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Intermediate stage HCC m anagement

Intermediate stage HCC m anagement. I ndex. Definition of intermediate stage HCC patients Treatment algorithms Treatment option: TACE Results supporting BCLC recommendations on TACE TACE contraindications Efficacy of TACE Indications for stopping or continuing TACE ART score

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Intermediate stage HCC m anagement

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  1. Intermediate stage HCC management

  2. Index • Definition of intermediate stage HCC patients • Treatment algorithms • Treatment option: TACE • Results supporting BCLC recommendations on TACE • TACE contraindications • Efficacy of TACE • Indications for stopping or continuing TACE • ART score • HAP score • Complications associated with TACE • Treatment option: Sorafenib • Treatment guidelines • SHARP • GIDEON • SOFIA • INSIGHT

  3. Intermediate stage HCC: Patient definition – BCLC 2010 • Definition of intermediate stage patients: • Single/large multifocal disease • Asymptomatic • No vascular invasion or extrahepatic spread • Preserved liver function (Child-Pugh A or B) HCC, hepatocellular carcinoma; TACE, transarterialchemoembolization. Forner A, et al. Seminars Liver Dis 2010; 30:6174.

  4. Intermediate stage HCC: Definition and Prognosis - EASL, EORTC • Definition of intermediate stage patients • Multinodular • Tumors without an invasive pattern • Asymptomatic Prognosis of intermediate stage patients • these patients have poor prognoses • median survival of 16 months or 49% at 2 year • outcome 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 ClinicalPracticeGuidelines: Management of hepatocellular carcinoma Journal of Hepatology 2012 vol. 56 j 908–943 Available on: http://www.easl.eu/assets/application/files/d38c7689f123edf_file.pdf

  5. Intermediate-stage HCC:Heterogeneous patient population • Patients with intermediate-stage HCC differ in:1-3 • Tumour burden • Liver function (Child-Pugh A or B) • Disease aetiology • General health status 1.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. 2011 May;37(3):212-20.

  6. Intermediate-stage HCC:BCLC B sub-classificationbased on tumorburden and liverfunction • Bolondi L, et al. Semin Liver Dis 2012;32:348–359

  7. Intermediate-stage HCC:BCLC B sub-classification *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, transarterialradioembolization. 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 degree1-3 • Some patients may benefit more from other treatment options3 • Prognostic factors for a response to TACE could improve treatment decisions and thus patient outcomes 1.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. 2011 May;37(3):212-20.

  9. Prognostic significance of the new BLBC B substaging system Cumulative survival 391 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 substagingproposalisable to refineprognosticprediction in the intermediate HCC stage EASL 2013 – From the presentation of F. Piscaglia– Abstract 109

  10. Intermediate stage HCC:Treatment algorithm – EASL, EORTC guidelines HCC Stage 0PS 0, Child–Pugh A Stage A–CPS 0–2, Child–Pugh A–B Stage DPS > 2, Child–Pugh C Very early stage (0) 1 HCC < 2 cmCarcinoma in situ Early stage (A) 1 HCC or 3 nodules< 3 cm, PS 0 Intermediate stage (B) Multinodular,PS 0 Advanced stage (C) Portal invasion, N1, M1, PS 1–2 End stage (D) 1 HCC 3 nodules ≤ 3 cm Portal pressure/bilirubin Increased Associated diseases Normal No Yes Resection Livertransplantation PEI/RFA TACE sorafenib BSC Curativetreatments (30%) 5-year survival (40–70%) Target: 20% OS: 20 mo (45-14) Target: 40% OS: 11 mo (6-14) Target: 10% OS: <3 mo PS, performance status; TACE, transarterialchemoembolization; BSC, Best Supportive Care EASL–EORTC ClinicalPracticeGuidelines: Management of hepatocellular carcinoma Journal of Hepatology 2012 vol. 56 j 908–943 Available on: http://www.easl.eu/assets/application/files/d38c7689f123edf_file.pdf.

  11. Intermediate stage HCC:Levels of evidence and grade of recommendation 1 Levels of evidence(NCI) Sorafenib Chemoembolization RF (<5 cm), RF/PEI (<2 cm) Adjuvant therapy after resection Resection OLT-Milan 2 LDLT Internal radiation Y90 OLT-extended Neoadjuvant therapy in waiting list Downstaging 3 External/palliative radiotherapy C B A C B A 1 (strong) 2 (weak) Grade of recommendation (GRADE) EASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma Journal of Hepatology 2012 vol. 56 j 908–943 Available on: http://www.easl.eu/assets/application/files/d38c7689f123edf_file.pdf

  12. Intermediate stage HCC:Treatment algorithm – AISF guidelines HCC notamenable to curative treatments No portal/hepaticveininvasion (exceptsegmental or subsegmentalportalbranches)) Child Pughclass A or B7 Performance Status ≤1 1sttreatment (cTACEor DEB-TACE) Liverfailureor severe adverseevents* Complete response MRI or CT** at 1 month Resolution No No complete response Yes Palliation 2ndtreatment (cTACEor DEB-TACE) MRI or CT every 3 months Diseaseprogression or stabledesease MRI or CT** at 1 month Diseaserecurrence Partialresponse Newlydeveloped HCC Consider another course of cTACE or DEB-TACE (and/or ablation techniques) sorafenib SORAFENIB * : each TACE; ** : with cTACE, MRI is preferred to CT *** : Response must be assessed by modified RECIST criteria Position paper AISF DLD 2013 45(2013) 712-723

  13. Intermediate stage HCC: JSH consensus-based treatment algorithm HCC No Yes Extrahepaticspread Liver function Child-Pugh A/B Child-Pugh C Child-Pugh B/C Child-Pugh A Vascular invasion No Yes No Yes Number Single 1-3 ≥4 Within Milan criteria andage ≤65 Exceeding Milan criteriaor age >65 Hypovascular early HCC Size ≤3 cm >3 cm • Intensive follow-up • Ablation • Resection • Ablation • ResectionTACE • TACE +ablation • TACE • HAIC • Resection • Ablation • HAIC (Vp3, 4) • Sorafenib (Vp3, 4) • TACE (Vp1, 2) • Resection (Vp1, 2) • Transplantation • TACE/ablation for Child-Pugh C patients Palliative care Sorafenib Treatment Sorafenib(TACE refractory, Child-Pugh A) HAIC: hepaticarterialinfusionchemoterapy; Kudo M, et al. Dig Dis 2011; 29: 339-64.

  14. Intermediate HCC:Proposed treatment algorithm for BCLC B sub-classification *with severe/refractory ascites and/or jaundice.; **only if up-to-7 IN and PS0, *** segmentary or subsegmentary BSC, best supportive care; PS, performance status; PVT, portal vein thrombosis; TARE, transarterialradioembolization. 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 countries • In Italian clinical practice adherence to guidelines is alarmingly low Borzio M, Sacco R. Future Oncol. (2013) 9(4), 465–467

  16. Intermediate stage HCC treatment options: TACE

  17. Non Surgical Treatments:TransArterialChemoEmbolization (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 arteries Forner 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 TACE • If 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 TACE • If vascular invasion is detected by imaging  increased risk of severe adverse events and liver failure; patients may not benefit at all from TACE • HCC, hepatocellular carcinoma; TACE, transarterialchemoembolization. Forner A, et al. Seminars Liver Dis 2010; 30:6174.

  19. BCLC recommendations on TACE are based on the results of a single meta-analysis Odds ratio (95% CI) Study Patients Lin, Gastroenterology 1998 63 96 GETCH, NEJM 1995 80 Bruix, Hepatology 1998 73 Pelletier, J Hepatol 1998 Lo, Hepatology 2002 79 p=0.086 p=0.017 112 Llovet, Lancet 2002 Overall 503 0.01 0.1 0.5 1 2 10 100 OR=0.53 [95% CI, 0.32–0.89]; p=0.017 Favours treatment Favours control - Child-Pugh B <10 % of all patients - Around 10% had tumor portal vein thrombosis • In most trials no selective TAE • Trials in EU e Asia Outcome assessed = 2 yr survival BCLC = Barcelona Clinic Liver Cancer; GRETCH = Groupe d'Etude et de Traitement du Carcinome Hépatocellulaire; HCC = hepatocellular carcinoma; TACE = transarterial chemoembolization Llovet JM, et al. Lancet 2003; 362: 1907–17

  20. TACE: long-term survival outcomes Llovet JM, et al. Lo C-M, et al. • 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 group1 100 80 60 40 20 0 100 80 60 40 20 0 Chemoembolization Control Chemoembolization Control p < 0.0091 p = 0.0022 Probability of survival (%) Probability of survival (%) 0 12 24 36 48 60 0 6 12 18 24 30 36 42 Time since randomization (months) Time since randomization (months) 1. Llovet JM, et al. Lancet. 2002;359:1734-9. 2. Lo C-M, et al. Hepatology. 2002;35:1164-71.

  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 required • Individual studies included in the meta-analysis reflect: • Heterogeneity of the intermediate patient population • Diversity in TACE methodologies BCLC, Barcelona Clinic Liver Cancer; TACE, transarterial chemoembolization. LlovetJM, et al. Lancet 2003; 362: 1907–17

  22. Indications and contraindications to TACE Raoul et al, Cancer Treatment Reviews 37 (2011) 212–220

  23. Efficacy of TACE • Objectiveresponse (OR) using WHO criteria: 40 ± 20% • Complete tumornecrosis: 44 ± 30% • Survival rate at 1, 2, 3 and 5 years: 62 ± 20%, 42 ± 17%, 30 ± 15%, 19 ± 16% respectively • Meansurvival time: 18 ± 9 months Marelli L et al. CardiovascInterventRadiol (2007) 30:6-25

  24. Non–responders vs responders to TACE treatment B A Target lesion responses Overall responses Kaplan–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 cTACE • Repeated 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, 2.1-5 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) Golfieri R, et al. J Vasc Interv Radiol 2013; 24(4): 509-17.

  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) vs7.5 months (cTACE) 60 52 44 50 40 DEB-TACE % of patients 27 TACE 30 22 20 10 0 In Precision V, only 52% of patients were reported to have an OR (with DEB-TACE) OR CR Many patients are refractory to TACE CR, complete response; cTACE, conventional transarterial chemoembolization; DEB, drug-eluting beads; ECOG PS, Eastern Cooperative Oncology Group performance status; OR, objective response; TACE transarterial chemoembolization LammerJ et al. Cardiovasc Intervent Radiol 2010;33:41–52

  27. Recurrence rate after TACE cycles Cohort study conducted on 151 patients consecutivelytreated with cTACEas a retrospective analysis of a prospective database. Recurrence Rate Percentage The 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. 2012 Dec;57(6):1258-67

  28. Factors that may negatively affect prognosis after TACE Patient characteristics: Tumour characteristics: Technique-related: • >3 liver lesions13 • Tumour diameter ≥5cm47 • Multi-nodular/diffuse tumour1,5,8 • Bilobar tumour1,3 • Portal vein thrombosis1,9 • Less selective TACE procedures (lobar or bilobar) 13 • Conventional TACE46 • Child-Pugh B1–9 • Alpha-fetoprotein (≥400 ng/mL)2,6,8,9 • Presence of grade 3 ascites5,10,11 • Bilirubin >3 mg/dL2,7,8,12 • Performance status ≥13,12,13 1. 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 VascInterventRadiol 2009;20:896-902;6. Yip WM, et al. Hong Kong Med J 2009;15:339-45;7. Gomes AS, et al. AJR Am J Roentgenol 2009;193:1665-71;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. AlimentPharmacolTher 2011;34:196–204; 13. Bruix J, et al. Hepatology 1994;20:64350. 1. Lladó L, et al. Cancer 2000;88:50–7; 2. Mabed et al. Eur J CancerCare 2009;18:492-9; 3. Vogl TJ, et al. Radiol 2000;214:349-57; 4. Sotiropoulos GC, et al. Dig Dis Sci 2009;54:2264-73; 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. CardiovascInterventRadiol 2010; 33:4152. 5. Malagari K et al. Cardiovasc Intervent Radiol 2010; 33:541-51. 6. Varela M et al. J Hepatol 2007;46:474–81.

  29. Current recommendations and contraindications for using TACE in HCC patients *Considered a relative contraindication *Considered a relative contraindication 1. Bruix J, Sherman M. Hepatology 2010 e-pub ahead of printavailableat: http://www.aasld.org/practiceguidelines/Pages/SortablePracticeGuidelinesAlpha.aspx;2. EASL–EORTC ClinicalPracticeGuidelines: Management of hepatocellular carcinoma Journal of Hepatology 2012 vol. 56 j 908–943 Available on: http://www.easl.eu/assets/application/files/d38c7689f123edf_file.pdf; 3. NCCN Clinical Practice Guidelines V.2 2012. Available at: http://www.nccn.org/ ; 4.Hepatology Research 2010; 40 (Suppl. 1): 8–9; 5. Raccomandazioni AISF per la gestione integrata del paziente con Epatocarcinoma; published on www.webaisf.orgAvailable on: http://www.webaisf.org/media/16110/raccomandazioni-aisf-per-hcc.pdf

  30. AISF guidelines: patient suitability for TACE • TACE is not indicated in patients with jaundice, untreatable ascites, main or branch portal vein thrombosis, hepatofugal portal blood flow, HCC nodules larger than 10 cm • TACE 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 considered Patients suitable for TACE Patients unsuitable for TACE Position paper AISF DLD 2013 45(2013) 712-723

  31. AIOM Guidelines AIOM Guidelines. Availableat: http://www.aiom.it

  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 TACE1,2 • This may be achieved in part by defining those patients who will respond well to TACE vs. those who are less likely to respond well1,2 • Generally 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)7,8 TACE, transarterial chemoembolization. 1. Cammà C, et al. Radiology 2002; 224:4754; 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 VascIntervRadiol 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.

  33. Potential indications for stopping or continuing TACE *Expert opinion expressed at a specialist workshop on TACE†CR as defined per the EASL guidelines5 SAE, serious adverse event; TACE, transarterial chemoembolization.1. Bruix J, et al. Hepatology 1998;27:1578–83; 2. Ahrar K, Gupta S. SurgOncolClin N Am 2003;12:10526; 3. Pleguezuelo M, et al. Expert Rev GastroenterolHepatol 2008;2:76184. 4. Cammà C, et al. Radiology 2002;224:47–54; 5. Bruix J, et al. J Hepatol 2001;35:42130.

  34. Assessment for Retreatment with TACE:the ART score • Developed by multivariate regression analysis of • baseline characteristics • radiological response after 1st TACE (EASL-response criteria) • changes of liver function after the 1st TACE • Determined prior to 2nd TACE in BCLC-A*/B patients, who received ≥ 2x TACE • Training cohort: n=107 (Vienna), validation cohort: n=115 (Innsbruck) *BCLC-A not suitable for liver transplantation/local ablative treatment AST, aspartate transaminase; BCLC, Barcelona Clinic Liver Cancer; CP, Child–Pugh; EASL, European Association for the Study of the Liver; TACE, transarterial chemoembolization Sieghart W et al. Hepatology 2013 Jan 12. doi: 10.1002/hep.26256

  35. ART score: prognostic significance Training cohort Validation cohort 0–1.5 points ART score 0–1.5 points ART score ≥2.5 points ART score ≥2.5 points ART score Cumulative survival Cumulative survival Time (months) Time (months) The 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<0.001 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=0.001 An ART score of ≥ 2.5 prior the second TACE identifies patients with a dismal prognosis who may not profit from further TACE sessions Sieghart W et al. Hepatology 2013 Jan 12. doi: 10.1002/hep.26256.

  36. The HepatomaArterial-embolisationPrognostic (HAP) score • Developed by multivariate analysis of prognostic factors • albumin (<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 TACE L. Kadalayil, et al. Annals of Oncology 24: 2565–2570, 2013

  37. The HepatomaArterial-embolisationPrognostic (HAP) score Training dataset Validation dataset Kaplan–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 were25.5 (95%CI 13.7–32.8), 18.1 (95% CI 9.9 to notestimable), 8.9 (95% CI 6.8–16.1) and 5.9 (95% CI 2.8–12.7) months, respectively. AHAP score of C or D defined poor prognosis groups which are unlikely to benefit from TACE and might be better served with systemictherapy L. 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 TACE • Multiple TACE cycles may: • Increase liver damage1,2 • Increase survival2,6 • Regular TACE cycles may increase complications3–6 • Repetition on demand may be more acceptable • Patients often refuse multiple TACE cycles because of side effects7 • Patient’s treatment goals should be considered • Quality of life can be increased by use of repetition on demand8 • Could regular increases in VEGF levels lead to increased vascularization of remaining and/or metastatic tumours?9–11 RCT, randomized controlled trial; TACE, transarterial chemoembolization; VEGF, vascular endothelial growth factor.1.Kwok PC, et al. J Hepatol 2000;32:95564;2.Grieco A, et al. Hepatogastroenterol 2003; 50:20712; 3.Cammà C, et al. Radiology 2002; 224:4754; 4.Herber SCA, et al. AJR 2008;190:103542; 5.Huo T, et al. Aliment PharmacolTher 2004; 19:13018;6. Ernst O, et al. AJR 1999;172:5964; 7.Savastano S, et al. J Clin Gastroenterol 1999;28:33440; 8.Venook AP, et al. J Clin Oncol 1990;8:110814; 9. Li X, et al. W J Gastroenterol 2004;10:287882; 10. Sergio A, et al. Am J Gastroenterol 2008;103:91421; 11. Wang B, et al. Acta Radiologica 2008;49:5239.

  39. Complications commonly associated with TACE *Defined as one or more of: encephalopathy, increasing ascites, increase in prothrombin time, increase in serum bilirubin, deterioration of CP status. GI, gastrointestinal; TACE, transarterialchemoembolization. 1. Cammà C, et al. Radiology 2002; 224:4754; 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;73:10914; 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;94:174752;8. Farinati F, et al. Dig Dis Sci 1996; 41:23329; 9. Kirchhoff TD, et al. Hepatobiliary Pancreat Dis Int 2007; 6:25966; 10. Lopez RR, et al. Arch Surg. 2002; 137:6538; 11. Savastano S, et al. J Clin Gastroenterol 1999; 28:33440; 12. Llovet JM, et al. Lancet 2002;359:1734–39; 13. Shi M, et al. World J Gastroenterol 2010; 16: 264–69.

  40. The number of patients with major or severe complications associated with TACE varies greatly ‡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;28:334–40.2. Lammer J, et al. CardiovascInterventRadiol. 2010 ;33:41–52. 3. Hsieh MY, et al. World J Gastroenterol 2004;10:505–8. 4. Kirchhoff TD, et al. HepatobiliaryPancreat Dis Int 2007;6:259–66. 5. Pelletier G, et al. J Hepatol 1990;11:181–4. 6. Molinari M, et al.ClinOncol (R CollRadiol) 2006;18:684–92. 7. Cammà C, et al. Radiology 2002;224:47–54.

  41. Factors reported to be associated with TACE-related complications * requiring anaesthetics for > 7 days 1.Pelletier G, et al. J Hepatol 1990;11:1814; 2. Chan AO, et al. Cancer 2002; 94:174752; 3. Lammer J, et al. CardiovascInterventRadiol 2010; 33:4152; 4. Hwang JI, et al. Anticancer Res 2005;25:25514; 5. Poon RT, et al. J Surg Oncol 2000;73:10914; 6. Huo T, et al. Aliment PharmacolTher 2004;19:1301–8; 7. Herber SC, et al. AJR 2008;190:103542;8. Cammà C, et al. Radiology 2002;224:4754; 9. Ernst O, et al. AJR 1999;172:5964.

  42. Factors associated with TACE-related complications DEB = drug-eluting beads. 1. Chan AO, et al. Cancer. 2002; 94:1747-52. 2. Hwang JI, et al. Anticancer Res. 2005;25:2551-4. 3. Chen MS, et al. World J Gastroenterol. 2002; 8:74-8. 4. Poon RT, et al. J Surg Oncol. 2000;73:109-14. 5. Shah SR, et al. QJM. 1998; 91:821-8. 6. Huo T, et al. Liver Int. 2004;24:210-5. 7. Herber SC, et al. AJR 2008;190:1035-42. 8. Cammà C, et al. Radiology. 2002;224:47-54. 9. Lencioni R, et al. ASCO-GI. 2009;[abstract 116].

  43. Most studies describing the use of TACE report some treatment-related death (0.5%1 to 17%2) Majority of studies report some TACE-related death within 30 days 1. Takayasu K, et al. Gastroenterol. 2006;131:461-9 2. Stuart K, et al. Cancer. 1993;72:3202-9. 3. Bruix J, et al. Hepatol. 1998;27:1578-83. 4. Pelletier G, et al. J Hepatol. 1998;29:129-34. 5. Chan AO, et al. Cancer. 2002; 94:1747-52.

  44. Factors reported to be associated with TACE-related mortality OR, 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;18:151726;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 TACE1 • Evidence of efficacy is limited2,3 • Most studies carried out in ‘pre-staging’ era • TACE protocols are highly heterogeneous • Intermediate-stage patient segment is not well defined • A number of guidelines/recommendations recognize that management strategies are needed for patients who have failed or are unsuitable for TACE Sub-analyses from the SHARP and Asia-Pacific studies suggest that sorafenib may benefit some patients with intermediate stage HCC4,5 HCC, hepatocellularcarcinoma; SHARP, Sorafenib Hepatocellular carcinoma Assessment Randomized Protocol; TACE, transarterialchemoembolization.1. Bruix J, Sherman M. Hepatology 2011;53:1020–2; full guidelines availableat: http://www.aasld.org/practiceguidelines/Pages/SortablePracticeGuidelinesAlpha.aspx; 2. Llovet JM, Bruix J. Hepatology 2003;37:429–42; 3. Oliveri et al. Cochrane Database Syst Rev 2011;3:CD004787. 4.Bruix J et al. J Hepatol 2009;50(Suppl 1):S28-9 [abstr 67]; 5. Cheng A, et al. Lancet Oncol 2009;10:2534; 6. Forner A et al. Semin Liver Dis 2010;30:61–74; 7. Raoul J-L et al. Cancer Treat Rev. 2011 May;37(3):212-20; 8. Thomas MB et al. J Clin Oncol 2010;28:3994–4005; 9. Piscaglia F, Bolondi L. Digestive Liver Dis 2010;42S:S258–63

  46. Intermediate stage HCC treatment options: sorafenib

  47. AIOM Guidelines In 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. Availableat: http://www.aiom.it

  48. Intermediate HCC: data from SHARP and real-world practice SHARP1 BCLC-B subgroup • Increased OS and TTP with sorafenib (n=54) vs placebo (n=51) • Median OS: 14.5 vs 11.4 months (HR: 0.72; 95% CI: 0.38-1.38) • Median TTP: 6.9 vs 4.4 months (HR: 0.47; 95% CI: 0.23-0.96) SHARP1 Previous TACE subgroup • Increased OS and TTP with sorafenib (n=86) vs placebo (n=90) • Median OS: 11.9 vs 9.9 months (HR: 0.75; 95% CI: 0.49-1.14) • Median TTP: 5.8 vs 4.0 months (HR: 0.57; 95% CI: 0.36-0.91) GIDEON final analysis2 • Similarsafetyprofile for sorafenibacross BCLC stages • Longersurvival in BCLC-B vs BCLC-C patients15.6 vs 9.1 months INSIGHT3 • Goodefficacydemonstrated in BCLC-B HCC • Longersurvival in BCLC-B vs BCLC-C patients: 25.4 vs 14.4 months SOFIA4 • Good efficacy demonstrated in BCLC-B HCC • Longer survival in BCLC-B vs BCLC-C patients: 20.6 vs 8.4 months BCLC= Barcelona Clinic Liver Cancer; HCC= hepatocellular carcinoma; HR= hazard ratio; OS= overall survival; TTP= time to progression 1. Bruixet al. J Hepatol. 2012:57:821-9; 2. Bronovicki J-P, et al. Presentedat ECC 2013. P 2594; 3. Koschny R, et al. Presentedat ESMO 2013. P437; 4. IavaroneM et al. Hepatology 2011;54:2055-63.

  49. Preliminary evidence from SHARP subgroup analysis suggests sorafenib has survival benefits in intermediate HCC Favours sorafenib Favours placebo Overall HRin SHARP Sorafenib: n=245 Placebo: n=252 Advanced HCC (BCLC C) Sorafenib: n=54 Placebo: n=51 Intermediate HCC (BCLC B) 0.5 1.0 1.5 HR (95% CI) for survival BCLC, Barcelona Clinic Liver Cancer; HCC, hepatocellular carcinoma; HR, hazard ratio; CI, confidence interval. BruixJ et al. J Hepatol 2009;50(Suppl 1):S28-9 [abstr 67].

  50. SHARP subgroup analysis:sorafenib prolongs OS in BCLC B patients Overall Survival Median (months) Sorafenibconsistently improved median OS compared with placebo in patients with intermediate HCC Adapted from BruixJ et al. J Hepatol. 2012 Oct;57(4):821-9. Epub 2012 Jun 19

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