Intermediate stage HCC management

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

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) 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 HCC, hepatocellular carcinoma; TACE, transarterial chemoembolization. Forner A, et al. Seminars Liver Dis 2010; 30:6174.

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 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

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.

There is no BCLC-B subclassification in the current BCLC system Intermediate-stage HCC: BCLC B sub-classification based on tumor burden and liver function Highly heterogeneous population Patients may differ according to tumour load, age, liver function and comorbidities Decision is only whether to TACE or not to TACE There is no BCLC-B subclassification in the current BCLC system Up-to-7 criterion for tumour burden Liver function Presence of peripheral/(sub)segmental portal vein thrombosis Evaluation of patient characteristics by a multidisciplinary team Proposed subclassification based on clinical evidence and expert opinion Bolondi L, et al. Semin Liver Dis 2012;32:348–359

Intermediate-stage HCC: BCLC B sub-classification Quasi C Child–Pugh score 5–6–7 5–6 7 8–9* A Beyond Milan and within up-to-7 IN OUT ANY Tumour-related ECOG PS 0–1 PVT NO YES *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.

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.

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 substaging proposal is able to refine prognostic prediction in the intermediate HCC stage EASL 2013 – From the presentation of F. Piscaglia – Abstract 109

Intermediate stage HCC: Treatment algorithm – EASL, EORTC guidelines Stage 0 PS 0, Child–Pugh A Stage A–C PS 0–2, Child–Pugh A–B Stage D PS > 2, Child–Pugh C Very early stage (0) 1 HCC < 2 cm Carcinoma 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 Liver transplantation PEI/RFA TACE sorafenib BSC Curative 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 mo PS, performance status; TACE, transarterial chemoembolization; BSC, Best Supportive Care 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.

Intermediate stage HCC: Levels of evidence and grade of recommendation Levels of evidence (NCI) 1 2 3 Sorafenib Chemoembolization RF (<5 cm), RF/PEI (<2 cm) Adjuvant therapy after resection LDLT Resection OLT-Milan Internal radiation Y90 OLT-extended Neoadjuvant therapy in waiting list Downstaging External/palliative radiotherapy C B A C B A 2 (weak) 1 (strong) 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 11

Intermediate stage HCC: Treatment algorithm – AISF guidelines SORAFENIB HCC not amenable to curative treatments Child Pugh class A or B7 Performance Status ≤1 No portal/hepatic vein invasion (except segmental or subsegmental portal branches)) 1st treatment (cTACE or DEB-TACE) 2nd treatment MRI or CT** at 1 month No complete response Partial response Newly developed HCC Complete response Disease recurrence MRI or CT every 3 months Consider another course of cTACE or DEB-TACE (and/or ablation techniques) Liver failure or severe adverse events* Yes No Resolution Palliation Disease progression or stable desease 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 12

Intermediate stage HCC: JSH consensus-based treatment algorithm No Yes Extrahepatic spread 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 and age ≤65 Exceeding Milan criteria or age >65 Hypovascular early HCC Size ≤3 cm >3 cm Treatment Intensive follow-up Ablation Resection Ablation Resection TACE 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 Sorafenib (TACE refractory, Child-Pugh A) HAIC: hepatic arterial infusion chemoterapy; Kudo M, et al. Dig Dis 2011; 29: 339-64.

Intermediate HCC: Proposed treatment algorithm for BCLC B sub-classification Quasi C Child–Pugh score 5–6–7 5–6 7 8–9* A Beyond Milan and within up-to-7 IN OUT ANY Tumour-related ECOG PS 0–1 PVT NO YES*** 1st option TACE TACE or TARE   BSC sorafenib Alternative Liver transplantation TACE + ablation Trials TACE sorafenib Liver transplantation** TACE TARE *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, transarterial radioembolization. Adapted from Bolondi L, et al. Semin Liver Dis 2012;32:348–359.

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

Intermediate stage HCC treatment options: TACE

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 arteries Forner A et al. Critical Reviews in Oncology/Hematology 2006;60:89–98

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, transarterial chemoembolization. Forner A, et al. Seminars Liver Dis 2010; 30:6174.

Outcome assessed = 2 yr survival BCLC recommendations on TACE are based on the results of a single meta-analysis Odds ratio (95% CI) Study Patients Lin, Gastroenterology 1998 63 GETCH, NEJM 1995 96 Bruix, Hepatology 1998 80 Pelletier, J Hepatol 1998 73 Lo, Hepatology 2002 79 p=0.086 Llovet, Lancet 2002 112 p=0.017 Overall 503 OR=0.53 [95% CI, 0.32–0.89]; p=0.017 0.01 0.1 0.5 1 2 10 100 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 19

TACE: long-term survival outcomes Llovet JM, et al. Lo C-M, et al. 100 80 60 40 20 100 80 60 40 20 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) 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 1. Llovet JM, et al. Lancet. 2002;359:1734-9. 2. Lo C-M, et al. Hepatology. 2002;35:1164-71.

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. Llovet JM, et al. Lancet 2003; 362: 1907–17 21

Indications and contraindications to TACE Reported absolute contraindications Decompensated cirrhosis (Child-Pugh B ≥8) including: - Jaundice - Clinical encephalopathy - Refractory ascites - Hepato-renal syndrome Extensive tumour with massive replacement of both entire lobes Severely 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 contraindications Tumour size ≥10 cm Comorbidities involving compromised organ function: - Active cardiovascular disease - Active lung disease Untreated varices at high risk of bleeding Bile-duct occlusion or incompetent papilla due to stent or surgery Raoul et al, Cancer Treatment Reviews 37 (2011) 212–220

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% respectively Mean survival time: 18 ± 9 months Marelli L et al. Cardiovasc Intervent Radiol (2007) 30:6-25

Non–responders vs responders to TACE treatment Overall responses Target lesion responses A B 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

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) Tumor size ≤ 2 cm (N=386) 2.1 - 5 cm (N=211) > 5 cm (N=36) Nodules, n % Risposta tumorale CR 263 68 134 64 9 25 PR 123 32 77 36 27 75 LR 52 20 6 57 Golfieri R, et al. J Vasc Interv Radiol 2013; 24(4): 509-17.

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) 52 27 44 22 10 20 30 40 50 60 OR CR % of patients DEB-TACE TACE In Precision V, only 52% of patients were reported to have an OR (with DEB-TACE) 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 Lammer J et al. Cardiovasc Intervent Radiol 2010;33:41–52

Recurrence rate after TACE cycles Cohort study conducted on 151 patients consecutively treated with cTACE as 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

Factors that may negatively affect prognosis after TACE Patient characteristics: Tumour characteristics: Technique-related: 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 >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 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 Vasc Intervent Radiol 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. Aliment Pharmacol Ther 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 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;54:2264-73; 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. Cardiovasc Intervent Radiol 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. 28

Current recommendations and contraindications for using TACE in HCC patients AASLD1 First-line non-curative for non-surgical pts with large/multifocal tumours EHS, vascular invasion EASL EORTC2 Intermediate (stage B) pts (PS 0 and Child-Pugh A–B) with multinodular, asymptomatic tumours NCCN3 Pts not eligible for curative therapies (resection, transplantation) Bilirubin >3 mg/dL,*PVT or Child-Pugh C JSH4 Child-Pugh A–B with large (>3 cm), multinodular tumours Child-Pugh C, single tumour AISF5 Pts with PS 0-1 and Child-Pugh A–B7 with multinodular, asymptomatic tumours Bilirubin >3 mg/dL,*EHS, PVT or Child-Pugh C *Considered a relative contraindication *Considered a relative contraindication 1. Bruix J, Sherman M. Hepatology 2010 e-pub ahead of print available at: http://www.aasld.org/practiceguidelines/Pages/SortablePracticeGuidelinesAlpha.aspx; 2. 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 ; 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.org Available on: http://www.webaisf.org/media/16110/raccomandazioni-aisf-per-hcc.pdf 29

AISF guidelines: patient suitability for TACE Patients suitable for TACE Patients unsuitable 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 Position paper AISF DLD 2013 45(2013) 712-723

AIOM Guidelines Grado di raccomandazione SIGN Raccomandazione clinica Forza della raccomandazione clinica A Nei 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 chirurgia Positiva forte AIOM Guidelines. Available at: http://www.aiom.it

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 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

Potential indications for stopping or continuing TACE Stopping TACE TACE can be stopped As soon as a complete response is obtained*† In the absence of response after 23 TACE sessions1 If there is progression of the treated lesion* TACE should be stopped in cases of: SAE Arterial thrombosis2 Liver failure3,4 Portal vein thrombosis4 Patient’s decision Continuing TACE TACE 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 guidelines5 SAE, 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;12:10526; 3. Pleguezuelo M, et al. Expert Rev Gastroenterol Hepatol 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.

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) ART score category Points Absence of radiological tumour response 1 (0 if present) AST increase >25% 4 (0 if absent) Increase in CP score by 1 point 1.5 (0 if absent) Increase in CP score by ≥2 points 3 (0 if absent) *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

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 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 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 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.

The Hepatoma Arterial-embolisation Prognostic (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 Prognostic factor Points Albumin (<36 g/dl) 1 AFP > 400 ng/ml Bilirubin > 17 μmol/l Maximum tumour diameter >7 cm HAP classification Points HAP A HAP B 1 HAP C 2 HAP D >2 L. Kadalayil, et al. Annals of Oncology 24: 2565–2570, 2013

The Hepatoma Arterial-embolisation Prognostic (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 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 therapy L. Kadalayil, et al. Annals of Oncology 24: 2565–2570, 2013

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 Pharmacol Ther 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. 38

Complications commonly associated with TACE Most frequent complications of TACE Liver failure (15–51% of pts)15 GI bleeding [variceal hemorrhage or GI ulcers] (10%)13 Ascites (10–17%)2,5 Post-embolization syndrome (>80%)57 Reported at <10% frequency 1,3,5,713 Tumour abscess formation Tumour rupture Haemoperitoneum Hepatic artery occlusion Portal vein thrombosis Ischemic cholecystitis or pancreatitis Renal failure Bacterial peritonitis Pleural effusion Pulmonary 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; 224:47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. 39

The number of patients with major or severe complications associated with TACE varies greatly TACE methodology Rate of major/severe complications,% (n/N) Epirubicin/ lipiodol + gelatin sponge1 ~9.7 (8/82) † Doxorubicin/DEB2 20.4 (19/93)‡ Doxorubicin/polyvinyl alcohol3 45.0 (9/20)§ Doxorubicin + cisplatin/ lipiodol + starch microsphere4 13.0 (6/47)** Doxorubicin + gelfoam5 4.7 (2/42)†† Doxorubicin/ lipiodol + polyvinyl alcohol6 17.5 (14/80) ‡‡ Various (meta-analysis of 18 RCTs)7 Range 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;28:334–40. 2. Lammer J, et al. Cardiovasc Intervent Radiol. 2010 ;33:41–52. 3. Hsieh MY, et al. World J Gastroenterol 2004;10:505–8. 4. Kirchhoff TD, et al. Hepatobiliary Pancreat Dis Int 2007;6:259–66. 5. Pelletier G, et al. J Hepatol 1990;11:181–4. 6. Molinari M, et al.Clin Oncol (R Coll Radiol) 2006;18:684–92. 7. Cammà C, et al. Radiology 2002;224:47–54. 40

Factors reported to be associated with TACE-related complications Variables Use of embolizing agents Severe post-embolization syndrome* (PES)1,2 Associated with duration of PES-related fever1 Low number of treatment cycles TACE method Lower rate of serious liver toxicity with DEB-TACE (2.9%) vs. conventional TACE (9.0%)3 Dose Larger doses of cisplatin/lipiodol associated with increased risk of hepatic decompensation 1,4,5 Multiple treatment cycles Potential to increase the risk of complications6–9 * 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. Cardiovasc Intervent Radiol 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 Pharmacol Ther 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.

Factors associated with TACE-related complications Patient characteristics Liver function Liver damage after TACE is more common in patients with poor liver function1–5 Child–Pugh B status is associated with risk of acute renal failure6 Disease characteristics Tumor size Larger tumor size associated with post-TACE liver failure (p < 0.001)4 TACE characteristics Number of sessions Multiple TACE sessions can increase the risk of complications6–8 TACE method Lower rate of serious liver toxicity with DEB-TACE (2.9%) versus “conventional” TACE (9.0%)9 Dose Larger doses of cisplatin/lipiodol are associated with an increased risk of hepatic decompensation1,2,4 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].

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 death Decompensated cirrhosis3,4 Liver failure Gastrointestinal bleeding Renal failure Hepatic encephalopathy Septic shock Embolic nature of TACE4,5 Tumor rupture Hepatic abscesses Perforated duodenal ulcer Perforation of an ischemic colon Portal vein thrombosis Respiratory failure 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.

Factors reported to be associated with TACE-related mortality Variables Number of TACE sessions Multiple TACE sessions are associated with a higher risk of post-treatment mortality (OR 1.50, p<0.0001)1 Portal vein thrombosis Treatment of patients with portal vein thrombosis was associated with a higher risk of post-TACE mortality (OR 3.24, p=0.013)1 Lobar vs. superselective Mortality at 30 days correlated with extent of embolization (lobar vs. superselective, p=0.03)2 Nature of embolic agents Can be associated with mortality due to tumour rupture, hepatic abscesses, perforated duodenal ulcer, perforation of an ischaemic colon, portal vein thrombosis, respiratory failure3,4 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.

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, 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: 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

Intermediate stage HCC treatment options: sorafenib

AIOM Guidelines Grado di raccomandazione SIGN Raccomandazione clinica Forza della raccomandazione clinica B Nei casi di controindicazione o di mancata risposta alla TACE deve essere considerato il trattamento con sorafenib Positiva forte 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. Available at: http://www.aiom.it

Intermediate HCC: data from SHARP and real-world practice 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 Similar safety profile for sorafenib across BCLC stages Longer survival in BCLC-B vs BCLC-C patients15.6 vs 9.1 months INSIGHT3 Good efficacy demonstrated in BCLC-B HCC Longer survival 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. Bruix et al. J Hepatol. 2012:57:821-9; 2. Bronovicki J-P, et al. Presented at ECC 2013. P 2594; 3. Koschny R, et al. Presented at ESMO 2013. P437; 4. Iavarone M et al. Hepatology 2011;54:2055-63.

Intermediate HCC (BCLC B) Preliminary evidence from SHARP subgroup analysis suggests sorafenib has survival benefits in intermediate HCC Favours sorafenib Favours placebo Overall HR in 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. Bruix J et al. J Hepatol 2009;50(Suppl 1):S28-9 [abstr 67]. 49

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

SHARP subgroup analysis: sorafenib prolongs OS and TTP in BCLC B patients Overall Survival Time to progression BCLC B patients treated with sorafenib (n = 54) had a longer median OS (14.5 vs. 11.4 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 HCC Bruix J et al. J Hepatol. 2012 Oct;57(4):821-9. Epub 2012 Jun 19

SHARP subgroup analysis: sorafenib prolongs OS and TTP post TACE failure Overall Survival Time to progression Patients 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 therapy Bruix J et al. J Hepatol. 2012 Oct;57(4):821-9. Epub 2012 Jun 19

GIDEON final analysis: sorafenib shows longer OS in BCLC-B vs BCLC-C patients Overall survival Bronovicki J-P, et al. Presented at ECC 2013. P 2594

GIDEON final analysis: sorafenib prolongs TTP in BCLC-B vs BCL-C patients Time to progression Bronovicki J-P, et al. Presented at ECC 2013. P 2594

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 sorafenib Objectives Primary: safety Secondary: treatment effectiveness [OS, early radiologic response, and time to radiologic progression] Treatment duration and cumulative dose BCLC-C BCLC-B unfit for any or failed to respond to locoablative treatments 296 pts 25% BCLC-B 75% BCLC-C Results: Median OS = 10,5 months Median OS BCLC-B = 20.6 months Median OS BCLC-C = 8.4 months Iavarone M et al. Hepatology 2011;54:2055-63

INSIGHT subgroup analysis: OS according to BCLC stage Overall survival according to BCLC stage 1: Stage A 1,00 2: Stage B 3: Stage C 0,75 4: Stage D Censored 0,50 p<0,0001 0,25 0,00 250 500 750 1000 1250 1 100 31 13 4 2 192 61 21 9 3 389 85 27 14 Median OS (months): BCLC A: 29.1 months BCLC C: 14.4 months BCLC B: 25.1 months BCLC D: 3.1 months Preliminary median overall survival for BCLC stage C for BCLC stage B is promising in this ongoing study Koschny R, et al. Presented at ESMO 2013. P437

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 burden technicalities alternative therapies Full 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:S238-43 Position paper AISF DLD 2013 45(2013) 712-723