8.01.11 Transcatheter Arterial Chememblizatin t Treat Primary r Metastatic Liver Malignancies Sectin 8.0 Therapy Subsectin Descriptin Effective Date February 27, 2015 Original Plicy Date February 27, 2015 Next Review Date February 2016 Transcatheter arterial chememblizatin (TACE) f the liver is a prpsed alternative t cnventinal systemic r intra-arterial chemtherapy, and t varius nnsurgical ablative techniques, t treat resectable and nnresectable tumrs. TACE cmbines the infusin f chemtherapeutic drugs with particle emblizatin. Tumr ischemia secndary t the emblizatin raises the drug cncentratin cmpared with infusin alne, extending the retentin f the chemtherapeutic agent and decreasing systemic txicity. The liver is especially amenable t such an apprach, given its distinct lbular anatmy, the existence f 2 independent bld supplies, and the ability f healthy hepatic tissue t grw and thus cmpensate fr tissue mass lst during chememblizatin. Related Plicies Crysurgical Ablatin f Primary r Metastatic Liver Tumrs Liver Transplant Micrwave Tumr Ablatin Radiemblizatin fr Primary and Metastatic Tumrs f the Liver Radifrequency Ablatin f Miscellaneus Slid Tumrs Excluding Liver Tumrs Radifrequency Ablatin f Primary f Metastatic Liver Tumrs Plicy Transcatheter hepatic arterial chememblizatin may be cnsidered medically necessary fr treatment f any the fllwing: Hepatcellular cancer when all f the fllwing are met: Hepatcellular cancer is unresectable but cnfined t the liver Patient is nt a candidate fr liver transplantatin* (see exceptin belw) Nt assciated with prtal vein thrmbsis Hepatcellular cancer as a bridge t transplant* when all f the fllwing are met: Intent is t prevent further tumr grwth and t maintain a patient s candidacy fr liver transplant Presence f hepatic tumr(s) meeting ne f the fllwing: Single tumr less than r equal t 5 cm 1
Presence f n mre than three tumrs each less than three cm in size Absence f extrahepatic disease r vascular invasin Child-Pugh scre f either A r B Liver metastases frm neurendcrine tumr when all f the fllwing criteria are met: Patient has symptmatic disease (e.g., wheezing, flushing f the skin, abdminal cramps, diarrhea, heart disease) Systems persist despite systemic therapy (e.g., Octretide therapy) Patient is nt a candidate fr hepatic surgical resectin Liver metastasis frm liver-dminant metastatic uveal (cular) melanma Transcatheter hepatic arterial chememblizatin is cnsidered investigatinal fr treatment f any f the fllwing: As neadjuvant r adjuvant therapy in hepatcellular cancer that is cnsidered resectable Hepatcellular tumrs prir t liver transplantatin except as indicated in the medically necessary criteria abve Hepatcellular cancer nt meeting the medically necessary criteria abve, including recurrent Hepatcellular cancer Liver metastases frm any ther types f tumrs with the exceptin f neurendcrine tumr r liver-dminant metastatic uveal (cular) melanma Unresectable chlangicarcinma Plicy Guidelines Dwnstaging (dwnsizing) therapy is used t reduce the tumr burden in selected patients with mre advanced HCC (withut distant metastasis) that are beynd the accepted transplant criteria. Child-Pugh Scre - Objective classificatin f perative risk in the setting f HCC based upn chemical and bichemical parameters. Class A: Gd perative risk Class B: Mderate perative risk Class C: Pr perative risk Neurendcrine Tumrs Neurendcrine tumrs (NETs) may be referred t by their anatmical lcatin (e.g., pulmnary neurendcrine tumr, gastrenterpancreatic neurendcrine tumr). Neurendcrine tumrs include the fllwing: Carcinid tumrs Islet cell tumrs (r pancreatic endcrine tumrs) Neurendcrine unknwn primary Adrenal gland tumrs 2
Phechrmcytma/paraganglima Prly differentiated (high grade r anaplastic)/small cell Multiple endcrine neplasia, Type 1 (als knwn as MEN-1 syndrme r Wermer's syndrme) Multiple endcrine neplasia, Type 2 a r b (als knwn as phechrmcytma and amylid prducing medullary thyrid carcinma, PTC syndrme, r Sipple syndrme) Symptmatic disease frm neurendcrine tumrs may include ht, red flushing f the face, severe and debilitating diarrhea, asthma attacks, palpitatins, lw bld pressure, fatigue, dizziness, and weakness. Extreme symptms may include heart disease, brnchial cnstrictin, and bwel bstructin. Systemic therapies fr neurendcrine tumrs vary depending n the lcatin and characteristics. Therapies may include, but are nt limited t: ctretide, interfern, cyttxic chemtherapy, angigenesis inhibitrs, and epidermal grwth factr inhibitrs. Cding One f the fllwing CPT cdes may be used t describe the TACE prcedure: 37243: Vascular emblizatin r cclusin, inclusive f all radilgical supervisin and interpretatin, intraprcedural radmapping, and imaging guidance necessary t cmplete the interventin; fr tumrs, rgan ischemia, r infarctin (new cde 1/1/14) 75894: Transcatheter therapy, emblizatin, any methd, radilgical supervisin and interpretatin (Nte: this cde cannt be reprted with cde 37243) The fllwing HCPCS cde may be used t describe chemtherapy administratin/chememblizatin: Q0083: Chemtherapy administratin by ther than infusin technique nly Benefit Applicatin Benefit determinatins shuld be based in all cases n the applicable cntract language. T the extent there are any cnflicts between these guidelines and the cntract language, the cntract language will cntrl. Please refer t the member's cntract benefits in effect at the time f service t determine cverage r nncverage f these services as it applies t an individual member. Sme state r federal mandates (e.g., Federal Emplyee Prgram (FEP)) prhibit Plans frm denying Fd and Drug Administratin (FDA) - apprved technlgies as investigatinal. In these instances, plans may have t cnsider the cverage eligibility f FDA-apprved technlgies n the basis f medical necessity alne. Ratinale Backrund Transcatheter arterial chememblizatin (TACE) f the liver has been assciated with ptentially life-threatening txicities and cmplicatins, including severe pstemblizatin syndrme, hepatic insufficiency, abscess, r infarctin. TACE has been 3
investigated t treat resectable, unresectable, and recurrent HCC, chlangicarcinma, liver metastases, and in the liver transplant setting. Treatment alternatives include resectin when pssible, chemtherapy administered systemically r by hepatic artery infusin (HAI). HAI invlves cntinuus infusin f chemtherapy with an implanted pump, while TACE is administered episdically. Als, HAI des nt invlve the use f emblic material. The TACE prcedure requires hspitalizatin fr placement f the hepatic artery catheter and wrkup t establish eligibility fr chememblizatin. Befre the prcedure, the patency f the prtal vein must be demnstrated t ensure an adequate psttreatment hepatic bld supply. With the patient under lcal anesthesia and mild sedatin, a superselective catheter is inserted via the femral artery and threaded int the hepatic artery. Angigraphy is then perfrmed t delineate the hepatic vasculature, fllwed by injectin f the emblic chemtherapy mixture. Emblic material varies but may include a viscus cllagen agent, plyvinyl alchl particles, r ethidized il. Typically, nly 1 lbe f the liver is treated during a single sessin, with subsequent emblizatin prcedures scheduled frm 5 days t 6 weeks later. In additin, because the emblized vessel recanalizes, chememblizatin can be repeated as many times as necessary. The mst recent literature review was perfrmed fr the perid f August 2013 thrugh September 17, 2014. The fllwing is a summary f key findings t date. This plicy was riginally based n a 2000 TEC Assessment 1 that ffered the fllwing bservatins and cnclusins: Five randmized trials fcused n the use f transcatheter arterial chememblizatin (TACE) t treat resectable hepatcellular carcinma (HCC), either in the adjuvant r neadjuvant setting. These trials reprted incnsistent results in terms f survival rates. Treatment-related mrbidity and mrtality were nt reprted cnsistently acrss studies. N randmized study fcused n TACE t treat pstperative recurrent HCC, and data were insufficient t permit scientific cnclusins n its effectiveness in this setting. Three randmized trials fcused n the use f TACE t treat unresectable HCC cmpared with supprtive care. Survival did nt differ significantly amng grups in any f the trials. There were n cntrlled trials fcusing n patients with unresectable hepatic metastases frm cln cancer. The utcmes f TACE in the available uncntrlled series appeared similar t utcmes reprted f hepatic artery infusin and systemic chemtherapy. The available data als did nt shw superirity fr either TACE r alternatives with respect t cmplicatin rates r treatment-related mrtality. There were n cntrlled trials cmparing TACE with alternatives in the treatment f hepatic metastases frm carcinid r islet cell tumrs. While 3 case series reprted that TACE reduced symptms due t excess hrmne prductin, there was n infrmatin regarding the efficacy f medical management t cntrl symptms. Data were als inadequate t permit cnclusins regarding tumr respnse rates and survival. The rle f TACE in the management f patients with HCC wh are awaiting liver transplantatin is an indicatin that was nt addressed in the 2000 TEC Assessment. 4
TACE fr Unresectable HCC Since the 2000 TEC Assessment, additinal randmized, cntrlled trials (RCTs) have cmpared TACE t cnservative (i.e., symptmatic) treatment in patients with unresectable HCC, as well as TACE versus systemic chemtherapy. Several case series and a chrt study are als utlined in the fllwing sectins. A 2011 systematic review included 9 trials with 645 patients treated with TACE r transarterial emblizatin fr unresectable HCC. 2 Six f these trials cmpared TACE versus cntrl. The review cncluded that all f the trials suffered frm bias, larger trials shuld be cnducted and that, despite the fact that TACE has been advcated as standard lcreginal treatment, there was n firm evidence t supprt r refute the use f TACE in patients with unresectable HCC. Als in 2011, Xie et al reprted n a meta-analysis f 13 studies n treatment fr unresectable HCC using chememblizatin (1233 patients) r micrsphere emblizatin (597 patients, using a glass r resin hepatic artery infusin). 3 Micrsphere emblizatin treatment was fund t result in statistically significant lnger verall survival (OS) (hazard rati [HR], 0.73; 95% cnfidence interval [CI]: 0.60 t 0.88; p<0.001) and time t prgressin (HR=0.61; 95% CI: 0.41 t 0.89; p=0.01) than chememblizatin. Hwever, this meta-analysis included uncntrlled bservatinal studies, which limits interpretatin. Tw randmized studies cmparing TACE with cnservative treatment enrlled cnsecutive patients wh met study criteria fr unresectable HCC frm amng larger series f patents seeking treatment at the respective institutins. 4,5 Patients in the L et al study 5 tended t have mre advanced disease based n Okuda stage, Eastern Cperative Onclgy Grup (ECOG) Perfrmance Status, and presence f tumrrelated symptms. The studies used a similar emblizatin regimen (lipidl and gelatin spnge) but different cyttxic agents (dxrubicin r cisplatin). Bth studies reprted significantly increased respnse and OS rates fllwing treatment with TACE. In the L study, the chememblizatin grup received a ttal f 192 curses f chememblizatin with a median f 4.5 (range, 1-15) curses per patient. Chememblizatin resulted in a marked tumr respnse, and the actuarial survival was significantly better in the TACE grup (1 year, 57%; 2 years, 31%; 3 years, 26%) than in the cntrl grup (1 year, 32%; 2 years, 11%; 3 years, 3%; p=0.002). After adjustments fr baseline variables that were prgnstic n univariate analysis made with a multivariate Cx mdel, the survival benefit f chememblizatin remained significant (relative risk [RR] f death, 0.49; 95% CI: 0.29 t 0.81; p=0.006). In the Llvet et al study, 4 patients received arterial emblizatin with gelatin spnge, TACE, r cnservative therapy. The trial was stpped when it was shwn that chememblizatin had survival benefits cmpared with cnservative treatment (HR f death, 0.47; 95% CI: 0.25 t 0.91; p=0.025). Survival prbabilities at 1 year and 2 years were 75% and 50% fr emblizatin; 82% and 63% fr chememblizatin, and 63% and 27% fr the cntrl grup (chememblizatin vs. cntrl, p=0.009), all respectively. Neither the L nr the Llvet study reprted an increase in serius r life-threatening treatment-related adverse events (AEs) after TACE. A randmized cntrlled trial cmpared TACE versus systemic chemtherapy fr patients with unresectable HCC. 6 Mabed et al randmized 100 patients t be treated with either TACE r intravenus dxrubicin. Fifty patients were treated with TACE using lipidl, dxrubicin, and cisplatin, and 50 patients were treated with systemic dxrubicin alne. A significantly higher respnse rate was seen in patients treated with TACE, with a partial respnse (PR) achieved in 32% versus 10% f patients in the chemtherapy arm (p=0.007). A significantly mre favrable tumr respnse t TACE was bserved in patients with a single lesin (p=0.02), Child class A (p=0.007), Okuda stage 1 (p=0.005), 5
and α-fetprtein less than 400 ng/ml (p<0.001). The prbability f tumr prgressin was significantly lwer with TACE, where the median prgressin-free survival (PFS) was 32 weeks (range, 16-70 weeks) versus 26 weeks (range, 14-54 weeks) fr patients treated with systemic chemtherapy (p=0.03). The median OS did nt differ significantly in cases treated with TACE (38 weeks) versus thse treated with chemtherapy (32 weeks) (p=0.08), except fr patients with serum albumin greater than 3.3 g/dl (60 vs. 36 weeks; p=0.003). Mrtality in the chememblizatin arm was due t tumr prgressin in 53% f patients, liver failure in 32%, and gastrintestinal tract bleeding in 15%. Mrtality in the chemtherapy arm was due t tumr prgressin in 64% f patients, liver failure in 25%, and gastrintestinal bleeding in 11%. Treatment-related mrtality was 4% in the TACE arm versus 0% in the chemtherapy arm. The authrs cncluded that the OS benefits f TACE and systemic dxrubicin were similar fr patients with unresectable HCC amenable t either treatment and that it is necessary t ptimize the risk/benefit rati f TACE and select the prper patient ppulatin that may benefit frm this prcedure. Takayasu et al reprted results frm an 8-year prspective chrt study f TACE frm Japan. 7 In this study, 8510 patients with unresectable HCC underwent TACE using emulsin f lipidl and anticancer agents fllwed by gelatin spnge particles as an initial treatment. Exclusin criteria were extrahepatic metastases and/r any previus treatment befre the present TACE. The mean fllw-up perid was 1.77 years. Fr OS rates by TACE, median and 1-, 3-, and 5-year survivals were 34 mnths, 82%, 47%, and 26%, respectively. The multivariate analyses shwed significant difference in degree f liver damage (p<0.001), α-fetprtein value (p<0.001), maximum tumr size (p<0.001), number f lesins (p<0.001), and prtal vein invasin (p<0.001). The TACE-related mrtality rate after the initial therapy was 0.5%. A large chrt study frm Biselli et al reprted n 56 cirrhtic patients with unresectable HCC underging at least 1 curse f TACE wh were matched 1:1 fr sex, age (in 5-year perids), parameters f Child-Pugh scre, Okuda stage, and tumr type with a cntrl grup that had received nly supprtive care. 8 The 2 grups were cmparable fr cause f cirrhsis; α-fetprtein serum levels and Cancer f the Liver Italian Prgram (CLIP) scre. The 56 patients in the TACE grup received a ttal f 123 treatment curses. Survival rates at 12, 24, and 30 mnths in patients receiving TACE were 74.3%, 52.1%, and 38.8%, respectively, with a median survival time f 25 mnths, whereas in supprtive-care patients, the rates were 39.4%, 25.4%, and 19%, respectively, with a median survival time f 7 mnths (p<0.001). At univariate analysis, TACE, tumr type, presence f ascites, α- fetprtein serum level, CLIP scre, and Okuda stage were assciated significantly with survival. Only TACE and CLIP scre prved t be independent predictrs f survival at multivariate analysis. In a prspective study frm a single center in Canada, Mlinari et al reprted n the effectiveness f TACE fr HCC in a Nrth American ppulatin. 9 Child-Pugh A cirrhsis r better patients with unresectable HCC and withut radilgic evidence f metastatic disease r segmental prtal vein thrmbsis were assessed between Nvember 2001 and May 2004. Of 54 patients wh satisfied the inclusin criteria, 47 underwent 80 TACE sessins. Chememblizatin was carried ut using dxrubicin and lipidl fllwed by an injectin f emblic particles, when necessary. Repeat treatments were carried ut at 2- t 3-mnth intervals fr recurrent disease. The survival prbabilities at 1, 2, and 3 years were 76.6%, 55.5%, and 50%, respectively. At 6 mnths after the first interventin, 31% f patients had a PR and 60% had stable disease. Majr AEs ccurred after 20% f sessins, including 2 treatment-related deaths (4% f patients). The authrs cncluded that these survival prbabilities at 1 and 2 years after TACE were cmparable with results in randmized studies frm Eurpe and Asia. 6
TACE fr Resectable HCC as Neadjuvant r Adjuvant Therapy Preperative TACE In 2013, Zhu et al reprted n a meta-analysis f 21 studies evaluating preperative TACE. 10 Included in the studies were 4 were RCTs and 17 nnrandmized studies with a ttal f 3210 patients. Preperative TACE was given t 1431 patients with the remaining 1779 serving as cntrls. In 18 studies, 5-year DFS fr preperative TACE ranged frm 7.0% t 57% and 8.0% t 48.8% in the cntrls. In 16 studies, the 5-year OS fr preperative TACE was 15.4% t 62.7% and 19.0% t 62.5% in the cntrls. In the pled analyses, there were n significant imprvements with preperative TACE versus cntrls in 5-year DFS (32.1% vs. 30.0%, p=0.17) and OS (40.2% vs. 45.2%, p=0.37). Intra- and extrahepatic recurrence were als nt significantly different in the pled analyses (51.2% vs. 53.6% and 12.9% vs10.3%, p=0.19, respectively). In 2009, Chua et al cnducted a systematic review f neadjuvant transarterial chememblizatin fr resectable HCC. 11 They evaluated 18 studies, including 3 randmized trials and 15 bservatinal studies, sme f which are utlined in detail in the fllwing sectin. The review cmprised 3927 patients, 1293 f whm underwent neadjuvant TACE. The cnclusins were that TACE culd be used safely and resulted in high rates f pathlgic respnses but did nt appear t imprve DFS in the TACE grup. N cnclusins culd be drawn with respect t OS differences between the TACE and nn-tace grups due t the hetergeneity f the results acrss studies. Frm July 2001 t December 2003, Zhu et al randmized 108 patients with resectable HCC ( 5 cm suitable fr a partial hepatectmy) t preperative TACE treatment (n=52) r n preperative treatment (cntrl grup) (n=56). 12 Five patients (9.6%) in the preperative TACE grup did nt receive surgical therapy because f extrahepatic metastasis r liver failure. The preperative TACE grup had a lwer resectin rate (n=47 [90.4%] vs. n=56 [100%]; p=0.017), and lnger perative time (mean, 176.5 minutes vs. 149.3 minutes; p=0.042). N significant difference was fund between the 2 grups in mrtality. At a median fllw-up f 57 mnths, 41 (78.8%) f 52 patients in the preperative TACE grup and 51 (91.1%) f 56 patients in the cntrl grup had recurrent disease (p=0.087). The 1-, 3-, and 5-year DFS rates were 48.9%, 25.5%, and 12.8%, respectively, fr the preperative TACE grup and 39.2%, 21.4%, and 8.9%, respectively, fr the cntrl grup (p=0.372). The 1-, 3-, and 5-year OS rates were 73.1%, 40.4%, and 30.7%, respectively, fr the preperative TACE grup and 69.6%, 32.1%, and 21.1%, respectively, fr the cntrl grup (p=0.679). Preperative TACE did nt imprve surgical utcme and resulted in drp-ut frm definitive surgery because f prgressin f disease and liver failure. Kaibri et al reprted n a trial f 124 patients randmized t receive preperative tumr-targeted TACE (42 patients), whle-liver TACE (39 patients), r n TACE (43 patients) befre surgical resectin fr HCC. 13 N significant differences were fund between the pled preperative TACE grups and the cntrl grup in DFS (p=0.660) r OS (p=0.412). Nr were there significant differences between the 3 grups in DFS (p=0.830) r OS (p=0.713). DFS at 1 and 3 years fr the tumr-targeted TACE grup was 67% and 29%, 63% and 27% fr the whle-liver TACE grup, and 53% and 32% fr the cntrl grup. OS at 1 and 3 years fr the tumr-targeted TACE grup was 91% and 80%, 84% and 70% fr the whle-liver TACE grup, and 83% and 60% in the cntrl grup. Zhang et al retrspectively analyzed the therapeutic results f 1457 HCC patients treated with hepatectmy, 120 f whm had received TACE befre surgical resectin. 14 They shwed that the 5-year DFS rates f the patients wh received mre than 2 sessins f TACE, thse wh received 1 sessin f TACE, and n TACE patients were 51.0%, 35.5%, 7
and 21.4%, respectively, and that the mean DFS times f the 3 grups were 66.4, 22.5, and 12.5 mnths, respectively. They cncluded that effective preperative TACE may be ne f the best methds that can be clinically perfrmed at present fr resectable HCC, including small HCC, fr imprving DFS after hepatectmy. On the ther hand, Chi et al studied 273 patients wh underwent curative resectin fr HCC, 120 f whm underwent preperative TACE. The 1-, 3-, and 5-year DFS rates were 76.0%, 57.7%, and 51.3%, respectively, in the TACE grup and 70.9%, 53.8%, and 46.8%, respectively, in the nn- TACE grup. Althugh a difference was nted between the TACE and nn-tace grups, it was nt significant. 15 Pstperative TACE Li et al described the results f their randmized study explring the efficacy f pstperative TACE and prtal vein chemtherapy (PVC) fr patients with HCC cmplicated by prtal vein tumr thrmbsis (PVTT) and t evaluate prgnstic factrs. 16 The study chrt cnsisted f 112 patients with HCC and PVTT randmly divided int 3 grups: grup A (37 patients), surgery nly; grup B (35 patients), peratin plus TACE; grup C (40 patients), peratin plus TACE and PVC. Prtal vein thrmbus extirpatin was perfrmed at the time f surgery. AEs and cmplicatins were mstly related t the peratin, catheters, and lcal chemtherapy and included liver decmpensatin (15.0%), catheter bstructin (11.6%), and nausea and lss f appetite (22.1%). The DFS curve was significantly different amng the 3 grups, as estimated by the Kaplan-Meier methd (bth p<0.05). Grup C shwed a higher DFS rate than grup A (p<0.05), but n statistical differences were fund between grup A and grup B, r grup B and grup C (bth p>0.05). The 1-, 3-, and 5-year DFS rates in grup A (resectin nly, n=37) were 50.7, 17.8, and 0%, respectively; in grup B (resectin + TACE, n=35), rates were 62.3%, 23.7%, and 4.0%, respectively, and in grup C (resectin + TACE + PVC, n=40) increased t 74.4%, 46.1%, and 11.5%, respectively. Tumr size, tumr number, PVTT lcatin, and treatment mdalities were independent prgnstic factrs (p<0.05). The authrs cncluded that pstperative TACE cmbined with PVC may benefit the survival f patients with HCC cmplicated by PVTT in the shrt-term (<60 mnths), but lng-term efficacy is nt yet certain and needs t be cnfirmed by further studies. TACE as a Bridge t Liver Transplant TACE has been explred in varius settings: as a technique t prevent tumr prgressin in patients n the liver transplant waiting list, t dwnstage tumrs such that the patient is cnsidered a better candidate fr liver transplantatin, and t decrease the incidence f psttransplant recurrence in patients with larger (T3) tumrs. All f these indicatins are in part related t the United Netwrk fr Organ Sharing (UNOS) liver allcatin plicy, which priritizes patients fr receiving dnr livers. The UNOS plicy and the previus 3 indicatins are discussed further in the fllwing sectins. UNOS Liver Allcatin Plicy 17 In 2002, UNOS intrduced a new liver allcatin system, mdel fr end-stage liver disease (referred t as MELD) fr adult patients awaiting liver transplant. The MELD scre is a cntinuus disease severity scale incrprating bilirubin, prthrmbin time (i.e., internatinal nrmalized rati [INR]), and creatinine int an equatin, prducing a number that ranges frm 6 (less ill) t 40 (gravely ill). Aside frm thse in fulminant liver failure, dnr livers are priritized t thse with the highest MELD number. This scale accurately predicts the risk f dying frm liver disease except fr thse with HCC, wh ften have lw MELD scres, because bilirubin, INR, and creatinine levels are near nrmal. Therefre, patients with HCC are assigned additinal allcatin pints accrding t the size and number (T stage) f tumr ndules as fllws: 8
T1: 1 ndule greater than 1 cm and1.9 cm r smaller T2: 1 ndule between 2.0 and 5.0 cm, r 2 r 3 ndules each 1cm r greater and up t 3.0 cm T3: 1 ndule larger than 5.0 cm, r 2 r 3 ndules with at least 1 larger than 3.0 cm In cnsidering hw t allcate the scarce dnr rgans, UNOS sught t balance risk f death n the waiting list against risk f recurrence after transplant. Patients with T1 lesins are cnsidered at lw risk f death n the waiting list, while thse with T3 lesins are at high risk f psttransplant recurrence and are generally nt cnsidered transplant candidates. Patients with T2 tumrs have an increased risk f dying while n the waiting list cmpared with thse with T1 lesins, and an acceptable risk f psttransplant tumr recurrence. Therefre, UNOS criteria, which were updated in 2013, priritize nly T2 HCC that meet specified staging and imaging criteria by allcating additinal pints equivalent t a MELD scre predicting a 15% prbability f death within 3 mnths. This definitin f T2 lesins is ften referred t as the Milan criteria, in reference t a key 1996 study that examined the recurrence rate f HCC accrding t the size f the initial tumr. 18 Nte that liver transplantatin fr thse with T3 HCC is nt prhibited, but these patients d nt receive any pririty n the waiting list. All patients with HCC awaiting transplantatin are reassessed at 3-mnth intervals. Thse whse tumrs have prgressed and are n lnger T2 tumrs will lse the additinal allcatin pints. Additinally, ndules identified thrugh imaging f cirrhtic livers are given an OPTN (Organ Prcurement and Transplantatin Netwrk) class 5 designatin. Class 5B and 5T ndules are eligible fr autmatic pririty. Class 5B criteria cnsist f a single ndule 2 cm r larger and up t 5 cm (T2 stage) that meets specified imaging criteria. Class 5T ndules have undergne subsequent lcreginal treatment after being autmatically apprved n initial applicatin r extensin. A single class 5A ndule (>1 cm and <2 cm) crrespnds t T1 HCC and des nt qualify fr autmatic pririty. Hwever, cmbinatins f Class 5A ndules are eligible fr autmatic pririty if they meet stage T2 criteria. Class 5X lesins are utside f stage T2 and are nt eligible fr autmatic exceptin pints. Ndules less than 1 cm are cnsidered indeterminate and are nt cnsidered fr additinal pririty. Therefre, the UNOS allcatin system prvides strng incentives t use lc-reginal therapies t dwnsize tumrs t T2 status and t prevent prgressin while n the waiting list. A 2010 reprt f a natinal cnference n liver allcatin in patients with HCC in the United States addressed the need t better characterize the lng-term utcmes f liver transplantatin fr patients with HCC and t assess whether it is justified t cntinue the plicy f assigning increased pririty fr candidates with early-stage HCC n the transplant waiting list in the United States. 19 At the cmpletin f the meeting, there was a general cnsensus fr the develpment f a calculated cntinuus HCC pririty scre fr ranking HCC candidates n the list that wuld incrprate the calculated MELD scre, α-fetprtein, tumr size, and rate f tumr grwth and that nly candidates with at least stage T2 tumrs wuld receive additinal HCC pririty pints. The reprt addressed the rle f lcreginal therapy t dwnstage patients frm T3 t T2 and stated that the results f dwnstaging befre liver transplantatin are hetergeneus, with n upper limits fr tumr size and number befre dwnstaging acrss studies, and the use f different end pints fr dwnstaging befre transplantatin. TACE as a Technique t Prevent Tumr Prgressin While n the Waiting List Several studies have reprted drput rates f waiting-listed patients treated with lcreginal therapy. Hwever, lacking cntrlled data, it is difficult t assess cntributins f lcreginal therapy t time n the waiting list. In additin, in 2002, as 9
discussed here, UNOS revised its liver allcatin plicy, such that wait times fr patients with HCC meeting the Milan criteria have nw declined. Given these limitatins, the fllwing case series have been reprted. Graziadei et al reprted n 48 patients with HCC awaiting transplantatin; all underwent TACE every 6 t 8 weeks until a cmplete respnse r a dnr rgan became available. 20 Nne was remved frm the list due t tumr prgressin, and mean waiting time was 178 (±105) days. Maddala et al studied the drput rates f 54 patients receiving TACE while awaiting transplantatin. 21 During a median waiting time f 211 days (range, 28-1099 days), the drput rate was 15%. Mre recently, Fisher et al reprted n 33 patients wh received multimdality ablatin therapy, cnsisting primarily f radifrequency ablatin (RFA) r TACE. Five patients (12%) were remved frm the waiting list after waits f 5 t 14 mnths. 22 In this prtcl, patients with tumrs larger than 5 cm were nt cnsidered transplant candidates until the tumr was cmpletely ablated using TACE, RFA, r anther technique. Yamashiki et al reprted n 288 patients given varius ablative therapies; the drput rate due t tumr prgressin at 1 and 3 years was 6.25 and 23%, respectively. Tumrs larger than 3 cm affected the drput rate due t tumr prgressin. 23 Obed et al reprted n 20 patients with nnprgressin f lesins after TACE wh had liver transplantatin; median survival in this grup was 92.3 mnths. 24 TACE t Dwnstage HCC Prir t Transplant/Reduce Recurrence Rates in Thse With T3 Lesins Published literature reflects an nging discussin as t whether the UNOS allcatin criteria shuld expand t include patients with larger tumrs. 19 Sme patients with T3 lesins apparently are cured with liver transplant, althugh mst experience recurrent tumr. Fr example, in the seminal 1996 study, 18 the 4-year recurrence-free survival (RFS) was 92% in thse wh met the Milan criteria (T2 lesin) cmpared with 59% in thse wh did nt; additinal studies cnfirm this difference in RFS rate. 25 Hwever, ther institutins have reprted similar utcmes with expanded criteria. Fr example, Ya et al at University f Califrnia at San Francisc (UCSF) reprted similar RFS after transplant in patients with T2 and a subset f thse with T3 tumrs. This T3 subset was defined as a single lesin 6.5 cm r smaller r n mre than 3 lesins with nne greater than 3 cm and with a sum f tumr diameters 8 cm r smaller. These expanded criteria are knwn as the UCSF criteria. 26 Lewandwski et al cmpared radiemblizatin with chememblizatin in the efficacy f dwnstaging 86 patients with HCC frm stage T3 t T2. 27 Patients were treated with either 90-yttrium micrspheres (n=43) r TACE (n=43). Median tumr size was similar between the 2 treatment grups (5.7 and 5.6 cm, fr TACE vs. radiemblizatin, respectively.) PR rates were 61% versus 37% fr radiemblizatin versus TACE, respectively, with dwnstaging frm T3 t T2 in 58% f patients treated with radiemblizatin versus 31% with TACE (p<0.05). The results and efficacy f dwnstaging with TACE t achieve a reductin in tumr burden t a T2 lesin remain cntrversial. There are retrspective data shwing the ability t dwnstage patients with TACE, hwever, there is n randmized evidence that tumr dwnstaging befre liver transplant cnfers a survival advantage. TACE fr Chlangicarcinma Intrahepatic chlangicarcinma (ICC) is the secnd mst cmmn primary liver malignancy after HCC (10% vs. 90%, respectively). Surgical resectin represents the nly frm f curative therapy; hwever, mst ICC patients are nt surgical candidates due t 10
their advanced disease at the time f diagnsis, which is caused by the lack f symptms until late in the disease. The verall prgnsis f ICC is far wrse than fr extrahepatic chlangicarcinma because f its late presentatin. Mst patients with ICC qualify fr palliative therapy, including systemic chemtherapy and raditherapy. Hwever, such palliative ptins affrd little t n survival imprvement ver supprtive therapy alne, as ICC respnds prly t such existing therapies. 28 The prgnsis fr patients with unresectable ICC is apprximately 5- t 8-mnth survival. In 2014 Behm et al reprted n a meta-analysis f 20 studies (N=657) n the hepatic artery therapies f TACE, hepatic artery infusin and Yttrium(90) fr ICC. 29 The median OS was lwest fr TACE and drug-eluting bead TACE (12.4 and 12.3 mnths, respectively) when cmpared with hepatic artery infusin (22.8 mnths) and Yttrium (90) (13.9 mnths). Cmplete and partial respnse t therapy was als lwest with TACE (17.3%) cmpared with Yttrium (90) (27.4%) and hepatic artery infusin (56.9%). Hwever, TACE had less grade III/IV txicity than hepatic artery infusin (0.26 vs. 0.35 events per patient, respectively). Park et al cnducted a retrspective review f the medical and imaging recrds f 155 patients with unresectable ICC wh were treated between 1996 and 2009 with TACE. 28 Patients wh had undergne previus lcal r systemic therapy were excluded. A ttal f 72 patients underwent TACE, and 83 received supprtive care, based n physician and patient preference. Supprtive care included pain and ascites cntrl and biliary drainage. Survival was the primary end pint. Baseline patient and tumr characteristics were well-balanced between the 2 grups. Mst patients had stage 3 r 4 disease. Tumr multiplicity was single and multiple r diffuse in 43% and 57% f the TACE patients, respectively, and 53% and 47% in the supprtive grup, respectively. Maximum tumr size in the TACE grup was 8.1±3.4 cm and 7.8±3.1 cm in the supprtive grup. The median number f sessins per patient in the TACE grup was 2.5 (range, 1-17 sessins). After TACE, the incidence f significant ( grade 3) hematlgic and nnhematlgic txicities was 13% and 24%, respectively, and n patients died within 30 days fllwing TACE. The Kaplan-Meier survival analysis shwed a median survival in the TACE grup f 12.2 mnths, versus a median f 3.3 mnths in the supprtive therapy grup (p<0.001). Survival rates als differed significantly between the 2 grups accrding t the presence r absence f extrahepatic metastases. In patients with liver-nly disease, the median survival perid was 13.3 mnths (95% CI: 9.2 t 17.4 mnths) fr the TACE grup and 4 mnths (95% CI: 3 t 5 mnths; p<0.001) fr the supprtive treatment grup. In patients with extrahepatic metastases, the median survival perid was 11.3 mnths (95% CI: 8.9 t 13.7 mnths) fr the TACE grup and 3.2 mnths fr the supprtive treatment grup (95% CI: 2.6 t 3.8 mnths; p<0.001). Knüppel et al reprted a retrspective review f 195 patients with intrahepatic (57%) r extrahepatic (43%) chlangicarcinma. 30 Patients received either chemtherapy r a cmbinatin f phtdynamic therapy r TACE with chemtherapy. Sme f the patients underwent surgical resectin. Patients wh nly received palliative care (n surgery) survived 9.8 mnths lnger with cmbinatin chemtherapy and TACE (n=14) versus chemtherapy alne (n=81) (median survival fr chemtherapy plus TACE 22.0 mnths vs. fr chemtherapy alne 12.2 mnths; p=0.039). Survival was nt reprted fr extrahepatic versus intrahepatic chlangicarcinma. Shen et al retrspectively cmpared 53 patients wh received TACE after surgical resectin f intrahepatic chlangicarcinma with 73 patients wh had surgical resectin withut TACE. 31 DFS rates at 1, 3, and 5 years (24.5%, 17.0%, and 17.0%, respectively) in the patients receiving TACE were nt significantly different frm the grup that did nt receive pstsurgical TACE [33.3%, 19.4%, and 15.3%, respectively 11
(p=0.659)]. OS rates were significantly better in the TACE grup at 1, 3, and 5 years (69.8%, 37.7%, and 28.3%, respectively) than the nn-tace grup [54.2%, 25.0%, and 20.8%, respectively (p=0.045)]. Hwever, the retrspective nature f this study limits interpretatin f its findings. Herber et al cnducted a retrspective study in 15 patients with inperable ICC treated with TACE between 2000 and 2006. 32 Nne f the patients had extrahepatic tumr spread. The decisin fr TACE was made by an interdisciplinary tumr bard in each individual case. Fifty-eight TACE sessins were perfrmed in the 15 patients (3.9±3.8; range, 1-15). Eight patients had unifcal tumr and 7 had multifcal disease. The mean tumr size was 10.8±4.6 cm (range, 2.0-18.0 cm). N deaths and n acute liver failure ccurred under TACE therapy. Majr cmplicatins were bserved in 2 patients, having anaphylactic shck wing t cntrast medium administratin in 1 and gastric ulceratin due t lipidl displacement in the secnd patient. Mean survival was 21.1 mnths (95% CI: 9.4 t 32.5 mnths). Burger et al prspectively cllected data n 17 patients with unresectable chlangicarcinma treated with TACE at their institutin between 1995 and 2004. 33 Amng the 17 patients, 11 presented withut any previus treatment, whereas 6 had received previus therapy including chemtherapy with r withut radiatin with evidence f prgressin. Fifteen patients had intrahepatic tumrs and 2 had perihilar tumrs. The prcedure was well-tlerated by 82% f the patients, wh experienced mild r n adverse effects that reslved with cnservative therapy alne. Tw patients had minr cmplicatins (12%), which were managed successfully, and 1 had a majr cmplicatin that resulted in a fatal utcme with a rapidly declining curse frm the time f diagnsis t death shrtly after TACE. Median survival fr the 17 patients was 23 mnths (95% CI: 15.4 t 30.6 mnths). Tw patients with previusly unresectable disease underwent successful resectin after TACE. TACE fr Hepatic Metastases Frm Neurendcrine Tumrs Neurendcrine tumrs are a hetergeneus grup that are typically slw-grwing tumrs with an indlent curse, with the capacity t synthesize and secrete hrmnes. Liver metastases may result in significant hrmnal symptms and are assciated with a pr prgnsis. Systemic chemtherapy fr these tumrs has shwn mdest respnse rates f limited duratin, and althugh smatstatin analgs are usually effective in cntrlling symptms, the disease eventually becmes refractry. Therefre, liverdirected therapies aim t reduce tumr burden t reduce hrmne levels and palliate symptms in patients with unresectable neurendcrine metastases t the liver. A 2010 review by Nazari and Gupta summarizes the experience t date with TACE (and transarterial emblizatin [TAE]), which is cmpsed f many nnrandmized, retrspective reprts that have demnstrated reduced tumr burden, reduced hrmne levels, and palliatin f symptms with these interventins. 34 The article summarizes the experience with TACE and TAE and metastatic neurendcrine tumrs as shwing radilgic respnse ranging frm 25% t 95%, and symptmatic respnse in 53% t 100% f patients. Five-year OS rates have varied frm 14% t 75%, likely a reflectin f the hetergeneity f the patient ppulatins and regimens f treatment used. Sme f the studies in the review are detailed next. Ruutiainen et al reprted n a study f 67 patients that cmpared bland emblizatin with TACE in neurendcrine tumrs metastatic t the liver. 35 In this study, 67 patients underwent 219 emblizatin prcedures: 23 patients received primarily bland emblizatin with plyvinyl alchl with r withut idized il and 44 primarily received chememblizatin with cisplatin, dxrubicin, mitmycin-c, idized il, and plyvinyl 12
alchl. Patients with disease relapse were treated again when feasible. Ten f 67 patients (15%) were lst t fllw-up. Txicities f grade 3 r wrse in severity ccurred after 25% f chememblizatin prcedures and 22% f bland emblizatin prcedures. Rates f freedm frm prgressin at 1, 2, and 3 years were 49%, 49%, and 35%, respectively, after chememblizatin and 0%, 0%, and 0%, respectively, after bland emblizatin, respectively (lg-rank test, p=0.16). Patients treated with chememblizatin and bland emblizatin experienced symptmatic relief fr means f 15 and 7.5 mnths, respectively (p=0.14). Survival rates at 1, 3, and 5 years after therapy were 86%, 67%, and 50%, respectively, after chememblizatin and 68%, 46%, and 33%, respectively, after bland emblizatin (p=0.18). The authrs cncluded that chememblizatin demnstrated trends tward imprvement in time t prgressin, symptm cntrl, and survival and indicated that a multicenter prspective randmized trial is warranted. These results are similar t thse reprted previusly by Gupta et al, wh nted that in a retrspective series f 81 patients, hepatic artery emblizatin r chememblizatin resulted in symptmatic and radigraphic respnse in mst patients with carcinid metastases t the liver. 36 Osbrne et al reprted n a nnrandmized study f 59 patients with neurendcrine tumrs wh received either cytreductin r emblizatin fr symptmatic hepatic metastases. 37 The duratin f symptm relief (35 vs. 22 mnths) and survival (43 vs. 24 mnths) bth favred the cytreductin apprach. The authrs cmmented that cytreductin shuld be pursued when pssible even if cmplete resectin may nt be achievable. TACE fr Hepatic Metastases Frm Uveal (Ocular) Melanma Uveal (cular) melanma is the mst cmmn primary cular malignancy in adults and shws a strng predilectin fr liver metastases. Even with successful treatment f the primary tumr, up t 50% f patients will subsequently develp systemic metastases, with liver invlvement in up t 90% f these patients. Metastatic uveal melanma is resistant t systemic chemtherapy, leading t the evaluatin f lcreginal treatment mdalities t cntrl tumr prgressin in the liver, including TACE. A 2010 review by Sat addresses the lcreginal management f hepatic metastases frm primary uveal melanma and summarizes the published studies t date, many f which are detailed in the fllwing sectin. 38 Huppert et al reprted the results f a pilt trial f 14 patients with hepatic metastases frm uveal melanma wh underwent TACE. 39 Patients received a mean f 2.4 treatments (34 ttal treatments amng the 14 patients). Respnses were partial fr 8 patients (57%). Fur patients (29%) had stable disease and 2 (14%) had tumr prgressin. Median time t prgressin was 8.5 mnths (range, 5-35 mnths), and median survival after the first TACE treatment was 14.5 mnths in respnders and 10 mnths in nnrespnders (p=ns). In this study, the survival rate was 86% at 6 mnths, 50% at 12 mnths, 28% at 18 mnths, and 14% at 24 mnths after the first TACE treatment. Survival advantage was mst prnunced fr patients with tumr ccupying less than 25% f the liver vlume (n=7) with a median f 17 mnths versus 11 mnths in the 7 patients with mre than 25% invlvement f the liver (p=0.02). The authrs state that, fr cmparisn, with n treatment, survival after detectin f liver metastases is 2 t 7 mnths with a median 1-year survival rate less than 30%. Respnse rates fr systemic chemtherapy are less than 10%, and 20% t 50% with immunchemtherapy, but with nly a median survival f 5 t 9 mnths and serius txicity. Sharma et al reprted n the use f TACE in the treatment f melanma metastatic t the liver reprted in a series f 20 patients (17 with cular melanma) treated between 13
2004 and 2007. 40 The 20 patients underwent 46 TACE sessins (mean, 2.4 sessins; range, 1-5). The mean and median OS times were 334 and 271 days, respectively. There were n deaths within 30 days f treatment. The authrs nted that this treatment resulted in lnger survival than has been nted amng histrical cntrls. This wrk builds n results reprted by Bedikien et al in 1995 that shwed that TACE had a 36% respnse rate (cisplatin chememblizatin) cmpared with a 1% respnse rate t systemic chemtherapy. 41 Patel et al reprted n BCNU treatment fr uveal melanma and demnstrated that thse wh respnded had imprved survival. 42 In this study, 18 f the 24 patients experienced regressin r stabilizatin f hepatic metastases fr at least 6 weeks. The verall respnse rates (cmplete respnses [CRs] and PRs) fr the intentin-t-treat ppulatin and fr patients wh were evaluable fr respnse were 16.7% and 20.4%, respectively. The median OS f the entire intentin-t-treat grup f patients was 5.2 mnths, fr patients with CR r PR in hepatic metastases it was 21.9 mnths, fr patients with stable disease, 8.7 mnths, and fr patients with prgressive disease, 3.3 mnths. Thus, fr patients with metastatic uveal melanma wh have disease cnfined t the liver, the metastatic liver disease may respnd t TACE treatment and patients wh respnd t TACE have imprved survival. TACE fr Hepatic Metastases Frm Clrectal Cancer Fr patients with liver metastases frm Clrectal Cancer (CRC) wh d nt qualify fr surgical resectin, traditinally, systemic chemtherapy is first-line treatment. Hwever, in mre than 60% f cases, the treatment fails and disease prgresses. Fr the large prprtin f patients in whm secnd- and third-fline medical treatment has failed, ther palliative therapies t cntrl disease prgressin and symptms have been studied, including TACE. 43 The literature has reprted a median survival in patients with liver-dminant clrectal metastases treated with chememblizatin frm 7 t 25 mnths. 44-46 Hwever, studies are difficult t cmpare, as sme patients wh were treated were still eligible fr systemic chemtherapy, and survival was smetimes calculated and reprted as a mean time frm the date f diagnsis f liver metastases rather than frm the first treatment with TACE. Vgl et al evaluated tumr cntrl and survival in 463 patients with unresectable liver metastases f clrectal rigin that did nt respnd t systemic chemtherapy and were treated with TACE. 47 Of the 463 patients, 67% had 5 r mre metastases, 8% had 1 metastasis, 10% had 2, and 14% had 3 r 4. Patients were treated at 4-week intervals, with a ttal f 2441 chememblizatin prcedures perfrmed (mean, 5.3 sessins per patient), using ne f 3 lcal chemtherapy prtcls. Lcal tumr cntrl was PR in 68 patients (14.7%), stable disease in 223 patients (48.2%), and prgressive disease in 172 patients (37.1%). Median survival frm the start f TACE treatments was 14 mnths (cmpared with the results frm a previus study by the same authr, in which untreated patients had a survival rate f 7 t 8 mnths). 48 One-year survival rate after TACE was 62% and 28%, respectively, at 2 years. N difference in survival was bserved between the 3 different lcal chemtherapy prtcls. Hng et al cmpared salvage therapy fr liver-dminant clrectal metastatic adencarcinma using TACE r 90-yttrium radiemblizatin. 43 Mean dminant lesin sizes were 9.3 cm and 8.2 cm in the chememblizatin and radiemblizatin grups, respectively. Multilbar disease was present in 67% and 87% f the respective grups, and extrahepatic metastases were present in 43% and 33%, respectively. Of 36 patients, 21 underwent TACE, with a median survival f 7.7 mnths (survival measured frm the 14
date f the first TACE treatment t the date f death r t April 2007, if still living). Survival results were cmparable with ther studies addressing CRC and TACE, which ranged frm 7 t 10 mnths. Median survival was 6.9 mnths fr the radiemblizatin grup (p=0.27). The 1-, 2-, and 5-year survival rates fr the 2 grups were 43%, 10%, and 0%, respectively, fr the chememblizatin grup and 34%, 18%, and 0%, respectively, fr the radiemblizatin grup. Richardsn et al reprted n a systematic review f 1 RCT and 5 bservatinal studies n TACE with irintecan-eluting beads fr unresectable clrectal liver metastasis. 46 Survival times ranged frm a median f 15.2 mnths t 25 mnths. The mst cmmn AE was pstemblizatin syndrme (abdminal pain, nausea, vmiting) fllwed by hypertensin. In the RCT included in the Richardsn systematic review, Firentini et al reprted n 74 patients randmly allcated t TACE with irintecan-eluting beads (n=36) r systemic irintecan, flururacil and leucvrin (n=38). 49 With irintecan-eluting beads, OS was significantly lnger with a median OS f 22 mnths (95% CI: 21 t 23 mnths) versus 15 mnths (95% CI: 12 t 18) fr the systemic chemtherapy grup (p=0.031). PFS was significantly lnger at 7 mnths (95% CI: 3 t 11) in the irintecan-eluting beads grup cmpared with 4 mnths (95% CI: 3 t 5) mnths in the systemic chemtherapy grup (p=0.006). Hwever, larger studies are needed t cnfirm these findings. TACE fr Hepatic Metastases Frm Breast Cancer Vgl et al reprted the efficacy f repeated treatments with TACE in 208 patients with unresectable hepatic metastases frm breast cancer. 50 A ttal f 1068 chememblizatins were perfrmed (mean, 5.1 sessins per patient; range, 3-25). Mean patient age was 56.4 years (range, 29-81). Patients received either 1 f 2 chemtherapeutic agents alne (mitmycin-c r gemcitabine) r in cmbinatin. Tumr respnse was evaluated by magnetic resnance imaging accrding t RECIST criteria. Fr all chemtherapy prtcls, lcal tumr cntrl was PF 13% (27/208), stable disease 50.5% (105/208), and prgressive disease 36.5% (76/208). The 1-, 2-, and 3-year survival rates after TACE were 69%, 40%, and 33%. Median and mean survival times frm the beginning f the TACE sessins were 18.5 and 30.7 mnths. Treatment with mitmycin-c nly shwed median and mean survival times f 13.3 and 24 mnths, and with gemcitabine nly 11 and 22.3 mnths. With a cmbinatin f mitmycin-c and gemcitabine, median and mean survival times were 24.8 and 35.5 mnths (all results are respectively). Onging and Unpublished Clinical Trials An nline search f ClinicalTrials.gv n September 18, 2014, identified several studies n TACE. A phase 3 trial is recruiting patients with unresectable HCC t be randmized t TACE with versus withut srafenib. (NCT01004978) Primary utcme measure is PFS, with secndary utcme measures including OS, anatmic patterns f failure, txicity and tumr respnse. Estimated enrllment is 400, with estimated trial cmpletin date September 2018. Srafenib with r withut TACE is als being evaluated in a phase 3 trial f 398 patients with an estimated cmpletin date f June 2016 (NCT01906216). In anther phase 3 trial, TACE with dxrubicin-eluting beads with r withut srafenib will be evaluated in 412 patients with an estimated cmpletin date f Nvember 2014 (NCT01324076). A phase 3 trial is recruiting patients with HCC with 1 lesin 5 cm r larger r multindular disease with 4 r mre lesins (at least ne >3 cm) t receive TACE with r withut brivanib as adjuvant treatment. (NCT00908752) Estimated enrllment is 870 and estimated study cmpletin date is September 2014. 15