1. Intermediate stage HCC management

2. 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.

3. 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:

4. 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:

5. 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
Desease 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
Desease 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) 5

6. Intermediate stage HCC treatment options: TACE

7. 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

8. 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.

9. 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: EASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma Journal of Hepatology 2012 vol. 56 j 908–943 Available on: ; 3. NCCN Clinical Practice Guidelines V Available at: ; 4.Hepatology Research 2010; 40 (Suppl. 1): 8–9; 5. Raccomandazioni AISF per la gestione integrata del paziente con Epatocarcinoma; published on Available on: 9

10. AISF guidelines: patient suitability for TACE
Patients suitable for TACE
Patients unsuitable 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
Position paper AISF DLD (2013)

11. 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 11

12. 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 <
p =
Probability of survival (%)
Probability of survival (%)
Time since randomization (months)
Time since randomization (months)
3-year overall survival (OS): 26%2–29%1 Sustained objective response rate (ORR) (3–6 months): 35%1–39%2 No difference in survival of intention-to-treat (ITT) population between non-responders and control group1
1. Llovet JM, et al. Lancet. 2002;359: Lo C-M, et al. Hepatology. 2002;35:

13. 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 13

14. 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: ; 6. Yip WM, et al. Hong Kong Med J 2009;15:339-45; 7. Gomes AS, et al. AJR Am J Roentgenol 2009;193: ; 8. Mabed et al. Eur J Cancer Care 2009;18:492-9; 9. Forner et al. Seminars Liver Dis 2010;30:61-74; 10. Cho YK, Cancer 2008;112:352-61; 11. Lladó L, et al. Cancer 2000;88:50–7; 12. Cabibbo G, et al. Aliment Pharmacol Ther 2011;34:196–204; 13. Bruix J, et al. Hepatology 1994;20:643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: ; 5. Dumortier J, et al. Dig Liver Dis 2006;38:125–33; 6. Savastano S, et al. J Clin Gastroenterol 1999; 28:334–40; 7. Doffoël M, et al. Eur J Cancer 2008; 44:528–38; 8. Lopez RR, et al. Arch Surg 2002; 137:653–658; 9. Stuart K, et al. Cancer 1993;72:3202–9.
1. Cammà C, et al. Radiology 2002;224:47–54; 2. Yip WM, et al. Hong Kong Med J 2009;15:339-45; 3. Kothary N, et al. J Vasc Interv Radiol 2007;18:1517–26; 4. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:41 Malagari K et al. Cardiovasc Intervent Radiol 2010; 33: Varela M et al. J Hepatol 2007;46:474–81. 14

15. 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 May;37(3):

16. There is no BCLC-B subclassification in the current BCLC system
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

17. 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.

18. 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 May;37(3):

19. 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

20. Proposed treatment algorithm for subclasses of BCLC-B HCC
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.

21. 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. 21

22. 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 Cammà C, et al. Radiology 2002;224:47–54; 5. Bruix J, et al. J Hepatol 2001;35:42130.

23. 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
(0 if present)
AST increase >25%
(0 if absent)
Increase in CP score by 1 point
1.5 (0 if absent)
Increase in CP score by ≥2 points
(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: /hep.26256

24. 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: /hep

25. Consider re-treatment
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 B
No EHS
No PVT
Sieghart W et al. Hepatology 2013 Jan 12. doi: /hep

26. 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. 26

27. 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

28. 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 Dec;57(6):

29. Non–responedrs 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

30. 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

31. 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. 31

32. 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– Lammer J, et al. Cardiovasc Intervent Radiol ;33:41– Hsieh MY, et al. World J Gastroenterol 2004;10:505– Kirchhoff TD, et al. Hepatobiliary Pancreat Dis Int 2007;6:259– Pelletier G, et al. J Hepatol 1990;11:181–4. 6. Molinari M, et al.Clin Oncol (R Coll Radiol) 2006;18:684– Cammà C, et al. Radiology 2002;224:47–54. 32

33. 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.

34. 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: Hwang JI, et al. Anticancer Res. 2005;25: Chen MS, et al. World J Gastroenterol. 2002; 8: Poon RT, et al. J Surg Oncol. 2000;73: Shah SR, et al. QJM. 1998; 91: Huo T, et al. Liver Int. 2004;24: Herber SC, et al. AJR 2008;190: Cammà C, et al. Radiology. 2002;224: Lencioni R, et al. ASCO-GI. 2009;[abstract 116].

35. 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: Stuart K, et al. Cancer. 1993;72: Bruix J, et al. Hepatol. 1998;27: Pelletier G, et al. J Hepatol. 1998;29: Chan AO, et al. Cancer. 2002; 94:

36. 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.

37. 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: Llovet JM, Bruix J. Hepatology 2003;37:429–42; 3. Oliveri et al. Cochrane Database Syst Rev 2011;3:CD Bruix J et al. J Hepatol 2009;50(Suppl 1):S28-9 [abstr 67]; 5. Cheng A, et al. Lancet Oncol 2009;10:2534; 6. Forner A et al. Semin Liver Dis 2010;30:61–74; 7. Raoul J-L et al. Cancer Treat Rev May;37(3): ; 8. Thomas MB et al. J Clin Oncol 2010;28:3994–4005; 9. Piscaglia F, Bolondi L. Digestive Liver Dis 2010;42S:S258–63

38. Intermediate stage HCC treatment options: sorafenib

39. 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: )
Median TTP: 6.9 vs 4.4 months (HR: 0.47; 95% CI: )
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: )
Median TTP: 5.8 vs 4.0 months (HR: 0.57; 95% CI: )
GIDEON interim analysis2
Similar safety profile for sorafenib across BCLC stages
INSIGHT3
Good efficacy demonstrated in BCLC-B HCC
Longer survival in BCLC-B vs BCLC-C patients: 19.6 vs 14.5 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. 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:

40. 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]. 40

41. 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 Oct;57(4): Epub 2012 Jun 19

42. 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 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 Oct;57(4): Epub 2012 Jun 19

43. 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 Oct;57(4): Epub 2012 Jun 19

44. 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:

45. Sorafenib treatment in HCC patients suffering from recurrence after LT
Survival from the time of untreatable progression
Survival after diagnosis of recurrence
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.
Sorafenib seems to be associated with an acceptable safety profile and benefit in survival in HCC patients suffering recurrence after LT.
Sposito C, et. al. Journal of Hepatology 2013 vol. xxx j xxx–xxx

46. Proposed treatment algorithm for LT HCC recurrence
Post-transplant HCC recurrence
Consider:
mTOR inhibitor
Decreasing calcineurin inhibitors
Decreasing overall immunosoppression
Hepatic
Extra-hepatic
Resectable
Non-resectable
Resectable
Non-resectable
Resection RFA
(if < 3 cm)
RFA (if < 3 cm)
TACE
TARE
sorafenib
Resection
sorafenib
Recurrence
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

47. 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)