Efficacy and Safety of Combination Therapy With Everolimus and Sorafenib for Recurrence of Hepatocellular Carcinoma After Liver Transplantation P. De Simone, L. Crocetti, D. Pezzati, I. Bargellini, D. Ghinolfi, P. Carrai, G. Leonardi, C. Della Pina, D. Cioni, L. Pollina, D. Campani, C. Bartolozzi, R. Lencioni, and F. Filipponi ABSTRACT Background. Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) is still associated with a dismal outcome. Combination therapy with everolimus (EVL) and vascular endothelial growth factor inhibitor sorafenib (SORA) is based on the role of both b-Raf and mammalian target of rapamycin/ protein kinase B pathways in the pathogenesis of HCC and is being investigated in clinical practice. Methods. This was a single-center retrospective analysis on LT recipients with unresectable HCC recurrence and undergoing combination therapy with EVL and SORA. Patients were included if they were switched to EVLþSORA at any time after surgery. Primary endpoint was overall survival (OS) after both LT and recurrence, and response to treatment based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST) in the intention-to-treat (ITT) population. Secondary analysis was safety of combination therapy with EVL and SORA in the population of patients who received 1 dose of the study drug. Results. Seven patients (100% male; median age 53 years [interquartile range (IQR) 9 years]) were considered for analysis. HCC recurrence was diagnosed at a median (IQR) interval since LT of 9 (126) months, and patients were administered EVLþSORA at a median interval since LT of 11 (126) months. Baseline immunosuppression was with tacrolimus (TAC) in 2 patients (28.6%), cyclosporine (CsA) in 2 (28.6%), and EVL monotherapy in 3 (42.8%). At a median (IQR) follow-up of 6.5 (14) months, 5 patients (71.4%) were alive, 4 of them (57.1%) with tumor progression according to the mRECIST criteria. Median (IQR) time to progression was 3.5 (12) months. Two patients died at a median (IQR) follow-up of 5 (1) months owing to tumor progression in 1 patient (14.3%) and sepsis in the other (14.3%). EVL monotherapy was achieved in 6 patients (85.7%), whereas 1patient (14.3%) could not withdraw from calcineurin inhibitor owing to acute rejection. Treatment complications were: hand-foot syndrome in 5 patients (71.4%), hypertension in 1 (14.3%), alopecia in 1 (14.3%), hypothyroidism in 1 (14.3%), diarrhea in 2 (28.6%), pruritus in 1 (14.3%), abdominal pain in 1 (14.3%), rash in 1 (14.3%), asthenia in 3 (42.8%), anorexia in 3 (42.8%), and hoarseness in 2 (28.6%). Adverse events led to temporary SORA discontinuation in 2 patients (28.6%) and to SORA dose reduction in 3 (42.8%).

From the Hepatobiliary Surgery and Liver Transplantation Unit (P.D.S., D.P., D.G., P.C., G.L., F.F.), Radiology Department (L.C., I.B., C.D.P., D.C., C.B., R.L.), and Pathology Department (L.P., D.C.), University of Pisa Medical School Hospital, Pisa, Italy. ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 46, 241e244 (2014)

Address reprint requests to Paolo de Simone, MD, Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Via Paradisa 2, 56124 Pisa, Italy. E-mail: [email protected] 0041-1345/14/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.10.035 241

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Conclusions. Treatment of HCC recurrence after LT with a combination regimen of EVLþ SORA is challenging because of SORA-related complications. Longer follow-up periods and larger series are needed to better capture the impact of such combination treatment on tumor progression and patient survival.

R

ecurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) is still associated with a dismal outcome [1]. Combination therapy with everolimus (EVL) and vascular endothelial growth factor inhibitor sorafenib (SORA) is based on the role of both b-Raf and mammalian target of rapamycin (mTOR)/protein kinase B (AKT) pathways in the pathogenesis of HCC [2], and use of SORA is being investigated in clinical practice for treatment of post-transplantation HCC recurrence [3e5], for pretransplantation downstaging/bridging [6], and as a posttransplantation adjuvant modality [7]. Concerns have been raised regarding the toxicity of EVL and SORA when used in combination [4] and about the best immunosuppressive strategy for patients receiving transplants for HCC [8]. We report on our experience on 7 LT recipients with HCC recurrence after transplantation and treated with a combination regimen with EVLþSORA. MATERIALS AND METHODS Study Design and Objectives This was a retrospective study based on a prospectively collected database including all LT recipients transplanted at our center. The current data analysis was run with the approval of the Institutional Review Board and in agreement with the principles set forth in the 2008 Declaration of Helsinki. The primary study objective was evaluation of the efficacy of combination of EVLþSORA in LT with HCC recurrence, according to patient survival (months) after both transplantation and diagnosis of recurrence. The secondary endpoint was evaluation of response to EVLþSORA, according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) [9], and the safety profile of EVLþSORA, according to the incidence of adverse events (AEs). The incidence of study drug (EVL, SORA) discontinuation was also assessed. Data were censored at time of last observation, patient’s death, or December 31, 2012.

Patient Selection Criteria The current study population included all adult (18 years old) LT recipients of a primary or secondary liver graft, transplanted for HCC within and beyond Milan criteria, who received EVLþSORA for HCC recurrence not amenable to surgical resection and/or locoregional treatment. It is our common policy to treat HCC recurrence by means of resection and/or locoregional therapies according to type, location and number of recurrent lesions, as well as underlying liver function, and to refer patients to molecular therapies in case of progression and/or untreatable disease.

Immunosuppression EVL (Certican; Novartis Italia, Origgio, Italy) was initiated at a dosage of 1.0 mg bid for patients on tacrolimus (TAC) and 0.75 mg bid for patients on cyclosporine (CsA), concurrent with elimination of steroids and/or any antimetabolite (mycophenolate mofetile,

mycophenolic acid, or azathioprine). For patients on TAC (Prograf or Advagraf; Astellas, Munich, Germany), TAC dosages was adapted after EVL was in the target range (3e8 ng/mL). For patients on CsA, this was reduced by 50% at the time of EVL initiation, owing to the pharmacokinetic interaction between CsA and EVL. EVL target range was 3e8 ng/mL on combination therapy with reducedexposure TAC (3e5 ng/mL) or CsA (C0 100 ng/mL, C2 450 ng/mL). After achieving an EVL trough target range (3e8 ng/mL), we proceeded with stepwise tapering of calcineurin inhibitor (CNI) to achieve elimination as rapidly as possible. Rejection was diagnosed histologically, graded according to the Banff histologic criteria, and expressed as rejection activity index (RAI) scores, as previously described [10]. We usually avoid steroid boluses in patients with HCC recurrence, regardless of the RAI score, and prefer CNI dose adjustments.

Sorafenib Administration SORA (Nexavar; Bayer, Basel, Switzerland) was initiated at a dosage of 400 mg bid. In case of AEs, the dose was tapered to 400 mg/d and eventually to 400 mg every other day, according to severity and persistence of symptoms. SORA-related AEs were graded according to the Clinical Grading for Adverse Events code book, with each event scored 1e5 (mild to fatal).

Data Collection and Handling All data were retrieved from clinical records and entered into an electronic data base (Excel for Windows 2007; Microsoft, Seattle, USA). According to type and distribution, data are expressed as means, standard deviations (SDs), medians, interquartile ranges (IQR), percentages, and frequencies as appropriate. Patient and graft survival was calculated with the use of the Kaplan-Meier curve. Data analysis was carried out with the Statistical Package for Social Sciences software (SPSS 18; IBM). Data analysis was conducted in accordance with the current Italian code protection law.

RESULTS

Table 1 presents the baseline demographic and clinical characteristics of the study population. All patients were male with a median (IQR) age of 53 (9) years. HCC recurrence was diagnosed at a median (IQR) interval since LT of 9 (126) months, and patients were administered EVLþSORA at a median interval since LT of 11 (126) months. Concurrent indication to LT besides HCC was hepatitis C infection in 3 patients (42.8%), hepatitis B (HBV) in 2 (28.6%), and alcoholic cirrhosis in 2 (28.6%). HCC stage on explant pathology was within the Milan criteria in 5 patients (71.4%), with microvascular invasion in all 7 patients (100%). Five patients (71.4%) were downstaged with transarterial chemoembolization (TACE) before LT. One patient (14.3%) had been resected as firstline treatment for his HCC recurrence in HBV-related cirrhosis and was administered EVLþSORA for eventual

EVEROLIMUS AND SORAFENIB

243 Table 3. Complications (n [ 7)

Table 1. Main Baseline Demographic and Clinical Characteristics of the Study Population (n [ 7)

Complication

Variable

Male, n (%) 7 Median (IQR) age, y 53 Median (IQR) interval since LT to HCC recurrence, mo 9 Median (IQR) interval since LT to EVLþSORA 11 introduction, mo Deceased donor LT, n (%) 7 Whole-size graft, n (%) 7 Primary LT, n (%) 7 Indication to LT beyond HCC, n (%) HCV 3 HBV (HDV) 2 Alcohol 2 HCC stage (within Milan) on explant 5 Microvascular invasion on explant pathology 7 Pre-transplantation tumor downstaging 5 Post-transplantation first-line treatment of HCC recurrence Surgery 1 TACE 2 EVL þ SORA 4 Baseline immunosuppression TAC þ MMF þ steroids 1 TAC þ MMF 1 CsA 2 EVL 3

(100) (9) (126) (126) (100) (100) (100) (42.8) (28.6) (28.6) (71.4) (100) (71.4) (14.3) (28.6) (57.1) (14.3) (14.3) (28.6) (42.8)

Abbreviations: CsA, cyclosporine; EVL, everolimus; HBV, hepatitis B virus; HDV, hepatitis delta virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; IQR, interquartile range; MMF, mycophenolate mofetile; SORA, sorafenib; TAC, tacrolimus; TACE, transarterial chemoembolization.

tumor recurrence. Two patients (28.6%) had undergone TACE after transplantation and were later treated with EVLþSORA for HCC progression. And 4 patients (57.1%) presented with HCC recurrence not amenable to resection/ locoregional treatment and were administered EVLþSORA as their first-line treatment. Baseline immunosuppression was with TAC in 2 patients (28.6%), CsA in 2 (28.6%), and EVL monotherapy in 3 (42.8%; 1 resection, 2 TACE). At a median (IQR) follow-up of 6.5 (14) months, 5 patients (71.4%) were alive, 4 (57.1%) with tumor progression according to the mRECIST criteria (Table 2). Median (IQR) time to progression was 3.5 (12) months. Two patients died at a median (IQR) follow-up of 5 (1) months Table 2. Results (n [ 7) Result

Follow-up, mo (median [IQR]) Progression,* n (%) Time to progression, mo (median [IQR]) Death, n (%) HCC progression, n (%) Sepsis, n (%) Time to death, mo (median [IQR]) EVL monotherapy achieved, n (%) t/BPAR, n (%)

6.5 [14] 5 (71.4) 3.5 [12] 2 (28.6) 1 (14.3) 1 (14.3) 5 [1] 6 (85.7) 1 (14.3)

Abbreviations: t/BPAR, treated and/or biopsy proven acute rejection; other abbreviations as in Table 1. *According to mRECIST criteria and or evidence of extrahepatic disease.

Hand-foot syndrome Hypertension Alopecia Hypothyroidism Diarrhea Pruritus Abdominal pain Rash Asthenia Anorexia Hoarseness SORA temporary discontinuation SORA dose reduction

5 1 1 1 2 1 1 1 3 3 2 2 3

(71.4) (14.3) (14.3) (14.3) (28.6) (14.3) (14.3) (14.3) (42.8) (42.8) (28.6) (28.6) (42.8)

Abbreviation: SORA, sorafenib.

owing to tumor progression in 1 patient (14.3%) and sepsis in the other (14.3%). EVL monotherapy was achieved in 6 patients (85.7%), and 1 patient (14.3%) could not withdraw TAC owing to acute rejection (Table 2). Table 3 presents the incidence of treatment complications: hand-foot syndrome was observed in 5 patients (71.4%), hypertension in 1 (14.3%), alopecia in 1 (14.3%), hypothyroidism in 1 (14.3%), diarrhea in 2 (28.6%), pruritus in 1 (14.3%), abdominal pain in 1 (14.3%), rash in 1 (14.3%), asthenia in 3 (42.8%), anorexia in 3 (42.8%), and hoarseness in 2 (28.6%). AEs led to temporary SORA discontinuation in 2 patients (28.6%) and to SORA dose reduction in 3 (42.8%; Table 3).

DISCUSSION

Combination treatment with EVL and SORA is appealing to the clinical setting owing to the potential of targeting both molecular pathways involved in HCC pathogenesis, ie, b-Raf and mTOR/AKT [2]. Furthermore, despite advancements in outcome after LT over the past years, HCC recurrence is still associated with a dismal prognosis [1]. Combining EVL with SORA bears the potential of exposing patients to the combined toxicity of both drugs and/or increasing the exposure to SORA side effects [4] due to competitive interaction of either drug on the CYP3A4 substrate. This was observed in our series, with patients experiencing SORA-like AEs and necessitating lower EVL exposure to avoid increased SORA toxicity. Our preliminary data show that combination of EVLþSORA is challenging regarding side effects and requires close patient monitoring to adapt EVL dosage to SORA exposure and toxicity. Median time to tumor progression was short (3.5 mo), but its variability (IQR 12 mo) underscores that HCC biology is the preeminent outcome determinant in this population. Longer follow-up periods are needed to better assess the impact of EVLþSORA on patient survival, and larger series will allow better identification of relevant clinical factors and help to fine tune treatment options for HCC recurrence after LT.

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ACKNOWLEDGMENTS The authors owe a deep debt of gratitude to the nursing staff of the Hepatobiliary Surgery and Liver Transplantation Unit, University of Pisa Medical School Hospital, Pisa, Italy. P.d.S. has received speaking fees from Novartis Pharma and Bayer. P.d.S. and F.F. have carried out clinical trial studies for Novartis Pharma.

REFERENCES [1] Rubin J, Ayoub N, Kaldas F, Saab S. Management of recurrent hepatocellular carcinoma in liver transplant recipients: a systematic review. Exp Clin Transplant 2012;10:531e43. [2] Bhoori S, Toffanin S, Sposito C, Germini A, Pellegrinelli A, Lampis A, Mazzaferro V. Personalized molecular targeted therapy in advanced, recurrent hepatocellular carcinoma after liver transplantation: a proof of principle. J Hepatol 2010;52:771e5. [3] Sposito C, Mariani L, Germini A, Flores Reyes M, Bongini M, Grossi G, et al. Comparative efficacy of sorafenib versus best supportive care in recurrent hepatocellular carcinoma after liver transplantation: a case-control study. J Hepatol 2013;59:59e66. [4] Zavaglia C, Airoldi A, Mancuso A, Vangeli M, Viganò R, Cordone G, et al. Adverse events affect sorafenib efficacy in patients with recurrent hepatocellular carcinoma after liver transplantation: experience at a single center and review of the literature. Eur J Gastroenterol Hepatol 2013;25:180e6.

DE SIMONE, CROCETTI, PEZZATI ET AL [5] Gomez-Martin C, Bustamante J, Castroagudin JF, Salcedo M, Garralda E, Testillano M, et al. Efficacy and safety of sorafenib in combination with mammalian target of rapamycin inhibitors for recurrent hepatocellular carcinoma after liver transplantation. Liver Transpl 2012;18:45e52. [6] Frenette CT, Boktour M, Burroughs SG, Kaseb A, Aloia TA, Galati J, et al. Pre-transplant utilization of sorafenib is not associated with increased complications after liver transplantation. Transpl Int 2013;26:734e9. [7] Jia N, Liou I, Halldorson J, Carithers R, Perkins J, Reyes J, et al. Phase I adjuvant trial of sorafenib in patients with hepatocellular carcinoma after orthotopic liver transplantation. Anticancer Res 2013;33:2797e800. [8] Rodríguez-Perálvarez M, Tsochatzis E, Naveas MC, Pieri G, García-Caparrós C, O0 Beirne J, et al. Reduced exposure to calcineurin inhibitors early after liver transplantation prevents recurrence of hepatocellular carcinoma [e-pub ahead of print]. J Hepatol http://dx.doi.org/10.1016/j.jhep.2013.07.012, published online July 15, 2013. [9] Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis 2010;30: 52e60. [10] Banff Working Group on Liver Allograft Pathology. Importance of liver biopsy findings in immunosuppression management: biopsy monitoring and working criteria for patients with operational tolerance. Liver Transpl 2012;18:1154e70.

Efficacy and safety of combination therapy with everolimus and sorafenib for recurrence of hepatocellular carcinoma after liver transplantation.

Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) is still associated with a dismal outcome. Combination therapy with ever...
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