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

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.
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):21220.
Intermediate-stage HCC:
BCLC B sub-classification based on tumor burden and
liver function
There is no BCLC-B
subclassification in the
current BCLC system
• 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
Proposed
subclassification based
on clinical evidence
and expert opinion
• 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
Bolondi L, et al. Semin Liver Dis 2012;32:348–359
Intermediate-stage HCC:
BCLC B sub-classification
Child–Pugh
score
Beyond Milan
and within
up-to-7
Tumour-related
ECOG PS
B1
B2
B3
B4
Quasi C
5–6–7
5–6
7
8–9*
A
IN
OUT
OUT
ANY
ANY
0
0
0
0–1
0
NO
NO
NO
NO
YES
PVT
*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
HCC
Stage 0
PS 0, Child–Pugh A
Stage A–C
PS 0–2, Child–Pugh A–B
Very early stage (0)
Early stage (A)
Intermediate stage (B)
1 HCC < 2 cm
Carcinoma in situ
1 HCC or 3 nodules
< 3 cm, PS 0
Multinodular,
PS 0
Portal pressure/
bilirubin
Increased
Resection
Advanced stage (C)
Portal invasion,
N1, M1, PS 1–2
End stage (D)
3 nodules ≤ 3 cm
1 HCC
Normal
Stage D
PS > 2, Child–Pugh C
Associated diseases
No
Liver transplantation
Curative treatments (30%)
5-year survival (40–70%)
Yes
PEI/RFA
TACE
sorafenib
Target: 20%
Target: 40%
OS: 20 mo (45-14) OS: 11 mo (6-14)
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.
BSC
Target: 10%
OS: <3 mo
Intermediate stage HCC:
Levels of evidence and grade of recommendation
Levels of
evidence
(NCI)
Sorafenib
1
Chemoembolization
RF (<5 cm),
Adjuvant therapy after resection
LDLT
RF/PEI (<2 cm)
Resection
OLT-Milan
Internal radiation Y90
2
OLT-extended
Neoadjuvant therapy in waiting list
Downstaging
3
External/palliative radiotherapy
C
B
2 (weak)
A
C
B
A
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
Intermediate stage HCC:
Treatment algorithm – AISF guidelines
HCC not amenable to curative treatments
No portal/hepatic vein invasion
(except segmental or subsegmental
portal branches))
Child Pugh class A or B7
Performance Status ≤1
1st treatment
(cTACE or DEB-TACE)
Complete response
Liver failure or
severe adverse events*
MRI or CT** at 1 month
No
Resolution
Palliation
Yes
No complete response
2nd treatment
(cTACE or DEB-TACE)
MRI or CT every 3 months
MRI or CT** at 1 month
Disease recurrence
Partial response
Newly developed HCC
Consider another course of cTACE or
DEB-TACE (and/or ablation techniques)
* : 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
Disease progression
or stable desease
sorafenib
SORAFENIB
Intermediate stage HCC:
JSH consensus-based treatment algorithm
HCC
No
Extrahepatic
spread
Liver function
Child-Pugh A/B
Vascular
invasion
Number
Yes
Child-Pugh C
No
Single
Yes
≤3 cm
Treatment
•Intensive
follow-up
•Ablation
• Resection
• Ablation
Within Milan
criteria and
age ≤65
>3 cm
Resection
TACE
• TACE +
ablation
•TACE
•HAIC
•Resection
•Ablation
Sorafenib
(TACE refractory, Child-Pugh A)
HAIC: hepatic arterial infusion chemoterapy;
Kudo M, et al. Dig Dis 2011; 29: 339-64.
No
Yes
≥4
1-3
Hypovascular
early HCC
Size
Child-Pugh B/C Child-Pugh A
Exceeding
Milan criteria
or age >65
• HAIC (Vp3, 4)
• Transplantation
• Sorafenib (Vp3, 4) • TACE/ablation
• TACE (Vp1, 2)
for Child-Pugh
• Resection (Vp1, 2) C patients
Palliative care
Sorafenib
Intermediate HCC:
Proposed treatment algorithm for BCLC B subclassification
Child–Pugh
score
Beyond Milan
and within
up-to-7
Tumour-related
ECOG PS
PVT
1st option
Alternative
B1
B2
B3
B4
Quasi C
5–6–7
5–6
7
8–9*
A
IN
OUT
OUT
ANY
ANY
0
0
0
0–1
0
NO
NO
NO
NO
YES***
TACE
TACE or
TARE
BSC
sorafenib
Liver
transplantation**
TACE
TARE
Liver
transplantation
TACE + ablation
sorafenib
Trials
TACE
sorafenib
*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.
BCLC recommendations on TACE are based on
the results of a single meta-analysis
Study
Patients
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
Overall
503
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
Odds ratio (95% CI)
p=0.086
p=0.017
0.01
0.1
0.5 1
Favours treatment
2
10
100
Favours control
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
TACE: long-term survival outcomes
Llovet JM, et al.
80
Chemoembolization
Control
p < 0.0091
60
40
20
100
Probability of survival (%)
Probability of survival (%)
100
Lo C-M, et al.
0
Chemoembolization
Control
p = 0.0022
80
60
40
20
0
0
12
24
36
48
60
Time since randomization (months)
0
6 12 18 24 30 36 42
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
Individual studies included in the meta-analysis reflect:
 Heterogeneity of the intermediate patient population
 Diversity in TACE methodologies
 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
BCLC, Barcelona Clinic Liver Cancer; TACE, transarterial chemoembolization.
Llovet JM, et al. Lancet 2003; 362: 1907–17
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
A
Target lesion responses
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
%
Nodules, n
%
Nodules, n
%
CR
263
68
134
64
9
25
PR
123
32
77
36
27
75
LR
52
20
36
27
6
57
Risposta tumorale
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:
Time to progression: not reached
– >8.9 months (DEB-TACE) vs 7.5 months (cTACE)
– ECOG PS 0/1 75/25%
% of patients
– Child–Pugh A/B 82/18%
60
52
50
DEB-TACE
TACE
44
40
27
30
22
20
10
0
OR
CR
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
70%
61%
Percentage
60%
59%
50%
40%
37%
40%
First cTACE
Second cTACE
30%
20%
10%
0%
6 mesi
12 mesi
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:
•Child-Pugh B1–9
•>3 liver lesions13
•Alpha-fetoprotein
(≥400 ng/mL)2,6,8,9
•Tumour diameter ≥5cm47
•Presence of grade 3
ascites5,10,11
•Bilirubin >3 mg/dL2,7,8,12
•Multi-nodular/diffuse
tumour1,5,8
Technique-related:
•Less selective TACE
procedures
(lobar or bilobar)
13
•Conventional TACE46
•Bilobar tumour1,3
•Portal vein thrombosis1,9
•Performance status ≥13,12,13
1. Dumortier J, et al. Dig Liver Dis 2006;38:125–33.;
2. Savastano S, et al. J Clin Gastroenterol 1999;
28:334–40; 3. Doffoël M, et al. Eur J Cancer 2008;
44:528–38;
4. Florio F, et al. Cardiovasc Intervent Radiol
1997;20:23–8; 5. Pietrosi G, et al. J 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.
Current recommendations and contraindications
for using TACE in HCC patients
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 ChildPugh 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
Pts with PS 0-1 and Child-Pugh A–B7 with
multinodular, asymptomatic tumours
*Considered a relative contraindication
AISF5
Bilirubin >3 mg/dL,*EHS, PVT
or Child-Pugh C
*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
AISF guidelines: patient suitability for TACE
Patients suitable
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
Position paper AISF DLD 2013 45(2013) 712-723
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
AIOM Guidelines
Grado di
raccomandazione SIGN
A
Raccomandazione clinica
Forza della
raccomandazione clinica
Nei pazienti con cirrosi epatica Child-Pugh
A la TACE deve essere preferita come
trattamento per le forme multinodulari e
Positiva forte
per i tumori singoli di grandi dimensioni (>
5 cm) in caso di controindicazione alla
chirurgia
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.
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
Cumulative survival
Cumulative survival
0–1.5 points ART score
≥2.5 points ART score
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
0–1.5 points ART score
≥2.5 points ART score
Time (months)
The ART score was externally validated in an
independent validation cohort.
0‒1.5 points (n=74): 28.0 months (CI: 23–33)
≥2.5 points (n=37): 8.1 months (CI: 6–11) P<0.001
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
HAP classification
Points
Albumin (<36 g/dl)
1
HAP A
0
AFP > 400 ng/ml
1
HAP B
1
Bilirubin > 17 μmol/l
1
HAP C
2
Maximum tumour diameter >7 cm
1
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.
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.
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
Doxorubicin/ lipiodol + polyvinyl alcohol6
Various (meta-analysis of 18 RCTs)7
4.7 (2/42)††
17.5 (14/80) ‡‡
Range 0–57%§§
‡Complications
in 80/182 patients (44%), 38% of complications were 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.
§ Major
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.
Factors reported to be associated with TACErelated 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 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 treatmentrelated death (0.5%1 to 17%2)
Causes of TACE-related death
Decompensated cirrhosis3,4
Embolic nature of TACE4,5











Liver failure
Gastrointestinal bleeding
Renal failure
Hepatic encephalopathy
Septic shock
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 TACErelated mortality
Variables
Number of TACE sessions
Multiple TACE sessions are associated with a higher risk of posttreatment 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):21220; 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
B
Raccomandazione clinica
Nei casi di controindicazione o di
mancata risposta alla TACE deve essere
considerato il trattamento con sorafenib
Forza della
raccomandazione clinica
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 realworld practice
Increased OS and TTP with sorafenib (n=54) vs placebo (n=51)
SHARP1
• Median OS: 14.5 vs 11.4 months (HR: 0.72; 95% CI: 0.38-1.38)
BCLC-B subgroup • Median TTP: 6.9 vs 4.4 months (HR: 0.47; 95% CI: 0.23-0.96)
SHARP1
Previous TACE
subgroup
GIDEON final
analysis2
INSIGHT3
SOFIA4
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)
•
•
Similar safety profile for sorafenib across BCLC stages
Longer survival in BCLC-B vs BCLC-C patients15.6 vs 9.1 months
Good efficacy demonstrated in BCLC-B HCC
•
Longer survival in BCLC-B vs BCLC-C patients: 25.4 vs 14.4 months
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.
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
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].
1.5
SHARP subgroup analysis:
sorafenib prolongs OS in BCLC B patients
Overall Survival
16
14.5
Median (months)
14
12
11.4
10.7
10
8
7.9
Sorafenib
Placebo
6
4
2
0
Overall SHARP population
BCLC B
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, noninterventional study to assess the safety and effectiveness of
sorafenib
• BCLC-C
• BCLC-B unfit for any or
failed to respond to
locoablative treatments
Objectives
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
• Primary: safety
• Secondary: treatment effectiveness
[OS, early radiologic response, and
time to radiologic progression]
• Treatment duration and cumulative
dose
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
p<0,0001
0,50
0,25
0,00
1
2
3
4
0
250
500
750
100
192
389
14
31
61
85
2
13
21
27
0
4
9
4
Median OS (months):
1000
1
1
2
1250
1
1
1
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