Liver transplantation for hepatocellular carcinoma

Best Practice & Research Clinical Gastroenterology Vol. 19, No. 1, pp. 147–160, 2005 doi:10.1016/j.bpg.2004.10.002 available online at http://www.sciencedirect.com

9 Liver transplantation for hepatocellular carcinoma Jelica Kurtovic BSc (Med), MBBS (Hons), FRACP Stephen M. Riordan MD, FRACP, FRCP Gastrointestinal and Liver Unit, The Prince of Wales Hospital and University of New South Wales, Sydney, NSW, Australia Roger Williams*

CBE, MD, FRCP, FRCS, FRCPE, FRACP, FMedSci, FRCPI (Hon), FACP (Hon)

Director Institute of Hepatology, Royal Free and University College London Medical School, 69-75 Chenies Mews, London WC1E 6HX, England

In patients with cirrhosis and hepatocellular carcinoma (HCC), orthotopic liver transplantation (OLT) offers hope for cure of both the complicating HCC and the underlying chronic liver disease. Excellent 5 year survival has been reported when the restrictive Milan criteria are used to select transplant candidates. Alternative recommendations have recently been proposed by groups at University of California San Francisco, University of Pittsburgh and Mount Sinai. We review current and evolving concepts regarding selection criteria for OLT in patients with HCC, along with strategies to reduce waiting times, such as the impact of the implementation of the model for end-stage liver disease (MELD) scoring system on organ distribution and the role of living donor OLT for this indication. The possible efficacy of adjuvant anti-tumour therapies in limiting HCC growth while waiting for OLT, along with factors influencing the risk of HCC recurrence post-OLT, the major cause of death in this setting, are also discussed. Key words: hepatocellular carcinoma; liver transplantation; selection criteria; immunosuppression.

Hepatocellular carcinoma (HCC) is currently the fifth most common neoplasm in the world.1 Its incidence is steadily rising in western countries2, largely due to the continued prevalence of hepatitis C virus infection in parenteral drug users and the long period of infectivity before disease manifestations appear, despite the introduction of

* Corresponding author. Fax: C44 20 7380 0405. E-mail address: [email protected] (R. Williams). 1521-6918/$ - see front matter Q 2004 Elsevier Ltd. All rights reserved.

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screening for the virus. HCC is the leading cause of death in cirrhotic patients.3 In patients with cirrhosis, orthotopic liver transplantation (OLT) offers hope for cure of both the complicating HCC and the underlying chronic liver disease. In patients with poor hepatic functional reserve, in whom resection of even small HCC’s is not feasible, OLT offers the only possible surgical option for cure. In those with well-compensated hepatic function and small, technically resectable HCC, it is increasingly recognised that OLT is preferable to resection in terms of long-term survival, because of the removal of the pre-neoplastic cirrhotic liver and, hence, risk of de novo tumour development.4,5 Nonetheless, with HCC being the third most common cause of cancer-related death1 and responsible for over one million deaths worldwide per annum6, the applicability of OLT is limited to only a small percentage of patients with this disorder. Using restrictive selection criteria based on tumour size and number, by which standards only a minority of HCC patients are deemed suitable for OLT at diagnosis, excellent 5 year post-OLT survival rates comparable to those in patients without HCC have been reported.7,8 However, overall efficacy of OLT for HCC is compromised by the widespread mismatch between cadaveric organ demand and availability, resulting in prolonged waiting times during which tumour growth beyond the limits of acceptable criteria may occur. Even with restrictive selection criteria, it has been suggested that, in the United States, the number of patients with HCC awaiting OLTwill soon exceed the total number of cadaveric liver donors available for all indications.9 At the same time, it has become apparent that many HCC patients who are currently excluded from OLTon the basis of an intrahepatic tumour burden in excess of current guidelines would nonetheless benefit from this procedure. The need for selection criteria that will reliably identify the greatest number of suitable candidates for OLT while excluding the smallest number of those who might benefit from transplantation has stimulated much debate as to what extent current criteria can be liberalised without impacting negatively upon outcome. Clearly, given the imbalance between cadaveric organ availability and supply that already exists, any expansion of selection criteria for OLT to include patients with more advanced HCC must be accompanied by strategies to both limit waiting times and control tumour growth whist waiting, if outcomes on an intention-to-treat basis are not to be further compromised. Here, we focus on current and evolving concepts regarding selection criteria for OLT in patients with HCC, along with strategies to reduce waiting times, such as the impact of the implementation of the model for end-stage liver disease (MELD) scoring system10 on organ distribution and the role of living donor OLT for this indication. The possible efficacy of adjuvant anti-tumour therapies in limiting HCC growth while waiting for OLT, along with factors influencing the risk of HCC recurrence post-OLT, the major cause of death in this setting, are also discussed.

SELECTION CRITERIA FOR OLT Patients with large, irresectable HCC’s, especially arising in a non-cirrhotic liver, were initially thought to be the most appropriate group for OLT11, a view that proved to be short-lived in view of unacceptably high early recurrence rates.12,13 Conversely, patients with incidental HCC’s discovered in the hepatic explant were shown to have a similar long-term survival rate to that of patients transplanted without HCC.12 Subsequent studies from Pittsburgh14, King’s College Hospital, London15, Hopital Paul Brousse, France5 and Milan7 reported excellent results when OLT is restricted to patients with

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Table 1. Restrictive selection criteria for OLT for HCC. Centre

HCC-related criteria

Outcome (reference)

Pittsburgh King’s College Hospital, London Hopital Paul Brousse, France

Unifocal, !5 cm in diameter Unifocal, !4 cm in diameter

68% 5 year survival14 57% 5 year survival15

%2 foci, !3 cm in diameter

Milan

Unifocal %5 cm in diameter or %3 foci, %3 cm in diameter

83% 3 year recurrence-free survival5 75% 4 year survival7 80% 5 year survival17

solitary HCC %5 cm in diameter or with %3 tumour nodules each %3 cm in diameter, in the absence of vascular invasion or extrahepatic spread. These studies formed the basis for restrictive selection criteria based on tumour size and number (Table 1). Nowadays, many transplant programs throughout the world have adopted the Milan selection criteria.7 In the original series, patients without major decompensation of hepatic function received adjuvant treatment, mostly chemoembolisation as further discussed later, prior to OLT. The 4 year actuarial overall survival and recurrence-free survival rates were 75 and 83%, respectively. In patients in whom pathological examination of the hepatic explant confirmed fulfillment of the pre-OLT selection criteria, the 4 year overall survival and recurrence-free survival rates were 85 and 92%, respectively. These survival figures were significantly better than those in patients whose hepatic explants revealed tumour burdens unexpectedly greater than pre-OLT selection limits (50 and 59%, respectively). These findings are in keeping with results of a recent analysis which demonstrated that patients exceeding the Milan criteria as judged by pathological examination of the explanted liver were over three times more likely to experience HCC recurrence during a median follow-up of 19.4 months than those fulfilling criteria.16 They also correlate well with earlier findings from King’s College Hospital that the 5 year actuarial survival rate post-OLT fell from 57% in patients with a single focus !4 cm in diameter to 44% in those with a single tumour 4–8 cm in diameter and only 11% in those with a single tumour in excess of 8 cm in diameter or multifocal disease.15 The most recently published results from Milan17 report 5 year patient survival and recurrence-free survival rates of 80 and 88%, respectively, comparable to those in the original report. Expanded access selection criteria Nonetheless, the need to reject a significant proportion of patients because their tumour burden falls outside these restrictive selection limits raised concerns as to whether the Milan criteria may be too stringent.18 Whether indications for transplantation can be expanded again and, if so, to what degree have become matters of great clinical relevance. Consequently, expanded access models have been proposed by workers at the University of California San Francisco (UCSF), the University of Pittsburgh and Mount Sinai (Table 2).19–21 As with the Milan criteria, UCSF criteria19 are based on the number and size of tumour nodules, while tumour volume is the major criterion underlying the Mount Sinai guidelines.21 The Pittsburgh criteria20 are more complex, with six stages based on vascular invasion, lobar distribution, size of the largest nodule, lymph node status

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Table 2. Proposed expanded access selection criteria for OLT for HCC. Centre 19

UCSF

HCC-related criteria Single nodule %6.5 cm in diameter or no more than three nodules, the largest of which is %4.5 cm in diameter and a total diameter for all nodules %8 cm

Pittsburgh20 Stage

Mount Sinai21

I I I II IIIA IIIB If bilobar disease, the tumour burden in the lobe with less involvement must be !5 cm in total diameter; the total tumour volume must be !75% of total liver volume

Vascular invasion

Lobar distribution

Largest nodule (cm)

Lymph node status

Metastasis

None None None Micro None Micro

Unilobar Bilobar Any Any Bilobar Bilobar

Any %2 %2 O2 O2 O2

Negative Negative Negative Negative Negative Negative

None None None None None None

and metastatic disease. Stages I to IIIB are considered suitable for transplantation. Some aspects of the Pittsburgh criteria, such as vascular invasion and lymph node status, can be difficult to properly assess prior to laparatomy or even pathological examination of the explanted liver, limiting their applicability to pre-transplant evaluation.18 This is especially so in the many centers that avoid biopsy of HCC’s prior to OLT for fear of dissemination of the tumour along the needle tract22, in which situation the preoperative determination of the presence or absence of microscopic vascular invasion is an impossibility. Evidence of extrahepatic dissemination and invasion of the main portal and hepatic veins represent contraindications to OLT in all of these models. Even with state of the art imaging at the time of pre-operative assessment, there remains the possibility of under-staging of patients due to the inability to detect small additional nodules less than 1–2 cm in diameter.23 In the original report of the Milan criteria, 27% of patients were under-staged when results of pre-OLT investigations including hepatic angiography with computerised tomography during the portal venous phase and lipiodol-computerised tomography were compared to pathological examination of the hepatic explant.7 Comparative efficacies of the Milan and expanded access UCSF and Pittsburgh criteria The performance of the UCSF criteria has been compared to that of both the Milan and Pittsburgh guidelines in a cohort of 70 patients transplanted at UCSF over a 12 year period from 1988 to 2000.24 In contrast to earlier studies, no significant difference in

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survival was found in 24 patients exceeding Milan criteria and 46 patients in whom these criteria were met. Patients fulfilling UCSF criteria but exceeding Milan guidelines had a 2 year survival rate of 86%. Survival for patients fulfilling Pittsburgh criteria was comparable to that in patients meeting UCSF criteria. Advanced tumour burdens in excess of UCSF criteria correlated with poor differentiation status and the presence of microvascular invasion, factors associated with a high risk of HCC recurrence, as further discussed later. A prospective study is currently underway to evaluate the impact on post-OLT outcome of the UCSF expanded criteria, which were originally derived from pathologic HCC characteristics in the hepatic explant, when applied to pre-operative tumour staging. The Pittsburgh group has also compared the Milan, UCSF and Pittsburgh selection criteria in a cohort of over 400 patients who underwent OLT for HCC at their own institution between 1981 and 2002, in many cases before the institution of the Milan, UCSF or current Pittsburgh recommendations.25 Milan criteria would have been fulfilled in 248 (63.1%) patients, in whom the 5 year patient survival and recurrence-free survival rates were 67 and 96%, respectively. Of 145 (37%) patients who would not have fulfilled Milan criteria, and who thus would have been denied cadaveric OLT, 72 (50%) have remained recurrence-free after a mean follow-up period of 3 years (range 0–19 years). UCSF criteria would have been met in 265 (67%) patients, in whom 1 and 5 year patient survival rates were 80 and 67%, respectively. The 5 year recurrence-free survival rate was 94%. Of 128 (33%) patients who would not have fulfilled UCSF criteria for OLT, 45% remained recurrence-free after a mean 3 years follow-up (range 0–19 years). Over 80% of patients would have fulfilled the current Pittsburgh criteria. Over 90% of patients remained recurrence-free after a mean follow-up of 5 years (range 0–19 years). Of 77 patients who would not have met current Pittsburgh guidelines, 27% have remained recurrence-free after mean follow-up of 1.5 years (range 0–11 years). Efficacy of Mount Sinai criteria Between October 1991 and January 1999, 43 HCC patients fulfilling Mount Sinai criteria underwent OLT at that institution, following interval chemoembolisation while on the waiting list.21 Patients also received six cycles of systemic adriamycin posttransplant. During a mean follow-up of 55 months, 5-year patient survival was 44%, with HCC recurrence seen in 52% of patients. Results with these UCSF, Pittsburgh and, to a lesser degree, Mount Sinai expanded access criteria are clearly better than those obtained in early series of OLT for HCC, in which large tumours constituted a substantial proportion of cases and formal selection criteria were non-existent. The observation that recurrence-free survival exceeds overall survival in these recent expanded access series does suggest that selection criteria have become too restrictive.18 However, over-relaxing existing guidelines has the potential to markedly impair both the results of OLT for HCC and availability of cadaveric OLT for non-HCC patients. A consensus as to the minimum acceptable survival rate following OLT for HCC is urgently required, so that selection criteria can be developed to achieve this outcome.25 A 5 year survival rate as low as even 30% might seem reasonable, especially when other possible therapeutic options are contraindicated, although the impact of such an approach on organ availability for non-HCC patients with a better post-OLT prognosis requires careful consideration. In the meantime, since the MELD-based organ allocation system currently operative in the United States does not grant priority to patients with HCC beyond Milan criteria

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and programmes in many other parts of the world do not prioritise patients with HCC for cadaveric transplantation at all, living donor OLT, as discussed in more detail later, has become the only feasible transplant option for this large group.

DISEASE PROGRESSION WHILE WAITING FOR OLT: ROLE OF ADJUVANT THERAPIES In the absence of anti-tumour treatment, Llovet et al26 in Barcelona found that approximately 25% of patients who initially fulfill Milan criteria will be excluded from the waiting list because of tumour growth when the waiting time reaches 6 months. Experience from the Mount Siani programme has shown that patients listed for OLT with more extensive intrahepatic tumour burdens experience an even higher drop-out rate in excess of 50% prior to a graft becoming available.21 Adjuvant therapies to prevent disease progression while waiting for OLT are thus commonly employed.27 These include percutaneous ethanol injection (PEI), radiofrequency ablation (RFA) and chemoembolisation. PEI is particularly effective for solitary, accessible, small HCC’s no larger than 2 cm in diameter but not useful when the diameter exceeds 4 cm.28 RFA is useful for tumours up to 6 cm in diameter and may more reliably achieve complete ablation of tumours ranging from 2 to 4 cm in diameter than PEI, as judged by the absence of enhancement on imaging studies.29 Maddala et al30 recently reported their experience of the impact of chemoembolisation on the drop-out rates of patients with HCC listed for OLT at the Mayo Clinic. Between January 1994 and August 2001, 54 patients with HCC were listed for OLT. Most fulfilled Milan criteria at the time of the first chemoembolisation. The median waiting time for patients who were eventually transplanted was a relatively short 211 days (range 28–1099 days). Eight patients (15%) were removed from the waiting list over time due to death or tumour progression. The cumulative probability of drop-out, as assessed by Kaplan–Meier methods, was 15% at 6 months and 25% at 12 months. No significant differences in patient age, gender, initial tumour stage or serum alphafetoprotein levels were apparent in those who eventually underwent OLT and those who dropped out. In patients who underwent OLT, the overall 5 year survival was 75%, comparable to that after OLT without HCC. The experience with drop-out from the waiting list for OLT in 70 patients with HCC at UCSF in relation to the selection criteria employed and use or otherwise of antitumour treatments has recently been reported.31 Thirty-eight patients (54%) eventually underwent OLT. Using UCSF selection criteria, the probabilities of dropout at 6, 12 and 18 months were 7.2, 37.8 and 55.1%, respectively. The drop-out rates would have been 11.0, 57.4 and 68.7%, respectively, had the more restrictive Milan criteria been applied, presumably because even a minor increase in tumour size over baseline was sufficient to exceed the maximum allowable tumour burden in the Milan guidelines but not when the more liberal UCSF criteria were applied. Predictors of drop-out using either criteria included the presence of three tumour nodules and a single lesion in excess of 3 cm in diameter at presentation. Risk of drop-out in such patients was 9-fold higher than in patients with a single lesion no larger than 3 cm in diameter at presentation. Pre-operative adjuvant chemoembolisation or tumour ablation was associated with a significantly lower rate of drop-out when the UCSF criteria, but not when the more restrictive Milan selection guidelines, were applied.

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STRATEGIES TO REDUCE WAITING TIMES FOR OLT Organ allocation according to MELD score The MELD scoring system is a marker of severity of impairment of hepatic function based on the serum creatinine, bilirubin, international normalised ratio for prothrombin time and aetiology of liver disease.10 The MELD score was initially found to predict survival rates in patients undergoing the transjugular intrahepatic porto-systemic shunt procedure.32 It has also been found to predict outcome in patients with end-stage liver disease awaiting OLT33,34 and, in some series, post-OLT outcome.35–37 The MELD scoring system was implemented as a means of prioritising organ allocation in the United States in 2002, replacing waiting-time-based allocation. In order to overcome the fact that patients with complicating HCC often have wellcompensated hepatic function, and would thus be disadvantaged by a relatively low MELD score, HCC patients receive arbitrarily determined additional points, provided they fulfill Milan criteria, in a bid to provide the prospect of timely transplantation. While patients with more extensive intrahepatic tumour burdens are not necessarily excluded from transplant candidacy, they are not eligible for priority listing based on the MELD score and, in reality given the widespread donor organ shortage, these patients are unlikely to receive a cadaveric graft. Initial experiences suggest that implementation of the MELD scoring system has resulted in a substantial increase in the number of OLT’s performed for HCC in the United States, with shorter waiting times and a reduction in the need to remove patients from waiting lists as a result of disease progression.38,39 Nonetheless, significant disparity in organ allocation from region to region has been reported.38 The number of additional points on the MELD scale awarded to HCC patients in the United States has recently been down-scaled, because of concern at the negative impact of the increased number of OLT’s for HCC on waiting times for those without tumours. Living donor OLT Living donor OLT also offers the potential for the earlier transplantation of patients with HCC, resulting in lower drop-out rates and improved outcomes, not only in terms of patient survival but also health resource utilisation, given that over 40% of the total expenses incurred by patients undergoing OLT are incurred while waiting.40 Outcome modeling of adult-to-adult living donor OLT predicts that the most significant gains in life expectancy and cost effectiveness occur when the waiting time for a cadaveric graft exceeds 7 months.41 Nonetheless, indirect costs, such as time lost from work and potential future liabilities for the donor, including inability to obtain health insurance, are difficult to estimate and often not included in costeffectiveness analyses.42 A recent retrospective study from the University of Hong Kong further addressed the impact of living donor OLT in cirrhotic patients with HCC.43 Fiftyone patients were listed for OLT, including 25 with a potential living donor. Of these, 84% underwent living donor OLTafter a median waiting time of only 24 days. The 3 year post-transplant actuarial survival was 81%, with a 3 year intention to treat survival of 66%. Of the 26 patients without a potential living donor, only 20% subsequently underwent cadaveric transplantation after a median 344 days waiting time, with most

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drop-outs due to HCC progression. While the 3 year actuarial survival of transplanted patients was 80%, the intention to treat survival rate was only 38%. Morbidity and mortality of the donor remains a major concern with living donor OLT, with the latter currently in the order of 0.2–0.5%.39,44 Thus, living donor OLT would seem justified only when there is little likelihood of a cadaveric organ becoming available in a timely manner. Of course, selection criteria that are too restrictive force those excluded from cadaveric transplantation to seek alternatives such as living donor OLT, as emphasised by recent experience from the Mount Sinai transplant programme, in which over 35% of their adult recipients of living donation had HCC.45 Based on reported outcomes in the cadaveric OLT setting, it would seem reasonable to consider living donor OLT for patients fulfilling the expanded criteria proposed by the groups at UCSF, Pittsburgh, and perhaps to a lesser extent, Mount Sinai. A major question is whether living donor OLT should also be used in patients with even more advanced HCC.39 As with cadaveric OLT for HCC, a concensus as to the minimum acceptable 5 year survival post-living donor OLT for this indication, bearing in mind the risk to the donor, is required.

FACTORS ASSOCIATED WITH DISEASE RECURRENCE POST-OLT In a broad sense, recurrence of HCC post-OLT must result from extrahepatic dissemination which has occurred either prior to or during the transplant procedure. Microvascular invasion, as demonstrated histologically18,46–48, and poor tumour differentiation status49,50 are likely to be among the most important risk factors. Recent data suggest that the particular post-OLT immunosuppression regimen employed51 and allelic loss of heterozygosity for various tumour suppressor genes52 are also important. Whether adjuvant anti-tumour therapies used in the pre-operative period reduce the risk of recurrent HCC is not clear from available data. Vascular invasion A number of studies have clearly demonstrated that vascular invasion is associated with an up to 15-fold increased risk of HCC recurrence following OLT.18,27,46–48 While modern imaging techniques can reliably detect invasion of major portal or hepatic venous branches, macrovascular invasion of segmental branches occasionally cannot be established prior to examination of the hepatic explant; the future appearance of metastases is highly likely in this circumstance. Microvascular invasion is a histological diagnosis, and hence not discernible pre-operatively in many centers, as discussed above. Nonetheless, there exists some correlation between the number and size of HCC nodules and the presence or absence of vascular invasion.53 In particular, small, encapsulated HCC’s less than 3 cm in diameter rarely demonstrate vascular invasion, whilst a substantial proportion of lesions in excess of 5 cm in diameter show microscopic invasion into portal venules and lymphatics around the periphery of the tumour.54 The tumour burden adopted in the Milan criteria may thus be adopted as a reasonable surrogate marker for the likelihood of vascular invasion in pre-operative staging, providing a scientific rationale for the current organ allocation system that exists in many parts of the world.

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Tumour differentiation status The tumour grade of HCC tends to increase as the tumour grows larger, with smaller lesions demonstrating well-differentiated histology and larger lesions typically demonstrating areas of moderate or poor differentiation.49 An association between tumour differentiation status, nodule size and risk of microvascular invasion has been demonstrated. In particular, HCC diameter in excess of 5 cm in association with poor differentiation reasonably predicts the presence of microvascular invasion.50 Small HCC’s occasionally exhibit poor differentiation. In a recently published series from Mount Sinai, tumour recurrence was noted in only 4 of 120 patients transplanted with HCC’s %3 cm in diameter; in each case, the tumour was poorly differentiated and demonstrated microscopic vascular invasion.27 Post-OLT immunosuppression Evidence that cyclosporine and tacrolimus stimulate hepatic regeneration raise the possibility that growth of HCC may be stimulated by these drugs.55 Indeed, an early study comparing growth rates of recurrent HCC’s in transplant recipients and patients having undergone hepatic resection raised concern that post-transplant immunosuppression may accelerate the growth of HCC56, although conflicting data have been reported.57 In a retrospective analysis of 82 patients, Vivarelli et al51 recently reported that risk of HCC recurrence post-OLT was significantly related to the cumulative dosage of cyclosporine received during the first post-operative year. In contrast to findings with regard to cyclosporine administration, the cumulative dosages of prednisone and azathioprine were not significantly associated with tumour recurrence. High cyclosporine dosage administered in the first 12 months after transplantation and the pTNM stage of the tumour were identified as independent variables predicting HCC recurrence at multivariate analysis. Conversely, fulfillment or otherwise of the Milan criteria did not influence recurrence-free survival, even when patients were stratified according to use of cyclosporine as the main immunosuppressive agent.51 These findings raise the possibility that outcomes of clinical studies performed in the early to mid 1990s, when restrictive criteria for OLT for HCC were first proposed, may have been influenced, at least to some extent, by the immunosuppression regimen adopted at the time. Additional studies are required to assess for any relationship between the cumulative dose of tacrolimus during the first post-operative year and risk of HCC recurrence, since most liver transplant centers nowadays base immunosuppression on tacrolimus rather than cyclosporine. Sirolimus is an alternate immunosuppressive drug which acts through a different signal transduction pathway to the calcineurin inhibitors and has been shown to possess, among other biological properties, anti-neoplastic effects. In particular, sirolimus has been shown in an animal model to inhibit primary and metastatic tumour growth by anti-angiogenesis mechanisms58, even when used in combination with cyclosporine.59 Serum levels of vascular endothelial growth factor (VEGF) were reduced by around 50%59, a finding of potential relevance to patients transplanted for HCC in view of the important role that VEGF plays in the pathogenesis of this tumour.60 Use of sirolimus for post-OLT immunosuppression in HCC patients has been reported by the Cambridge group61, although reported experience to date

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is too limited to allow any meaningful assessment as to whether risk of HCC recurrence might be reduced. Allelic loss of heterozygosity for tumour suppressor genes A recent report from the Pittsburgh group investigating tumour suppressor gene loss suggests that genotyping of HCC in OLT recipients adds substantial predictive power for determining recurrence-free survival.52 Tumour suppressor gene loss is a frequent event in liver carcinogenesis.62 Although a full understanding of all the genes involved in the development and progression of HCC is lacking at present, it is likely that malignant transformation involves not one but a constellation of gene alterations occurring over time.52 In the Pittsburgh study, microdissected tissue samples from 103 patients followed for at least 5 years post-OLT were evaluated for allelic loss of heterozygosity for 18 microsatellites and 10 genomic loci, namely 1p, 3p, 5q, 7q, 8q, 9p, 10q, 17p, 17q and 18q. Genotyping results, in combination with a previously developed artificial neural network model constructed using pTNM-based pathologic tumour characteristics and the patient’s gender, correctly predicted tumour-free survival in 91/103 (88%) patients. The genotyping analysis improved the discriminatory power of the neural network model by 15%.52 Nonetheless, the need to biopsy not only one but all detected tumours would seem to limit the widespread application of this technology in the pre-operative setting, as the current clinical practice in many centers is to avoid biopsy for fear of precipitating tumour dissemination, even though the risk is only small.22

SUMMARY In patients with cirrhosis and hepatocellular carcinoma (HCC), orthotopic liver transplantation (OLT) offers hope for cure of both the complicating HCC and the underlying chronic liver disease. Excellent 5 year survival rates, comparable to those in patients without HCC, have been reported when the restrictive Milan criteria are used to select HCC patients for OLT. Recent data based on expanded access selection criteria proposed by groups at University of California San Francisco, University of Pittsburgh and, to a lesser extent, Mount Sinai, suggest that selection criteria for OLT may be liberalised without substantially adversely influencing postOLT survival. Living donor OLT has a role in patients with little likelihood of receiving a cadaveric graft within a timely period, especially when the waiting time exceeds 7 months. Strategies to reduce tumour growth while awaiting OLT are important so that HCC patients remain transplantable. Further prospective studies will be important to clarify to what extent current selection guidelines for OLT can be expanded without compromising post-OLT survival due to early tumour recurrence. The minimum acceptable 5 year post-OLT survival rate in HCC patients, bearing in mind the impact of expanded access criteria on accessibility of cadaveric organs to non-HCC patients, remains to be defined. The role of post-OLT immunosuppression in promoting HCC recurrence and whether sirolimus, in particular, holds any advantage over other immunosuppressive agents with regard to reducing this risk warrant further investigation.

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Practice points † excellent 5 year survival rates, comparable to those in patients without HCC, have been reported when the restrictive Milan criteria are used to select HCC patients for OLT † recent data based on expanded access selection criteria proposed by groups at University of California San Francisco, University of Pittsburgh and, to a lesser extent, Mount Sinai, suggest that selection criteria for OLT may be liberalised without substantially adversely influencing post-OLT survival † living donor OLT has a role in patients with little likelihood of receiving a cadaveric graft within a timely period, especially when the waiting time exceeds 7 months † strategies to reduce tumour growth while awaiting OLT are important so that HCC patients remain transplantable

Research agenda † further prospective studies, based on pre-operative imaging rather than the pathological examination of the hepatic explant, will be important to clarify to what extent current selection guidelines for OLT in patients with HCC can be expanded without compromising post-OLT survival due to early tumour recurrence † the role of post-OLT immunosuppression in promoting HCC recurrence and whether current selection guidelines can be further expanded if sirolimus is used require further investigation

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