Survival Benefit of Transplantation for Recurrence of HepatocellularCarcinoma After Liver Resection

F. Tucia, A. Vitalea,*, F. D’Amicoc, E. Gringeria, D. Neria, G. Zanusa, D. Bassia, M. Polaccoa, R. Boettoa,E. Lodoa, G. Germanib, P. Burrab, P. Angelic, and U. Cilloa

aUnità di Chirurgia Epatobiliare e Trapianto Epatico, Azienda, Università di Padova, Padua, Italy; bUnità di Trapianto Multiviscerale,Azienda, Università di Padova, Padua, Italy; and cUnità di Emergenze Trapiantologiche, Azienda, Università di Padova, Padua, Italy

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Transplantat

ABSTRACT

Background. Liver transplantation (LT) for hepatocellular carcinoma (HCC) can beused for tumor recurrence after liver resection (LR) both for initially transplant-eligiblepatients as conventional salvage therapy (ST) and for nonetransplant-eligible patients(beyond Milan criteria) with a goal of downstaging (DW). The aim of this study was tocompare the intention-to-treat (ITT) survival rates of patients who are listed for LT,according to these two strategies.Methods. We analyzed a prospective database of 399 consecutive patients who under-went hepatic resection for HCC from 2002 to 2011 to identify patients included in thewaiting list for tumor recurrence. Intention-to-treat (ITT) survivals were compared withthose of patients resected for HCC within and beyond Milan criteria in the same periodand not included in the LT waiting list.Results. The study group consisted of 42 patients, 28 in the ST group (within Milan) and14 in the DW group (beyond Milan). The 5-year ITT survival rate was similar between the2 groups, being 64% for ST and 60% for DW (P ¼ .84). Twenty-five patients (15 ST and 10DW) underwent LT, 13 (10 ST and 3 DW) were still awaiting LT, 4 (3 ST and 1 DW)dropped out of the waiting list because of tumor progression, and 7 (5 ST [33%] and 2DW [20%]) had tumor recurrence. The 5-year ITT survival of ST patients was similar tothat of 252 in-Milan HCC patients resected only (P ¼ .3), whereas 5-year ITT survivalof DW patients was significantly higher (P < .01) than that of 105 beyond-Milan HCCpatients resected only.Conclusions. LR seems to be a safe and effective therapy both as alternative to trans-plantation and as downstaging strategy for intermediate-advanced HCC. The survivalbenefit of salvage LT, however, seems to be higher in the 2nd than in the 1st group.

*Address correspondence to Dr Alessandro Vitale, Unità diChirurgia Epatobiliare e Trapianto Epatico, Dipartimento diChirurgia Generale e Trapianti, Via Giustiniani 2, 35128 Padova,Italy. E-mail: alessandro.vitale@unipd.it

HEPATOCELLULAR carcinoma (HCC) is now theleading cause of death among patients with cirrhosis

in Europe [1]. The best outcomes in survival terms (5-yearsurvival rates of 50%e70%) have been reported for care-fully selected HCC patients [2] treated with liver resection(LR) or liver transplantation (LT). Because these 2 majortreatments have not been compared in randomized clinicaltrials, there is no firm evidence to establish the optimumfirst-line treatment for patients with primary liver cancer.Underlying liver disease intrinsically limits the curative po-tential of LR, in the sense of the prevalence of resectabilityor the chances of a true oncologic recovery. Only few HCC

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ion Proceedings, 46, 2287e2289 (2014)

patients with a well preserved liver function can be selectedfor LR, and, even after radical treatment, they carry a highrisk of de novo tumors owing to the multifocal carcinogenicpotential of cirrhosis [2]. LT is theoretically the best treat-ment for HCC in cirrhotic patients, but this solution suffersfrom the limited availability of donor organs [2].

0041-1345/14http://dx.doi.org/10.1016/j.transproceed.2014.07.031

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2288 TUCI, VITALE, D’AMICO ET AL

Recent studies evaluating the survival benefit of LT inHCC patients [3,4] showed that transplantation allowedonly a minimal gain in life expectancy compared with LR,whereas a higher LT benefit was achievable for patients withunresectable HCC.In such a transplant benefit perspective, LR should always

be considered as the first-line therapy in HCC patientsjudged to be simultaneously resectable and transplanteligible. Some debate, however, remains about treatingtransplant-eligible recurrences after LR, because recentevidence has shown a higher risk of post-LT tumor recidi-vism in patients within Milan criteria [5] undergoing salvageLT [6].Moreover, LT for HCC can be used for tumor recurrence

after liver resection (LR) both for initially transplant-eligible patients as conventional salvage therapy (ST) andfor nonetransplant-eligible patients (beyond Milan criteria)with a goal of downstaging (DW). The aim of the presentstudy was to compare the intention-to-treat (ITT) survivalrates of patients who are listed for LT according to these 2strategies, and to explore the potential benefit of the samestrategies with respect to LR without secondary LT.

Table 1. Patient and Tumor Characteristics Both Before LiverResection and at Listing in the Study Groups

Variables SLT (n ¼ 28) DW (n ¼ 14)

Age (years) 59 (50e62) 64 (54e62)Female sex 5 (18%) 2 (14%)HCV 19 (70%) 8 (57%)MELD 9 (8e10) 9 (8e10)CRPH 18 (64%) 8 (57%)Macroscopic vascular invasion* 0 3 (21%)Diameter largest nodule (mm) 34 (19e50) 43 (35e50)Multinodular* 6 (21%) 13 (93%)AFP (ng/ml) 20 (12e50) 41 (5e94)Time between LR and listing

(months)*13.9 (5.4e36.0) 8.9 (5.5e14.9)

Time between LR and LT(months)*

30.2 (19.7e46.9) 14.9 (11.7e20.4)

Milan Out at listing* 9 (33%) 8 (57%)Transplant pathology

Size of the largestnodule (mm)†

30 (22e40) 40 (24e45)

Number of nodules† 4 (2e7) 6 (3e8)Macrovascular invasion 0 0Microvascular invasion† 9 (62%) 4 (38%)Poor grade* 6 (38%) 0

Abbreviations: ST, salvage therapy; DW, downstaging; HCV, hepatitis C virus;MELD, Model for End-Stage Liver Disease; AFP, alpha-fetoprotein; CRPH:Clinically relevant portal hypertension.*P < .05.†P < .01.

METHODS

We analyzed a prospective database of 399 consecutive patientswho underwent LR for HCC on cirrhotic liver from 2002 to 2011.As previously reported [7], LR was considered at our institutionfor HCC patients with preserved liver function (Child-Pugh A-B)and a technically resectable liver tumor without extra hepaticmetastasis. Differently from our previously published series [7],from 2002 salvage LT was adopted in our liver unit for selectedpatients with HCC recurrences. Size and number of nodules werenot considered as absolute selection criteria for either LR or LT,as previously reported [7,8]. Patients with recurrent HCC after LRnot fulfilling LT criteria [8] were assessed for a new LR or otherlocoregional treatments [9]. We identified 42 patients included inour LT waiting list for tumor recurrence after LR, 28 in the STgroup (within Milan before LR) and 14 in the DW group (beyondMilan before LR).

Baseline characteristics of the patients are expressed as median(interquartile range) for continuous data and as frequency forcategoric data. For subgroup comparisons, quantitative variableswere compared with the use of Student t or Wilcoxon rank sumtests, and categoric variables were compared with the use of c2 orFisher exact tests as appropriate. Follow-up length and survival areexpressed as median (range). ITT survival was calculated from theday of LR until death or last follow-up control. Recruitment offollow-up data was closed on December 31, 2012. Probability curvesof ITT survival were calculated according to the Kaplan-Meiermethod and compared by log rank test. To describe the perfor-mance in ITT survival of the study groups, we finally take asreference a group of patients undergoing LR and not receiving LTin the same period. These were divided into 2 reference groups: 252resected-only in-Milan HCC patients (RMI), and 105 resected-onlybeyond-Milan HCC patients (RMO). For descriptive purposes only,ITT survival curves of HCC patients undergoing LR and listed forLT and those undergoing LR only were also compared by means ofthe log rank test. The calculations were done with the JMP package(1989e2003, SAS Institute).

RESULTS

Characteristics of enrolled patients and tumors at the timesof LR and of listing are described in Table 1. Patients in theDW group had a significantly higher proportion of multi-nodular HCC and macroscopic vascular invasion at radi-ology before LR than patients in the ST group; similarly, theproportion of beyond-Milan patients at the moment oflisting, the time to LT, and the number and size of noduleswere higher in the first than in the second group. It isinteresting to note, however, that the proportion ofaggressive tumor features (microscopic vascular invasionand poor grade) in the DW group at the explant pathologyat the time of LT was significantly lower than in the STgroup.The 5-year ITT survival rate was similar between the 2

groups (Fig 1), being 64% for ST and 60% for DW (P¼ .84).Twenty-five patients (15 ST and 10 DW) underwent LT, 13(10 ST and 3 DW) were still awaiting LT, 4 (3 ST and 1 DW)dropped out from the waiting list for tumor progression, and7 (5 ST [33%] and 2 DW [20%]) had tumor recurrence. Wefound only a marginal statistical significance in the higherproportions of transplantations and HCC recurrences afterLT in the ST than in the DW group.The 5-year ITT survival of ST patients was similar to that

of 252 in-Milan HCC patients resected only (P ¼ .3),whereas 5-year ITT survival of DW patients was significantlyhigher (P < .01) than that of 105 beyond-Milan HCC pa-tients resected only.

Fig 1. Kaplan-Meier intention-to-treat (ITT) survival curves ofHCC patients undergoing resection at our institution. Abbrevia-tions: ST, resection 1st and conventional salvage liver transplan-tation group; DW, resection for downstaging and salvage livertransplantation group; RMI, resection-only within-Milan group;RMO, resection-only beyond-Milan group.

TRANSPLANTATION AFTER RESECTION FOR HCC 2289

DISCUSSION

The 1st result of this study is that the ITT survival after LRused for downstaging before LT appears to be similar tothat of LR and conventional salvage LT. This is an inter-esting result supporting the feasibility and effectiveness ofdownstaging protocols to make tumors eligible for trans-plant that were originally beyond accepted inclusion criteriafor LT [10].As a 2nd point, this study confirms that salvage LT

strategy after LR for in-Milan patients remains controver-sial due to the high risk of dropout from the waiting list andthe relatively high risk of recurrence after LT [6]. It isimportant to underscore, however, that this result does notsupport the use of LT as first-line therapy for resectable in-Milan patients [11]. On the contrary, considering the scarcedonor resources and a transplant benefit perspective [3,4],we could argue that LR should be considered as the first-line therapy for simultaneously resectable and transplant-eligible HCC patients, and that a further savings of organcould derive from avoiding to treat recurrences after LRwith LT, because the benefit of salvage LT strategy seemedto be negligible (Fig 1). On a pure speculative basis, we

could suggest using some of these spared organs for patientswith HCC recurrence after downstaging resection, becausethe transplant benefit in this group seems to be clinicallyrelevant (Fig 1). It has to be underscored, however, that thispeculiar result could be influenced by the higher priority toLT given to patients in the DW group (Table 1).In conclusion, LR seems to be a safe and effective therapy

both as alternative to transplantation and as downstagingstrategy for intermediate-advanced HCC. The survivalbenefit of LT to treat recurrences after LR, however, seemshigher in the 2nd than in the 1st group.

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