The prognosis and treatment outcomes ofpatients with recurrent hepatocellularcarcinoma after liver transplantation

Roh Y-N, Kwon CHD, Shin M, Song S, Shin M, Kim JM, Kim S,Joh J-W, Lee S-K. The prognosis and treatment outcomes of patientswith recurrent hepatocellular carcinoma after liver transplantation.

Abstract: Liver transplantation (LT) is performed in patients withhepatocellular carcinoma (HCC), but recurrent HCC after LT remains aproblem. We retrospectively reviewed the data from 63 patients withrecurrent HCC who underwent LT at a single institution betweenSeptember 1996 and March 2011 to determine the prognosis of patientswith recurrent HCC after LT. A survival analysis was performed with thepreoperative data, histological findings, patterns of recurrence, andtreatment methods. Univariate and multivariate analyses were performedto determine the factors associated with early (<1 yr) cancer-relateddeath. The independent prognostic factors, according to the multivariateanalysis, were recurrence within six months (hazards ratio [HR] = 4.557,p = 0.021) and initial multiple-organ involvement (HR = 5.494,p = 0.015). The survival rates of patients differed according to thetreatment type. The combined treatment with local and systemictreatment resulted in increased survival even in patients with HCCrecurrences involving multiple organs.

Young-Nam Roha, Choon HyuckDavid Kwonb, Sanghyun Songb,Milljae Shinb, Jong Man Kimb,Sungjoo Kimb, Jae-Won Johb andSuk-Koo Leeb

aDepartment of Surgery, Ilsan Paik Hospital,

Inje University College of Medicine, Goyang

and bDepartment of Surgery, Samsung

Medical Center, Sungkyunkwan University

School of Medicine, Seoul, Korea

Key words: mTOR inhibitor – rapamycin –

sorafenib – locoregional treatment –

metastasis

Corresponding author: Choon Hyuck David

Kwon, MD, PhD, Department of Surgery,

Samsung Medical Center, Sungkyunkwan

University School of Medicine, #81 Irwonro,

Gangnamgu, Seoul 135-710, Korea.

Tel.: 82 2 3410 1281;

fax: 82 2 3410 0040;

e-mail: chdkwon@skku.edu

Conflicts of interest: None.

Accepted for publication 1 November 2013

Liver transplantation (LT) is accepted as the besttreatment option for hepatocellular carcinoma(HCC) because of the multifocal potential ofHCC. Survival rates for HCC patients haveimproved since the introduction of the Milan crite-ria and University of California at San Francisco(UCSF) criteria. However, currently, LT is beingperformed worldwide in patients who do not meetthese criteria (1, 2), and recurrent HCC after LT isone of the most significant problems to overcome.A few studies have dealt with the management andprognosis of patients with recurrent HCC after LT(3–11).

Until now, the major concern has beenpredicting the probability of HCC recurrence andidentifying patients with a high risk of recurrencebefore LT (7). However, problems regarding thetreatment of recurrent lesions and improvement of

survival after HCC recurrence have arisen sincethe above-described expansion of the indicationsfor LT. Currently, we are unable to predict thesurvival of patients with HCC recurrence after LTand do not know the efficacy of local or systemicadjuvant therapy. It is known that the progressionof recurrent HCC after LT is rapid and theprognosis is poor (5, 8). However, in ourexperience some patients presented with good out-comes in response to adjuvant treatments. Thisfinding brought about the hypothesis that patientswith recurrent HCC after LT comprise a heteroge-neous group of clinical situations with differingprognoses.In this study, we investigated the prognosis for

HCC recurrence after LT and attempted todetermine the risk factors associated with early(<1 yr) cancer-related death. We also assessed

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© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Clin Transplant 2014: 28: 141–148 DOI: 10.1111/ctr.12286 Clinical Transplantation

patient survival according to treatment type andevaluated the efficacy of adjuvant treatment.

Patients and methods

Study population

Between September 1996 and March 2011, 458patients underwent LT due to HCC at a singleinstitution. Seventy-two patients (16%) who hadrecurrences were identified. Among the patientswith recurrences, 63 who were followed for morethan one yr after the HCC recurrence wereenrolled in this study. The medical records of thesepatients were reviewed retrospectively. Themean follow-up duration after LT was 29.8� 25.1 months (range: 3.0–108.2 months), and themean follow-up duration after HCC recurrencewas 16.9 � 17.1 months (range: 1.1–86.6 months).The baseline characteristics of the 63 patients aresummarized in Table 1. Hepatitis B was the mostcommon cause of HCC (87%), and 78% (49/63) ofthe patients had a history of treatment for HCCbefore LT. Of these patients, 89% (56/63) receiveda living donor LT. Upon histological examinationsof the explanted livers, 71% (45/63) exceeded theMilan criteria and 68% (43/63) exceeded theUCSF criteria.

Preoperative evaluation and staging

Before LT, all patients with known HCC wereexamined for the existence of metastasis byabdominal computed tomography (CT) or mag-netic resonance imaging (MRI), chest CT, and abone scan with or without positron emissiontomography (PET). LT was performed in patientswithout any evidence of HCC metastasis on theseradiological evaluations. The indication of LT fora patient with HCC was the fulfillment of theMilan criteria on radiological evaluation. How-ever, due to the nature of living donor LT, we didnot have a maximal upper limit for the size andnumber of tumors, except in cases of major portalvein tumor thrombosis and extrahepatic metastasis(12). If the tumor number/size did not fulfill theMilan criteria, we explained the risk of HCC recur-rence to these patients and obtained their informedconsent before LT.

Histological studies

The explanted livers were examined by experiencedhistopathologists according to the Edmonsoncriteria for the degree of tumor differentiation.Necrotic lesions caused due to transarterial

chemoembolization (TACE) or radiofrequencyablation (RFA) were included in the tumor mea-surements, since these necrotic lesions reflected the

Table 1. Demographic, clinical, and pathological characteristics of

63 patients with HCC recurrence after LT (N = 63)

Characteristics No. patients

PreLT data

Age, mean (range) 52 � 8.0 yr (32–69 yr)

Sex (%)

Male: female 57 (90): 6 (10)

Underlying disease (%)

HBV 55 (87)

HCV 5 (8)

ALD 1 (2)

AIH 1 (2)

Budd-Chiari syndrome 1 (2)

Child-Pugh classification (%)

A:B:C 14 (22): 34 (54):15 (24)

MELD score, mean (range) 13.6 � 6.4 (6–35)

Prior treatment (before transplantation) (%)

Surgical resection 20 (32)

TACE 46 (73)

RFA 13 (21)

None 14 (22)

AFP level, ng/mL

Median (range) 139.3 � 29 120.7

(1.3–169 306.5)

<1000 ng/mL (%) 43 (68)

≥1000 ng/mL (%) 20 (32)

Type of transplantation (%)

Living donor: deceased donor 56 (89): 7 (11)

Histologic findings of explanted liver (%)

Tumor grade

I–II 57 (90)

III–IV 6 (10)

Tumor number

1–3 26 (41)

4–5 10 (16)

6–9 10 (16)

≥10 17 (27)

Fulfilling pa-Milan criteria

No 45 (71)

Yes 18 (29)

Fulfilling pa-UCSF criteria

No 43 (68)

Yes 20 (32)

Microvascular invasion

No 13 (21)

Yes 50 (79)

Portal vein invasion

No 40 (63)

Segmental 12 (19)

Main 11 (17)

Bile duct invasion

No 53 (84)

Yes 10 (16)

Imunosuppression before recurrence

Tacrolimus: cyclosporine 61 (97): 2 (3)

AFP, alpha-fetoprotein; LT, liver transplantation; HBV, hepatitis B virus;

HCV, hepatitis C virus; HCC, hepatocellular carcinoma; ALD, alcoholic

liver disease; AIH, autoimmune hepatitis; MELD, model for end-stage

liver disease; TACE, transarterial chemoembolization; RFA, radiofrequen-

cy ablation; UCSF, University of California at San Francisco.aPathologic.

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initial extent of HCC and might have displayedresidual foci of viability. The results of the histo-logical studies are shown in Table 1.

Post-transplantation management and follow-up

After LT, the immunosuppressant regimen con-sisted of a calcineurin inhibitor (CNI), a myco-phenolate, and a corticosteroid. The serum level ofalpha-fetoprotein (AFP) was measured duringevery follow-up visit. All patients who underwentLT due to HCC were evaluated with an abdominalCT and chest radiography within three monthsafter LT. After the initial post-surgical evaluation,an abdominal CT was repeated at least everysix months and chest radiography was repeated atleast every three months. Further evaluations bychest CT, bone scans, or PET scans were per-formed if clinically indicated.

Diagnosis of recurrence

The diagnosis of HCC recurrence was made byradiological evaluations, including abdominal CT orMRI, chest CT, bone scans, and PET scans, withouthistological confirmation. If recurrent lesions weredetected by imaging during the post-operative fol-low-up, the initial extent of recurrence was investi-gated with an abdominal CT, chest CT, and a bonescan within six months. These radiological evalua-tions were repeated at least annually to determine ifthere was disease progression. The PET scan wasused selectively if the results of the CT scan, theMRI, or the bone scan were uncertain or equivocal.

Treatment of recurrent lesions

Our treatment strategies for recurrent lesions weredivided into three types: local treatment, systemictreatment, and combined treatment. The localtreatment consisted of surgical resection (hepaticor extrahepatic), TACE, and RFA. The systemictreatment consisted of intravenous chemotherapy,sirolimus (mammalian target of rapamycin[mTOR] inhibitor), and Nexavar medication. Thecombined treatment consisted of local andsystemic treatment. All solitary recurrent lesions,whether hepatic or extrahepatic, were consideredfor surgical resection. Hepatic recurrences that didnot fit the indication for surgical resection due tothe location or number were initially treated withTACE or RFA. Prior to 2007, there was noestablished protocol for the systemic treatment ofHCC recurrences, and only three patients hadreceived intravenous chemotherapy. Since 2007,we have adopted a protocol that replaces CNI with

sirolimus in patients with HCC recurrences, andintravenous chemotherapy was no longer given tothese patients. Additionally, since 2007 Nexavarwas recommended if the patients accepted the cost,and the side effects were tolerated.

Survival and statistical analysis

To investigate the effect of recurrent tumor onearly (<1 yr) death after recurrence, we definedthe cancer-related death as death related to organfailure due to excessive growth of tumor in theorgan involved. We excluded the early (<1 yr)death due to the definite other causes which werenot related to recurrent tumor. The risk factoranalysis for early (<1 yr) cancer-related death wasperformed with variables that included the preop-erative data, histological findings of the explantedlivers, and the patterns of recurrence. The univari-ate analysis of categorical variables was per-formed with the chi-square test or Fisher’s exacttest. Only variables that were determined to bestatistically significant by the univariate analysiswere used in the subsequent multivariate analysis,which used a logistic regression model with binaryvariables. The Kaplan–Meier method with thelog-rank test was used to calculate survival proba-bilities according to the initial site of recurrenceand treatment method. The results are reported ashazard ratios (HR) with 95% confidence intervals.A p < 0.05 was considered statistically significantin all analyses.

Statement of ethics

This study was reviewed and approved by the insti-tutional review board (No. 2011-10-016-001). Therequirement for informed consent was waived dueto the retrospective nature of the study.

Results

Characteristics of HCC recurrence and follow-up

results

The characteristics of HCC recurrence after LT areshown in Table 2. Table 3 shows the follow-upresults for HCC recurrence according to the initialrecurrence site. The details of the treatments forrecurrent lesions are summarized in the notes ofTables 2 and 3. Early recurrences (withinsix months) were noted in 43% (27/63) of thepatients, and the initial recurrence sites were thelungs only in 16% (10/63) patients, the liver only in22% (14/63) patients, and multi-organ in 52% (33/63) patients. After investigating the extent of the

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recurrences, curative resections were possible inonly 6% (4/63) patients. The proportion ofpatients with multiple-organ recurrences increasedfrom 52% (33/63) to 71% (45/63) during the fol-low-up period (mean follow-up duration afterrecurrence: 16.9 � 17.1 months; range: 1.1–86.6 months).The median survival time after HCC recurrence

was 12 months (range: 1.1–86.6 months). Overallsurvival curve and the survival curve according tothe initial recurrence sites are shown in Fig. 1.Fig. 1A,B shows the survival after transplantationand the survival after the diagnosis of recurrence,respectively. The one-, two-, and three-yr survivalrates of patients with recurrences only in the lungwere 90%, 75%, and 45%, respectively, while thesurvival rates for patients with recurrences only inthe liver were 71%, 50%, and 36%, respectively.In patients with recurrences in multiple organs, theone-, two-, and three-yr survival rates were 33%,4%, and 0%, respectively (Fig. 1B). The survivalof patients with recurrences in multiple organs wassignificantly lower in comparison to those withrecurrences in the lung only (p < 0.0001) and liveronly (p = 0.0002).

Factors related to early death

Tables 4 and 5 show the results of the univariateand multivariate analyses of risk factors for early(<1 yr) cancer-related death, respectively. The uni-variate analysis showed that a tumor number >10,a recurrence within six months, bone metastasis atinitial diagnosis, and multi-organ involvement atinitial diagnosis all correlated with early (<1 yr)cancer-related death (Table 4). The independentrisk factors, according to the binary logistic regres-sion model for multivariate analysis, were recur-rences within six months (HR = 4.557, p = 0.021)and initial multi-organ involvement (HR = 5.494,p = 0.015, Table 5). The preoperative characteris-tics and the results of the histological studies of theexplanted livers did not correlate with early (<1 yr)cancer-related death.

HCC recurrence according to treatment type

In order to evaluate the results of treatmentaccording to the treatment type, we investigatedthe survival of patients with multi-organ involve-ment. We excluded the data from patients withrecurrences involving the lung only, liver only, oranother single organ, since the extent of recurrencesignificantly affected patient survival. Amongthem, we further excluded three patients whoreceived IV chemotherapy in early series, since thismight distort the effect of systemic therapy basedon sirolimus and sorafenib. Finally 42 patientswith recurrence involving multiple organs wereenrolled. The one-, two-, and three-yr survivalrates after diagnosis of recurrence for patients withmultiple-organ recurrences were 38%, 9%, and0%, respectively in the local treatment group,60%, 20%, and 0%, respectively, in the systemictreatment group, and 73%, 65%, and 25%, respec-tively, in the combined treatment group (Fig. 2).The six patients who did not receive any treatmentshowed the worst survival rate. (one-, two-, andthree-yr survival were 17%, 0%, and 0%, respec-tively.) However, since this might be the result ofselection bias due to the retrospective design ofstudy, this was not specified in Fig. 2.

Discussion

LT is performed liberally worldwide, but untilnow, no consensus has been reached regarding theexpanded indications for LT in patients with HCC.For this reason, transplantation teams will becalled upon to provide proper care for a growingnumber of patients with recurrent HCC after LT.Several reports about recurrent HCC after LT

Table 2. Characteristics of HCC recurrence after LT and treatment

details (N = 63)

Characteristics No. patients

Time of recurrence

Mean (range) 12.9 � 14.4 months (0.4–82.4 months)

Early (<6 months) (%) 27 (43)

Late (≥6 months) (%) 36 (57)

Site of recurrence, initial (%)

Lung only 10 (16)

Liver only 14 (22)

Multiple organ 33 (52)

Others 6a (10)

Alpha-fetoprotein (AFP) level at recurrence

Median 81.0 � 26 163.7 (1.3–171 792)

<1000 ng/mL (%) 49 (78)

>1000 ng/mL (%) 14 (22)

Curative resectability, initial (%)

No 59 (94)

Yes 4 (6)

Treatment (%)

None 8 (13)

Local treatment only 24b (38)

Systemic treatment only 10c (16)

Combined treatment 21d (33)

HCC, hepatocellular carcinoma; LT, liver transplantation; RFA, radiofre-

quency ablation; TACE, transarterial chemoembolization.aAdrenal gland, 2; bone, 2; peritoneal seeding, 1; lymph node, 1.bLiver resection, 1; TACE, 13; RFA, 2; extra-hepatic resection, 6; liver

resection/lung resection, 1; RFA/lung resection, 1.cIV chemotherapy, 1; sirolimus, 3; sirolimus/Nexavar, 6.dLiver resection, 2; extra-hepatic resection, 6; TACE, 16; RFA, 4; IV che-

motherapy, 1; sirolimus, 12; Nexavar, 3; sirolimus/Nexavar, 4; IV chemo-

therapy/Nexavar, 1.

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have been published, but these studies evaluatedonly small numbers of patients with recurrentHCC after LT. In contrast, our study is based onthe largest number of patients ever reported.

Several reports have been published recentlyabout the prognostic factors for recurrent HCCafter LT (5, 8, 10). Vascular invasion and histologi-cal grade were considered to be important indepen-

Fig. 1. Survival of the patients with hepatocellular carcinoma (HCC) recurrence according to initial recur site (*Including six recur-rences involving single organ except lung or liver). (A) Post-transplantation survival. (B) Post-recurrence survival.

Table 3. Follow-up result of HCC recurrence according to initial site (N = 63; mean follow-up duration after recurrence: 16.9 � 17.1 months, 1.1

–86.6 months)

At initial recurrence, n After follow-up, n

Lung only 10 (16%) 4 (6%)

Time of recurrence Treatment type

Early (<6 months) 3 (30) None –

Late (≥6 months) 7 (70) Local Tx. 1a

Curative resection 2 (20) Systemic Tx. 2b

Combined Tx. 1c

Liver only 14 (22%) 10 (16%)

Time of recurrence Treatment type

Early (<6 months) 4 (29) None –

Late (≥6 months) 10 (71) Local Tx. 5d

Curative resection 4 (29) Systemic Tx. –

Combined Tx. 5e

Multiple organs 33 (52%) 45 (71%)

Time of recurrence Treatment type

Early (<6 months) 19 (58) None 6

Late (≥6 months) 14 (42) Local Tx. 17f

Curative resection – Systemic Tx. 7g

Combined Tx. 15h

Etc. 6 (10%) 4 (6%)

Time of recurrence Treatment type

Early (<6 months) 1 (17) None 2

Late (≥6 months) 5 (83) Local Tx. 1a

Curative resection – Systemic Tx. 1i

Combined Tx. –

HCC, hepatocellular carcinoma; RFA, radiofrequency ablation; TACE, transarterial chemoembolization.aResection.bSirolimus/Nexavar.cResection/sirolimus.dResection, 1; TACE, 2; RFA, 2.eTACE/sirolimus, 3; TACE/RFA/sirolimus, 1; resection/TACE/RFA/sirolimus, 1.fTACE, 11; resection, 5; resection/RFA, 1.gSirolimus/Nexavar, 4; sirolimus, 2; chemotherapy, 1.hLocal Tx.: TACE, 9; RFA, 1; resection, 3; TACE/resection, 1; TACE/RFA/resection, 1 systemic Tx: sirolimus, 6; sirolimus/Nexavar, 4; Nexavar, 3; IV chemo-

therapy/Nexavar, 1; IV chemotherapy, 1.iSirolimus.

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dent prognostic factors along with tumor size andnumber (13, 14). In our data, recurrence withinsix months and initial multi-organ involvementwere independent risk factors for early (<1 yr) can-cer-related death. The results of a histologicalstudy, including the number of tumors, tumorgrade, vascular invasion, and bile duct invasion,did not indicate a significant correlation withsurvival. In our study, grade III or IV tumorscomprised only 10% (6/63) of the evaluated casesand might be the reason for the absence of anobserved relationship between the histologicalgrade and survival. We failed to find anysignificant preoperative variables or histologicalfeatures of the explanted livers. The patterns ofrecurrence, including the time to recurrence andthe site of recurrence, were the only significant riskfactors according to a multivariate analysis. Thenumber of tumors >10 upon histological examina-tion of explanted livers correlated with early(<1 yr) cancer-related death in univariate analysis,but not in multivariate analysis.

Data concerning the treatment modalities forrecurrent HCC after LT are scarce. There is littleinformation available for patient prognosisaccording to the treatment modality for HCCrecurrence after LT. The effect of post-transplantimmunosuppression on tumor recurrence wasrecently outlined, and the beneficial effect ofmTOR inhibitors (including sirolimus) was dem-onstrated (4, 11, 15). However, prospective ran-domized studies are lacking. The effects ofsorafenib (Nexavar�), a multikinase inhibitor thatexhibits antitumor and antiangiogenic activity,have been reported (16, 17). In non-transplantedpatients, the administration of several drugs,including doxorubicin, cisplatin, and fluorouracil,produced some response rates (9, 18). However,there have been no studies to support the useful-ness of systemic chemotherapy for recurrent HCCafter LT. In this study, we investigated patientsurvival according to the treatment method forHCC recurrences involving multiple organs. Sirol-imus was the primary drug (73% of cases [16/22])used for the systemic treatment, and the additionof this systemic treatment yielded better survivalin comparison to local treatment only (Fig. 2).Due to the small number of patients and the clus-tering of heterogeneous treatments, these resultsare not conclusive. However, these findings sug-gest a positive effect of systemic treatment includ-ing sirolimus as an adjuvant treatment forrecurrent HCC after LT. Sirolimus-based immu-nosuppression already has been proven effectivein LT associated with HCC (15). But our datasuggest that sirolimus-based immunosuppression

Table 4. Univariate analysis of risk factors affecting early (within

one yr) cancer-related death after HCC recurrence (N = 63)

Variables

No (%)

p-Value

Survival > 1

yr (n = 35)

Death < 1

yr (n = 28)

PreLT AFP >1000 ng/mL 8 (23) 12 (43) 0.090a

PreLT Tx. 27 (77) 22 (79) 0.892a

Grade III or IV 2 (6) 4 (14) 0.393b

Microvascular invasion 28 (80) 22 (79) 0.889a

Portal vein invasion 10 (29) 13 (47) 0.144a

Bile duct invasion 4 (11) 6 (21) 0.318b

p-Milan criteria 23 (66) 22 (79) 0.262a

p-UCSF criteria 23 (66) 20 (71) 0.628a

Tumor number >10 6 (17) 11 (39) 0.049a

AFP at

recurrence >1000 ng/mL

5 (14) 9 (32) 0.090a

Recur < 6 months 8 (23) 19 (68) 0.001a

Bone meta, initial 5 (14) 12 (43) 0.011a

Multi-organ involve, initial 11 (31) 22 (79) 0.001a

Local Tx. 25 (71) 20 (71) 1.000a

Systemic Tx. 21 (60) 10 (36) 0.055a

AFP, alpha-fetoprotein; HCC, hepatocellular carcinoma; LT, liver trans-

plantation; UCSF, University of California at San Francisco.aChi-square test.bFisher’s exact test.

Table 5. Multivariate analysis of risk factors affecting early (within

one yr) cancer-related death after hepatocellular carcinoma (HCC)

recurrence by binary logistic regression model

Variables p-Value HR (95% CI)

Tumor number >10 0.414 1.881 (0.414–8.553)

Recur within 6 months 0.021 4.557 (1.262–16.459)

Bone meta, initial 0.493 1.700 (0.373–7.738)

Multi-organ, initial 0.015 5.494 (1.393–21.665)

Fig. 2. Survival of the patients after hepatocellular carcinoma(HCC) recurrence involving multiple organs according to treat-ment type.

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will remain effective even after recurrences are evi-dent and multiple, and it will be associated withimproved survival rate even though it is intro-duced after HCC recurrence.

According to our data, the prognosis forpatients with HCC recurrence after LT variedaccording to the recurrence time and site. There-fore, prior to choosing a treatment plan, earlyscreenings for recurrence and the investigation oftumor extent are mandatory. If a suspicious lesionis detected, a systemic investigation that includesthe chest, bone, and abdomen must be performed.In our study, 71% (45/63) of patients with recur-rences progressed to multi-organ recurrences dur-ing the follow-up period (Table 3). Therefore, werecommend that a systemic treatment that includessirolimus or Nexavar must be added to the loco-regional treatment in all patients with recurrences.An incomplete treatment, such as repeated TACEwithout systemic treatment, might miss opportuni-ties to prevent disease progression. All recurrencesmust be regarded as systemic disease, and our datasupport the efficacy of an aggressive combinedtreatment.

The major limitations of this study are the retro-spective design and the heterogeneous treatmentmethods with regard to the local and systemictreatments. Due to the retrospective design of thestudy, the treatment method was not randomizedto the patients and the treatment selection mighthave affected the survival rates. However, severalfactors partially compensate for these limitations.First, in 2007, we adopted a protocol in which si-rolimus is administered after a diagnosis of recur-rent HCC after LT. The use of sirolimus was notaffected by the tumor extent, the site of recurrence,the time of the recurrence, or other variables.Patients who received sirolimus were not selectedpatients with lower tumor extent or better prog-nostic factors. Second, most of the patients beganto receive sirolimus immediately after the diagnosisof HCC recurrence. Sirolimus was given immedi-ately to the patients after a diagnosis of recurrence,so the patients receiving sirolimus were not theonly survivors during the follow-up period. Third,all of our patients were followed up for more thana short duration; in this study, the duration of fol-low-up for all patients was longer than one yr afterthe recurrence.

In conclusion, HCC recurrence after LT presentswith different clinical courses and patient survivalrates, according to the recurrence time and site. Arecurrence within six months and initial multi-organ involvement were independent risk factorsassociated with early (<1 yr) cancer-related death.The combined treatment was effective and seemed

to offer a survival benefit in patients with HCCrecurrence after LT.

Acknowledgements

This study was supported by the 2012 Inje UniversityResearch grant.

Authors’ contributions

Young-Nam Roh performed the study, analyzeddata, and wrote the manuscript. Choon HyuckDavid Kwon designed the study and analyzeddata. Sanghyun Song, Milljae Shin, and Jong ManKim collected data. Sung-Joo Kim, Jae-Won Joh,and Suk-Koo Lee analyzed data.

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