2 Index Definition of intermediate stage HCC patients Treatment algorithmsTreatment option: TACEResults supporting BCLC recommendations on TACETACE contraindicationsEfficacy of TACEIndications for stopping or continuing TACEART scoreHAP scoreComplications associated with TACETreatment option: SorafenibTreatment guidelinesSHARPGIDEONSOFIAINSIGHT
3 Intermediate stage HCC: Patient definition – BCLC 2010 Definition of intermediate stage patients:Single/large multifocal diseaseAsymptomaticNo vascular invasion or extrahepatic spreadPreserved liver function (Child-Pugh A or B)If liver function is compensatedOptimal candidates for TACEIf liver function is decompensated or fitting into Child-Pugh B classificationIncreased risk of severe adverse events and liver failure; patients may not benefit at all from TACEIf vascular invasion is detected by imagingHCC, hepatocellular carcinoma; TACE, transarterial chemoembolization.Forner A, et al. Seminars Liver Dis 2010; 30:6174.
4 Intermediate stage HCC: Definition and Prognosis - EASL, EORTC Definition of intermediate stage patientsMultinodularTumors without an invasive patternAsymptomaticPrognosis of intermediate stage patientsthese patients have poor prognosesmedian survival of 16 months or 49% at 2 yearoutcome prediction is heterogeneous for BCLC B subclass patients, and has been reported to range from around 36–45 months for the best responders to chemoembolization in recent series, to 11 months for the worst scenario of untreated candidates (placebo arm SHARP study)EASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma Journal of Hepatology 2012 vol. 56 j 908–943Available on:
5 Intermediate-stage HCC: Heterogeneous patient population Patients with intermediate-stage HCC differ in:1-3Tumour burdenLiver function (Child-Pugh A or B)Disease aetiologyGeneral health status1. Forner A et al. Semin Liver Dis 2010;30:61-74; 2. Piscaglia F & Bolondi L. Digestive Liver Dis 2010;42S:S258-63; 3. Raoul J-L et al. Cancer Treat Rev May;37(3):
6 There is no BCLC-B subclassification in the current BCLC system Intermediate-stage HCC: BCLC B sub-classification based on tumor burden and liver functionHighly heterogeneous populationPatients may differ according to tumour load, age, liver function and comorbiditiesDecision is only whether to TACE or not to TACEThere is no BCLC-B subclassification in the current BCLC systemUp-to-7 criterion for tumour burdenLiver functionPresence of peripheral/(sub)segmental portal vein thrombosisEvaluation of patient characteristics by a multidisciplinary teamProposed subclassification based on clinical evidence and expert opinionBolondi L, et al. Semin Liver Dis 2012;32:348–359
7 Intermediate-stage HCC: BCLC B sub-classification Quasi CChild–Pugh score5–6–75–678–9*ABeyond Milan and within up-to-7INOUTANYTumour-related ECOG PS0–1PVTNOYES*with severe/refractory ascites and/or jaundice.; **only if up-to-7 IN and PS0.BSC, best supportive care; PS, performance status; PVT, portal vein thrombosis; TARE, transarterial radioembolization.Adapted from Bolondi L, et al. Semin Liver Dis 2012;32:348–359.
8 Intermediate-stage HCC: Implications of a heterogeneous patient population Implications of this heterogeneity:Not all patients will benefit from TACE to the same degree1-3Some patients may benefit more from other treatment options3Prognostic factors for a response to TACE could improve treatment decisions and thus patient outcomes1. Forner A et al. Semin Liver Dis 2010;30:61-74; 2. Piscaglia F & Bolondi L. Digestive Liver Dis 2010;42S:S258-63; 3. Raoul J-L et al. Cancer Treat Rev May;37(3):
9 Prognostic significance of the new BLBC B substaging system Cumulative survival391 BCLC-B patients, included in the ITA.LI.CA. (Italian Liver Cancer) database, were divided into subgroups (B1–B4) according to the sub-classification. Survival of each group was assessed and compared using Kaplan-Meyer method and log-rank test, after a follow-up of 60 months. The new substaging proposal is able to refine prognostic prediction in the intermediate HCC stageEASL 2013 – From the presentation of F. Piscaglia – Abstract 109
10 Intermediate stage HCC: Treatment algorithm – EASL, EORTC guidelines Stage 0 PS 0, Child–Pugh AStage A–C PS 0–2, Child–Pugh A–BStage D PS > 2, Child–Pugh CVery early stage (0)1 HCC < 2 cm Carcinoma in situEarly stage (A)1 HCC or 3 nodules < 3 cm, PS 0Intermediate stage (B)Multinodular, PS 0Advanced stage (C) Portal invasion, N1, M1, PS 1–2End stage (D)1 HCC3 nodules ≤ 3 cmPortal pressure/ bilirubinIncreasedAssociated diseasesNormalNoYesResectionLiver transplantationPEI/RFATACEsorafenibBSCCurative treatments (30%)5-year survival (40–70%)Target: 20%OS: 20 mo (45-14)Target: 40%OS: 11 mo (6-14)Target: 10%OS: <3 moPS, performance status; TACE, transarterial chemoembolization; BSC, Best Supportive CareEASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma Journal of Hepatology 2012 vol. 56 j 908–943Available on:
11 Intermediate stage HCC: Levels of evidence and grade of recommendation Levels of evidence (NCI)123SorafenibChemoembolizationRF (<5 cm),RF/PEI (<2 cm)Adjuvant therapy after resectionLDLTResectionOLT-MilanInternal radiation Y90OLT-extendedNeoadjuvant therapy in waiting listDownstagingExternal/palliative radiotherapyCBACBA2 (weak)1 (strong)Grade of recommendation(GRADE)EASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma Journal of Hepatology 2012 vol. 56 j 908–943Available on:11
12 Intermediate stage HCC: Treatment algorithm – AISF guidelines SORAFENIBHCC not amenable to curative treatmentsChild Pugh class A or B7Performance Status ≤1No portal/hepatic vein invasion (except segmental or subsegmental portal branches))1st treatment(cTACE or DEB-TACE)2nd treatmentMRI or CT** at 1 monthNo complete responsePartial responseNewly developed HCCComplete responseDisease recurrenceMRI or CT every 3 monthsConsider another course of cTACE or DEB-TACE (and/or ablation techniques)Liver failure orsevere adverse events*YesNoResolutionPalliationDisease progressionor stable deseasesorafenib* : each TACE; ** : with cTACE, MRI is preferred to CT *** : Response must be assessed by modified RECIST criteriaPosition paper AISF DLD (2013)12
13 Intermediate stage HCC: JSH consensus-based treatment algorithm NoYesExtrahepatic spreadLiver functionChild-Pugh A/BChild-Pugh CChild-Pugh B/CChild-Pugh AVascular invasionNoYesNoYesNumberSingle1-3≥4Within Milan criteria and age ≤65Exceeding Milan criteria or age >65Hypovascular early HCCSize≤3 cm>3 cmTreatmentIntensive follow-upAblationResectionAblationResection TACETACE + ablationTACEHAICResectionAblationHAIC (Vp3, 4)Sorafenib (Vp3, 4)TACE (Vp1, 2)Resection (Vp1, 2)TransplantationTACE/ablation for Child-Pugh C patientsPalliative careSorafenibSorafenib (TACE refractory, Child-Pugh A)HAIC: hepatic arterial infusion chemoterapy;Kudo M, et al. Dig Dis 2011; 29:
14 Intermediate HCC: Proposed treatment algorithm for BCLC B sub-classification Quasi CChild–Pugh score5–6–75–678–9*ABeyond Milan and within up-to-7INOUTANYTumour-related ECOG PS0–1PVTNOYES***1st optionTACETACE or TAREBSCsorafenibAlternativeLiver transplantation TACE + ablationTrials TACE sorafenibLiver transplantation**TACE TARE*with severe/refractory ascites and/or jaundice.; **only if up-to-7 IN and PS0, *** segmentary or subsegmentaryBSC, best supportive care; PS, performance status; PVT, portal vein thrombosis; TARE, transarterial radioembolization.Adapted from Bolondi L, et al. Semin Liver Dis 2012;32:348–359.
15 Intermediate stage HCC: Treatment algorithm adherence The proliferation of so many guidelines reflects broad geographic differences in HCC epidemiology, etiology, high-risk patients, health systems and resources, medical technology and clinical impact of HCC in different countriesIn Italian clinical practice adherence to guidelines is alarmingly lowBorzio M, Sacco R. Future Oncol. (2013) 9(4), 465–467
17 Non Surgical Treatments: TransArterial ChemoEmbolization (TACE) Example of transarterial embolization. On the left we can see the typical arterial hypervascularization of HCC on arteriography.The right picture shows the result after selective embolization of the feeding arteriesForner A et al. Critical Reviews in Oncology/Hematology 2006;60:89–98
18 Intermediate stage HCC: candidates to TACE If liver function is compensated optimal candidates for TACEIf liver function is decompensated or fitting into Child-Pugh B classification increased risk of severe adverse events and liver failure; patients may not benefit at all from TACEIf vascular invasion is detected by imaging increased risk of severe adverse events and liver failure; patients may not benefit at all from TACEHCC, hepatocellular carcinoma; TACE, transarterial chemoembolization.Forner A, et al. Seminars Liver Dis 2010; 30:6174.
19 Outcome assessed = 2 yr survival BCLC recommendations on TACE are based on the results of a single meta-analysisOdds ratio (95% CI)StudyPatientsLin, Gastroenterology 199863GETCH, NEJM 199596Bruix, Hepatology 199880Pelletier, J Hepatol 199873Lo, Hepatology 200279p=0.086Llovet, Lancet 2002112p=0.017Overall503OR=0.53 [95% CI, 0.32–0.89]; p=0.0170.010.10.51210100Favours treatmentFavours control- Child-Pugh B <10 % of all patients- Around 10% had tumor portal vein thrombosisIn most trials no selective TAETrials in EU e AsiaOutcome assessed = 2 yr survivalBCLC = Barcelona Clinic Liver Cancer; GRETCH = Groupe d'Etude et de Traitement du Carcinome Hépatocellulaire; HCC = hepatocellular carcinoma; TACE = transarterial chemoembolizationLlovet JM, et al. Lancet 2003; 362: 1907–1719
20 TACE: long-term survival outcomes Llovet JM, et al.Lo C-M, et al.1008060402010080604020ChemoembolizationControlChemoembolizationControlp <p =Probability of survival (%)Probability of survival (%)Time since randomization (months)Time since randomization (months)3-year overall survival (OS): 26%2–29%1 Sustained objective response rate (ORR) (3–6 months): 35%1–39%2 No difference in survival of intention-to-treat (ITT) population between non-responders and control group11. Llovet JM, et al. Lancet. 2002;359: Lo C-M, et al. Hepatology. 2002;35:
21 Concluding observations on the meta-analysis by Llovet et al Outcome is a function of patient characteristics, tumour characteristics, and TACE technique To allow a more differentiated prognosis of outcome following TACE, additional data on these factors are requiredIndividual studies included in the meta-analysis reflect:Heterogeneity of the intermediate patient populationDiversity in TACE methodologiesBCLC, Barcelona Clinic Liver Cancer; TACE, transarterial chemoembolization.Llovet JM, et al. Lancet 2003; 362: 1907–1721
22 Indications and contraindications to TACE Reported absolute contraindicationsDecompensated cirrhosis (Child-Pugh B ≥8) including:- Jaundice- Clinical encephalopathy- Refractory ascites- Hepato-renal syndromeExtensive tumour with massive replacement of both entire lobesSeverely reduced portal vein flow (e.g. non-tumoural portal vein occlusion or hepatofugal blood flow)Technical contraindications to hepatic intra-arterial treatment (e.g. untreatable arteriovenous fistula)Renal insufficiency (creatinine ≥2 mg/dL or creatinine clearance <30 mL/min)Reported relative contraindicationsTumour size ≥10 cmComorbidities involving compromised organ function:- Active cardiovascular disease- Active lung diseaseUntreated varices at high risk of bleedingBile-duct occlusion or incompetent papilla due to stent or surgeryRaoul et al, Cancer Treatment Reviews 37 (2011) 212–220
23 Efficacy of TACE Objective response (OR) using WHO criteria: 40 ± 20% Complete tumor necrosis: 44 ± 30%Survival rate at 1, 2, 3 and 5 years: 62 ± 20%, 42 ± 17%, 30 ± 15%, 19 ± 16% respectivelyMean survival time: 18 ± 9 monthsMarelli L et al. Cardiovasc Intervent Radiol (2007) 30:6-25
24 Non–responders vs responders to TACE treatment Overall responsesTarget lesion responsesABKaplan–Meier curves were generated to compare survival between responders and non-responders according to mRECIST radiological assessment methods.Assessments were also defined according to overall responses (A) and target lesion responses (B)Adapted from Gillmore R et al. Journal of Hepatology 2011 vol. 55 j 1309–1316
25 Evaluation of per-nodule efficacy of TACE 271 cirrhotic patients with 635 nodules underwent a first cTACERepeated TACE "on demand" after local recurrences (LR) or partial responses (PR)Aim of the study: evaluation of complete response (CR), time to nodule progression (TTnP), and local recurrence rate (LRR), according to three size classes (≤ 2 cm, cm, and>5 cm)Evaluation of tumor response according to mRECIST (after 1 month and every 3-4 months afterwards)Median follow-up: 12 months (1-51)Tumor size≤ 2 cm (N=386)cm (N=211)> 5 cm (N=36)Nodules, n%Risposta tumoraleCR2636813464925PR1233277362775LR5220657Golfieri R, et al. J Vasc Interv Radiol 2013; 24(4):
26 Precision V study: only half of eligible patients respond to TACE Phase II Precision V study (n=2121)Patient population:ECOG PS 0/1 75/25%Child–Pugh A/B 82/18%Time to progression: not reached>8.9 months (DEB-TACE) vs 7.5 months (cTACE)52274422102030405060ORCR% of patientsDEB-TACETACEIn Precision V, only 52% of patients were reported to have an OR (with DEB-TACE)Many patients are refractory to TACECR, complete response; cTACE, conventional transarterial chemoembolization; DEB, drug-eluting beads; ECOG PS, Eastern Cooperative Oncology Group performance status; OR, objective response; TACE transarterial chemoembolizationLammer J et al. Cardiovasc Intervent Radiol 2010;33:41–52
27 Recurrence rate after TACE cycles Cohort study conducted on 151 patients consecutively treated with cTACE as a retrospective analysis of a prospective database.Recurrence RatePercentageThe estimated recurrence rate in patients with complete response was 37% and 61% at 6 and 12 months after first cTACE and 40% and 59% after second cTACE.Terzi E. J Hepatol Dec;57(6):
28 Factors that may negatively affect prognosis after TACE Patient characteristics:Tumour characteristics:Technique-related:Child-Pugh B1–9Alpha-fetoprotein (≥400 ng/mL)2,6,8,9Presence of grade 3 ascites5,10,11Bilirubin >3 mg/dL2,7,8,12Performance status ≥13,12,13>3 liver lesions13Tumour diameter ≥5cm47Multi-nodular/diffuse tumour1,5,8Bilobar tumour1,3Portal vein thrombosis1,9Less selective TACE procedures (lobar or bilobar) 13Conventional TACE461. Dumortier J, et al. Dig Liver Dis 2006;38:125–33.; 2. Savastano S, et al. J Clin Gastroenterol 1999; 28:334–40; 3. Doffoël M, et al. Eur J Cancer 2008; 44:528–38; 4. Florio F, et al. Cardiovasc Intervent Radiol 1997;20:23–8; 5. Pietrosi G, et al. J Vasc Intervent Radiol 2009;20: ; 6. Yip WM, et al. Hong Kong Med J 2009;15:339-45; 7. Gomes AS, et al. AJR Am J Roentgenol 2009;193: ; 8. Mabed et al. Eur J Cancer Care 2009;18:492-9; 9. Forner et al. Seminars Liver Dis 2010;30:61-74; 10. Cho YK, Cancer 2008;112:352-61; 11. Lladó L, et al. Cancer 2000;88:50–7; 12. Cabibbo G, et al. Aliment Pharmacol Ther 2011;34:196–204; 13. Bruix J, et al. Hepatology 1994;20:64350.1. Lladó L, et al. Cancer 2000;88:50–7; 2. Mabed et al. Eur J Cancer Care 2009;18:492-9; 3. Vogl TJ, et al. Radiol 2000;214:349-57; 4. Sotiropoulos GC, et al. Dig Dis Sci 2009;54: ; 5. Dumortier J, et al. Dig Liver Dis 2006;38:125–33; 6. Savastano S, et al. J Clin Gastroenterol 1999; 28:334–40; 7. Doffoël M, et al. Eur J Cancer 2008; 44:528–38; 8. Lopez RR, et al. Arch Surg 2002; 137:653–658; 9. Stuart K, et al. Cancer 1993;72:3202–9.1. Cammà C, et al. Radiology 2002;224:47–54; 2. Yip WM, et al. Hong Kong Med J 2009;15:339-45; 3. Kothary N, et al. J Vasc Interv Radiol 2007;18:1517–26; 4. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:41 Malagari K et al. Cardiovasc Intervent Radiol 2010; 33: Varela M et al. J Hepatol 2007;46:474–81.28
29 Current recommendations and contraindications for using TACE in HCC patients AASLD1First-line non-curative for non-surgical pts with large/multifocal tumoursEHS, vascular invasionEASL EORTC2Intermediate (stage B) pts (PS 0 and Child-Pugh A–B) with multinodular, asymptomatic tumoursNCCN3Pts not eligible for curative therapies (resection, transplantation)Bilirubin >3 mg/dL,*PVT or Child-Pugh CJSH4Child-Pugh A–B with large (>3 cm), multinodular tumoursChild-Pugh C, single tumourAISF5Pts with PS 0-1 and Child-Pugh A–B7 with multinodular, asymptomatic tumoursBilirubin >3 mg/dL,*EHS, PVT or Child-Pugh C*Considered a relative contraindication*Considered a relative contraindication1. Bruix J, Sherman M. Hepatology 2010 e-pub ahead of print available at: 2. EASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma Journal of Hepatology 2012 vol. 56 j 908–943 Available on: ; 3. NCCN Clinical Practice Guidelines V Available at: ; 4.Hepatology Research 2010; 40 (Suppl. 1): 8–9; 5. Raccomandazioni AISF per la gestione integrata del paziente con Epatocarcinoma; published on Available on:29
30 AISF guidelines: patient suitability for TACE Patients suitable for TACEPatients unsuitable for TACETACE is not indicated in patients with jaundice, untreatable ascites, main or branch portal vein thrombosis, hepatofugal portal blood flow, HCC nodules larger than 10 cmTACE is indicated in BCLC stage patients, not eligible for surgery or ablation. The best candidates for TACE are asymptomatic Child-Pugh class A patients, although those with a Child- Pugh score of B7 or ECOG PS 1 can also be consideredPosition paper AISF DLD (2013)
31 AIOM Guidelines Grado di raccomandazione SIGN Raccomandazione clinica Forza della raccomandazione clinicaANei pazienti con cirrosi epatica Child-Pugh A la TACE deve essere preferita come trattamento per le forme multinodulari e per i tumori singoli di grandi dimensioni (> 5 cm) in caso di controindicazione alla chirurgiaPositiva forteAIOM Guidelines. Available at:
32 Repeating TACE or switching To ensure that patients have the best possible outcomes it is important to understand when to repeat and when to switch TACE1,2This may be achieved in part by defining those patients who will respond well to TACE vs. those who are less likely to respond well1,2Generally TACE is carried out through:Regular repetition (usually every 2 months, range 1-6 months)3-6‘On-demand’ (driven by response to previous cycle of TACE)7,8TACE, transarterial chemoembolization.1. Cammà C, et al. Radiology 2002; 224:4754; 2. Peck-Radosavljevic M. Liver Int. 2010;30:3-4; 3. Vogl TJ, et al. Radiology 2000;214:349–35; 4. Saccheri S, et al. J Vasc Interv Radiol 2002;13:995–9; 5. Grieco A, et al. Hepatogastroenterology 2003;50:207–12; 6. Farinati F, et al. Dig Dis Sci 1996; 41:2332–9; 7. Lu W, et al. Hepatogastroenterology 2003; 50:2079–83; 8. Ernst O et al. AJR 1999;172:59–64.32
33 Potential indications for stopping or continuing TACE Stopping TACETACE can be stoppedAs soon as a complete response is obtained*†In the absence of response after 23 TACE sessions1If there is progression of the treated lesion*TACE should be stopped in cases of:SAEArterial thrombosis2Liver failure3,4Portal vein thrombosis4Patient’s decisionContinuing TACETACE can be continued in cases of:Local tumour recurrence*New tumour growth**Expert opinion expressed at a specialist workshop on TACE †CR as defined per the EASL guidelines5SAE, serious adverse event; TACE, transarterial chemoembolization. 1. Bruix J, et al. Hepatology 1998;27:1578–83; 2. Ahrar K, Gupta S. Surg Oncol Clin N Am 2003;12:10526; 3. Pleguezuelo M, et al. Expert Rev Gastroenterol Hepatol 2008;2:761 Cammà C, et al. Radiology 2002;224:47–54; 5. Bruix J, et al. J Hepatol 2001;35:42130.
34 Assessment for Retreatment with TACE: the ART score Developed by multivariate regression analysis ofbaseline characteristicsradiological response after 1st TACE (EASL-response criteria)changes of liver function after the 1st TACEDetermined prior to 2nd TACE in BCLC-A*/B patients, who received ≥ 2x TACETraining cohort: n=107 (Vienna), validation cohort: n=115 (Innsbruck)ART score categoryPointsAbsence of radiological tumour response(0 if present)AST increase >25%(0 if absent)Increase in CP score by 1 point1.5 (0 if absent)Increase in CP score by ≥2 points(0 if absent)*BCLC-A not suitable for liver transplantation/local ablative treatmentAST, aspartate transaminase; BCLC, Barcelona Clinic Liver Cancer; CP, Child–Pugh; EASL, European Association for the Study of the Liver; TACE, transarterial chemoembolizationSieghart W et al. Hepatology 2013 Jan 12. doi: /hep.26256
35 ART score: prognostic significance Training cohortValidation cohort0–1.5 points ART score0–1.5 points ART score≥2.5 points ART score≥2.5 points ART scoreCumulative survivalCumulative survivalTime (months)Time (months)The ART score was developed in the training cohort by using a stepwise Cox regression model. Patients were then investigated for the effect of the first TACE on cumulative survival (OS, long rank test).0‒1.5 points (n=60): 23.7 months (CI: 16–32)≥2.5 points (n=37): 6.6 months (CI: 5–9) P=0.001The ART score was externally validated in an independent validation cohort.0‒1.5 points (n=74): 28.0 months (CI: 23–33)≥2.5 points (n=37): 8.1 months (CI: 6–11) P<0.001An ART score of ≥ 2.5 prior the second TACE identifies patients with a dismal prognosis who may not profit from further TACE sessionsSieghart W et al. Hepatology 2013 Jan 12. doi: /hep
36 The Hepatoma Arterial-embolisation Prognostic (HAP) score Developed by multivariate analysis of prognostic factorsalbumin (<36 g/dl)bilirubin (>17 μmol/l)AFP (>400 ng/ml)size of dominant tumour (7 cm)Training dataset: n=114 patients treated with TACE/TAE; validation dataset: n=167 treated with TACEPrognostic factorPointsAlbumin (<36 g/dl)1AFP > 400 ng/mlBilirubin > 17 μmol/lMaximum tumour diameter >7 cmHAP classificationPointsHAP AHAP B1HAP C2HAP D>2L. Kadalayil, et al. Annals of Oncology 24: 2565–2570, 2013
37 The Hepatoma Arterial-embolisation Prognostic (HAP) score Training datasetValidation datasetKaplan–Meier survival curves according to the Hepatoma arterial-embolisation prognostic (HAP) score in the training dataset (A) and the validation dataset (B). For the training dataset, the median overall survival (OS) times were 27.6 months (95% CI16 to not estimable), 18.5 months (95% CI15.5–30.4), 9.0 months (95% CI 6.9–15.4) and 3.6 months (95% CI 1.7–8.5) for HAP A, B, C and D, respectively. For the validation set, OS median values were 25.5 (95%CI 13.7–32.8), 18.1 (95% CI 9.9 to not estimable), 8.9 (95% CI 6.8–16.1) and 5.9 (95% CI 2.8–12.7) months, respectively.A HAP score of C or D defined poor prognosis groups which are unlikely to benefit from TACE and might be better served with systemic therapyL. Kadalayil, et al. Annals of Oncology 24: 2565–2570, 2013
38 Considerations for multiple TACE cycles There is a lack of RCTs that compare regular with on-demand TACEMultiple TACE cycles may:Increase liver damage1,2Increase survival2,6Regular TACE cycles may increase complications3–6Repetition on demand may be more acceptablePatients often refuse multiple TACE cycles because of side effects7Patient’s treatment goals should be consideredQuality of life can be increased by use of repetition on demand8Could regular increases in VEGF levels lead to increased vascularization of remaining and/or metastatic tumours?9–11RCT, randomized controlled trial; TACE, transarterial chemoembolization; VEGF, vascular endothelial growth factor. 1. Kwok PC, et al. J Hepatol 2000;32:95564; 2. Grieco A, et al. Hepatogastroenterol 2003; 50:20712; 3. Cammà C, et al. Radiology 2002; 224:4754; 4. Herber SCA, et al. AJR 2008;190:103542; 5. Huo T, et al. Aliment Pharmacol Ther 2004; 19:13018; 6. Ernst O, et al. AJR 1999;172:5964; 7. Savastano S, et al. J Clin Gastroenterol 1999;28:33440; 8.Venook AP, et al. J Clin Oncol 1990;8:110814; 9. Li X, et al. W J Gastroenterol 2004;10:287882; 10. Sergio A, et al. Am J Gastroenterol 2008;103:91421; 11. Wang B, et al. Acta Radiologica 2008;49:5239.38
39 Complications commonly associated with TACE Most frequent complications of TACELiver failure (15–51% of pts)15GI bleeding [variceal hemorrhage or GI ulcers] (10%)13Ascites (10–17%)2,5Post-embolization syndrome (>80%)57Reported at <10% frequency 1,3,5,713Tumour abscess formationTumour ruptureHaemoperitoneumHepatic artery occlusionPortal vein thrombosisIschemic cholecystitis or pancreatitisRenal failureBacterial peritonitisPleural effusionPulmonary thromboembol.Sepsis/septic shock*Defined as one or more of: encephalopathy, increasing ascites, increase in prothrombin time, increase in serum bilirubin, deterioration of CP status.GI, gastrointestinal; TACE, transarterial chemoembolization.1. Cammà C, et al. Radiology 2002; 224:4754; 2. Pelletier G, et al. J Hepatol 1998;29:129–34; 3. Saccheri S, et alJ Vasc Interv Radiol 2002;13:995–9; 4. Poon RT-P, et al. J Surg Oncol 2000;73:10914; 5. Hsieh MY, et al. World J Gastroenterol 2004;10:505–8; 6. Bruix J, et al. Hepatol 1998;27:1578–83; 7. Chan AO, et al. Cancer 2002;94:174752; 8. Farinati F, et al. Dig Dis Sci 1996; 41:23329; 9. Kirchhoff TD, et al. Hepatobiliary Pancreat Dis Int 2007; 6:25966; 10. Lopez RR, et al. Arch Surg. 2002; 137:6538; 11. Savastano S, et al. J Clin Gastroenterol 1999; 28:33440; 12. Llovet JM, et al. Lancet 2002;359:1734–39; 13. Shi M, et al. World J Gastroenterol 2010; 16: 264–69.39
40 The number of patients with major or severe complications associated with TACE varies greatly TACE methodologyRate of major/severe complications,% (n/N)Epirubicin/ lipiodol + gelatin sponge1~9.7 (8/82) †Doxorubicin/DEB220.4 (19/93)‡Doxorubicin/polyvinyl alcohol345.0 (9/20)§Doxorubicin + cisplatin/ lipiodol + starch microsphere413.0 (6/47)**Doxorubicin + gelfoam54.7 (2/42)††Doxorubicin/ lipiodol + polyvinyl alcohol617.5 (14/80) ‡‡Various (meta-analysis of 18 RCTs)7Range 0–57%§§‡Complications in 80/182 patients (44%), 38% of complications were major.§ Major complications were regarded as any prolongation of stay in hospital caused by hepatic failure, pulmonary embolism, stroke, pneumonia, upper GI bleeding, or refractory ascites.** Focal liver necrosis, partial dissection of the hepatic artery, gastric ulcer, and cholecystitis. † †Death from renal failure and GI bleeding; ‡‡ Complications by number of TACE sessions (major complications included: partial portal vein thrombosis , upper GI bleeding , dehydration and cachexia requiring re-admission, flare of hepatitis B virus hepatitis, neutropenic fever requiring parenteral antibiotics, femoral artery pseudo aneurysm , paraduodenal chemotherapy extravasation and psoas muscle abscess).. § §Serious AEs (those AEs resulting in death or were immediately life-threatening or resulted in permanent or significant disability/incapacity or required extending inpatient hospitalization or congenital anomaly/birth defects) occurring within 30 days of treatment.AEs, adverse events; RCTs, randomized controlled trials; DEB, drug-eluting beads ; TACE, transarterial chemoembolization. 1. Savastano S, et al. J Clin Gastroenterol 1999;28:334– Lammer J, et al. Cardiovasc Intervent Radiol ;33:41– Hsieh MY, et al. World J Gastroenterol 2004;10:505– Kirchhoff TD, et al. Hepatobiliary Pancreat Dis Int 2007;6:259– Pelletier G, et al. J Hepatol 1990;11:181–4. 6. Molinari M, et al.Clin Oncol (R Coll Radiol) 2006;18:684– Cammà C, et al. Radiology 2002;224:47–54.40
41 Factors reported to be associated with TACE-related complications VariablesUse of embolizing agentsSevere post-embolization syndrome* (PES)1,2Associated with duration of PES-related fever1Low number of treatment cyclesTACE methodLower rate of serious liver toxicity with DEB-TACE (2.9%) vs. conventional TACE (9.0%)3DoseLarger doses of cisplatin/lipiodol associated with increased risk of hepatic decompensation 1,4,5Multiple treatment cyclesPotential to increase the risk of complications6–9* requiring anaesthetics for > 7 days1. Pelletier G, et al. J Hepatol 1990;11:1814; 2. Chan AO, et al. Cancer 2002; 94:174752; 3. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152; 4. Hwang JI, et al. Anticancer Res 2005;25:25514; 5. Poon RT, et al. J Surg Oncol 2000;73:10914; 6. Huo T, et al. Aliment Pharmacol Ther 2004;19:1301–8; 7. Herber SC, et al. AJR 2008;190:103542; 8. Cammà C, et al. Radiology 2002;224:4754; 9. Ernst O, et al. AJR 1999;172:5964.
42 Factors associated with TACE-related complications Patient characteristicsLiver functionLiver damage after TACE is more common in patients with poor liver function1–5Child–Pugh B status is associated with risk of acute renal failure6Disease characteristicsTumor sizeLarger tumor size associated with post-TACE liver failure (p < )4TACE characteristicsNumber of sessionsMultiple TACE sessions can increase the risk of complications6–8TACE methodLower rate of serious liver toxicity with DEB-TACE (2.9%) versus “conventional” TACE (9.0%)9DoseLarger doses of cisplatin/lipiodol are associated with an increased risk of hepatic decompensation1,2,4DEB = drug-eluting beads.1. Chan AO, et al. Cancer. 2002; 94: Hwang JI, et al. Anticancer Res. 2005;25: Chen MS, et al. World J Gastroenterol. 2002; 8: Poon RT, et al. J Surg Oncol. 2000;73: Shah SR, et al. QJM. 1998; 91: Huo T, et al. Liver Int. 2004;24: Herber SC, et al. AJR 2008;190: Cammà C, et al. Radiology. 2002;224: Lencioni R, et al. ASCO-GI. 2009;[abstract 116].
43 Majority of studies report some TACE-related death within 30 days Most studies describing the use of TACE report some treatment- related death (0.5%1 to 17%2)Causes of TACE-related deathDecompensated cirrhosis3,4Liver failureGastrointestinal bleedingRenal failureHepatic encephalopathySeptic shockEmbolic nature of TACE4,5Tumor ruptureHepatic abscessesPerforated duodenal ulcerPerforation of an ischemic colonPortal vein thrombosisRespiratory failure1. Takayasu K, et al. Gastroenterol. 2006;131: Stuart K, et al. Cancer. 1993;72: Bruix J, et al. Hepatol. 1998;27: Pelletier G, et al. J Hepatol. 1998;29: Chan AO, et al. Cancer. 2002; 94:
44 Factors reported to be associated with TACE-related mortality VariablesNumber of TACE sessionsMultiple TACE sessions are associated with a higher risk of post-treatment mortality (OR 1.50, p<0.0001)1Portal vein thrombosisTreatment of patients with portal vein thrombosis was associated with a higher risk of post-TACE mortality (OR 3.24, p=0.013)1Lobar vs. superselectiveMortality at 30 days correlated with extent of embolization (lobar vs. superselective, p=0.03)2Nature of embolic agentsCan be associated with mortality due to tumour rupture, hepatic abscesses, perforated duodenal ulcer, perforation of an ischaemic colon, portal vein thrombosis, respiratory failure3,4OR, odds ratio; TACE, transarterial chemoembolization. 1. Cammà C, et al. Radiology 2002;224:47–54; 2. Kothary N, et al. J Vasc Interv Radiol 2007;18:151726; 3. Pelletier G, et al. J Hepatol 1998;29:129–134; 4. Chan AO, et al. Cancer 2002; 94:1747–52.
45 TACE may not be suitable for all patients with intermediate stage HCC Not all patients are suitable for TACE1Evidence of efficacy is limited2,3Most studies carried out in ‘pre-staging’ eraTACE protocols are highly heterogeneousIntermediate-stage patient segment is not well definedA number of guidelines/recommendations recognize that management strategies are needed for patients who have failed or are unsuitable for TACESub-analyses from the SHARP and Asia-Pacific studies suggest that sorafenib may benefit some patients with intermediate stage HCC4,5HCC, hepatocellular carcinoma; SHARP, Sorafenib Hepatocellular carcinoma Assessment Randomized Protocol; TACE, transarterial chemoembolization. 1. Bruix J, Sherman M. Hepatology 2011;53:1020–2; full guidelines available at: Llovet JM, Bruix J. Hepatology 2003;37:429–42; 3. Oliveri et al. Cochrane Database Syst Rev 2011;3:CD Bruix J et al. J Hepatol 2009;50(Suppl 1):S28-9 [abstr 67]; 5. Cheng A, et al. Lancet Oncol 2009;10:2534; 6. Forner A et al. Semin Liver Dis 2010;30:61–74; 7. Raoul J-L et al. Cancer Treat Rev May;37(3): ; 8. Thomas MB et al. J Clin Oncol 2010;28:3994–4005; 9. Piscaglia F, Bolondi L. Digestive Liver Dis 2010;42S:S258–63
47 AIOM GuidelinesGrado diraccomandazione SIGNRaccomandazione clinicaForza della raccomandazione clinicaBNei casi di controindicazione o di mancata risposta alla TACE deve essere considerato il trattamento con sorafenibPositiva forteIn caso di mancata risposta o di progressione dopo TACE o di controindicazione alla TACE, se la funzione epatica è buona, è raccomandata la terapia con sorafenib (Livello di evidenza 1+). I pazienti con questo tipo di HCC trattati con sorafenib nell’ambito dello studio prospettico randomizzato controllato con placebo (studio SHARP) dimostrano un significativo miglioramento della sopravvivenza (14,5 vs 10,2 mesi; HR=0,52; IC 95%: 0,32-0,85)AIOM Guidelines. Available at:
48 Intermediate HCC: data from SHARP and real-world practice BCLC-B subgroupIncreased OS and TTP with sorafenib (n=54) vs placebo (n=51)Median OS: 14.5 vs 11.4 months (HR: 0.72; 95% CI: )Median TTP: 6.9 vs 4.4 months (HR: 0.47; 95% CI: )SHARP1Previous TACE subgroupIncreased OS and TTP with sorafenib (n=86) vs placebo (n=90)Median OS: 11.9 vs 9.9 months (HR: 0.75; 95% CI: )Median TTP: 5.8 vs 4.0 months (HR: 0.57; 95% CI: )GIDEON final analysis2Similar safety profile for sorafenib across BCLC stagesLonger survival in BCLC-B vs BCLC-C patients15.6 vs 9.1 monthsINSIGHT3Good efficacy demonstrated in BCLC-B HCCLonger survival in BCLC-B vs BCLC-C patients: 25.4 vs 14.4 monthsSOFIA4Good efficacy demonstrated in BCLC-B HCCLonger survival in BCLC-B vs BCLC-C patients: 20.6 vs 8.4 monthsBCLC= Barcelona Clinic Liver Cancer; HCC= hepatocellular carcinoma; HR= hazard ratio; OS= overall survival; TTP= time to progression1. Bruix et al. J Hepatol. 2012:57:821-9; 2. Bronovicki J-P, et al. Presented at ECC P 2594; 3. Koschny R, et al. Presented at ESMO P437; 4. Iavarone M et al. Hepatology 2011;54:
49 Intermediate HCC (BCLC B) Preliminary evidence from SHARP subgroup analysis suggests sorafenib has survival benefits in intermediate HCCFavours sorafenibFavours placeboOverall HR in SHARPSorafenib: n=245Placebo: n=252Advanced HCC (BCLC C)Sorafenib: n=54Placebo: n=51Intermediate HCC (BCLC B)0.51.01.5HR (95% CI) for survivalBCLC, Barcelona Clinic Liver Cancer; HCC, hepatocellular carcinoma; HR, hazard ratio; CI, confidence interval.Bruix J et al. J Hepatol 2009;50(Suppl 1):S28-9 [abstr 67].49
50 SHARP subgroup analysis: sorafenib prolongs OS in BCLC B patients Overall SurvivalMedian (months)Sorafenib consistently improved median OS compared with placebo in patients with intermediate HCCAdapted from Bruix J et al. J Hepatol Oct;57(4): Epub 2012 Jun 19
51 SHARP subgroup analysis: sorafenib prolongs OS and TTP in BCLC B patients Overall SurvivalTime to progressionBCLC B patients treated with sorafenib (n = 54) had a longer median OS (14.5 vs months) and TTP (6.9 vs.4.4 months) and a higher DCR (50.0% vs. 43.1%) than those who received placebo (n = 51).These exploratory subgroup analysis shows that sorafenib consistently improves median OS and TTP compared with placebo in patients with BCLC B HCCBruix J et al. J Hepatol Oct;57(4): Epub 2012 Jun 19
52 SHARP subgroup analysis: sorafenib prolongs OS and TTP post TACE failure Overall SurvivalTime to progressionPatients treated with sorafenib (n = 86) post TACE failure had a longer median OS (11.9 vs. 9.9 months) and TTP (5.8 vs.4.0 months) and a higher DCR (44.2% vs. 34.4%) than those who received placebo (n = 90).Sorafenib improved TTP and demonstrated a trend toward improved OS, irrespective of prior therapyBruix J et al. J Hepatol Oct;57(4): Epub 2012 Jun 19
53 GIDEON final analysis: sorafenib shows longer OS in BCLC-B vs BCLC-C patients Overall survivalBronovicki J-P, et al. Presented at ECC P 2594
54 GIDEON final analysis: sorafenib prolongs TTP in BCLC-B vs BCL-C patients Time to progressionBronovicki J-P, et al. Presented at ECC P 2594
55 SOFIA analysis: sorafenib prolongs OS in BCLC B vs BCLC C patients Multicenter (6 centers), investigator sponsored, observational, non- interventional study to assess the safety and effectiveness of sorafenibObjectivesPrimary: safetySecondary: treatment effectiveness [OS, early radiologic response, and time to radiologic progression]Treatment duration and cumulative doseBCLC-CBCLC-B unfit for any or failed to respond to locoablative treatments296 pts25% BCLC-B75% BCLC-CResults:Median OS = 10,5 monthsMedian OS BCLC-B = 20.6 monthsMedian OS BCLC-C = 8.4 monthsIavarone M et al. Hepatology 2011;54:
56 INSIGHT subgroup analysis: OS according to BCLC stage Overall survival according to BCLC stage1: Stage A1,002: Stage B3: Stage C0,754: Stage DCensored0,50p<0,00010,250,00250500750100012501100311342192612193389852714Median OS (months): BCLC A: 29.1 months BCLC C: 14.4 monthsBCLC B: 25.1 months BCLC D: 3.1 monthsPreliminary median overall survival for BCLC stage C for BCLC stage B is promising in this ongoing studyKoschny R, et al. Presented at ESMO P437
57 Treatment of Intermediate stage HCC: key messages Intermediate patients with contraindications to TACE (and not suitable for alternative locoregional therapies) or suffering from severe side effects of TACE or refractory to 2(-3) cycles of TACE should be considered for treatment, from a practical point of view, as if they were advanced.The decision when to stop or repeat TACE is not univocal and should be tailored for each individual patient by a multidisciplinary team, considering:liver function,tumor burdentechnicalitiesalternative therapiesFull dose sorafenib is the recommended treatment for HCC patients with preserved liver function who are not amenable to surgery and loco-regional treatments or in whom TACE failed, according to the Italian National Health Service rules (1b-A).Piscaglia and Bolondi Dig Liver Dis 2010;42:S238-43Position paper AISF DLD (2013)