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Digestive and Liver Disease 44 (2012) 432– 437

Contents lists available at SciVerse ScienceDirect

Digestive and Liver Disease

jou rn al h om epage: www.elsev ier .com/ locate /d ld

ncology

orafenib for recurrence of hepatocellular carcinoma after liver transplantation�

rndt Weinmanna, Ina Maria Niederlea, Sandra Kocha, Maria Hoppe-Lotichiusb, Michael Heiseb,hristoph Düberc, Marcus Schuchmanna, Gerd Ottob, Peter Robert Gallea, Marcus-Alexander Wörnsa,∗

Department of Internal Medicine I, University Medicine of the Johannes Gutenberg University, Mainz, GermanyDepartment of Transplantation and Hepatobiliopancreatic Surgery, University Medicine of the Johannes Gutenberg University, Mainz, GermanyDepartment of Interventional and Diagnostic Radiology, University Medicine of the Johannes Gutenberg University, Mainz, Germany

r t i c l e i n f o

rticle history:eceived 4 October 2011ccepted 12 December 2011vailable online 20 January 2012

eywords:dvanced diseaseiver cancerosttransplant recurrenceargeted therapy

a b s t r a c t

Background: Recurrence of hepatocellular carcinoma after orthotopic liver transplantation not amenableto surgical approaches is associated with poor outcome.Aims: Retrospective evaluation of the safety and efficacy of sorafenib in patients with post-transplanthepatocellular carcinoma recurrence.Methods: Patients with post-transplant hepatocellular carcinoma recurrence were treated with sorafenib.Adverse events were assessed using National Cancer Institute Common Toxicity Criteria of AEs version3.0, tumour response was evaluated according to Response Evaluation Criteria in Solid Tumours.Results: First-line therapy after recurrence was surgery (n = 6), radiation therapy (n = 1), chemotherapy(n = 1), and sorafenib (n = 3). Finally, 11 patients were treated with sorafenib. Nine patients (82%) receivedan additionally targeted therapy with sirolimus as part of their immunosuppressive regimen. Most com-mon grade 3 adverse events included diarrhoea (46%), hand-foot skin reaction (27%), nausea, fatigue, andleucopoenia (all 18%). Sorafenib had to be discontinued in two patients due to adverse events and sixadditional patients required a dose adjustment. No deterioration of liver graft function occurred. Median

time to progression was 4.1 months; however, patients were treated with ongoing sorafenib in case ofclinical benefit (median 8.9 months). Median overall survival after initiation of sorafenib treatment was20.1 months.Conclusion: Sorafenib in combination with immunosuppression including sirolimus may be adminis-tered to patients with post-transplant hepatocellular carcinoma recurrence with acceptable toxicity andwithout deterioration of liver graft function.

Gast

© 2011 Editrice

. Introduction

Hepatocellular carcinoma (HCC) is the third leading cause ofancer-related death worldwide and the leading cause of deathmongst patients with liver cirrhosis [1,2]. Orthotopic liver trans-lantation (OLT) represents a potentially curative treatment optionlso for selected patients beyond the Milan criteria [3–5]; how-ver, HCC recurrence occurs in approximately 8–20% of patientsith a significant impact on survival [6–8]. Surgical resection of

ntra- and extrahepatic recurrence may be the treatment of choice

or amenable patients; unfortunately, this approach is often notossible due to extended extrahepatic tumour dissemination [6–8].

� This work was not supported by any grant or funding source.∗ Corresponding author at: Department of Internal Medicine I, Universityedicine of the Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz,ermany. Tel.: +49 6131 176863; fax: +49 6131 176249.

E-mail address: woerns@uni-mainz.de (M.-A. Wörns).

590-8658/$36.00 © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevieroi:10.1016/j.dld.2011.12.009

roenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

The management of patients with advanced HCC includingrecurrence after OLT not amenable to surgical approaches is charac-terised by limited therapeutic options due to the lack of efficacy ofconventional cytotoxic chemotherapy [7,9,10]. Positive data fromtwo pivotal phase III trials assessing the safety and efficacy ofthe multikinase inhibitor sorafenib (Nexavar®, Bayer Pharmaceuti-cals Corporation, Leverkusen, Germany) broadened the therapeutichorizon for patients with advanced disease [11,12]. Sorafenibblocks both tumour cell proliferation and angiogenesis by targetingmultiple pathways including the Raf-1/B-Raf kinase and vascularendothelial growth factor receptor-2/-3 (VEGFR-2/-3) and platelet-derived growth factor receptor beta (PDGFR-�) tyrosine kinases[13]. Sorafenib was the first agent to demonstrate a significantimprovement in the overall survival (OS) of patients with advancedHCC and is now considered the standard of care in this stage of thedisease.

However, only scarce or inconsistent data are available regard-ing the safety and efficacy of sorafenib in patients with HCCrecurrence after OLT [14–25]. History of liver transplantationand immunosuppressive medication rendered these patients

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A. Weinmann et al. / Digestive a

neligible for previous phase II/III trials [11,12,26]. Concerns couldrise from potential drug to drug interactions with immuno-uppressive medication possibly causing a higher number oforafenib-related adverse events (AEs) or a deterioration of liverraft function. In addition, the course of HCC after OLT might beegatively influenced by immunosuppression per se [27–29]. Onhe other hand, the generally preserved liver function in patientsfter OLT may be associated with better tolerance of and responseo sorafenib treatment noting data suggesting poorer outcomes inatients with Child-Pugh B or greater liver dysfunction [30,31].

Herein, we report our retrospective single-institution eval-ation of the safety and preliminary efficacy of sorafenib inombination with immunosuppression including sirolimus inatients with HCC recurrence after OLT.

. Patients and methods

We reviewed retrospectively data of patients with HCC recur-ence after OLT who were treated at the University Medicine ofhe Johannes Gutenberg University Mainz between January 2007nd October 2010. Demographic data, aetiology of underlying liverisease, medical history, laboratory results, histopathological andadiological findings, and the type of treatment were extractedrom medical files. HCC recurrence was either confirmed by his-ology or diagnosed according to the non-invasive criteria of themerican Association for the Study of Liver Disease (AASLD) guide-

ines [32]. After diagnosis of HCC recurrence, immunosuppressionas routinely switched to a regimen including the mammalian

arget of rapamycin (mTOR) inhibitor sirolimus (mean plasma lev-ls between 4 and 8 �g/l). Due to its antineoplastic properties,irolimus in combination with the most commonly used calcineurinnhibitors (CNI) tacrolimus and cyclosporine may be more suit-ble for patients undergoing OLT for end-stage liver disease andoncomitant HCC either in a preemptive intent or as treatmentor HCC recurrence [8,29,33–36]. Some patients received sirolimusfter OLT due to their participation in a clinical trial evaluatingirolimus in an adjuvant setting to prevent HCC recurrence afterLT (www.clinicaltrials.gov identifier: NCT00355862).

All consecutive patients with HCC recurrence after OLT notmenable to or after failure of surgical or other locoregional treat-ent approaches were treated with sorafenib at our institution

uring the last few years. The investigation was conducted withritten informed consent from each patient and was performed

ccording to the ethical guidelines of the 1975 Declaration ofelsinki (6th revision, 2008). Before the approval of sorafenib

n autumn 2007 in Germany, an off-label use was individuallypproved for each patient by the health care insurance.

.1. Treatment modalities and safety assessments

A target dose of 400 mg sorafenib twice daily was administered.ll patients received prescriptions for loperamide for the treatmentf diarrhoea and urea-containing ointments for the prevention andreatment of skin reactions. Clinical visits were performed every–4 weeks on an outpatient basis and included the assessmentf AEs, laboratory findings, physical examination, vital signs, andeight. AEs were graded according to the National Cancer Insti-

ute Common Toxicity Criteria of AEs version 3.0 (NCI-CTCAE v3.0)37]. Grade 3/4 AEs resulted in a dose modification (200 mg twiceaily) or a treatment interruption if the AE represented a clini-ally relevant event. A dose reduction or treatment interruption

as maintained until toxicity was grade 2 or better. After recov-

ry, patients were re-exposed to target dose. A dose modificationas also performed at grade 2 toxicity on patient’s request or

f the AE represented a clinically relevant event. Treatment was

er Disease 44 (2012) 432– 437 433

continued until unacceptable toxicity, both radiological and clini-cal disease progression or death. Patients were followed up untildeath or October 31st, 2010.

2.2. Treatment modalities and efficacy assessments

Tumour response was assessed using the revised Response Eval-uation Criteria in Solid Tumours (RECIST) guideline (version 1.1)[38] based on dynamic contrast-enhanced computed tomographyperformed at baseline and approximately every 3 months there-after during treatment administration. All patients had measurabledisease according to RECIST at baseline. As previously reported,almost all patients with advanced HCC treated at our institutionshowed radiological progression according to RECIST sooner orlater under targeted therapy [30,39]. However, according to recentrecommendations [40,41], tumour assessment according to RECISTmay not be the most appropriate measure to evaluate tumourresponse in the era of targeted therapy. According to modifiedRECIST (mRECIST), it is important to take into account also theconcept of viable tumour tissue in typical hepatic lesions show-ing uptake in the arterial phase of contrast-enhanced radiologicimaging techniques [41]. In addition, in the phase III trial, patientswere allowed to stay on sorafenib treatment despite radiologicalprogression if they achieved an ongoing clinical benefit [11]. There-fore, and due to the lack of an established second-line therapy,patients were treated in our institution with ongoing sorafenib incase of clinical benefit despite of radiological progression accord-ing to RECIST. Treatment was discontinued only in case of a markedincrease in tumour volume without a decrease of intratumouralarterial enhancement and particularly in case of new lesions.

2.3. Statistical analysis

Patients’ baseline characteristics were analysed by descriptivestatistical methods. Continuous variables are summarised as medi-ans and ranges, and categorical variables are presented as absoluteand relative frequencies. OS, time to progression (TTP), and time onsorafenib were estimated using the Kaplan–Meier method. Anal-yses were performed using Medcalc 11.3.3 (MedCalc Software,Belgium).

3. Results

Between January 1998 and December 2009, 178 OLTs were per-formed at our institution due to the indication of HCC. 29 out of 178patients were diagnosed with HCC recurrence after OTL (recurrencerate 16%). A total of 11 patients were treated with sorafenib duringthe time from January 2007 and October 31st, 2010 (end of follow-up), either as primary therapy or after failure of surgical or otherlocal treatment approaches.

3.1. Patients’ demographics at the time of OLT

5 patients were male (46%), 6 were female (54%), and medianage at the time of OLT was 51.1 years (range 33.6–68.9). Aetiology ofunderlying liver disease was mainly chronic hepatitis C virus (HCV)(46%) and chronic hepatitis B virus (HBV) (36%) infection, respec-tively. All patients were routinely treated with repeated cycles oftransarterial chemoembolisation (TACE) as bridging therapy beforeOLT to prevent tumour progression [42]. By explant evaluation, 5patients (46%) fulfilled the Milan criteria at the time of OLT. Most

tumours were moderately differentiated (55%), and microvascu-lar invasion was detected in 1 case (9%). Demographic and clinicalcharacteristics of patients at the time of OLT are presented inTable 1.

434 A. Weinmann et al. / Digestive and Liv

Table 1Patients’ baseline characteristics at the time of liver transplantation.

Total number 11

Gender, n (%)Male 5 (46)Female 6 (54)

Ethnic groupCaucasian 10 (91)Asian 1 (9)

Aetiology of underlying liver disease, n (%)Hepatitis C virus 5 (46)Hepatitis B virus 4 (36)�1-antitrypsin deficiency 1 (9)No known underlying liver disease 1 (9)

Median age at the time of HCC diagnosis in years (range) 50.5 (32.1–68.1)Median age at the time of OLT in years (range) 51.1 (33.6–68.9)Milan criteria fulfilled in the explanted liver, n (%) 5 (46)

GradingG2 6 (55)G3 2 (18)Unknown (due to complete necrosis) 3 (27)

Microvascular invasion, n (%) 1 (9)

H

3

(O3rmOri

TOr

Hm

Median follow-up time from OLT in months (range) 50.1 (22.7–74.2)

CC, hepatocellular carcinoma; OLT, orthotopic liver transplantation.

.2. Management of recurrence

Median age at the time of HCC recurrence was 55.5 yearsrange 33.9–69.4), and there was a wide range in the time fromLT to the diagnosis of HCC recurrence, with the median being7.5 months (range 4.2–59.0) (Table 2). After diagnosis of HCCecurrence, 8 patients (73%) received an immunosuppressive regi-

en with sirolimus in combination with reduced dose tacrolimus.ne patient received tacrolimus monotherapy, and one patient

eceived sirolimus monotherapy, respectively. In one patient,mmunosuppression had to be switched back from sirolimus

able 2verview of sorafenib treatment in patients with hepatocellular carcinoma recur-

ence after liver transplantation.

Median time from OLT to recurrence in months (range) 37.5 (4.2–59.0)Median age at the time of recurrence in years (range) 55.5 (33.9–69.4)

Immunosuppression after HCC recurrence (n, %)Sirolimus + tacrolimus 8 (73)Sirolimus 1 (9)Tacrolimus + MMF 1 (9)Tacrolimus 1 (9)

Site of recurrence at the initiation of sorafenib treatment, n (%)Intrahepatic 1 (9)Extrahepatic 7 (64)Both intra- and extrahepatic 3 (27)Lung 8 (73)Liver 4 (36)Lymph nodes 3 (27)Peritoneum 2 (18)Bones 1 (9)

Sorafenib dose modifications includingdiscontinuation, n (%)

8 (73)

Discontinuation of sorafenib therapy due to AEs, n (%) 2 (18)Median time to progression under sorafenib in months

(range)4.1 (1.8–10.2)

Median duration of sorafenib treatment in months(range)

8.9 (0.9–18.3)

Overall survival after initiation of sorafenib treatmentin months (range)

20.1 (2.2–40.2)

Overall survival after HCC recurrence in months(range)

34.9 (7.9–57.0)

CC, hepatocellular carcinoma; OLT, orthotopic liver transplantation; MMF,ycophenolate mofetil; AEs, adverse events.

er Disease 44 (2012) 432– 437

to tacrolimus and mycophenolate mofetil due to sirolimus-intolerance.

A surgical treatment approach (liver resection or metastasec-tomy) for HCC recurrence was considered to be the first-linetreatment in 6 patients (55%). One patient was primarily treatedwith radiation therapy due to bone metastases, and one patientreceived conventional systemic chemotherapies (doxorubicin andgemcitabine/oxaliplatin) in the pre-sorafenib era. 3 out of 11patients (27%) received sorafenib as first-line treatment for HCCrecurrence (Table 3).

3.3. Sorafenib treatment and safety

Median duration from recurrence to initiation of sorafenib treat-ment was 3.9 months (range 0.6–20.3). At initiation of sorafenibtreatment, recurrence was intrahepatic in 1 patient, extrahepaticin 7 patients, and both intra- and extrahepatic in 3 patients. Primarysites of recurrence included the lung (n = 8), liver (n = 4), lymphnodes (n = 3), peritoneal seeding (n = 2), and bones (n = 1). A detaileddescription of tumour characteristics at initiation of sorafenib ther-apy is included in Table 3. All patients had completely preservedliver function at initiation of sorafenib treatment and the targetdose of 400 mg twice daily was administered to all patients.

All patients experienced AEs according to CTCAE v3.0 undersorafenib treatment (Table 4); however, pattern of AEs was sim-ilar to them described amongst non-transplanted patients [11,26].Predominant AEs were diarrhoea (n = 9, 81%), fatigue (n = 8, 73%),nausea (n = 7, 64%), hand-foot skin reaction, hair loss, and weightloss (all n = 6, 55%). AEs were predominantly grade 1/2 in sever-ity. Relevant grade 3 AEs included diarrhoea (n = 5, 46%), hand-footskin reaction (n = 3, 27%), nausea, fatigue, and leucopoenia (all n = 2,18%). No grade 4 or 5 drug-related event (death) occurred. However,only 27% (n = 3) of patients tolerated the target dose of 400 mg twicedaily during the whole treatment period. Treatment interruptionand dose adjustments (200 mg twice daily, permanently in mostcases) due to AEs were performed in 8 patients (73%) including dis-continuation of sorafenib therapy due to AEs in two cases (18%).In one patient due to combined grade 2 diarrhoea and weight loss,and in one patient due to combined grade 2 hand-foot skin reac-tion, mucositis, and diarrhoea, respectively. There was no evidenceof acute cellular rejection or deterioration of liver graft functionduring sorafenib treatment. In addition, no patient required a doseadjustment or change in the regimen of immunosuppression dur-ing sorafenib treatment.

3.4. Sorafenib treatment and efficacy

A first radiological follow-up under sorafenib treatment wasperformed in 10 patients after a median of 2.9 months (range1.8–4.1). In 1 patient, treatment period was too short to performradiological follow-up. According to RECIST, no partial or completeresponse was observed. Stable disease was observed in 4 patients,resulting in a disease control rate (DCR) of 36%. Further radiologicalfollow-up in patients with initial radiological response showed dis-ease progression according to RECIST in three cases. Seven patientsshowed disease progression according to RECIST already in the firstradiological follow-up. The median TTP according to RECIST was4.1 months (range 1.8–10.2). However, patients were allowed tostay on sorafenib treatment despite radiological progression, if theyachieved ongoing clinical benefit resulting in a median sorafenibtreatment time of 8.9 months (range 0.9–18.3).

Sorafenib treatment was discontinued in 4 patients due to

marked radiological disease progression. Sorafenib had to bediscontinued in one patient due to clinically rapid disease pro-gression and, as already mentioned, in 2 patients due to AEs. Fourpatients (36%) are still under sorafenib treatment at the end of

A. Weinmann et al. / Digestive and Liver Disease 44 (2012) 432– 437 435Ta

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Table 4Most common adverse events under sorafenib treatment in patients with hepato-cellular carcinoma after liver transplantation.

All grades Grade 1/2 Grade 3 Grade 4

n % n % n % n %

GastrointestinalDiarrhoea 9 81 4 36 5 46 0 0Nausea 7 64 5 46 2 18 0 0Vomiting 3 27 3 27 0 0 0 0Mucositis 2 18 1 9 1 9 0 0

DermatologicDry skin 2 18 2 18 0 0 0 0Rash/desquamation 3 27 3 27 0 0 0 0Hand-foot skin reaction 6 55 3 27 3 27 0 0Hair loss/alopecia 6 55 6 55 0 0 0 0

ConstitutionalWeight loss 6 55 5 46 1 9 0 0Fatigue 8 73 6 55 2 18 0 0Pain 5 46 5 46 0 0 0 0Pruritus 1 9 1 9 0 0 0 0

HaematologicalLeucopoenia 4 36 2 18 2 18 0 0Thrombocytopenia 1 9 1 9 0 0 0 0Infection in leucopoenia 1 9 0 0 1 9 0 0

OthersArterial hypertension 3 27 3 27 0 0 0 0

Increased lipase 2 18 2 18 0 0 0 0Increased aminotransferases 1 9 1 9 0 0 0 0Dyspnoea 2 18 2 18 0 0 0 0

follow-up. After discontinuation of sorafenib treatment, 3 patients(27%) received a systemic therapy with the multikinase inhibitorsunitinib, and 2 patients were treated with TACE or radioembolisa-tion to control intrahepatic tumour growth in a solely palliativeintention. Two patients did not receive any specific anti-cancertherapy other than best supportive care. During the observationperiod, 6 patients (55%) died due to tumour progression aftera median of 19.7 months (range 2.2–40.2) after the initiation ofsorafenib treatment. Median OS after the initiation of sorafenibtreatment was 20.1 months (range 2.2–40.2), and median OS afterHCC recurrence was 34.9 months (7.9–57.0), respectively.

4. Discussion

The management of patients with HCC recurrence after OLT notamenable to surgical or other local treatment approaches is char-acterised by limited therapeutic options due to the lack of efficacyof conventional cytotoxic chemotherapy. A former study with dif-ferent regimens of systemic chemotherapy revealed a median TTPof 7.0 weeks and a median OS of 16.8 weeks [10]. Sorafenib wasthe first agent to demonstrate a significant improvement in the OSof patients with advanced HCC [11,12]; however, only a few casereports, small series and abstracts reported data on the safety andpreliminary efficacy of sorafenib in patients with HCC recurrenceafter OLT [14–25] (overview in Table 5). In these reports, aetiologyof underlying liver disease was mainly chronic viral hepatitis, andthere was a wide range in the time from OLT to the diagnosis ofHCC recurrence (4 months to 11 years). About half of the patientsreceived an mTOR inhibitor as part of their immunosuppressiveregimen, and most patients needed a sorafenib dose adjustment.Median OS after initiation of sorafenib treatment was >11 monthsin about half of the reports.

Herein, we demonstrate in one of the largest single-institution

cohorts that sorafenib and particularly sorafenib in combinationwith sirolimus may be administered to patients with HCC recur-rence after OLT with acceptable toxicity. No deterioration of livergraft function occurred, and AEs were manageable with sorafenib

436 A. Weinmann et al. / Digestive and Liver Disease 44 (2012) 432– 437

Table 5Literature overview of sorafenib treatment in patients with hepatocellular carcinoma after liver transplantation.

Study No. ofpatients

Mainaetiology

Median timeto recurrence

Immunosuppression inmost cases

Median timesorafenib

Patientswith doseadjustment

Radiologicalresponse

Median TTPon sorafenib

Median OSafter initiationof sorafenib

Lee [10] 2 n. r. 4.4 n. r. n. r. n. r. 2 PD 0.5/1.4 0.8/2.1Yoon [14] 13 HBV 12.3 CNI ± MMF 2.4 4 (31%) 6 SD 2.9 5.4Kim [15] 9 HCV 12.4 Sirolimus + tacrolimus At least 2.8 6 (67%) 1 CR, 4 SD Not reached Not reachedTana [16] 10 HBV n. r. Tacrolimus n. r. Yes (20%) 7 SD n. r. 14Valdivieso [17] 5 HCV 23.4 Everolimus n. r. n. r. n. r. n. r. 18.8Yeganeh [18] 1 HBV 27 Tacrolimus + MMF At least 18 Yes 1 CR Not reached At least 18Wang [19] 1 HCV 20 Tacrolimus/sirolimus At least 15 Yes 1 PD, 1 PRb 2 At least 15Bhoori [20] 1 HCV 11 years Cyclosporine/everolimus 11 Yes 1 PD, 1 PRb 3 At least 11Waidmann [21] 3 Alcohol 16/20/78 Sirolimus/everolimus 5/3.5/0.8 3 (100%) 1 SD, 1 PD n. r. 1/at least 7/16Feun [22] 11 n. r. n. r. n. r. n. r. 60% 1 PR 4 n. r.Herden [23] 1 Alcohol 4 Cyclosporine 5 days Yesc n. r. n. r. n. r.Takahara [24] 2 HCV 3/25 Cyclosporine/tacrolimus 16/n. r. Yes 1 CR n. r. n. r.Gomez-Martin [25] 31 HCV 22.6 Everolimus/sirolimus n. r. 12 (46%) 1 PR, 13 SD 6.8 19.3Present study 11 HCV 37.5 Sirolimus + tacrolimus 8.9 8 (73%) 4 SD (36%) 4.1 20.1

Time in months.HCC, hepatocellular carcinoma; OLT, orthotopic liver transplantation; no., number; TTP, time to progression; OS, overall survival; n. r., not reported; PD, progressive disease;HBV, hepatitis B virus; CNI, calcineurin inhibitors; MMF, mycophenolate mofetil; SD, stable disease; HCV, hepatitis C virus; CR, complete response; PR, partial response.

a Patients were treated with sorafenib and transarterial chemoembolisation.olimu

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ose adjustment (200 mg twice daily) in most patients. Despitehe only moderate radiological response and advanced extrahep-tic tumour dissemination in most patients, our cohort exhibited

promising OS with a median of 20.1 months after the initiationf sorafenib treatment. With regard to OS after HCC recurrence34.9 months), our data indicate the need for multimodality treat-

ent approaches in patients with HCC recurrence after OLT.It is beyond doubt that our investigation has some limitations.

nterpretation of our data is limited due to the small number ofatients, the retrospective design of the study, the heterogene-

ty of immunosuppressive regimens, and the diversity of pre- andost-sorafenib treatment approaches. Particularly, efficacy has toe interpreted with caution due to the small heterogeneous datasetnd the absence of a control group.

AEs in our cohort were predominantly grade 1/2 in severity andhe pattern of AEs was similar to them described amongst non-ransplanted patients in Western countries [11,26]. About one thirdf patients tolerated the target dose of 400 mg twice daily duringhe whole treatment period; however, in accordance with previ-us reports in this setting (Table 5), most of our patients required

permanent dose reduction due to sorafenib-related AEs. Underorafenib 200 mg twice daily the treatment was well toleratedith no further dose reduction in most patients. Most importantly,o deterioration of liver graft function or acute cellular rejectionas noted which was one of the major concerns rendering theseatients ineligible for the phase II/III trials of sorafenib in advancedCC. From our opinion, patients with HCC recurrence after OLT

hould be started on a reduced sorafenib dose of 200 mg twice dailynd escalated to 400 mg twice daily in selected cases only.

Despite of the pivotal role of mTOR signalling in HCC [33,43,44],here are only scarce data on the efficacy of mTOR inhibitors for thereatment of HCC recurrence after OLT. However, preclinical datahowed that combination of sorafenib and sirolimus may lead toynergistic effects by inhibition of multiple targets [45–47]. As inrevious reports (Table 5), sirolimus was the most common used

mmunosuppressant in our patients at the time of initiation oforafenib therapy. No patient required a dose adjustment or changen the immunosuppressive regimen during sorafenib treatment.

owever, the role of sirolimus and other mTOR inhibitors for the

reatment of HCC and particularly for HCC recurrence after OLT isot defined by robust clinical data, and the contribution of sirolimuso tumour response in our cohort remains speculative. The

s.

development of the mTOR inhibitor everolimus in combinationwith sorafenib was stopped recently due to an increased num-ber of AEs in a phase I study [48]. The results of the ongoingtrials are urgently needed to clarify the role of mTOR inhibitorsin advanced HCC (www.clinicaltrials.gov identifier: NCT00355862,NCT01035229).

From our own experiences [30,39], patients with preserved liverfunction and preserved performance status are often treated withongoing targeted therapy in clinical practice despite radiologicaltumour progression according to RECIST, either due to an assumedOS benefit or due to the lack of an established second-line treatmentoption. Based on these experiences, sorafenib treatment was dis-continued in our cohort at a later time point (8.9 months) than thefirst radiological progression according to RECIST (4.1 months). Wealso tried to assess the tumour response according to mRECIST [41];however, only a small proportion of our patients presented withtypical hepatic lesions with intratumoural arterial enhancement.In contrast, almost all patients (n = 10) presented with extrahepaticnon-enhancing lesions and for these lesions, conventional RECISTshould prevail [41]. Therefore, no additional information could beobtained from this assessment.

Apart from the efficacy of sorafenib, the promising OSin our cohort might be explained by additional facts. Ourpatients exhibited completely preserved liver graft function and5 patients received a specific anticancer treatment with suni-tinib or TACE/radioembolisation after discontinuation of sorafenibtreatment probably influencing the OS. In addition, late recur-rence (median 37.5 months) and the fact that 6 patients wereprimarily amenable to surgery may be hints that the reportedmedian OS is due to a selection bias of patients with a less aggres-sive tumour. Nevertheless, almost all patients presented withadvanced extrahepatic tumour dissemination (n = 10) at initiationof sorafenib treatment and the OS rate in our cohort was com-parable to recent reports in this setting [17–19,25] suggestinga potentially favourable outcome in patients with HCC recur-rence after OLT under combined therapy with sorafenib and mTORinhibitors. In addition, our data and particularly the median OS rateof 34.1 months after HCC recurrence indicate again the need for

multimodality treatment approaches in patients with HCC recur-rence after OLT [7,8,17].

In conclusion, we could demonstrate that sorafenib in com-bination with immunosuppression including sirolimus may be

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[lular carcinoma and anti-tumoral effect of combined sorafenib and rapamycin

A. Weinmann et al. / Digestive a

dministered to patients with HCC recurrence after OLT withcceptable toxicity and without deterioration of liver graft func-ion. Prospective clinical trials are urgently needed to confirm theafety and particularly the efficacy of sorafenib in combination withTOR inhibitors in this special group of patients with advancedCC.

onflict of interest statementW, MS, PRG, and MAW have received consulting and lecture fees

rom Bayer Vital, Leverkusen, Germany. The other authors discloseo potential conflict of interest.

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