hepatocellular carcinoma, haemophilia, treatmen

BRUERA, G

GIORDANO,A V

LAPECORELLA,M

LUCCHESI,A

MARIANI,G

NAPOLITANO, Mariasanta

RICEVUTO,E

TUDINI,M

Archivio istituzionale della ricerca - Università di Palermo

LETTER TO THE EDITORSorafenib as a feasible therapeutic option in haemophiliacswith hepatocellular carcinomaM. LAPECORELLA,* M. NAPOLITANO,* M. TUDINI, G. BRUERA, A. LUCCHESI,*A. V. GIORDANO, G. MARIANI* and E. RICEVUTO*Haemophilia and Thrombosis Centre; Medical Oncology, Department of Experimental Medicine; and Department ofRadiology, University of LAquila, ItalySorafenib (Nexavar; Bayer, Leverkusen, Germany)is a multikinase inhibitor that shows efficacy in avariety of tumours and has been recently approvedfor the treatment of multifocal and surgically unre-sectable hepatocellular carcinoma (HCC). Sorafenibblocks the growth of tumour cells by inhibition ofseveral pathways that both interfere with angiogen-esis and induce apoptosis of HCC cells. Both in HCCcell lines and in murine models, sorafenib has beenshown to antagonize the angiogenic effect of vascularendothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) on their receptorsVEGFR2 and PDGFR respectively. Furthermore,sorafenib has a direct effect on cell proliferationwith mechanisms that are partly unknown but thatinvolve the RAF/MEK/ERK signalling pathway,which plays a key role in the development of manytumours including HCC [1]. Antiangiogenic drugsshow a variegate spectrum of both thrombotic andhaemorrhagic complications. Among angiogenesisinhibitors, treatment with sorafenib is poorly com-plicated with thrombotic episodes. Conversely,bleeding has been extensively reported with anincidence of 2–3% of treated patients, ranging fromfrequent and mild [2] to rare severe haemorrhages,including intracranial [3].Hepatocellular carcinoma frequently occurred inhaemophiliacs as most patients became infected withHBV and HCV from concentrates before virusinactivation was available. Since infected concen-trates were used in the early-mid 1980s, HCCemerged as a cause of death in haemophiliacsbeginning from the mid 1990s [4]. Liver transplan-tation and chemoembolization are the therapeuticoptions [5] while the use of sorafenib for HCCtreatment has never been reported in haemophiliacsto date.A 65 year-old severe haemophiliac A with chronicHBV/HCV-related liver co-infection referred to ourCentre for a markedly increased serum alpha-fetoprotein (AFP) (4102 ng/mL). A liver ultrasoundwas performed, showing a nodular lesion (diameter5 cm) between the 6th and 7th segments. A furthersuperficial, extruding lesion (diameter 3 cm, 6thsegment) was detected at MRI. Hilar lymphadenop-athy was present. Clinical diagnosis of multifocalHCC was therefore made according to AmericanAssociation for the Study of Liver Diseases (AASLD)diagnostic criteria (lesion >2 cm in cirrhotic liver, thetypical pattern of vascularization, confirmed by twoimaging studies, AFP >200 ng/mL). The patient wasasymptomatic at the time of observation. The func-tional liver status, according to Child-Pugh score wasCHILD A (6 points). The patient fell in the stage B,intermediate, thus surgically unresectable, accordingto the Barcelona Clinic Liver Cancer Criteria (BCLC)and chemoembolization of the nodular lesionbetween the 6th and 7th segments with doxorubicin(30 mg total dose) and Lipiodol was performed. Asthe patients treatment regimen was on-demandbasis, adequate peri-operative coverage with hisplasma-derived factor VIII (FVIII) concentrate (Emo-clot; Kedrion, Castelvecchio Pascoli, Italy) wasobtained. The subsequent CT scan, performed4 weeks after the procedure, showed progression insize of the main lesion (Fig. 1a), expansion of hilarlymphadenopathy and the occurrence of new smallerhepatic lesions, with worsening of performancestatus (PS 2), thus determining a stage C, accordingto BCLC criteria. At this point, the only residualtreatment option was a systemic therapy with theCorrespondence: Dr Mario Lapecorella, MD, Centro Emofilia eTrombosi - Unita` Operativa Medicina Interna 2 – Ematologia,Universita` de LAquila - Ospedale San Salvatore, Via Vetoio 1,67100 Coppito - LAquila, Italy.Tel.: + 39 33 9758 5281; fax: + 39 08 0522 7253;e-mail: emofilia.aq@cc.univaq.itAccepted after revision 28 August 2009Haemophilia (2009), 1–2 DOI: 10.1111/j.1365-2516.2009.02114.x 2009 Blackwell Publishing Ltd 1angiogenesis inhibitor sorafenib. Several co-morbid-ities were present, including hypertension and hyper-trophic cardiomyopathy, type II diabetes, andespecially haemorrhagic diathesis resulting fromhaemophilia A, in that the patient was characterizedas unstable according to the Cumulative IllnessRating Scale (CIRS) co-morbidity index score.Therefore, treatment with sorafenib was started atthe 50% dose reduction of 400 mg/day. In order toprevent bleeding episodes, the regimen ofsubstitution treatment with his plasma-derived FVIIIconcentrate was shifted to prophylaxis (40 U/Kgof body weight three times a week) as such regimenis associated with a better long-term outcomewhen compared with on-demand treatment. After4 weeks of treatment, the patient only experiencedtransient diarrhoea, and both moderate asthenia anddyspnoea, while no bleeding episode was reported.Furthermore, a consistent reduction of AFP (26.5 ng/mL) was observed. Treatment was continued at thesame dose for further 4 weeks. Then a completerestaging was performed. CT scan showed a goodresponse consisting in 50% reduction with extensivecentral necrosis of the larger lesion (Fig. 1b), stabilityof the superficial lesion, and disappearance of theother satellite smaller nodules. AFP further decreaseddown to 8 ng/mL and no bleeding symptom wasreported. Three months after discontinuing sorafenibtreatment, our patient preserved his basic perfor-mance status and AFP still fell into the normal range(8.9 ng/mL). Prophylaxis with FVIII has not beendiscontinued.This is, to date, the first report of the use ofsorafenib for treatment of HCC in a haemophiliac.Our experience suggests that Sorafenib may be afeasible therapeutic option in these patients. As aresult of the bleeding complications described withthe use of this drug, prophylaxis with FVIII concen-trates is advised. The reasons for such an effectiveresponse when compared with the case of non-haemophiliac patients after an 8-week course ther-apy administered at half the full dose require furtherstudies and sorafenib needs a large scale comparisonwith other treatment options in hemophiliac patientsaffected by HCC.DisclosuresThe authors stated that they had no interests whichmight be perceived as posing a conflict or bias.References1 Liu L, Cao Y, Chen C et al. Sorafenib blocks the RAF/MEK/ERKpathway, inhibits tumor angiogenesis, and induces tumor cellapoptosis in hepatocellular carcinoma model PLC/PRF/5. CancerRes 2006; 66: 11851–8.2 Escudier B, Eisen T, Stadler WM et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007; 356: 125–34.3 Abou-Alfa GK, Schwartz L, Ricci S et al. Phase II study of sorafenibin patients with advanced hepatocellular carcinoma. J Clin Oncol2006; 24: 4293–300.4 Rumi MG, De Filippi F, Santagostino E, Colombo M. Hepatitis Cin haemophilia: lights and shadows. Haemophilia 2004; 10(Suppl.4): 211–5.5 Santagostino E, Colombo M, Rivi M et al. A 6-month versus a12-month surveillance for hepatocellular carcinoma in 559 hemo-philiacs infected with the hepatitis C virus. Blood 2003; 102: 78–82.Fig. 1. (a) CT scan performed 4 weeks after chemoembolization shows progression in size of the nodular lesion between the 6th and 7thsegments with persistence of viable tissue (arrow). (b) CT scan performed after 8-week course treatment with sorafenib shows markedreduction in size of the nodular lesion between the 6th and 7th segments with intra-lesional necrosis (arrow).2 LETTER TO THE EDITORHaemophilia (2009), 1–2  2009 Blackwell Publishing Ltd

Sorafenib as a feasible therapeutic option in haemophiliacs
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Sorafenib as a feasible therapeutic option in haemophiliacs with hepatocellular carcinoma

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