Liver transplantation for hepatocellular carcinoma
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Leading article Liver transplantation for hepatocellular carcinoma C.-M. Lo and S.-T. Fan Department of Surgery, The University of Hong Kong Medical Centre, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, China (e-mail: [email protected]) Published online in Wiley InterScience (www.bjs.co.uk). DOI: 10.1002/bjs.4503 Liver transplantation may be the best curative treatment for hepatocellu- lar carcinoma (HCC). It not only removes the tumour with the widest margin, it also cures the underlying cirrhosis that is responsible for both postoperative hepatic decompensa- tion and tumour recurrence after par- tial hepatectomy. Nevertheless, the practice of evidence-based medicine, which depends on the accrual of lev- els of evidence demonstrating signifi- cant advantages for one therapy over another, is hardly applicable to liver transplantation. The limited availabil- ity of liver grafts demands a sys- tem that selects the best recipient of a transplant rather than one that selects the best treatment for a patient. To justify organ allocation, candidacy must be restricted to those whose sur- vival is likely to be similar to that of other transplant recipients. Identification of the prognostic fac- tors for survival has been a focus of research on liver transplantation for HCC. Indeed, the considerable improvement in the outcome of liver transplantation in this context in recent years is attributable almost entirely to better patient selection rather than to better surgery or adju- vant therapy. The presence of vascular invasion is probably the most impor- tant predictor of a poor outcome. As such invasion is identified only after histological examination of the whole hepatectomy specimen, surro- gate markers (such as the size and number of tumours that can be deter- mined by preoperative imaging) are the best selection criteria in practice. Using the Milan criteria 1 , which limit transplantation to patients with a solitary tumour no greater than 5 cm in diameter or with two to three tumour nodules no larger than 3 cm, a 4-year survival rate of 75 per cent can be achieved. However, there is a second obstacle for even these highly selected patients, namely tumour progression and death during the waiting period. Therefore, intention- to-treat analysis is appropriate. In a study from Spain, where the organ donation rate is the highest in the world and the average wait- ing time is less than 6 months, 23 per cent of patients who met the Milan criteria dropped out and the 2-year intention-to-treat survival rate was only 54 per cent 2 . The result of such an intention-to-treat analysis argues against a strategy of primary liver transplantation for resectable early tumours. Partial hepatectomy should be the preferred approach in patients with relatively preserved liver function, with salvage transplantation reserved for those with tumour recur- rence or hepatic decompensation. Attempts have been made to extend the benefits of liver transplantation to more patients with HCC. Pro- posals that the tumour size limits might be expanded without com- promising patient survival have been put forward 3 , and single-institution pilot studies have evaluated adjuvant chemotherapy for more advanced dis- ease to permit transplantation. How- ever, adjuvant therapies are more usu- ally administered to patients on the waiting list to reduce tumour growth and hence avoid drop-out 4 . Nonethe- less, increasing the number of patients who may benefit from transplantation will have little effect on the actual number who eventually do benefit from it. The truth is that demand has far exceeded supply. Without an increase in cadaver organ availability, any measure that increases demand will compete for the existing supply; paradoxically, this will have an adverse effect on the waiting time and drop- out rate of all those on the waiting list. The high drop-out rate for patients with HCC has prompted a redefini- tion of the scheme of organ allocation in the USA to give greater priority to those who fulfil the Milan criteria. The Model for End-Stage Liver Dis- ease score has been adopted as the main determinant of organ alloca- tion, based on the predicted prob- ability of candidate death. Patients with tumours smaller than and larger than 2 cm are registered with scores equivalent to an 8 and 15 per cent probability of death within 3 months respectively. In addition, for every 3 months on the waiting list, a 10 per cent increase in mortality rate is assigned. Although there are good arguments to support such favouring of patients with HCC, the change in the scheme simply diverts liver grafts from those with benign disease. In addition, the advantage of listing with a diagnosis of HCC may be abused. As many as 15 per cent of patients listed with a diagnosis of HCC are eventually found to have no tumour identifiable in the liver explant. Recent advances in adult living- donor liver transplantation (LDLT) may produce a drastic change in the role of transplantation surgery. Living donors can potentially provide what is essentially an unlimited source of liver grafts for a planned transplant Copyright 2004 British Journal of Surgery Society Ltd British Journal of Surgery 2004; 91: 131–133 Published by John Wiley & Sons Ltd
Transcript of Liver transplantation for hepatocellular carcinoma
Leading article
Liver transplantation for hepatocellular carcinomaC.-M. Lo and S.-T. FanDepartment of Surgery, The University of Hong Kong Medical Centre, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, China(e-mail: [email protected])
Published online in Wiley InterScience (www.bjs.co.uk). DOI: 10.1002/bjs.4503
Liver transplantation may be the bestcurative treatment for hepatocellu-lar carcinoma (HCC). It not onlyremoves the tumour with the widestmargin, it also cures the underlyingcirrhosis that is responsible for bothpostoperative hepatic decompensa-tion and tumour recurrence after par-tial hepatectomy. Nevertheless, thepractice of evidence-based medicine,which depends on the accrual of lev-els of evidence demonstrating signifi-cant advantages for one therapy overanother, is hardly applicable to livertransplantation. The limited availabil-ity of liver grafts demands a sys-tem that selects the best recipientof a transplant rather than one thatselects the best treatment for a patient.To justify organ allocation, candidacymust be restricted to those whose sur-vival is likely to be similar to that ofother transplant recipients.
Identification of the prognostic fac-tors for survival has been a focusof research on liver transplantationfor HCC. Indeed, the considerableimprovement in the outcome of livertransplantation in this context inrecent years is attributable almostentirely to better patient selectionrather than to better surgery or adju-vant therapy. The presence of vascularinvasion is probably the most impor-tant predictor of a poor outcome.As such invasion is identified onlyafter histological examination of thewhole hepatectomy specimen, surro-gate markers (such as the size andnumber of tumours that can be deter-mined by preoperative imaging) arethe best selection criteria in practice.
Using the Milan criteria1, whichlimit transplantation to patients with
a solitary tumour no greater than5 cm in diameter or with two to threetumour nodules no larger than 3 cm,a 4-year survival rate of 75 per centcan be achieved. However, there is asecond obstacle for even these highlyselected patients, namely tumourprogression and death during thewaiting period. Therefore, intention-to-treat analysis is appropriate.
In a study from Spain, where theorgan donation rate is the highestin the world and the average wait-ing time is less than 6 months, 23per cent of patients who met theMilan criteria dropped out and the2-year intention-to-treat survival ratewas only 54 per cent2. The resultof such an intention-to-treat analysisargues against a strategy of primaryliver transplantation for resectableearly tumours. Partial hepatectomyshould be the preferred approach inpatients with relatively preserved liverfunction, with salvage transplantationreserved for those with tumour recur-rence or hepatic decompensation.
Attempts have been made to extendthe benefits of liver transplantationto more patients with HCC. Pro-posals that the tumour size limitsmight be expanded without com-promising patient survival have beenput forward3, and single-institutionpilot studies have evaluated adjuvantchemotherapy for more advanced dis-ease to permit transplantation. How-ever, adjuvant therapies are more usu-ally administered to patients on thewaiting list to reduce tumour growthand hence avoid drop-out4. Nonethe-less, increasing the number of patientswho may benefit from transplantationwill have little effect on the actual
number who eventually do benefitfrom it. The truth is that demandhas far exceeded supply. Without anincrease in cadaver organ availability,any measure that increases demandwill compete for the existing supply;paradoxically, this will have an adverseeffect on the waiting time and drop-out rate of all those on the waiting list.
The high drop-out rate for patientswith HCC has prompted a redefini-tion of the scheme of organ allocationin the USA to give greater priorityto those who fulfil the Milan criteria.The Model for End-Stage Liver Dis-ease score has been adopted as themain determinant of organ alloca-tion, based on the predicted prob-ability of candidate death. Patientswith tumours smaller than and largerthan 2 cm are registered with scoresequivalent to an 8 and 15 per centprobability of death within 3 monthsrespectively. In addition, for every3 months on the waiting list, a 10per cent increase in mortality rate isassigned. Although there are goodarguments to support such favouringof patients with HCC, the change inthe scheme simply diverts liver graftsfrom those with benign disease. Inaddition, the advantage of listing witha diagnosis of HCC may be abused.As many as 15 per cent of patientslisted with a diagnosis of HCC areeventually found to have no tumouridentifiable in the liver explant.
Recent advances in adult living-donor liver transplantation (LDLT)may produce a drastic change in therole of transplantation surgery. Livingdonors can potentially provide whatis essentially an unlimited source ofliver grafts for a planned transplant
Copyright 2004 British Journal of Surgery Society Ltd British Journal of Surgery 2004; 91: 131–133Published by John Wiley & Sons Ltd
132 C.-M. Lo and S.-T. Fan
operation as soon as the diagnosis ofHCC is made. The uncertainty ofa prolonged waiting period can virtu-ally be eliminated. Hypothetical studyusing a decision analytical model5 hasdemonstrated the theoretical survivalbenefit conferred by LDLT. How-ever, although the results suggest thatthis may become the dominant strat-egy for patients with early irresectableHCC, there are serious limitations insuch a model.
The first and perhaps the strongestargument against such a propositionstems from risk to the living donor.For some, one death of a healthydonor is too many, and the philosoph-ical question of how many waiting-listdeaths need to be averted in order tojustify one donor death will never beanswered. Furthermore, of the variousassumptions made in the hypotheticalmodel, many have yet to be con-firmed. First, to assume that a livingdonor is readily available and thatimmediate transplantation is alwayspossible ignores various factors, suchas donor voluntarism and selectioncriteria. Second, one might ques-tion the validity of the assumptionthat survival and quality of life afterliving-donor and cadaver-donor livertransplantation for HCC are equal.Right-lobe LDLT is a novel proce-dure with a relatively short history,and many transplant programmes arestill in the early learning phase.
A case–control study of 728 living-donor liver transplants in adults in theUSA showed that recipients of living-donor transplants had more stableliver disease and yet the graft sur-vival rate at 2 years was only 64·4per cent, compared with 73·3 per centfor cadaver grafts6. Apart from thehigher risk of biliary complicationsthat has been widely recognized, it ispossible, although not proven, thatLDLT for HCC could be associ-ated with a higher risk of tumourrecurrence. Such a hypothesis arises,
paradoxically, as a result of the abilityof LDLT to eliminate the waitingperiod during which tumours witha poor prognosis may declare them-selves. Furthermore, a graft from a liv-ing donor is frequently small for sizeand, theoretically, the acute-phaseinjury and subsequent regenerationand angiogenesis may create an envi-ronment favourable for tumour recur-rence. Hence, the conclusion of thesehypothetical studies should be inter-preted with caution; the impact ofthe strategy of LDLT can be definedonly by clinical study, preferably onan intention-to-treat basis.
Unfortunately, there are few clin-ical data on the role of LDLT forirresectable early HCC. The issueis problematic as almost all earlyreports7–10 have focused on extendedindications for more advanced disease,because a living-donor liver graft isa private gift to a dedicated recipi-ent, and is not subject to a systemof equitable allocation. The Kyotogroup adopted selection criteria thatincluded patients with tumours of anynumber and size, excluding only thosewith extrahepatic metastases or vas-cular invasion7. Twenty-five of 56patients did not meet the Milan cri-teria and the overall 3-year survivalrate was only 55 per cent. Despitethe lack of data and the controversy,some transplant programmes alreadyregard HCC as a prime indication forLDLT8.
While arguing for, and respect-ing the autonomy of, the decision ofthe donor and recipient, surgeons areobliged to provide unbiased informa-tion and carry the ultimate responsi-bility when any decision is executed.Objective data are needed, rather thansubjective claims regarding the out-come for donors and recipients, andsurgeons have an obligation to definea limit below which the recipient’scompromised outcome would not jus-tify the risk to the donor. At present,
LDLT for HCC with extended indi-cations is at best an experimentalprocedure of unknown cost effective-ness. Its routine practice cannot berecommended. In addition, to ensurethat this new group of candidates whowere not eligible for cadaver graftallocation will not later compete forthe existing supply, retransplantationusing cadaver graft should not be donefor graft failure.
Each year, although HCC accountsfor more than one million deathsworldwide, there are only about10 000 liver transplant operations andless than 10 per cent of these areconducted in patients with this cancer.Liver transplantation, regarded by somany as so good, is far from beinga general solution. For the very few,selection remains the key word. Thereis no doubt that live organ donationwill contribute, but its exact roleand impact in different parts of theworld remain unclear. Surgeons whoperceive a benefit in initiating livingdonation for patients with HCC mustundertake vigilant data collection andevaluation to ensure that their clinicalperceptions are evidence based.
References
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