis from any cause (e.g. alcohol, nonalcoholic steatohepatitis) predisposes to the development of HCC. The incidence is particularly high in the setting of hereditary tyrosinemia,⁵ where HCC develops in childhood, and in primary hemochromatosis.² The use of sex steroids, both estrogenic and androgenic, is associated with the development of HCC in the absence of cirrhosis.⁶

Natural history of hepatocellular carcinoma

The mechanism of HCC development differs according to the underlying disease. Infection with HBV can clearly lead to HCC without the intermediate step of cirrhosis, although the majority of patients with HBV-related HCC have cirrhotic disease. Conversely, HCV-related HCC almost always arises in the setting of advanced fibrosis or cirrhosis; a direct hepatocarcinogenic role of HCV has not been clearly proven. Typically, patients who develop HCC in the setting of HBV or HCV have infection that is long-standing (i.e. more than 30 years).⁷

Hepatocarcinogenesis in patients with cirrhosis is a stepwise process that begins with the development of dysplastic nodules (DN).⁸ These nodules are evident on gross examination of the liver as distinct lesions more than 1 mm in size that differ from the surrounding hepatic parenchyma in terms of size, color, texture, or degree of bulging at the cut surface. DN are classified as low-grade or high-grade on the basis of cytological and architectural atypia on microscopic examination.⁹ Transforming growth factor- (TGF-) and insulin-like growth factor 2 (IGF-2) are among the mediators of accelerated hepatocyte proliferation during this phase.¹⁰ Over a 2-year follow-up period, about one-third of high-grade DN will progress to HCC, and at 5-years the risk of HCC increases to 81%.¹¹

The distinction between high-grade DN and very early HCC can be difficult, and different pathologists might classify the same lesion differently. Identification of stromal invasion is key to identifying this transition.¹² Early HCC (i.e. 2 cm in diameter or smaller) is typically nodular and well-differentiated. As disease progression occurs, microscopic vascular invasion begins, leading to intrahepatic invasion and ultimately to systemic dissemination, typically as the tumor reaches a diameter of around 3 cm.¹³ With further progression, the tumor can extend into larger hepatic vessels, most commonly portal, but also hepatic veins. Once this occurs, curative treatment is rarely possible.

Screening for hepatocellular carcinoma

It is possible to define a population at risk of HCC, because there are known risk factors. Screening for HCC is, therefore, feasible. Patients with cirrhosis due to HCV have an annual risk of developing HCC of approximately 5%,¹⁴ and patients with HBV cirrhosis have a similar risk. Notably, patients with long-standing HBV infection, even in the absence of cirrhosis, have a 0.5% annual risk that rises with advancing age.¹⁵ It is currently recommended that patients with cirrhosis undergo surveillance with liver imaging every 6 months. Guidelines recently published by the American Association for the Study of Liver Diseases (AASLD) recommend ultrasound for this purpose on the basis of its low cost and wide applicability,¹⁶ but the sensitivity of ultrasound is low compared with CT or MRI.¹⁷ In the US, where the prevalence of obesity further limits the sensitivity of ultrasound and priority for transplantation depends on early detection of HCC, routine surveillance with dual-phase helical CT is carried out at many centers. While the tumor marker -fetoprotein (AFP) has long been employed in screening for HCC, it is increasingly clear that it is an inadequate marker, both because of the high false-positive rate in patients with active hepatitis and because AFP typically begins to rise only as vascular invasion begins to occur,^{18, 19} making it very insensitive for detection of early lesions at a curable stage. The AASLD guidelines have, in fact, eliminated AFP as a recommended screening test.

Treatment of hepatocellular carcinoma

HCC has, thus far, proven to be a difficult target for systemic therapies. The mainstays of treatment are, thus, physical treatments that in one way or another directly attack the tumor or its blood supply. The additional challenge posed by the fact that most cases of HCC develop in the setting of cirrhosis with impaired liver function, makes the selection of treatment a science unto itself. An excellent discussion of the subject from a predominantly hepatologic viewpoint is presented in the AASLD HCC guidelines.¹⁶

Liver resection for hepatocellular carcinoma

In the minority of patients with HCC who do not have cirrhosis, resection is the treatment of choice. While some cirrhotic patients with HCC are also best treated with resection, the decision in these cases is far less straightforward. Cirrhosis limits resectability and is the cause of HCC; in the setting of HCV cirrhosis, 75–80% of patients experience tumor recurrence within 5 years of resection.²⁰ Nonsurgical therapies such as percutaneous ethanol injection (PEI) and radiofrequency ablation (RFA) reportedly yield survival rates similar to resection.²¹ Ultimately, the success of both resection and percutaneous treatment depends on careful follow-up and treatment of new tumors; therefore, what is the role of resection?

Most patients with cirrhosis have abnormal liver function and are not candidates for resection. Many tests of liver function (e.g. indocyanine green clearance)²² have been used to judge resectability, but none has proved more useful than the Child–Pugh classification (Table 1).²³ Portal hypertension seems to be an independent factor in determining post-resection outcome; patients with Child–Pugh class A cirrhosis and minimal portal hypertension (e.g. platelet count >100,000/mm³ and/or hepatic venous pressure gradient <10 mmHg)^{24, 25} are optimum resection candidates.²⁰

Table 1 The Child–Pugh Classification system, which defines three classes of liver function^a

Full tableFigures & Tables indexDownload Power Point slide (238K)

Tumor size is not relevant to resectability; patients who have circumscribed single tumors are potentially resectable regardless of tumor size.²⁶ Patients with multiple tumors, however, are not ideal resection candidates, because in most cases the presence of multiple tumors implies intrahepatic metastasis.²⁷ Macroscopic vascular invasion is a strong risk factor for recurrence, but in selected cases with normal liver function, no portal hypertension, and with a unilateral intraportal tumor that does not completely occlude the portal bifurcation, resection and portal tumor extraction²⁸ can yield long-term survival that is well in excess of the natural history of the disease (median 3–4 months) in 25–30% of patients.²⁹

Postresection survival rates are in the range 80–92% at 1 year, 61–86% at 3 years, and 41–74% at 5 years.^{20, 30} Predictors of short-term success are primarily related to liver function, including Child–Pugh class, degree of hepatic fibrosis, total bilirubin level, presence of clinically relevant portal hypertension, and platelet count.³⁰ Long-term results are a function of tumor recurrence, which occurs in approximately 20%, 50% and 75% of patients at 1 year, 3 years and 5 years, respectively.^{20, 31} Predictors of recurrence include tumor grade, microscopic and macroscopic vascular invasion, tumor size, number of tumors, presence of satellites, AFP levels, and positive surgical margins.

The most common site of postresection recurrence is the remaining liver. There are two aspects to the problem of intrahepatic recurrence: unrecognized metastases from the resected HCC, and the de novo development of new primary HCC. In the past the distinction was based on clinical grounds: multiple small nodules that develop early after resection in the same anatomic region as a large resected tumor, for example, are likely to be metastases, while a solitary nodule that presents late after resection in the opposite lobe is more likely a new primary HCC. With the advent of molecular techniques such as the analysis of patterns of integration of HBV into the host genome³² and analysis of microsatellite allelic imbalance,³³ it is possible to accurately identify recurrent HCC as either metastatic or de novo. On the basis of such analyses, it has become clear that, even among recurrences clinically judged as being de novo, the majority are in fact metastatic lesions.

During the first 2 years after resection, the predominant issue is the appearance of intrahepatic metastases from the resected primary site. Data from a small randomized controlled trial suggest that infusion of ¹³¹iodine-labeled lipiodol into the hepatic artery supplying the liver remnant can alter the incidence of this occurrence and thereby prolong survival.³⁴ The radioactive lipiodol is trapped in the HCC nodules because of their altered microcirculation, thus, delivering local radiotherapy to undetected micrometastases. Trials that used ¹³¹iodine-labeled lipiodol have been conducted in Hong Kong and in France;³⁵ the agent is not available in the US.

The second type of recurrence is the development of de novo primary tumors owing to the underlying liver disease, and the most promising approach to prevention of de novo HCC is treatment of the underlying disease. Current pegylated interferon-based treatment of HCV is now able to achieve a sustained virologic response in up to half of patients treated; patients who have clearance of HCV have a markedly reduced likelihood of developing new HCCs.³⁶ Treatment of hepatitis B with antiviral drugs such as lamivudine or adefovir, while unable to eradicate infection, reduces viral replication, and this has been shown to correlate with a reduced incidence of de novo HCC.³⁷ Polyprenoic acid, a retinoid thought to inhibit hepatocarcinogenesis, was shown to significantly reduce the incidence of de novo HCC after resection, but since the initial publication no confirmation of the efficacy of this drug has been reported.³⁸

Nonsurgical treatment of hepatocellular carcinoma

There are many patients who, due to either tumor characteristics or underlying liver disease, are not candidates for resection. Nonsurgical modalities including PEI, RFA, and transarterial chemoembolization (TACE) have well-documented antitumor effects and, in the case of TACE, proven survival benefit over no treatment.

PEI has a long track record and is very effective in destroying small HCCs.²¹ Performed under percutaneous ultrasound guidance, a needle is placed into the tumor and absolute alcohol is injected. The physical characteristics of a soft HCC within a firm cirrhotic liver facilitate diffusion of the alcohol within the tumor, while limiting extranodular diffusion. For HCC tumors that are 2 cm in diameter, PEI seems to have efficacy similar to that of RFA.³⁹

Over recent years RFA has largely replaced PEI at most centers. RFA is also typically performed percutaneously, advancing a specially designed electrode into the tumor and applying radiofrequency energy to generate a zone of thermal destruction that encompasses the tumor and a 1 cm margin of surrounding liver. For tumors between 2 to 4 cm, RFA has been shown to be more successful than PEI in achieving complete response and requires fewer treatment sessions. RFA is, thus, preferable to ethanol injection for patients with solitary tumors 2–4 cm in size.^{39, 40} For tumors smaller than 4 cm, RFA can achieve initial complete response rates of over 90%, with subsequent local failure in 15% or less.^{39, 40}

TACE is the treatment of choice when the tumor is greater than 4 cm in diameter, or when there are multiple lesions within the liver.⁴¹ TACE takes advantage of the fact that, while the liver is perfused by both the portal vein and the hepatic artery, HCC derives its blood supply almost entirely from the hepatic artery. This technique is performed by advancing an angiographic catheter into the branches of the hepatic artery supplying the tumor and injecting a chemotherapeutic agent (most commonly doxorubicin) typically mixed with an oily contrast agent (e.g. lipiodol or ethiodol), followed by an occluding agent such as polyvinyl alcohol beads. These beads, which range from 100 to 300 m in diameter, are carried by the circulation into the terminal hepatic arterioles, where they lodge and occlude the vessels, resulting in ischemic tumor necrosis. TACE has been shown to prolong survival in patients with intermediate-stage HCC, and objective responses were observed in the majority of patients.⁴²

Liver transplantation for hepatocellular carcinoma

Since the publication by Mazzaferro et al.⁴³ demonstrated that patients with either one tumor with a diameter 5 cm, or patients with 2–3 tumors each with a diameter 3 cm (the Milan criteria) show post-liver transplantation survival similar to that of patients without HCC, liver transplantation has become the preferred treatment for early-stage unresectable HCC. The major questions currently related to liver transplantation for HCC are whether these criteria can be safely expanded, and how to increase the scarce supply of donor organs with which to perform the procedures. It must be borne in mind when considering a transplant that factors other than HCC have significant impact on outcome. Chief among these is the nature of the underlying liver disease: patients with active hepatitis C infection, for example, suffer universal hepatitis C recurrence after transplant, which decreases survival compared with patients with other underlying diseases.⁴⁴

Excellent results are achieved when liver transplantation for HCC within the Milan criteria is performed in a timely fashion, these patients are, therefore, accorded priority in the US organ allocation system. Nevertheless, patients can wait a year or more before receiving a liver. HCC beyond the Milan criteria does not exclude a patient from candidacy, but no priority is granted them, they are, thus, highly unlikely to receive a liver from a deceased donor.

When the Milan criteria are adhered to, 5-year survival rates are around 70–80% and tumor recurrence rates are typically in the range of 10%.^{20, 45} A number of centers, including ours, have explored expansion of the transplant eligibility beyond the Milan criteria.^{46, 47} When expanded criteria are based solely on clinical parameters (i.e. size and number of lesions, vascular invasion), the incidence of tumor recurrence increases in parallel.^{32, 48, 49} In a cohort of 43 patients with HCC of diameter 5 cm or greater transplanted at the Mount Sinai Hospital, post-transplant survival at 5 years was 44%.⁴⁷ It should be noted that an additional 37 patients entered this protocol but dropped out before transplant. These results, while excellent from a cancer surgery perspective and in view of the fact that there is no effective alternative treatment, are considered at many centers to be too poor to justify the use of scarce donor organs.

Incorporation of histologic tumor grade into selection criteria has been reported to reduce recurrence after liver transplantation, despite inclusion of patients with HCC beyond the Milan criteria.⁵⁰ Recently, tumor genotyping data analyzing allelic imbalance of microsatellites situated near the loci of tumor-related genes have been shown to correlate with risk of post-transplant HCC recurrence, adding significantly to the ability to predict outcome of post-transplant HCC when applied in conjunction with models based on clinical data.⁵¹

Implicit in the listing of patients with HCC for liver transplantation is the need to define criteria for removal of patients from the list because of tumor progression. In the US, patients lose waiting list priority when HCC progresses to a stage beyond that of the Milan criteria, whereas in many European centers, patients are only removed from the waiting list upon the development of extrahepatic disease or macroscopic vascular invasion.⁵⁰ Clearly, inclusion of patients with more advanced tumors will lead to a higher rate of drop-out, but in view of the fact that there is no other potentially curative treatment, the drop-out rate is of secondary importance.

Nonsurgical tumor management before transplantation

Owing to the waiting time inherent in deceased donor liver transplantation, tumor progression while on the waiting list is a major problem; patients who meet the Milan criteria but have two or three tumors or a single tumor 3–5 cm in diameter at the time they are placed on the list have a drop-out rate of nearly 50%.⁵² It is, thus, important to view liver transplantation on an intention-to-treat basis when comparing it with alternative treatments.²⁰ Nonsurgical treatment of HCC in patients on the waiting list is an important aspect of pretransplant management. While post-transplant survival has not been shown to be improved as a result,⁵³ centers with long waiting times routinely apply these treatments—which have well-documented response rates—in an effort to prevent waiting list drop-out due to tumor progression.

Living donor transplantation and hepatocellular carcinoma

Living donor liver transplantation (LDLT) for adults is now a clinical reality. One of the best applications of LDLT is for patients with HCC, because, firstly, it eliminates the need to wait and the attendant risk of drop-out and, secondly, since most patients transplanted for HCC do not have advanced liver failure, a graft that is relatively small-for-size can be sufficient.⁵⁴ An analysis employing a Markov model (a statistical method of modeling complex systems that consists of comprehensive representations of possible chains of events) suggests that LDLT is cost-effective in treating HCC when the waiting time for deceased donor organs exceeds 7 months.⁵⁵

With LDLT there is no competition for organs, and as such, patients with HCC beyond the Milan criteria may be offered this procedure. At the Mount Sinai Hospital, HCC has been the indication for nearly 40% of the LDLT's performed, the majority of which were for tumors outside the Milan criteria.⁵⁶ Thus far, the world experience suggests that survival after LDLT for HCC, stage for stage, is similar to that using deceased donor organs.^{56, 57} While not scarce, organs from living donors are precious; donor risk must be balanced by a reasonable chance of success in the recipient. Recent regulations adopted in the state of New York require the estimated survival of a recipient to be at least 50% for LDLT to be considered.

Immunosuppression and hepatocellular carcinoma

While immunosuppression is known to promote the development of virally mediated cancers such as papilloma virus-related cervical cancer and Epstein-Barr virus-related lymphoma, immunosuppression has little effect on solid tumors such as breast cancer, colon cancer, or HCC.⁵⁸ Nevertheless, the calcineurin inhibitors cyclosporine and tacrolimus, which are the backbone of routine post-transplant immunosuppression, have been shown to promote HCC progression through nonimmunologic mechanisms.⁵⁹ Sirolimus, a more recently available alternative to tacrolimus, does not have this effect and is, in fact, an antiproliferative agent that has been shown to have significant activity against a number of cancers.⁶⁰ Data from uncontrolled clinical studies indicate that a sirolimus-based regimen may delay the appearance and retard the progression of recurrent HCC;^{61, 62} isolated case reports, document significant regression of recurrent HCC after the initiation of sirolimus therapy.^{63, 64} While these reports do not provide high-level evidence of benefit, use of sirolimus is, nevertheless, becoming increasingly widespread after liver transplantation for HCC.

Potential applications of novel systemic therapies

To date, there is no first-line systemic treatment for unresectable HCC; commonly administered cytotoxic chemotherapy has been repeatedly shown to have no impact on patient survival.^{65, 66} The hypervascular nature of HCC has led a number of investigators to explore the potential of antiangiogenic therapy in this disease. The first antiangiogenic agent tested was thalidomide, but poor tolerability limited treatment and no clinical benefit was demonstrated.⁶⁷

Bevacizumab, a humanized monoclonal antibody against VEGF, has been approved for the treatment of a number of cancers. A phase II study of bevacizumab in advanced HCC is currently underway; initial favorable results were reported at the 2005 American Society of Clinical Oncology (ASCO) meeting.⁶⁸ In this study, 24 patients with unresectable HCC limited to the liver and without portal vein invasion were evaluable for bevacizumab efficacy. Following therapy at a dose of 5 mg/kg or 10 mg/kg every 14 days, 2 patients had partial responses, and 17 had stable disease for at least 6 months.

Sorafenib is a small molecule tyrosine kinase inhibitor that acts against Raf kinase, VEGF, PDGFR-, c-KIT and Flt3.⁶⁹ The results of a recently completed phase III trial in advanced renal cell carcinoma led to the US FDA approval of this agent. In this study, treatment with sorafenib increased progression-free survival from 12 to 24 months.⁷⁰ On the basis of promising results for sorafenib in early clinical studies,⁷¹ a large international multicenter phase III trial is now underway in patients with advanced HCC.

Erlotinib, an EGFR tyrosine kinase inhibitor, is approved for the treatment of lung cancer, and a recent phase II study in HCC demonstrated that this agent prolonged progression-free survival.⁷² Erlotinib's effects include antiangiogenic activity resulting from decreased levels of VEGF.⁷³ As in the development of most cancer treatments, new drugs—for example, bevacizumab, sorafenib, and erlotinib—are first being tested in patients with advanced disease, but their greatest application may come in the adjuvant or neoadjuvant setting. In contrast to cytotoxic therapy, these agents work by diminishing tumor vascularity and inhibiting tumor progression rather than by cytotoxic effects. While there are, as yet, no reports of trials employing these newer agents as adjuvant or neoadjuvant therapies, there is a strong rationale for such indication. As adjuvant treatment after liver transplantation or resection, their application in the setting of minimal disease would maximize the likelihood of benefit; as neoadjuvant therapy before resection, they might be expected to facilitate the surgical procedure by decreasing tumor vascularity. A particularly intriguing concept is the use of these agents to inhibit angiogenesis after nonsurgical therapies such as TACE or RFA, where microscopic residual tumor nests must re-establish their blood supply in order to progress. This approach holds great appeal and is being explored in a number of transplant centers⁷⁴ as a means of prolonging the treatment response and thereby minimizing the risk of drop-out from the waiting list.

Conclusions

In 2006, surgery remains the treatment of choice for HCC; however, because of underlying liver disease, only a minority of those affected are candidates for resection, and access to transplantation is limited by organ availability. Local tumor ablation is effective for early HCC, and chemoembolization is of proven benefit in intermediate-stage disease; thus far, no first-line therapy has emerged for advanced HCC. As cytotoxic chemotherapy has proven ineffective, current research efforts are focused on targeted therapies.

Note added in proof On 12 February, 2007 the sponsors of an international phase III study comparing sorafenib to placebo in 602 patients with advanced HCC in the setting of Child–Pugh A cirrhosis reported that a planned interim analysis had concluded that the trial met its primary end point of demonstrating superior patient survival in the sorafenib arm without any difference in the incidence of serious adverse events. On the basis of these findings, the study was unblinded and the patients in the placebo group offered the opportunity to receive the drug. The study data will be reported in full at the annual ASCO meeting in June, 2007. As a result of the study findings, sorafenib seems destined to become first-line therapy for advanced HCC. Future studies examining the use of sorafenib in the adjuvant setting and sorafenib in combination with other targeted therapies are now in development.

Acknowledgments

This work was supported by NIH K24 award # DK 60498-01 entitled, "Systematic integration of patient-oriented research into the clinical pathway for hepatocellular carcinoma", Myron Schwartz, MD Principal Investigator.

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Subject areas under which this article appears: Medical Oncology