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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
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
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