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International audience; Purpose: To evaluate transarterial chemoembolization (TACE) use prior to and concomitantly with sorafenib in patients with unresectable hepatocellular carcinoma (HCC) across different global regions.Materials and Methods: GIDEON is an observational registry study of more than 3000 HCC patients. Patients with histologically, cytologically, or radiographically diagnosed HCC, and for whom a decision had been made to treat with sorafenib, were eligible. Patients were enrolled into the registry from 39 countries beginning in January 2009, with the last patient follow-up in April 2012. Detailed data on treatment history, treatment patterns, adverse events, and outcomes were collected. All treatment decisions were at the discretion of the treating physicians. Documented approval from local ethics committees was obtained, and all patients provided signed informed consent. Descriptive statistics, including minimum, median, and maximum, were calculated for metric data, and frequency tables for categorical data. Kaplan-Meier estimates with 95% confidence intervals were calculated for survival end points.Results: A total of 3202 patients were eligible for safety analysis, of whom 2631 (82.2%) were male. Median age was 62 years (range, 15-98 years). A total of 1511 (47.2%) patients underwent TACE prior to sorafenib; 325 (10.1%) underwent TACE concomitantly. TACE prior to sorafenib was more common in Japan and Asia- Pacific compared with all other regions (362 [71.3%] and 560 [60.3%] vs 12-209 [13.3%-37.1%]). Adverse events were reported in 2732 (85.3%) patients overall, with no notable differences in the incidence of adverse events, regardless of TACE treatment history. Overall survival was 12.7 months in prior-TACE patients, 9.2 months in non-prior-TACE patients, 21.6 months in concomitant-TACE patients, and 9.7 months in non-concomitant-TACE patients.Conclusion: Global variation exists in TACE use in sorafenib-treated HCC patients. The combination of TACE with sorafenib appears to be a well-tolerated and viable therapeutic approach.

To evaluate the pharmacokinetic profile (PK) and embolization effect of 70-150-μm doxorubicin eluting beads (DEBs) following intra-arterial injection (i.a.) in the rabbit liver VX2 tumour model.In this ACUC-approved study, 25 white New Zealand rabbits were randomly assigned into a small DEB group (SDB, n = 7, 70-150-μm DEBs), large DEB group (LDB, n = 7, 100-300-μm DEBs), untreated controls (n = 7), and doxorubicin controls (n = 4, without tumour, received i.a. 12.5 mg doxorubicin). Plasma PK was assessed up to 180 min post-injection. Drug tissue and liver enzyme levels, radiologic tumor response and histopathologic tumour necrosis were assessed at 7 days.Mean tumour doxorubicin concentrations were 922.83 nM (SD = 722.05) and 361.48 nM (SD = 473.23) for the SDB and LDB, respectively (p = 0.005). There was no statistically significant difference in tumour doxorubicinol, plasma doxorubicin and doxorubicinol PK values. More beads were observed in the SDB tumours (p = 0.01). Liver enzymes increased and gradually declined over the observation period, with significantly higher values in the SDB.In this preclinical study, plasma PK of i.a.-injected 70-150-μm DEBs was not different than that of 100-300-μm DEBs. More beads and higher tissue doxorubicin levels were observed in the SDB tumours.• Small and large doxorubicin-eluting beads show similar plasma pharmacokinetic profiles. • Higher tissue doxorubicin levels were observed in the small bead group. • Liver enzymes were overall significantly higher in the small bead group.

OBJECTIVES: To compare the effectiveness, survival and cost in patients with unresectable hepatic cell carcinoma (HCC) treated with trans-arterial chemoembolization using doxorubicin-eluting beads (DEB-TACE) versus conventional TACE (cTACE) in clinical practice. MATERIAL AND METHODS: This single-centered retrospective observational study compared 60 consecutive HCC unresectable patients: 30 were treated with DEB-TACE and 30 used cTACE. Comparisons were with chi(2) test, Student t-test, and Kaplan Meier method. RESULTS: Of the 60 patients with HCC in non-curative stage, baseline characteristics were similar for both groups of treatment, and of these we observed lower survival in male patients and those who had hepatitis C virus (p=0.014 and p=0.003, respectively). No statistically significant differences were observed as a function of treatment employed with respect to overall survival (OS) at 5 years (29.99 months; 95%CI: 21.38-38.60 versus 30.67 months; 95%CI:22.65-38.70; p=0.626) and progression free survival (PFS) median of 11.57 months (95%CI: 0.97-22.18) versus 12.80 months (95%CI:0.00-32.37; p=0.618). The median length of hospital admission were 2.6 and 5.4 days (p

Background and Aim Doxorubicin-eluting bead transarterial chemoembolization (DEB-TACE) is a novel locoregional treatment for unresectable hepatocellular carcinoma (HCC). However, to date, the benefits of DEB-TACE versus conventional transarterial chemoembolization (TACE) remain unclear. This meta-analysis was conducted to evaluate the efficacy and safety of the two treatments for patients with unresectable HCC. Methods We searched for relevant articles by means of computerized bibliographic search and complementary manual search. Objective tumor response, overall survival, and adverse events were then calculated and analyzed. Results A total of seven clinical studies with 700 participants were included in the current meta-analysis. Significantly better objective tumor response was found for DEB-TACE than for conventional TACE (OR = 1.92, 95% CI [1.34, 2.77]; P = 0.0004), with relative risk difference of 0.15 [0.07, 0.24] (P = 0.0003). One-year and 2-year survival rates were statistically significantly higher for DEB-TACE compared with conventional TACE (Peto OR, 95% CI: 0.64 [0.46, 0.89], P = 0.007; 0.61 [0.47, 0.80], P = 0.0003, respectively). Peto ORs of 6-month and 3-year survival were 0.72 [0.46, 1.14] (P = 0.16) and 0.77 [0.55, 1.06] (P = 0.11), respectively, showing no difference statistically. However, we could still find a tendency favoring DEB-TACE. Adverse side effects were similar in both groups, with postembolization syndrome occurring most commonly. Conclusions This meta-analysis shows that DEB-TACE provides significantly better tumor response compared with conventional TACE. One-year and 2-year survival are better with DEB-TACE. In addition, DEB-TACE is as safe as conventional TACE. Therefore, DEB-TACE is a better choice for HCC patients for whom curative treatments like liver transplantation and liver resection are not suitable.

The purpose of this study was to report on the 5-year survival of hepatocellular carcinoma (HCC) patients treated with DC Bead loaded with doxorubicin (DEB-DOX) in a scheduled scheme in up to three treatments and thereafter on demand.173 HCC patients not suitable for curable treatments were prospectively enrolled (mean age 70.4 ± 7.4 years). Child-Pugh (Child) class was A/B (102/71 [59/41 %]), Okuda stage was 0/1/2 (91/61/19 [53.2/35.7/11.1 %]), and mean lesion diameter was 7.6 ± 2.1 cm. Lesion morphology was one dominant ≤5 cm (22 %), one dominant5 cm (41.6 %), multifocal ≤5 (26 %), and multifocal5 (10.4 %).Overall survival at 1, 2, 3, 4, and 5 years was 93.6, 83.8, 62, 41.04, and 22.5 %, with higher rates achieved in Child class A compared with Child class B patients (95, 88.2, 61.7, 45, and 29.4 % vs. 91.5, 75, 50.7, 35.2, and 12.8 %). Mean overall survival was 43.8 months (range 1.2-64.8). Cumulative survival was better for Child class A compared with Child class B patients (p = 0.029). For patients with dominant lesions ≤5 cm 1-, 2-, 3-, 4-, and 5-year survival rates were 100, 95.2, 71.4, 66.6, and 47.6 % for Child class A and 94.1, 88.2, 58.8, 41.2, 29.4, and 23.5 % for Child class B patients. Regarding DEB-DOX treatment, multivariate analysis identified number of lesions (p = 0.033), lesion vascularity (p0.0001), initially achieved complete response (p0.0001), and objective response (p = 0.046) as significant and independent determinants of 5-year survival.DEB-DOX results, with high rates of 5-year survival for patients, not amenable to curative treatments. Number of lesions, lesion vascularity, and local response were significant independent determinants of 5-year survival.

Retrospective study to evaluate local tumor control and survival data after transcatheter arterial chemoembolization with doxorubicin eluting beads in the treatment of hepatocellular carcinoma. Between April 2007 and November 2008, a total of 47 patients (mean age 61,7 years; range 42-84 years) with hepatocellular carcinoma were treated with transcatheter arterial chemoembolization. In total 73 chemoembolization procedures were performed in superselective manner with microcatheter (mean 1,57 procedures per patient). The local chemoembolization protocol consisted of doxorubicin eluting beads mainly 300-500 micra but also 500-700 micra and 700-900 micra, to a maximum dose per session of 150 mg doxorubicin. Tumor response was evaluated with CT imaging. Change in tumor size was calculated and response was evaluated according to the European Association for the Study of the Liver (EASL) criteria. Survival from first chemoembolization was calculated in the subgroup treated between April 2007 and January 2008 (24 patients). Follow-up imaging was performed until January 2009 or patient death. Evaluation of tumor response resulted in complete response in 13 patients (27,7%), partial response in 15 patients (31,9%), stable disease in 9 patients (19,1%) and progressive disease in 10 patients (21,3%). The one year survival rate after chemoembolization in the 24-patient subgroup was 54%. Chemoembolization with doxorubicin eluting beads is a minimally invasive, safe and effective therapy option for palliative treatment of hepatocellular carcinoma.

Resume Objectifs Le but de notre etude etait de decrire la technique de chimio-embolisation par catheterisme trans-arteriel aux billes chargees a la doxorubicine et d'evaluer sa tolerance et son efficacite a court terme sur un petit nombre de patients. Materiel et methodes Notre etude retrospective a dure huit mois (de decembre 2007 a juillet 2008). Elle a eu lieu au centre hospitalier universitaire de Brest (France) dans les services de Radiologie et d'Hepato-gastro-enterologie (HGE) de l'Hopital de la Cavale Blanche. Nous avons effectue une chimioembolisation trans-arterielle aux billes chargees a la doxorubicine a neuf patients porteurs d'un carcinome hepatocellulaire dans un contexte de cirrhose alcoolique. Resultats 8 patients sur 9 ont beneficie d'une procedure complete (soit 88,9% de succes technique) et dans 100% des cas il n'y a eu aucune complication clinique ni de modification biologique en post embolisation immediate. A 4 semaines, il y a eu 7 cas de regression de plus de 30% de la taille du nodule tumoral, 6 cas de necrose tumorale complete, 2 cas de prise de contraste au sein du nodule (necrose tumorale partielle). Dans 3 cas (37,5%), il y a eu apparition de nouveaux nodules tumoraux. Conclusion La chimio-embolisation par catheterisme trans-arteriel utilisant les billes chargees a la doxorubicine constitue probablement une technique d'avenir pour le traitement palliatif des carcinomes hepatocellulaires (CHC). La technique est assez facile a realiser. Elle semble etre bien toleree par le patient tant sur le plan clinique que sur le plan biologique.

The purpose of this study was to evaluate the added role of a chemotherapeutic in transarterial chemoembolization (TACE) of intermediate-stage hepatocellular carcinoma (HCC). The issue is of major importance since, as suggested by recent evidence, hypoxia or incomplete devascularization of the tumor is a potent stimulator of angiogenesis, and there are not many papers supplying level one evidence confirming the value of a chemotherapeutic. The hypothesis was that since drug-eluting bead (DEB)-TACE is standardized and reproducible, a comparison with bland TACE can readily reveal the potential value of the chemotherapeutic. Two groups were randomized in this prospective study: group A (n = 41) was treated with doxorubicin DEB-TACE, and group B (n = 43) with bland embolization. Patients were randomized for tumor diameter. Patients were embolized at set time intervals (2 months), with a maximum of three embolizations. Tumor response was evaluated using the EASL criteria and alpha-fetoprotein levels. At 6 months a complete response was seen in 11 patients (26.8%) in the DEB-TACE group and in 6 patients (14%) in the bland embolization group; a partial response was achieved in 19 patients (46.3%) and 18 (41.9%) patients in the DEB-TACE and bland embolization groups, respectively. Recurrences at 9 and 12 months were higher for bland embolization (78.3% vs. 45.7%) at 12 months. Time to progression (TTP) was longer for the DEB-TACE group (42.4 +/- 9.5 and 36.2 +/- 9.0 weeks), at a statistically significant level (p = 0.008). In conclusion, DEB-TACE presents a better local response, fewer recurrences, and a longer TTP than bland embolization with BeadBlock. However, survival benefit and bland embolization with smaller particles must be addressed in future papers to better assess the clinical value.

Purpose To analyze the safety and efficacy of transarterial chemoembolisation (TACE) with doxorubicin loaded drug eluting beads (DEB) in the treatment of hepatocellular carcinoma (HCC) in a South East Asian population. Materials and Methods Between Feb 2008 to Nov 2011, 116 patients underwent 182 sessions of DEB-TACE. Excluding the patients with inadequate follow-up, 83 patients (60 males; 23 females; mean age 66.74 years) from the above cohort were included into the study. DEB-TACE was done with 100-300, 300-500 and/ 500-700 micron beads. Follow up CT or MRI were reviewed and treatment response classified as a complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) as per EASL (European Association for the Study of Liver) guidelines. Periprocedual clinical and laboratory data was also analyzed. The average pre-treatment tumor volume was 105 cc. The mean number of DEB-TACE sessions per patient was 1.7 (range; 1-5). The median duration of follow up was 6 months (range; 2-40). Results At one month, 68.7 % of patients showed an objective response (OR) with CR in 31.3%, PR in 37.3%, SD in19.2% and PD in 12% patients. Twelve and 25 patients were censored from the study at 3 and 6 months from the baseline, respectively. The CR, PR, SD and PD at 3 and 6 month follow- up were 43.7%, 33.8%, 12.6%, 9.8% and 53.4%, 31%, 3.4% and 12 % respectively. A sustained OR for at least 6 months was seen in 56.6% of patients. The mean baseline volume of CR tumors was lower compared to tumors showing other responses. PD was mostly due to appearance of new lesions while base line tumor volume showed measurable decrease in response to TACE. Tumors with marked arterial enhancement had statistically significant better objective response than those with only capillary phase blush as seen at angiography. The liver- function tests showed only transient post embolisation changes. The major complications were non-flow limiting arterial dissection in one (1.2%) and self limiting bile lakes in 3 (3.6%) with no procedure related mortality. Conclusion DEB-TACE is safe and effective in the treatment of HCC with good objective response.

multivariate Cox model for cumulative local recurrence rates, selective chemoembolization of the tumor-feeding arteries was a significant important factor in lower local recurrence rates (hazard ratio, 0.255; 95% CI: 0.089,0.731; P1⁄40.011). Conclusion: C-arm CT obtained at the proper hepatic artery or equivalent level can demonstrate most of the tumor-feeding arteries supplying HCCs in the caudate lobe.

Purpose To present our experience using HepaSphere™ microspheres (Biosphere Medical) loaded with Doxorubicin in patients with unresectable Hepatocellular Carcinoma and to compare this series with our precedent series of traditonal TACE: TACE with Lipiodol and Spongostan (340 pts treated from December 1991 to April 1996) and TACE with Lipiodol and Embosphere (46 pts treated from February 2000 to November 2005). Materials and Methods From December 2005 to June 2012, 165 patients (134 male, 31 female, mean age 71 years, medium follow-up 9-month) were treated by selective TACE using HepaSphere™ loaded with Doxorubicin. The diameter of the lesions ranged from 25 to 176 mm, with a mean diameter of 64.2 mm and a maximum of 4 lesions. Results Technical success rate was 100%, with complete devascularization of the lesions at the end of all procedures. One month CT follow-up shows complete necrosis (90-100%) of lesions in 39.4%, partial necrosis (50-89%) in 44,2%, and progression disease (0-49%) in 6.4%. 9 month follow-up shows complete necrosis in 26,6%, partial necrosis in 42.2% and progression disease in 19%; Survival at 12 months was 80.3% in HepaSphere™, 73.9% in Embosphere and 59.1% in Spongostan group; survival at 24 months was 72% in HepaSphere™ group. Conclusion Our experience demonstrates that TACE using HepaSphere™ is feasible, with low complication rate and promising efficacy. The results seem to be better than standard TACE with Embosphere and Gelfoam. Larger series and randomized studies are mandatory to confirm these preliminary results. References 1. Llovet JM, et al. Forging Partnerships in the Management of Hepatocellular Carcinoma: Multidisciplinary Strategies to Provide Continuity of Care 2002, Lancet 359:1734-1739. 2. Grosso M et al. Transarterial Chemoembolization for Hepatocellular Carcinoma with Drug-Eluting Microspheres: Preliminary Results from an Italian Multicentre Study. 2008, Cardiovasc Intervent Radiol 31(6):1141-9. 3. Malagari et al. ransarterial Chemoembolization of Unresectable Hepatocellular Carcinoma with Drug Eluting Beads: Results of an Open-Label Study of 62 Patients. 2008, Cardiovasc Intervent Radiol 31(2):269-80.

143 Background: HAE using particles is a method of treatment for HCC. The added role of doxorubicin has never been fully understood biologically. To date, no study has demonstrated any difference in outcome using HAE versus trans-arterial chemoembolization (TACE). Methods: Patients (pts) with unresectable Okuda stage I or II HCC with adequate liver function were randomized to BB or LC loaded with 150 mg of doxorubicin. Pts were evaluated by multiphasic CT 2-3 weeks post-treatment. Progression by RECIST and/or evidence of ≤5% necrosis was considered treatment failure. Otherwise pts were followed with CT every 3 months until progression or death. Pts with either recurrent tumor or new tumor outside the treated area could be re-treated. The primary objective was response rate (RR) by RECIST. With 50 pts in each arm response rates can be estimated to within +/- 14%. Secondary objectives included assessing safety and tolerability, time to progression (TTP), progression free survival (PFS), and overall survival (OS). Quantification of tumor necrosis (TN) using CT volumetric data was correlated with outcome. Analyses were intention-to-treat. Results: Between December of 2007 and March of 2012, 101 pts were randomized, 51 to BB and 50 to LC. Demographics in the two groups were comparable: median age was 67, 77% were male and 81% were Okuda I. Median number of embolizations was 2 in both arms. There was no difference in adverse events, the most common being post-embolization syndrome of pain, fever, nausea, or vomiting (84% in both groups). There was no difference in RR: BB 11% vs LC 9% (p=0.58). Median TTP was not reached. 12 month TTP was 49 versus 56% (p=0.84), median PFS was 7 versus 9 (p=0.6), and OS 14 versus 16 months (p=0.7) for BB and LC respectively. Change in TN/tumor volume post treatment did not predict OS in either group (p=0.28). Conclusions: No difference in response was noted between pts treated with BB versus LC. Given the comparable safety profile, TTP, PFS and OS, HAE should be considered a reasonable and cost-effective therapeutic option and may be preferable to LC. Clinical trial information: NCT00539643.

LBA154^ Background: The global SPACE trial was conducted to evaluate the efficacy and safety of S in combination with TACE with DEBDOX in patients (pts) with intermediate-stage HCC (BCLC B). Methods: Pts were eligible if they had asymptomatic, unresectable, multinodular tumors without vascular invasion (VI) or extrahepatic spread (EHS); Child-Pugh A liver functional status; and ECOG PS 0. Pts were randomized to receive S 400 mg bid or matching P continuously (1 cycle = 4 wks) until progression. All pts received TACE with DEBDOX (150 mg doxorubicin; Biocompatibles UK Ltd) 3-7d after first dose of study drug, and then on d1 (±4d) of months 3, 7, and 13, and q6 months thereafter. The primary endpoint was time to radiologic progression (TTP) by independent review (predefined alpha = 0.15). Secondary endpoints were overall survival (OS), time to VI/EHS, time to untreatable progression (TTUP), and safety. Results: Of 452 pts screened, 307 were randomized to S (n=154) or P (n=153). The HR for TTP was 0.797 (95% CI, 0.588, 1.080; p=0.072). Median TTP (50th percentile) was 169d/166d in the S and P groups, respectively; TTP at the 25th and 75th percentiles (preplanned) was 112/88d and 285/224d in the S and P groups, respectively. There were no unexpected safety findings. Median treatment duration in the S and P groups was 4.8 and 6.3 months, respectively, and median daily dose of study drug was 566 mg and 791 mg, respectively. Conclusions: The study met its primary endpoint of improving TTP when S was added to a regimen of TACE with DEBDOX, compared with TACE with DEBDOX alone. The combination was well tolerated; no new safety findings that would preclude use of the combination were observed. The encouraging efficacy signal requires confirmation with data from ongoing phase III trials evaluating the combination of S plus TACE. [Table: see text]

e15614 Background: Transcatheter therapy with drug eluting beads (DEB) with Doxorubicin is a relatively new modality of palliative treatment of patients with unresectable HCC. It is important to identify prognostic factors which affect survival after treatment with DEB to enable optimal patient selection and to ensure maximal survival benefit. Methods: Fifty consecutive patients with unresectable HCC who were treated with transcatheter therapy with DEB between the period of 2005 and 2008 were studied. Kaplan Meier test was used to study survival. Categorical variables were compared with Log rank test and continuous variable with Cox proportional hazards method. Results: The survival rates at one year from first transcatheter therapy in patients belonging to Okuda stage I, II and III were 67%, 35% and 27% (p=0.043). The survival rates at one year from the first transcatheter therapy in Child Pugh Class A, B and C were 60%, 39% and 13% (p=0.003). Portal vein thrombosis was present in 24%(12/50). Median survivals in patients with and without portal vein thrombosis were 335 days(31–638) and 610 days(482–738)(p=0.285). The median survival in patients with tumor thrombus and bland thrombus were 169 days and 335 days(p=0.69). The median survival in patients with main portal vein thrombosis and branch portal vein thromboses were 316 days(135–497) and 550 days(202–897)(p=0.89).Pre- procedure albumin, bilirubin and MELD score were found to be prognostic factors on univariate analysis ( Table 1 ).On multivariate analysis, pre-procedure serum albumin and Okuda staging were found to be independent prognostic factors. Conclusions: On multivariate analysis, serum albumin and Okuda staging were found to independently influence survival of patients treated with Doxorubicin eluting beads for unresectable hepatocellular carcinoma. The presence of portal vein thrombosis did not affect the long term survival. [Table: see text] No significant financial relationships to disclose.

4598 Background: Level 1A of evidence proves that TACE may prolong survival in HCC patients, for whom potentially curative treatment is no longer possible. DEB-TACE is a drug delivery system compri...