Clinical Study Transcatheter Arterial Chemoembolization of Hepatocellular Carcinoma as a Bridge to Liver Transplantation: A Retrospective Study

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1 SAGE-Hidawi Access to Research Iteratioal Joural of Hepatology Volume 2011, Article ID , 7 pages doi: /2011/ Cliical Study Trascatheter Arterial Chemoembolizatio of Hepatocellular Carcioma as a Bridge to Liver Trasplatatio: A Retrospective Study Atoie Bouchard-Fortier, 1 Réal Lapoite, 1 Pierre Perreault, 2 Louis Bouchard, 2 ad Gilles Pomier-Layrargues 3 1 Departmet of Surgery, Cetre Hospitalier de l UiversitédeMotréal, 264, East Reé-Lévesque Blvd, 3rd floor, Motreal, QC, Caada H2X 1P1 2 Departmet of Radiology, Cetre Hospitalier de l UiversitédeMotréal, 264, East Reé-Lévesque Blvd, 3rd floor, Motreal, QC, Caada H2X 1P1 3 Liver Uit, Cetre Hospitalier de l UiversitédeMotréal, 264, East Reé-Lévesque Blvd, 3rd floor, Motreal, QC, Caada H2X 1P1 Correspodece should be addressed to Gilles Pomier-Layrargues, gilles.pomier.layrargues@umotreal.ca Received 5 July 2010; Revised 7 December 2010; Accepted 10 December 2010 Academic Editor: Takuji Torimura Copyright 2011 Atoie Bouchard-Fortier et al. This is a ope access article distributed uder the Creative Commos Attributio Licese, which permits urestricted use, distributio, ad reproductio i ay medium, provided the origial work is properly cited. Backgroud. Trascatheter arterial lipiodol chemoembolizatio (TACE) ca be used i cirrhotic patiets with hepatocellular carcioma to avoid tumor progressio before trasplatatio. Objective. To evaluate the efficacy ad safety of TACE used as a bridge to liver trasplatatio. Methods. TACE was performed i 30 cirrhotic patiets with hepatocellular carcioma. Mila criteria were used to select patiets for trasplat. Patiets had a good or moderately impaired liver fuctio, o arterioportal fistulae, ad a good portal perfusio. Results. 48 TACE were performed i 30 patiets. Before trasplatatio, 4 patiets were dropped off the list due to tumor extesio or liver failure. Complete ecrosis of the tumor was observed i 11 patiets ad partial ecrosis i 15 patiets. After trasplatatio, 6 patiets died ad tumor recurrece was observed i 5 patiets with a tumor beyod Mila criteria or o respose to TACE. Coclusio. TACE is useful as a bridge to liver trasplatatio i a selected group of cirrhotic patiets with hepatocellular carcioma. A combied therapeutic approach before surgery might improve the progosis i these patiets. 1. Itroductio Icidece of hepatocellular carcioma (HCC) has icreased sigificatly over the last decades. Worldwide it represets the fifth most commo cacer ad the third cause of cacer mortality amog the geeral populatio [1, 2]. Hepatitis B ad C ad alcohol abuse are major risk factors for HCC. Several treatmet modalities exist based o tumor locatio ad size. Amog others, liver trasplatatio was cofirmed as a valuable treatmet for HCC durig the 1990s as it was observed that small icidetal HCC discovered i the explated liver had o adverse impact o posttrasplatatio outcome [3, 4]. Thus, over the years, orthotopic liver trasplatatio (OLT) has become the maistay of treatmet for small cetrally located HCC i a cirrhotic liver. Sice the late ieties, most trasplatatio ceters have agreed to perform liver trasplatatio for HCC based o Mila criteria. The Mila criteria were elaborated by Figueras et al. who showed that patiets with oe hepatic lesio smaller tha 5 cm or with three lesios smaller tha 3 cm ca expect a 5-year survival rate after liver trasplatatio of 70% with recurrece rate below 15% [5]. Those results were supported byseveralotherresearchgroups[6 8]. However, the time waitig for a orga represets a major pitfall to liver trasplatatio. This may lead to tumor progressio ad subsequet ieligibility for trasplatatio.

2 2 Iteratioal Joural of Hepatology I Europe ad USA, there are reports that liver trasplat waitig lists are gettig loger so that a growig umber of patiets must be removed from the lists due to tumor progressio exceedig the accepted trasplat criteria [2]. Dropout rates of more tha 20% have recetly bee reported [9]. Trascatheter arterial chemoembolizatio (TACE) has bee proposed as a treatmet to bridge the waitig time betwee the diagosis ad liver trasplatatio. I some studies, it has bee demostrated that TACE may limit tumor growth, dimiish dropout rate, ad cause sigificat tumor ecrosis, which may reduce tumor dissemiatio durig surgery ad possibly recurreces [10]. However, some studies have also showed opposite results [5, 11, 12]. The aim of this study was to evaluate retrospectively the usefuless ad tolerace of TACE before OLT i cirrhotic patiets with hepatocellular carcioma. 2. Methods From Jauary 1st 1996 to Jauary 1st 2008, all cirrhotic patiets with HCC listed for OLT ad treated with TACE at our trasplatatio ceter were icluded for aalysis. Diagosis of HCC was made i accordace with the Europea Associatio for the Study of the Liver (EASL) guidelies: typical lesios o 2 imagig studies (computed tomographic (CT) sca, magetic resoace imagig (MRI), ultrasoud) or o 1 imagig modality with a elevated serum alfa-fetoprotei over 400 g/ml or liver biopsy with histologic cofirmatio of HCC [13]. The selectio of patiets with HCC for TACE was based o the followig iclusio criteria: good or moderately impaired hepatic fuctio (Child Pugh classes A ad B), hepatopetal portal blood flow, absece of portal vei thrombosis, absece of arterioportal fistula, absece of extesive portosystemic shutig, ad a waitig time for liver trasplatatio estimated to be more tha 3 moths. TACE aimed both at limitig tumor progressio ad dowstagig. Dowstagig was coducted i a limited umber of patiets exceedig the Mila criteria. I those patiets, TACE treatmets were admiistered util Mila criteria were reached i order to become eligible for OLT. All the patiets siged a iformed coset form ad the procedures were doe i accordace with the Helsiki declaratio of Selective TACE were performed by itervetioal agioradiologists (PP ad LB) usig cisplati ad lipiodol. Gel Foam (Pfizer, Caada) was added to stasis followig the ijectio of the cisplati-lipiodol solutio ito the hepatic artery. Tumor respose was assessed by CT sca ad/or MRI every 3 moths post chemoembolizatio. Chages i the tumor size of at least 5 mm i diameter were cosidered to be sigificat. TACE was performed every 3 moths accordig to respose or util trasplatatio if patiets were eligible. Child Pugh scores ad complicatios were moitored followig every treatmet. All patiets trasplated received a cadaveric liver. Explated livers uderwet extesive histologic aalysis ad stagig of HCC. The modified Edmodso scorig system was used to grade the level of differetiatio of HCC odules [14]. All patiets were followed util death or Jauary I the follow-up period, surgical complicatios, hepatitis recurrece, HCC recurrece, ad patiets survival were aalysed. Categorical data were compared usig the Fischer exact test. Hazard ratio associated with the Mila criteria ad cacer recurrece were calculated usig 95% cofidece itervals. Survival rate was calculated for patiets with ad without cacer recurrece after OLT accordig to the Kapla-Meier method, groups were compared usig the log rak test. Oe sided P-values <.05 were cosidered sigificat. Aalysis were doe usig SAS statistical software (versio 8.2). 3. Results 3.1. Patiets Characteristics (Table 1). A total of 30 patiets were icluded for aalysis. There were 23 me ad 7 wome (mea age: 55 years, rage years) (22 Caucasias, 4 Asias, 3 South Americas, ad 1 Africa). Liver cirrhosis was mostly caused by hepatitis C virus (HCV) ad/or hepatitis B virus (HBV). Other etiologies of cirrhosis were also idetified such as alcohol abuse, oalcoholic steatohepatitis (NASH), ad combied causes (4 HCV + alcoholism, 2 HCV + hemochromatosis, 1 HCV + HBV, 1 HBV + alcoholism, 1 hemochromatosis + alcoholism). Diagosis of HCC was based o the presece of typical lesios o 2 imagig studies (18 patiets) or o 1 imagig study with elevatio of serum alpha-fetoprotei (9 patiets), ad liver biopsy was doe to cofirm the diagosis i 3 patiets. At the time of diagosis, the majority of patiets had either 1 (60%) or 2 (10%) suspected tumoral odules (size: 23,8 mm ± 13.7 mm (mea ± SD). A total of 6 patiets (20%) exceeded Mila criteria (Table 2) Listig. All patiets aalysed were listed for OLT. Thirtee patiets (43%) were listed before havig TACE ad 17 (57%) after. At the time of listig, 24 patiets (80%) were withi Mila criteria ad 6 patiets (20%) were ot withi those criteria. Therefore, i these 6 patiets, TACE was a dowstagig attempt TACE. Forty-eight TACE treatmets were admiistered to the 30 patiets (mea 1.6/patiet; rage 1 7). The majority of itervetios were doe i Pugh class A patiets (40 itervetios or 83%) before TACE. Icrease i the Pugh class from A to B was observed followig 3 TACE (6%). Complicatios associated with TACE were divided ito mior ad major categories (Table 3). Amog the 48 TACE procedures, 20 (42%) did ot suffer from ay complicatios. A total of 27 itervetios (56%) resulted i complicatios, which were essetially of the mior category (Table 3) mostly abdomial pai ad ausea. As for major complicatios,

3 Iteratioal Joural of Hepatology 3 Table 1: Baselie patiets characteristics. Number of patiets 30 Sex (M/F) 23/7 Media age at listig years (rage) 55 (35 68) Origi (%) Caucasia 22 (73) Asia 4 (13) South America 3 (10) Africa 1 (3) Cause of liver cirrhosis (%) Hepatitis C virus 9 (33) Hepatitis B virus 8 (27) Combied causes 9 (30) Alcohol abuse 2 (7) NASH 2 (7) Hepatocellular carcioma (%) 30 (100) Diagosis (%) 2 imagig studies 18 (60) 1 imagig study + alfa-foeto proteis 9 (30) Biopsy 3 (10) Media AFP, g/ml (rage) 27,8 ( ) Mea lesio size, mm (rage) 23,8 (10 60 mm) Number of lesios, patiets (%) Oe lesio 18 (60) Two lesios 3 (10) Three lesios 7 (23) Four lesios 2 (7) Mila at diagosis (%) I 24 (80) Out 6 (20) Table 2: Characteristics of hepatocarcioma outside Mila criteria at diagosis. Patiet umber Number of lesios Size of lesios (mm) # /30/26 # /22 # # /25/10/10 # # /22/10 we idetified 2 ischemic cholecystitis, 1 acute liver failure, 1 thrombosis of the femoral artery, 1 spleic ifarctio, ad 1 ischemic atrophy of the left hepatic lobe. I additio, 1 patiet died from acute liver failure, sepsis, ad acute real failure thought to be directly related to the TACE procedure Radiologic Follow-Up (Table 4). Radiologic follow-up after TACE treatmet showed a decrease of tumoral size of at least 5 mm i 13 patiets (43%) (rage: 5 34 mm). I 6 patiets (20%), tumoral size remaied stable (±5 mm) ad 5 patiets (17%) had a icrease of tumoral size of at Table 3: Adverse evets followig trasarterial chemoembolizatio (TACE) (48 treatmets i 30 patiets). Number of TACE/patiet (mea, rage) 1.6 (1 7) Adverse evets (%) Noe 20 (42) Yes 28 (58) Mior evets, umber of TACE (%) 24 (50) Pai i right upper quadrat 18 (38) Nausea/emesis 7 (15) Chemical arteritis 5 (10) Corticosteroids-related diabetes ubalaces 2 (4) Ischemic hepatitis 2 (4) Leucocytosis 1 (2) Fever 1 (2) Allergic reactio 1(2) Major evets, umber of TACE (%) 7 (15) Ischemic cholecystitis 2 (4) Trasiet acute hepatic failure 2 (4) Thrombosis of superficial femoral artery 1 (2) Spleic ifarctio 1 (2) Ischemic atrophy of the left hepatic lobe 1 (2) Acute real failure Spotaeous bacterial peritoitis Sepsis Death Those evets occurred i the same patiet. least 5 mm. New liver lesios were observed i 9 patiets (30%) after TACE. Therefore, a total of 10 patiets (33%) did ot respod to TACE due to tumor progressio ad/or appearace of ew hepatic lesios. There were 6 patiets (20%) withi Mila criteria at listig that were trasplated before havig radiologic follow-up after TACE ad thus, radiological respose to TACE could ot be assessed i these patiets Dowstagig. As metioed before, dowstagig was attempted i 6 patiets that were exceedig Mila criteria at HCC diagosis. Aalysis of their radiological respose to TACE showed that dowstagig could be obtaied i 3 of the 6 patiets (50%) Drop-Off (DO). Durig the time waitig for OLT, 4 out of 30 patiets (13%) were removed from the trasplat list. Three patiets were excluded because of HCC progressio over trasplat criteria ad 1 died followig his first TACE treatmet. The mea delay betwee listig ad DO was 109 days (rage: days). All 4 dropouts received 1 TACE each before exclusio Orthotopic Liver Trasplatatio (OLT) (Table 5). Twety-six patiets (87%) were trasplated with a mea waitig time o the trasplat list of 110 days (rage: days). At trasplatatio, 22 patiets (85%) met Mila

4 4 Iteratioal Joural of Hepatology Table 4: Radiologic evolutio after trasarterial chemoembolizatio (TACE). Tumor size (%) Reductio >5 mm 13 (43) Stability +/ 5 mm 6 (20) Progressio >5 mm 5 (17) Ukow 6 (20) New lesios (%) No 15 (50) Yes 9 (30) Ukow 6 (20) Overall respose (%) Regressio (size reductio >5 mm ad o ew lesios) 10 (33) Stability (size stability +/ 5 mm ad o ew lesios) 4 (13) Progressio (size progressio ad/or ew lesios) 10 (33) Ukow 6 (20) Dowstagig (6 patiets) Yes 3 (50) No 3 (50) These patiets did ot have imagig after TACE before trasplatatio. Table 5: Orthotopic liver trasplatatio. Patiets with OLT/Patiets listed for OLT 26/30 Mea waitig time i days (rage) 110 (4 460) Mila at trasplatatio (%) I 22 (85) Out 4 Progressio beyod Mila criteria 2 Failed dowstagig withi Mila criteria 2 criteria but 4 patiets (15%) exceeded Mila criteria; tumor growth from withi to beyod Mila criteria after beig listed was observed i 2 patiets, dowstagig failed i 2 others. These patiets were trasplated despite beig beyod Mila criteria either because the tumor was at the margi of the criteria or because of ucertaity about the maligat ature of some odules Pathology of Explated Livers. The histopathologic aalysis of the 26 explated livers showed complete tumoral ecrosis i 10 cases (42%) ad partial ecrosis i 15 cases (48%). The mea Edmodso score of patiets with viable cacer was 2,5/4. Microvascular ivasio was observed i 3 cases ad macrovascular ivasio i oe patiet. I the patiets trasplated exceedig Mila criteria just before OLT (4 cases), 1 had complete tumoral ecrosis (a successful dowstagig attempt) ad 3 patiets (75%) had HCC that remaied outside Mila criteria at pathological aalysis. I the 10 livers where complete HCC ecrosis was observed, 9 were withi Mila before trasplatatio. Seve patiets had a regressio of the tumor followig TACE, 2 had stable lesios, ad 1 had ew lesios idetified. Table 6: Characteristics of patiets with ad without cacer recurrece after OLT (mea follow-up 56 moths; rage: moths). No cacer recurrece Cacer recurrece 21 5 Tumor respose to TACE regressio/stability (%) 15 (71) Progressio 2 (10) 4 (80) Not evaluated 4 (19) 1 (20) Mila criteria before OLT (%) withi Mila 19 (90) 3 (60).1548 outside Mila 2 (10) 2 (40) Pathological tumor aalysis (%) complete ecrosis 10 (48) microscopic ivasio 0 3 (60).004 Mortality 2 (10) 4 (80).002 Oe sided P-values calculated usig the Fisher exact test Follow-Up. Table 6 summarizes patiets characteristics after OLT with a mea follow-up of 56 moths (rage: moths). At follow-up, we idetified 21 patiets (81%) without cacer recurrece ad 5 with cacer recurrece (19%). I patiets idetified with cacer recurrece, 3 (60%) had cacer i the trasplated liver ad 2 (40%) had lug metastasis. Mea time to recurrece was 13.8 moths (rage 6 22 moths). Patiets without cacer recurrece had more tumoral regressio/stability after TACE tha patiets with cacer recurrece (71% versus 0%; P =.051). I additio, patiets with o tumoral recurrece were almost all withi Mila criteria before trasplatatio (90%) as opposed to patiets with tumoral recurrece (60%). Therefore, Mila status was associated to a relative risk of cacer recurrece posttrasplatatio of 6.33 with a 95% CI ( ). Patiets with o cacer recurrece showed more complete ecrosis (48% versus 0%; P =.066) ad sigificatly less microscopic ivasio (0% versus 60%; P =.004) o pathological aalysis. Six patiets died (23%) at follow-up: 1 from postoperative complicatios, 4 from cacer recurrece, ad 1 from cirrhosis associated with hepatitis C 7 years posttrasplatatio (Figure 1). Therefore, survival of patiets with tumor recurrece was poor, mortality was sigificatly lower i patiets without cacer recurrece compared to patiets with cacer recurrece (10% versus 80%; P =.002) Subgroup Aalysis accordig to Mila Status. I the 4 patiets that exceeded Mila criteria before trasplatatio, 2 represeted a failed attempt at dowstagig ad cacer progressio was observed i 2. Three of the 4 patiets (75%) exceedig Mila at OLT had HCC discovered at histology. At follow-up, HCC recurrece was observed i 2 of these patiets (50%). Hece, beig outside Mila before OLT sigificatly icreased risk of cacer recurrece after OLT (RR: 6.33, 95% CI: ). I the 22 patiets withi Mila criteria before trasplatatio, 10 (45%) had complete HCC ecrosis ad all P

5 Iteratioal Joural of Hepatology 5 Survival (%) (moths) Cacer recurrece No cacer recurrece Figure 1: Cumulative proportio of patiets survivig after OLT (Kapla-Meier plot) with ad without cacer recurrece. The differece betwee the 2 groups was sigificat (P <.01; log rak test). remaiig HCC were withi Mila criteria at pathology. So far, 3 patiets (14%) had HCC recurrece after OLT. Five died (23%), 1 from postoperative complicatios, 3 from HCC recurrece, ad 1 from cirrhosis 7 years after OLT. 4. Discussio Hepatocellular carcioma represets a serious disease with a high mortality rate. Whe a tumor is cetrally located withi a uderlyig cirrhosis, the best treatmet is liver trasplatatio. However, tumoral size is a major determiat of eligibility for trasplatatio. Moreover, time waitig for a orga is associated with tumoral growth, which is resposible for most dropouts. Over the years, several approaches icludig TACE were used to limit tumoral growth i cirrhotic patiets o the waitig list ad hopefully tumor recurrece after trasplatatio. Some researchers stated that the respose to TACE could be used to predict risks of tumor recurrece after liver trasplatatio [15 18]. However, these studies are difficult to aalyse as they are either usig differet chemotherapeutic agets or do ot iclude a pathological aalysis of explated livers. Mila criteria are used i most trasplat ceters to select patiets eligible for liver trasplatatio. Exteded criteria are ucommoly used i some ceters, with the most recogized beig the Sa Fracisco criteria. It has also bee suggested that TACE ca be used to dowstage the tumor withi Mila criteria or withi Sa Fracisco criteria before trasplatatio [19 24]. The preset study reports our experiece with cirrhotic patiets with HCC who uderwet TACE ad who were listed for OLT betwee Jauary 1996 ad Jauary Oly patiets withi Mila criteria were eligible for trasplatatio. We aalysed retrospectively tumoral respose followig TACE treatmets, icidece of dropouts o the waitig list, histopathological characteristics of HCC o explated livers, ad evolutio of patiets after trasplatatio. Although a small umber of patiets were aalyzed, iterestig fidigs were observed. We cofirm that TACE ca ifluece tumoral growth i most patiets while waitig for trasplatatio. Fortyeight TACE i 30 patiets were performed: a decrease of tumoral size was observed i 13 patiets ad a icrease i 5 patiets. Twelve patiets had stable lesios. Therefore, amog 30 trasplat cadidates, 26 could be operated, with 4 beig dropped out (3 due to tumor progressio). Histopathological aalysis of the 26 explated liver showed complete ecrosis of HCC i 10, reiforcig the effectiveess of TACE treatmets. Subgroup aalysis of these patiets with o residual carcioma showed that 9 patiets (90%) were withi Mila before OLT ad that oe had cacer progressio observed after TACE treatmets. Despite our itet to trasplat oly patiets withi the Mila criteria, 4 patiets exceedig these criteria were operated. This emphasizes the difficulty to evaluate correctly the tumoral stage usig radiologic imagig. I these four patiets, the disease was thought to be at the margi of Mila criteria or the exact ature of some odules was falsely presumed to be beig. This difficulty of correctly evaluatig tumoral size ad extesio is observed i most trasplat ceters. As previously stated, TACE could be used either to limit tumoral growth withi Mila criteria or to dowstage HCC. I 6 patiets, dowstagig was attempted usig TACE before trasplatatio ad this was successful for 3 patiets (50%). I these patiets, the pathological aalysis either demostrated variable level of HCC ecrosis (2 patiets) or complete ecrosis of HCC (1 patiet). Follow-up after trasplatatio showed that oe of these 3 patiets had tumor recurrece or died. Such effective dowstagig withi the trasplat criteria usig TACE without icreasig the risk of cacer recurrece has also bee reported by other research teams [19 24]. Our results support the use of Mila criteria to select patiets for liver trasplatatio. Patiets withi Mila treatedwitholthadhighlevelsofecrosisohistopathological aalysis (45% did ot have residual HCC), very low rate of HCC recurrece (14%), ad low mortality rate durig follow-up (23%), which is i accordace with the literature [19, 20, 23, 24]. Patiets exceedig Mila before trasplatatio had little ecrosis o histopathological aalysis (75% had viable HCC), high rate of cacer recurrece, ad death withi 2 years of surgery. As show by others [15 18], the respose to TACE provides importat iformatio for the progosis after trasplatatio. A sigificat umber of patiets who did ot respod to TACE, eve if the tumor was still withi the Mila criteria, demostrated postoperative tumoral recurrece. This is best explaied by the aggressiveess of the tumor. Therefore, respose to TACE could be used as a additioal tool i order to better select patiets for trasplatatio [25]. The tolerace to TACE was rather good as previously reported [13] but several major complicatios occurred after

6 6 Iteratioal Joural of Hepatology TACE icludig acute trasiet hepatic isufficiecy, 1 ischemic cholecystitis, femoral artery thrombosis, ad spleic ifarctio; oly oe patiet died from sepsis ad acute hepato-real failure. These ecouragig results must be tempered by the fact that our populatio was small ad highly selected ad also by the possible adverse evets followig TACE. TACE was oly performed i patiets with good liver fuctio, patet portal vei, ad absece of sigificat portosystemic shutig. Therefore, our coclusios caot be extrapolated to a larger populatio. 5. Coclusio I coclusio, the preset study cofirms the usefuless of TACE as a bridge to liver trasplatatio i cirrhotic patiets with hepatocellular carcioma withi the Mila criteria ad also to dowstage some highly selected patiets. This approach is associated with a good survival rate ad a low rate of cacer recurrece. TACE was also well tolerated. These ecouragig results could be improved i the future by a better selectio of trasplat cadidates based o more accurate imagig techiques ad better assessmet of biological characteristics of HCC. Ackowledgmet The authors wat to thak Mrs. Mao Bourcier for editig the mauscript. Refereces [1] F. X. Bosch, J. Ribes, R. Cléries, ad M. Díaz, Epidemiology of hepatocellular carcioma, Cliics i Liver Disease, vol. 9, o. 2, pp , [2] H. B. El-Serag ad A. C. Maso, Risig icidece of hepatocellular carcioma i the Uited States, The New Eglad Joural of Medicie, vol. 340, o. 10, pp , [3] V. Mazzaferro, E. Regalia, R. Doci et al., Liver trasplatatio for the treatmet of small hepatocellular carciomas i patiets with cirrhosis, The New Eglad Joural of Medicie, vol. 334, o. 11, pp , [4] J. M. Llovet, J. Fuster, ad J. Bruix, Itetio-to-treat aalysis of surgical treatmet for early hepatocellular carcioma: resectio versus trasplatatio, Hepatology, vol. 30, o. 6, pp , [5] J. Figueras, E. Jaurrieta, C. 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