ORIGINAL ARTICLE

Sorafenib treatment is save and may affect survivalof recurrent hepatocellular carcinoma after livertransplantation

Jan Pfeiffenberger & Ronald Koschny & Katrin Hoffmann &

Arianeb Mehrabi & Anne Schmitz & Boris Radeleff &Wolfgang Stremmel & Peter Schemmer & Tom M. Ganten

Received: 5 April 2013 /Accepted: 2 September 2013 /Published online: 4 October 2013# Springer-Verlag Berlin Heidelberg 2013

AbstractIntroduction Recurrent hepatocellular carcinoma (HCC) afterliver transplantation (LT) is a rare but challenging condition.In most cases, the recurrent tumor is presented with extrahe-patic spread. Therefore, systemic treatment with sorafenib hasto be assessed. Because of a plethora of possible drug inter-actions, e.g., with immunosuppressant or anti-infective thera-py, safety and feasibility of sorafenib treatment requires spe-cial attention.Materials and methods We retrospectively analyzed 18 pa-tients who suffered from recurrent advanced HCC after LTbetween January 2002 and December 2010 at the UniversityHospital Heidelberg regarding safety of sorafenib treatmentand survival.Results Results showed that 8 patients were eligible for treat-ment with sorafenib showing a median time to progression(TTP) of 4.5 months and an overall survival of 9 months.Mostcommon side effects were grades I and II diarrhea and hand–foot syndrome (HFS) which could be managed by sorafenibdose reduction. No grade III or IVadverse events (AEs) werenoticed. No patient had to discontinue treatment due to AEs.

The ten patients not amenable for sorafenib treatment, due toinitial poor performance status or its deterioration after firstline treatment, were treated with surgical resection (n =3),locoregional therapies (n =1), or palliative radiation therapy(n =1). They showed a median overall survival of 2.3 months.Conclusion Sorafenib may represent a therapeutic option forrecurrent HCC after LT with manageable side effects. Theclinical benefit of sorafenib in this setting is promising butneeds to be confirmed in a prospective randomized trial.

Keywords Recurrent hepatocellular carcinoma . Livertransplantation . Sorafenib . mTORi

Introduction

Hepatocellular carcinoma (HCC) leads to more than onemillion deaths per year worldwide and is the third mostfrequent cause of cancer-related death [1, 2]. Treatmentof HCC is dependent on both tumor stage and stage ofliver disease.

Liver transplantation (LT) is a curative treatment option forHCC. Introduction of the Milan criteria (HCC ≤5 cm or up to3 nodules ≤3 cm, no macrovascular invasion or extrahepaticdisease) dramatically improved the formerly poor long-termsurvival after LT for HCC. Following these criteria, 4-yearsurvival rates of 75 % and recurrence rates below 15% can beachieved [3]. Despite strict selection criteria for LT in HCCpatients, there are still a number of patients who will sufferfrom HCC relapse after LT. Moreover, these patients oftensuffer from disseminated disease and therefore only benefitfrom systemic treatment [4].

J. Pfeiffenberger :R. Koschny :W. Stremmel : T. M. Ganten (*)Department of Gastroenterology and Hepatology, UniversityHospital Heidelberg, Heidelberg, INF 410, 69120 Heidelberg,Germanye-mail: Tom.Ganten@med.uni-heidelberg.de

K. Hoffmann :A. Mehrabi : P. SchemmerDepartment of General and Transplant Surgery, University HospitalHeidelberg, Heidelberg, Germany

A. Schmitz : B. RadeleffDepartment of Diagnostic and Interventional Radiology, UniversityHospital Heidelberg, Heidelberg, Germany

Langenbecks Arch Surg (2013) 398:1123–1128DOI 10.1007/s00423-013-1114-1

The only medical agent approved for treatment of ad-vanced HCC is sorafenib. The tyrosine kinase inhibitorshowed superior survival with modest side effects in two largerandomized phase III trials [5, 6].Whether sorafenib treatmentafter LT in case of tumor relapse is beneficial was onlyinvestigated in several small case series. The largest including39 patients showed a significant survival benefit for sorafenibtreatment compared to best supportive care [7].

The aim of the present study was to investigate the clinicalcourse of HCC patients with recurrent disease after LT at ourfacility.

Material and methods

Patients

The medical records of adult patients who underwent LT forHCC within the Milan criteria at the University HospitalHeidelberg between January 2002 and December 2010 wereretrospectively reviewed in accordance with the local ethicsboard. We assessed etiology of underlying liver diseases,therapy prior to LT, liver function at the time of transplanta-tion, and the regimen of immunosuppression after LT. In caseof tumor recurrence, diagnosis was confirmed by fine needlebiopsy. Time to recurrence, tumor localization, model of end-stage liver disease (MELD) score, as well as applied therapiesfor recurrent HCC were analyzed.

Treatment of recurrent disease after transplantation

Every case of tumor recurrence was discussed in our interdis-ciplinary tumor conference. Patients eligible for curative re-section were referred to surgery, patients eligible forlocoregional therapies received radiofrequency ablation(RFA), transarterial chemo embolisation (TACE), or selectiveinternal radiation therapy (SIRT). In cases of symptomaticmetastasis (pain or functional losses), additional radiationtherapy was evaluated.

We divided the patients into two groups, those who re-ceived sorafenib (sorafenib group, n =8) and those who werenot treated with sorafenib (no sorafenib group, (n =10).Reasons for not treating patients with sorafenib were a poorperformance status at the time of HCC recurrence in four casesand deterioration of performance status after locoregionaltreatment in three cases. One patient suffered from extensivehyperbilirubinemia. One patient was treated with sorafenibprior to LT and denied sorafenib treatment due to the sideeffects of the prior treatment.

Of the patients treated with sorafenib, four patients hadsystemic disease at time of tumor recurrence and were treatedsystemically from the beginning. Four patients received

locoregional treatment and were switched to sorafenib treat-ment because of systemic tumor progression.

Sorafenib was prescribed at a starting dose of 400 mg bidand reduced in steps of 200 mg in case of toxicities.Assessment of tumor response was performed by CT scansevery 3 months. Side effects and adverse events (AEs) wererecorded according to the National Cancer Institute commontoxicity criteria for AEs version 4.0.

Statistical analysis

Survival analysis was calculated using the Kaplan–Meiermethod. Comparison of patients characteristic was performedby Mann–Whitney test. All p -values were two-sided, p <0.05indicated statistical significance. Statistical analysis was car-ried out using Graphpad Prism 5. Overall survival was definedas time between recurrence of HCC and death.

Results

Patient characteristics

Between January 2002 and December 2010, 136 patientswithin Milan criteria underwent LT for HCC. A number of18 patients (13.2 %) developed recurrent HCC (see Table 1).

No sorafenib group

A group of ten patients with recurrent HCC after LTwere not treated with sorafenib. The median age at timeof HCC recurrence was 56 years (range 42–67). Allpatients in the no-sorafenib group were male.Etiologies of underlying liver diseases were hepatitis Cin five cases (50 %), alcohol abuse in four cases(40 %), and hepatitis B in one case (10 %). Detailedpatient characteristics and HCC treatments modalitiesbefore LT are listed in Table 1. All patients were withinMilan cr i ter ia before and at the t ime of LT.Immunosuppression consisted of ciclosporin A in fourpatients (40 %), tacrolimus in two patients (20 %), anda combination of tacrolimus and mycophenolate mofetilin four patients (40 %). Median time to recurrence was15.5 months (range 5–42). Places of recurrences wereadrenal in three cases (25 %), pulmonary in three cases(25 %), hepatic in two cases (17 %), lymphatic in twocases (17 %), peritoneal in two cases (17 %), andcerebral in one case (8 %). The median MELD scoreat time of recurrence was 12 (range 6–23). Two patientshad Eastern Cooperative Oncology Group (ECOG) per-formance status 0, three patients had ECOG perfor-mance status 1, four had ECOG performance status 2,

1124 Langenbecks Arch Surg (2013) 398:1123–1128

and one patient had performance status 3. For individualpatient characteristics, see Table 2.

Sorafenib group

The sorafenib group consisted of eight patients. Themedian age at time of recurrence was 55 years (range50–70). Seven patients were male, one patient wasfemale. Three patients (37.5 %) suffered from hepatitisC, three patients (37.5 %) had hepatitis B, one patient(12.5 %) suffered from alcoholic liver cirrhosis, and onepatient (12.5 %) had cryptogenic liver cirrhosis(Table 1). For HCC treatment modalities, see Table 3.Pathological analysis after hepatectomy showed micro-vascular invasions in five cases (62.5 %). All patientswere within Milan criteria before and at the time of LT.The immunosuppressant regimes were carried out withciclosporin A in three patients (37.5 %), tacrolimus infour patients (50 %), and combination of tacrolimus andmycophenolate mofetil in one patient (12.5 %).

The median time to recurrence was 16 months (range 6–61.5). Tumor recurrence was located in the liver in six cases(54.5 %), lung in one case (9 %), bone in two cases (18 %),lymphatic in one case (9 %). and the adrenal gland in one case(9 %). The median MELD score at time of recurrence was 7(range 5–15). Five patients (62.5 %) were presented withECOG performance status 0, and three patients (37.5 %) hadECOG performance status 1. For detailed patient characteris-tics, see Table 3.

Treatment of recurrent disease

In the no sorafenib group, recurrent HCC was treated withsurgical resection in three cases. One patient received TACEtherapy, one patient had palliative radiotherapy, and one pa-tient was treated with doxorubicin due to sorafenib intoler-ance, which he had received on an individual basis before LTin a “bridge to transplant” concept. Four patients did notreceive any treatment. The median overall survival was2.3 months (range 0.5–26.3). Two patients who receivedcyclosporin A as immunosuppressant were switched tosirolimus at time of recurrence (Table 3).

In the sorafenib group, the median duration of treat-ment was 3.7 months (range 2.5–15.7) with a mediandosage of 570 mg/day (range 200–800). Locoregionalfirst-line treatment after HCC recurrence was TACE andSIRT in two patients. Three patients received additionalpalliative local radiation due to symptomatic metastasis.Sorafenib was commenced 1.5 months (range 0.3–8)after HCC recurrence. The median time to progression(TTP) under sorafenib was 4.5 months (range 1.8–13)with a median overall survival of 9 months (range 6.5–20). One patient in the sorafenib group progressed un-der sorafenib but is still alive receiving best supportivecare. In two patients, the immunosuppressant regimenwas switched to sirolimus.

Table 1 Patients characteristics and treatment summaries

No sorafenibgroup

Sorafenibgroup

N 10 8

Male/female 10/0 7/1

Median age in years (range) 56 (42–67) 55 (50–70)

Etiology of cirrhosis

Hepatitis C 5 (50 %) 3 (37.5 %)

Alcohol 4 (40 %) 1 (12.5 %)

Hepatitis B 1 (10 %) 3 (37.5 %)

Cryptogenic 0 1 (12.5 %)

Therapy before OLT

TACE 7 (70 %) 6 (75 %)

Surgery 0 1 (12.5 %)

None 2 (20 %) 1 (12.5 %)

RFA 1 (10 %) 0

Immunosuppression

CsA 4 (40 %) 3 (37.5 %)

Tacrolimus 2 (20 %) 4 (50 %)

Csa+MMF 4 (40 %) 1 (12.5 %)

Time to recurrence in months (range) 15.5 (5–42) 16 (6–61.5)

Places of recurrence

Liver 2 (17 %) 6 (54.5 %)

Adrenal gland 3 (25 %) 1 (9 %)

Lung 3 (25 %) 1 (9 %)

Bone 0 2 (18 %)

Lymph node 2 (17 %) 1 (9 %)

Peritoneum 2 (17 %) 0

Brain 1 (8 %) 0

MELD score at recurrence (range) 12 (6–23) 7 (5–15)

ECOG performance status

0 2 (20 %) 5 (62.5 %)

1 3 (30 %) 3 (37.5 %)

2 4 (40 %) 0

3 1 (10 %) 0

Therapy post OLT

Radiotherapy 1 (8 %) 3 (33 %)

Surgery 3 (25 %) 0

TACE 1 (8 %) 2 (22 %)

SIRT 0 2 (22 %)

Doxorubicin 1 (8 %) 0

None 4 (34 %) 0

mTOR inhibitor 2 (17 %) 2 (22 %)

Sorafenib 0 8 (100 %)

TTP in months (range) Na 4.5 (1.8–13)

OS in months (range) 2.3 (0.5–26.3) 9 (6.5–30)

CsA cyclosporin A,MMF mycophenolate mofetil, TTP time to progres-sion, OS overall survival

Langenbecks Arch Surg (2013) 398:1123–1128 1125

Adverse events

All except one patient experienced sorafenib-related AEs ofany grade. No grade III or IVAEs were noted. All AEs weregrade I or II [hand–foot syndrome (HFS), n =5; diarrhea, n =6]. Rare side effects included dyspepsia (grade II), nausea(grade II), and constipation (grade I). In six patients, sorafenibdoses were reduced due to these side effects (Table 3).

Effects of mTOR inhibitors

In four patients immunosuppressive therapy was switched tosirolimus after HCC recurrence to take advantage of thesuggested antiproliferative effect of mTOR inhibitors [8].Patients who encountered organ rejection were not consideredas candidates for switiching the immunosuppressant. Alsopatients who had difficulties in adjusting an adequate serumconcentration of their immunosuppressive medication werenot switched. In patients with leucopenia or thrombopeniachanging the immunosuppressive regimen to an mTOR an-tagonist was also considered too risky. The overall survival ofthe patients receiving mTOR inhibitors was 8 months (range6.7–26), which did not significantly differ from the patientsnot receiving mTOR inhibitors [6.5 months (range 0.5–20)].

Discussion

Recurrent HCC after LT is a rare but challenging condition.Risk factors for HCC recurrence after LT seem to be diseaseprogression during the waiting time as well as tumor size [9].In general, treatment options are similar to HCC before LT, buttransplanted patients feature some special characteristics.They are usually under a combination of medication including

one or more immunosuppressive agents, most of which areknown to promote tumor growth [10, 11]. Another problem isthe site of recurrence after LT, which is extrahepatic in 50% ofcases [12]. In our cohort, only 5/18 patients were presentedwith sole intrahepatic lesions and were therefore eligible forlocoregional therapies.

One treatment option for recurrent HCC after LT is com-plete resection of metastasis. Median survival times of 29–65 months have been reported [13, 14]. In our study, onlythree patients were amenable to surgical resection, showing amedian survival of 13 months.

Several uncontrolled case series reporting aboutsorafenib treatment for recurrent HCC after LT werepublished. The largest series so far was reported bySposito and colleagues. Their 15 patients receivingSorafenib showed a significant longer OS in comparisonto matched 24 patients receiving best supportive care(21.3 months versus 11.8 months) [7]. Yoon and col-leagues [15] described 13 patients treated with sorafenibafter recurrence of HCC after LT when locoregionaltherapies showed to be ineffective. They reported aTTP of 2.9 months and a median overall survival of5.4 months. Pfiffer et al. [14], who treated eight patientswith recurrent HCC after LT with sorafenib, four ofwhom had received prior treatment, reported a mean overallsurvival of 6.7 months. Weinmann and colleagues [16]showed a median TTP of 4.1 months under sorafenib. In ourcohort, the median TTP under therapy with sorafenib was4.5 months, which is in line with these data and the data fromthe SHARP trial in advanced HCC (TTP 5.5. months) [5].

Our findings regarding tolerability of sorafenib in LTpatients are similar to most other studies investigatingsorafenib treatment for recurrent HCC after LT [15, 17].In contrast, Weinmann et al. [16] reported on a significant

Table 2 Characteristics of the patients not receiving sorafenib

Patient Age Gender Etiology ofcirrhosis

TTR(months)

Place ofrecurrence

BCLCstage

MELD score atrecurrence

Therapy OS (months)

1 50 m Hep C 6.4 Cerebral/Adrenal D 23 None 1.5

2 57 m Hep C 6.5 Adrenal/Lymphatic D 6 Radiotherapy 2.5

3 52 m Hep C 5 Lung/Lymphatic C 6 Doxorubicin, mTORi 6.7

4 63 m Hep C 5.5 Hepatic D 18 None 2

5 59 m Hep C 22.5 Adrenal C 10 Surgery 2.1

6 64 m Alcohol 13.6 Peritoneal D 12 None 1

7 67 m Alcohol 141.8 Adrenal C 16 Surgery 13

8 61 m Alcohol 21 Lung D 18 None 0.5

9 62 m Alcohol 17.4 Peritoneum C 12 Surgery, mTORi 26.3

10 45 m Hep B 6 Hepatic B 6 TACE 3.1

Tac tacrolimus, CsA cyclosporin A, MMF mycophenolate mofetil, mTORi mTOR inhibitor

*Patient returned to his home country, followup not possible

1126 Langenbecks Arch Surg (2013) 398:1123–1128

number of grade 3 AEs by sorafenib leading not only to doseadjustments but also to discontinuation of sorafenib treat-ment in 2/11 patients. Recently, another case series of 13patients with recurrent HCC after LT reported a rate of 92 %of grade III or IV AEs, especially under combination ofsorafenib and mTOR inhibitor [18]. The reasons for thisare not clear. In particular, the frequent hepatotoxicity ofsorafenib in this study cannot be elucidated. Nonetheless,our study and the majority of published series show that thetolerability of sorafenib for recurrent HCC after LT is com-parable to the palliative setting of advanced HCC [5, 19].Therefore, sorafenib treatment of LT patients seems to befeasible in case of HCC recurrence although no randomizedcontrolled trials have addressed this topic yet.

The main limitation of our study is its retrospective na-ture. Although the OS in the sorafenib group was longer thanin the no sorafenib group, a selection bias is likely despite thefact that the differences in terms of performance status arenot significant.

In HCC cells, many signaling pathways are altered, includ-ing the mammalian target of rapamycin (mTOR) pathway[20]. Bhorri and colleagues [21] were among the first to showthat addition of everolimus, an mTOR inhibitor to sorafenibtreatment for recurrent HCC after LT improved tumor re-sponse in a selected single patient. In general, mTORinhibitor-based immunosuppression seems to be favorable incomparison to other immunosuppression agents in cases of LTfor HCC [22], although other studies reported severe sideeffects of this treatment (e.g., pneumonitis, deterioration ofblood count) [23]. A recently published meta-analysis of fivestudies addressing this topic showed a significant decrease ofHCC recurrence and a significant decrease of mortality whensirolimus was used as the primary immunosuppressive drugafter LT [24]. In our study cohort, four patients were switchedto the mTOR inhibitor sirolimus after diagnosis of recurrentHCC showing a median OS of 8 months.

Conclusion

Sorafenib treatment for recurrent HCC was well tolerated inpatients after LT. Side effects were manageable and did notdiffer to patients with sorafenib treated for advanced HCC ina nontransplantation setting. However, prospective random-ized trials are needed to demonstrate a survival benefit ofsorafenib treatment in recurrent HCC after LT not amenableto locoregional therapy.

Financial disclosure JP has no financial disclosures. TG and RKreceived funding from Bayer.

Conflicts of interest None.Tab

le3

Characteristicsof

thepatientsreceivingsorafenib

Patient

Age

Gender

Etio

logy

ofcirrhosis

TTR

(months)

Place

ofrecurrence

BCLC

stage

MELDscoreat

recurrence

Other

therapy

MeanSo

rafenib

dose

Treatmentd

uration

(months)

Sorafenib

Side

effects

TTP

(months)

OS

(months)

164

mHep

C14.5

Hepatic

B8

SIRT

540mg

3.5

HFS

I5.8

18.3

250

mHep

C6

Hepatic/lu

ngC

6mTORi

400mg

4None

1.8

8

351

mHep

C6.3

Hepatic/bone

B6

TACE,

radiation

400mg

2DiarrheaI

3.3

6.5

466

mAlcohol

35.6

Hepatic

C14

None

800mg

3.4

DiarrheaII,

dyspepsiaII

49.3

549

mHep

B6

Lym

phatic

C7

Radiatio

n500mg

5HFS

II,diarrheaII

5.3

8.3

649

fHep

B161.5

Bone

C7

Radiatio

n600mg

8.8

HFS

II,diarrheaII

4.8

14.4

746

mHep

B50

Hepatic

B12

TACE,

mTORi

800mg

2.6

DiarrheaII

2.5

Aliv

e

860

mCryptogenic

17.4

Hepatic/

Adrenal

C6

SIRT

640mg

5HFS

I12.8

20

Tactacrolim

us,C

sAcyclosporinA,M

MFmycophenolatemofetil,

mTO

RimTORinhibitor,TTR

timeto

recurrence

Langenbecks Arch Surg (2013) 398:1123–1128 1127

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