Intermediate stage HCC management

HCC, hepatocellular carcinoma; TACE, transarterial chemoembolization.Forner A, et al. Seminars Liver Dis 2010; 30:6174.

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

Increased risk of severe adverse events and liver failure; patients may not benefit at all from TACE

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 908–943Available on: http://www.easl.eu/assets/application/files/d38c7689f123edf_file.pdf

Portal pressure/bilirubin

HCC

PEI/RFA sorafenib

Stage 0PS 0, Child–Pugh A

Very early stage (0)

1 HCC < 2 cmCarcinoma in situ

Early stage (A)

1 HCC or 3 nodules< 3 cm, PS 0

End stage (D)

Liver transplantation TACEResection

Curative treatments (30%)

5-year survival (40–70%)

Associated diseases

YesNo

3 nodules ≤ 3 cm

Increased

Normal

1 HCC

Stage DPS > 2, Child–Pugh C

Intermediate stage (B)

Multinodular,PS 0

Advanced stage (C) Portal invasion, N1, M1, PS 1–2

Stage A–CPS 0–2, Child–Pugh A–B

PS, 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: http://www.easl.eu/assets/application/files/d38c7689f123edf_file.pdf.

Intermediate stage HCC:Treatment algorithm – EASL, EORTC guidelines

Target: 40%

OS: 11 mo (6-14)

Target: 20%

OS: 20 mo (45-14)

BSC

Target: 10%

OS: <3 mo

Treatment algorithm – AISF guidelines

* : 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

SORAFENIB

HCC not amenable to curative treatments

Child Pugh class A or B7Performance Status ≤1

No portal/hepatic vein invasion (except segmental or subsegmental

portal branches))

1st treatment(cTACE or DEB-TACE)

2nd treatment(cTACE or DEB-TACE)

MRI or CT** at 1 month

MRI or CT** at 1 month

No complete response

Partial response Newly developed HCC

Complete response

Desease recurrence

MRI or CT every 3 months

Consider another course of cTACE or DEB-TACE (and/or ablation techniques)

Liver failure orsevere adverse events*

Yes

No Resolution

Palliation

Desease progressionor stable desease

sorafenib

Intermediate stage HCC treatment options:

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

Non Surgical Treatments:TransArterial ChemoEmbolization (TACE)

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; 30:6174.

Current recommendations and contraindications for using TACE in HCC patients

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

*Considered a relative contraindication

Recommendation Contraindications

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

EHS, vascular invasion

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

AISF guidelines: patient suitability for TACE

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

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

Patients suitable for TACE

Patients unsuitable for TACE

Position paper AISF DLD 2013 45(2013) 712-723

Odds ratio (95% CI)Study

Overall

Favours treatment Favours control

Patients

503

Lin, Gastroenterology 1998 63

GETCH, NEJM 1995 96

Bruix, Hepatology 1998 80

Pelletier, J Hepatol 1998 73

Lo, Hepatology 2002 79

Llovet, Lancet 2002 112

0.01 0.1 0.5 1 2 10 100

BCLC recommendations on TACE are based on the results of a single meta-analysis

p=0.017p=0.086

OR=0.53 [95% CI, 0.32–0.89]; p=0.017

- 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

BCLC = Barcelona Clinic Liver Cancer; GRETCH = Groupe d'Etude et de Traitement du Carcinome Hépatocellulaire; HCC = hepatocellular carcinoma; TACE = transarterial chemoembolization

Outcome assessed = 2 yr survival

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

1. Llovet JM, et al. Lancet. 2002;359:1734-9. 2. Lo C-M, et al. Hepatology. 2002;35:1164-71.

TACE: long-term survival outcomes

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

0 12 24 36 48 60 0 6 12 18 24 30 36 42

ChemoembolizationControl

ChemoembolizationControl

100

80

60

40

20

0

p < 0.0091 p = 0.0022

Time since randomization (months)

Pro

babi

lity

of s

urvi

val (

%)

Pro

babi

lity

of s

urvi

val (

%)

Time since randomization (months)

Llovet JM, et al. Lo C-M, et al.

Concluding observations on the meta-analysis by Llovet et al

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.

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

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

Factors that may negatively affect prognosis after TACE

• >3 liver lesions13

• Tumour diameter ≥5cm47

• Multi-nodular/diffuse tumour1,5,8

• Bilobar tumour1,3

• Portal vein thrombosis1,9

Tumour characteristics:

• 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

Patient characteristics:

• Less selective TACE procedures (lobar or bilobar) 13

• Conventional TACE46

Technique-related:

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; 33:4152. 5. Malagari K et al. Cardiovasc Intervent Radiol 2010; 33:541-51. 6. Varela M et al. J Hepatol 2007;46:474–81.

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. 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;20:64350.

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.

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

BCLC B sub-classification

B1 B2 B3 B4 Quasi C

Child–Pugh score 5–6–7 5–6 7 8–9* A

Beyond Milan and within up-to-7 IN OUT OUT ANY ANY

Tumour-related ECOG PS 0 0 0 0–1 0

PVT

NO NO NO 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

EASL 2013 – From the presentation of F. Piscaglia – Abstract 109

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

Cumulative survival

Proposed treatment algorithm for subclasses of BCLC-B HCC

B1 B2 B3 B4 Quasi CChild–Pugh score

5–6–7 5–6 7 8–9* A

Beyond Milan and within up-to-7

IN OUT OUT ANY ANY

Tumour-related ECOG PS

0 0 0 0–1 0

PVT NO NO NO NO YES***

1st optionTACE

TACE or TARE

  BSC sorafenib

Alternative Liver transplantation

TACE + ablationsorafenib

Trials / TACEsorafenib

Liver transplantation**

TACETARE

*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.

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; 224:4754; 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.

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 23 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*

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;12:10526; 3. Pleguezuelo M, et al. Expert Rev Gastroenterol Hepatol 2008;2:76184. 4. Cammà C, et al. Radiology 2002;224:47–54; 5. Bruix J, et al. J Hepatol 2001;35:42130.

*Expert opinion expressed at a specialist workshop on TACE†CR as defined per the EASL guidelines5

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)

Assessment for Retreatment with TACE:the ART score

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≥2.5 points ART score

Time (months)

Cum

ula

tive

sur

viva

l

Cum

ula

tive

sur

viva

l

Sieghart W et al. Hepatology 2013 Jan 12. doi: 10.1002/hep.26256.

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

0–1.5 points ART score≥2.5 points ART score

An ART score of ≥ 2.5 prior the second TACE identifies patients with a dismal prognosis who may not profit from further TACE sessions

Proposed treatment algorithm for TACE repetition according to ART score

* ART score assessment > 14 days and < 90 days

after 1st TACE

Consider SORAFENIB

Consider re-treatment with TACE

1st TACE

CT or MRI

ART score*0–1.5 points ≥2.5 points

Child–Pugh A or BNo EHSNo PVT

Sieghart W et al. Hepatology 2013 Jan 12. doi: 10.1002/hep.26256.

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;32:95564; 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.

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%

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

52

27

44

22

0

10

20

30

40

50

60

OR CR

% o

f pat

ient

s

DEB-TACE TACE

In Precision V, only 52% of patients were reported to have an OR (with DEB-TACE)

• Time to progression: not reached

– >8.9 months (DEB-TACE) vs 7.5 months (cTACE)

Many patients are refractory to TACE

Terzi E. J Hepatol. 2012 Dec;57(6):1258-67

Recurrence rate after TACE cycles

Recurrence Rate

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.

6 mesi 12 mesi0%

10%

20%

30%

40%

50%

60%

70%

37%

61%

40%

59%

First cTACE

Second cTACE

Per

cen

tag

eCohort study conducted on 151 patients consecutively treated with cTACE as a retrospective analysis of a prospective database.

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)

A B

Adapted from Gillmore R et al. Journal of Hepatology 2011 vol. 55 j 1309–1316

Non–responedrs vs responders to TACE treatment

Overall responses Target lesion responses

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

Complications commonly associated with TACE

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.

*Defined as one or more of: encephalopathy, increasing ascites, increase in prothrombin time, increase in serum bilirubin, deterioration of CP status.

Most frequent complications of TACE

• Liver failure (15–51% of pts)15

• GI bleeding [variceal hemorrhage or GI ulcers] (10%)13

• Ascites (10–17%)2,5

• Post-embolization syndrome (>80%)57

Reported at <10% frequency 1,3,5,713

• 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

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%§§

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.

‡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.

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

Associated with duration of PES-related fever1

TACE methodLower 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;11:1814; 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.

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

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].

DEB = drug-eluting beads.

Majority of studies report some TACE-related death within 30 days

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

Most studies describing the use of TACE report some treatment-related death (0.5%1 to 17%2)

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;18:151726; 3. Pelletier G, et al. J Hepatol 1998;29:129–134; 4. Chan AO, et al. Cancer 2002; 94:1747–52.

Sub-analyses from the SHARP and Asia-Pacific studies suggest that sorafenib may benefit some patients with intermediate stage HCC4,5

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 definedA number of guidelines/recommendations recognize that

management strategies are needed for patients who have failed or are unsuitable for TACE

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;10:2534; 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

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)

Intermediate HCC: data from SHARP and real-world practice

SHARP1

BCLC-B 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)

SHARP1

Previous TACE subgroup

Good efficacy demonstrated in BCLC-B HCC• Longer survival in BCLC-B vs BCLC-C patients: 20.6 vs 8.4 months

SOFIA4

Good efficacy demonstrated in BCLC-B HCC• Longer survival in BCLC-B vs BCLC-C patients: 19.6 vs 14.5 monthsINSIGHT3

• Similar safety profile for sorafenib across BCLC stagesGIDEON interim

analysis2

1. Bruix et al. J Hepatol. 2012:57:821-9; 2. Lencioni R et al. Eur J Cancer 2011; 47(Suppl 1):abstract 6500; 3. Ganten TM et al. ESMO 2012, poster 77; 4. Iavarone M et al. Hepatology 2011;54:2055-63.

BCLC= Barcelona Clinic Liver Cancer; HCC= hepatocellular carcinoma; HR= hazard ratio; OS= overall survival; TTP= time to progression

Preliminary evidence from SHARP subgroup analysis suggests sorafenib has survival benefits in intermediate HCC

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].

Advanced HCC (BCLC C)

Favours placebo

HR (95% CI) for survival

0.5 1.0 1.5

Overall HRin SHARP

Favours sorafenib

Intermediate HCC (BCLC B)

Sorafenib: n=245 Placebo: n=252

Sorafenib: n=54Placebo: n=51

Adapted from Bruix J et al. J Hepatol. 2012 Oct;57(4):821-9. Epub 2012 Jun 19

SHARP subgroup analysis:sorafenib prolongs OS in BCLC B patients

Overall Survival

Sorafenib consistently improved median OS compared with placebo in patients with intermediate HCC

Overall SHARP popula-tion

BCLC B0

2

4

6

8

10

12

14

16

10.7

14.5

7.9

11.4

SorafenibPlacebo

Med

ian

(m

onth

s)

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).

Bruix J et al. J Hepatol. 2012 Oct;57(4):821-9. Epub 2012 Jun 19

These exploratory subgroup analysis shows that sorafenib consistently improves median OS and TTP compared with placebo in patients with BCLC B HCC

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).

Bruix J et al. J Hepatol. 2012 Oct;57(4):821-9. Epub 2012 Jun 19

Sorafenib improved TTP and demonstrated a trend toward improved OS, irrespective of prior therapy

• BCLC-C

• BCLC-B unfit for any or failed to respond to locoablative treatments

Objectives

• Primary: safety

• Secondary: treatment effectiveness [OS, early radiologic response, and time to radiologic progression]

• Treatment duration and cumulative dose

296 pts

25% BCLC-B

75% BCLC-C

Results: Median OS = 10,5 monthsMedian OS BCLC-B = 20.6 months Median OS BCLC-C = 8.4 months

Iavarone M et al. Hepatology 2011;54:2055-63

Multicenter (6 centers), investigator sponsored, observational, non-interventional study to assess the safety and effectiveness of sorafenib

SOFIA analysis:sorafenib prolongs OS in BCLC B vs BCLC C patients

Sorafenib treatment in HCC patients suffering from recurrence after LT

Survival of 39 patients suffering recurrence after LT and treated either with sorafenib or receiving best supportive care.

Survival of patients treated either with sorafenib or receiving best supportive care after desease untreatable progression.

Sposito C, et. al. Journal of Hepatology 2013 vol. xxx j xxx–xxx

Sorafenib seems to be associated with an acceptable safety profile and benefit in survival in HCC patients suffering recurrence after LT.

Survival from the time of untreatable progressionSurvival after diagnosis of recurrence

Proposed treatment algorithm for LT HCC recurrence

Post-transplant HCC recurrence

Consider:

• mTOR inhibitor

• Decreasing calcineurin inhibitors

• Decreasing overall immunosoppression

Extra-hepaticHepatic

Resectable Non-resectable Resectable Non-resectable

Resection RFA(if < 3 cm)

RFA (if < 3 cm)TACETAREsorafenib

Recurrence

Resection sorafenib

Recurrence

*Treatment invasiveness should be modulated according to the expected outcome: late recurrences have better potential outcomes and may warrant more aggressive approaches. **Alone or combined to hepatic HCC recurrence Toso C, et. al. Journal of Hepatology 2013 vol. xxx j xxx–xxx

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.

Piscaglia and Bolondi Dig Liver Dis 2010;42:S238-43

Treatment of Intermediate stage HCC:key messages

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).

Position paper AISF DLD 2013 45(2013) 712-723