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![Page 1: Highlights in the management of gastrointestinal cancer Roma, 21 Maggio, 2010 Treatment algorithm for hepatocellular carcinoma Franco Trevisani Semeiotica.](https://reader031.fdocuments.in/reader031/viewer/2022013100/5514304a550346dd488b5f64/html5/thumbnails/1.jpg)
Highlights in the management of gastrointestinal cancer
Roma, 21 Maggio, 2010
Treatment algorithm for
hepatocellular carcinoma
Franco Trevisani
Semeiotica Medica
Dipartimento di Medicina Clinica
Alma Mater Studiorum - Università di Bologna
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Strategy for staging and treatment assignment(BCLC)
Bruix and Sherman, Hepatology 2005
C
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Trapianto: - Chi trapiantare? - Resezione o trapianto HCC suscettibile di entrambi?
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Bruix and Sherman, Hepatology 2005
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Linee guida: rapidi cambiamenti delle evidenze.Chi trapiantare?
Toso et al., Hepatology 2009
Scientific Registry of Transplant Recipients (USA) 2003-07: 6478 OLT
% Milano-out
Total tumor volume
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Mazzaferro et al., Lancet Oncol 2009
1556 pts. from 36 centres (1122 Milano-out at pathology examination)5-year overall-survival
Chi trapiantare?Il sistema “metro ticket”
10 20 30 40 50 60 70 80 90 100
Size of the largest (mm)
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Linee guida: rapidi cambiamenti delle evidenze. Criteri down-staging di Bologna
0
20
40
60
80
100
0 12 24 36
Act
uari
al s
urvi
val (
%)
Milano-in Down-staging
Post-Tx (88 vs. 32 pts)
0
20
40
60
80
100
0 12 24 36
Act
uari
al s
urvi
val (
%)
Milano-in Down-staging
Intention-to-treat (129 vs. 48 pts)
Down-staging:- 5.1-6 cm - 3.1-5 cm “Milano-in” dopo down-staging- ≤4 cm ciascuno, somma Ø 12 cm- AFP <400 ng/mL
Ravaioli et al., Am J Transplant 2008
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Resezione: - Chi resecare?
Bruix and Sherman, Hepatology 2005
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Resection for HCCOnly single? Only without PHT?
Ishizawa et al., Gastro 2008
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Resection for HCC The Bologna-Torino experience
466 resections
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Resection for HCC The Bologna-Torino model
0 - 3.3% 0 – 2.5%0Mortalità
Bilirubin
Creatinine
INR
MELD
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Percutaneous ablation: for whom?
• PEI is ineffective against: - satellites - microvascular invasion• PEI-induced necrosis is not predictable
Bruix and Sherman, Hepatology 2005
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Percutaneous ablation: for whom?
59%
Ethanol injection
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HCC size and microsatellites
2 cm
0.5 cm
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PEI and RF outcome: the results of 5 RCT
Author Tumor
number x size
Initial CR (%)
Treatment failure (%) (§)
3-year survival
(%)
P value
Lencioni, 2003
PEI (n. 50)
RF (n. 52)
1 x 5 cm
or
3 x 3 cm
92
98
34
8
73
81
NS
Lin, 2004
PEI (n. 52)
RF (n. 52)
1-3 x 3 cm
91
96
45
17
50
74
0.014
Shiina, 2005
PEI (n. 114)
RF (n. 118)
1-3 x 3 cm
100
100
11
2
63
80
0.02
Lin, 2005
PEI (n. 62)
RF (n. 62)
1-3 x 3 cm
89
97
42
16
51
74
0.031
Brunello, 2008
PEI (n. 69)
RF (n. 70)
1-3 x 3 cm
66
96
64
34
57
59
NS
(§): incomplete initial response and/or local recurrence
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RF vs. PEI(meta-analisi di RCT)
Cho et al., Hepatology 2009
Sopravvivenza a 3 anni
RF PEI
Odds ratio 0.48 (95%CI: 0.34-0-67)
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RF results in Child-Pugh A patients with asingle HCC 2 cm
Livraghi et al., Hepatology 2008
Mortality 0
Major complications 1.8% (1 seeding case)
Complete radiological necrosis - 1st course 86% - 2nd course 12% - Total 98%
Sustained complete response 97%(median follow-up 31 mo)
Treatment failure 3%
232 pts
218 pts
6 pts(2.6%)
unfeasibility
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Survival of patients with single HCC 2 cm treated by RF (218 patients)
Livraghi et al., Hepatology 2008
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Survival of patients with singleHCC <2 cm treated by ablation
Analysis by surgical candidacy (100 vs 118)
Livraghi et al., Hepatology 2008
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Terapie ablative percutanee:
Termoblazione o alcolizzazione?
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Strategy for staging and treatment assignment(BCLC)
Bruix and Sherman, Hepatology 2005
C
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Dynamic imaging techniques: arterial phase
TC
MRI
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Conventional TACE
+ Embolic Embolic agentagent =
• Gelatine sponge
• PVA
• Microspheres
• N-isobutilcyanoacrialate
Gelatine sponge
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TACE
Pre- TACE
Post-TACE
Cortesia dott.ssa R. Golfieri
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1. Proper patient selection2. Proper tumor selection3. Proper technical procedure4. Proper timing of treatments
Tumor Progression Treatment-inducedliver failure
Potential factors determining the results of TACE
Trevisani et al., J Clin Gastroenterol 2001
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TACE for intermediate-advanced HCC
Llovet, Hepatology 2002
Overall 2-year mortality OR (95% C.I.)
- Embolization 0.59 (0.29-1.20)
- Chemoembolization 0.42 (0.20-0.88)
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• DC Bead (Biocompatibles, UK) sulphonate-modified compressible hydrogel PVA microspheres designed to release chemotherapy at a slow rate
• Designed to be loaded with Doxorubicin: recommended dose of 25 mg/ml (maximum 37.5 mg/ml)
• Bead sizes 100-300 µm, 300-500 µm, 500-700 µm, 700-900 µm
DRUG-ELUTING BEADS: DC BeadsTM (DEB-TACE)
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Lewis et al J. Vasc. Interv. Radiol. 2006; 17(8):1335 -43
CONVENTIONAL TACE
DC Bead TACE
DRUG-ELUTING BEADS: DC BeadsTM (DEB-TACE)
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0
10
20
30
40
50
60
70
80
0 100 200 300 400
Time (hrs)
[Do
x]
(ng
/mL
)
DEB
TACE
0
10
20
30
40
50
60
70
80
90
100
DEB TACE
Procedure
[Do
x]
in t
um
ou
r @
72
h(n
mo
les
/g t
iss
ue
)
• Doxorubicin in the tumor: more and longer
– Doxorubicin presence in the tumor peaks at 3 days and remains in the tumor for 14 days
– 4 times more Doxorubicin in the tumor compared to conventional TACE
DRUG-ELUTING BEADS: DC BeadsTM (DEB-TACE)
Area under the curveDEB-TACE
TACE
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RCT with DC Beads vs. TACE(Precision V study)
- 212 pz. arruolati: C-P A/B, ECOG 0/1, lobi 1/2, precedente tx.- Procedure bimestrali- End points:
1. risposta tumorale (criteri EASL) a 6 mesi 2. effetti avversi severi
P=0.11
Lammer et al., J Cardiovasc Intervent Radiol 2010
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RCT with DC Beads vs. TACE(Precision V study)
Picco ALT P<0.001
FEVs P=0.018
EA doxo-dipendenti P=0.0001 Alopecia 1% v. 20%
Lammer et al., J Cardiovasc Intervent Radiol 2010
- 212 pz. arruolati: C-P A/B, ECOG 0/1, lobi 1/2, precedente tx.- Procedure bimestrali- End points:
1. risposta tumorale (criteri EASL) a 6 mesi 2. effetti avversi severi
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RCT with DC Beads vs. TACE(Precision-Italy)
117 pazienti arruolati
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YTTRIUM-90 microspheres:
20-40 μm particles emitting
β-radiation, delivered via the
hepatic arterial route.
Average penetration range in tissue: 2.5 mm (maximum 11 mm).
TAR(adio)E
90Y-Radioembolization
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Hypovascular-infiltrative HCCs
Very large HCCs ± Portal invasion
ECOG 2 No extrahepatic spread Child-Pugh class A-B Bilirubin <2 mg (risk of further liver deterioration)
>2 mg: TACE preferable!!
PATIENT SELECTION for 90Y vs. TACE in intermediate-advanced HCC
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01/06 02/0605/0608/06
“Radiation segmentectomy”
TAR(adio)E
90Y-Radioembolization
Cortesia dott.ssa R. Golfieri
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HCC: response (WHO modified-EASL)HCC: response (WHO modified-EASL)
1 month
17 pts
3 months
14 pts
6 months
7 pts
9 months
5 pts
>12 months
4 pts
CR 8 (47%) 6 (43%) 5 (71%) 2 (40%) 2 (50%)
PR 6 (35%) 4 (29%) 1 (14.5%) - -
SD 3 (18%) 2 (14%)
DP in target lesions
0 0 0 0 0
DP new lesions 0 2 (14%)
(1 retreat.)
1 (14.5%)
(1 retreat.)
3 (60%) 2 (50%)
Deaths (liver failure)
0 1 2 3 3
Mean dose: 1350 MBq (range: 740-2010) Mean follow-up: 9.6 months
17 pts (19 treatments)17 pts (19 treatments)
Cortesia dott.ssa R. Golfieri
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Strategy for staging and treatment assignment(BCLC)
Bruix and Sherman, Hepatology 2005
Sorafenib
El-Seragh et al., Gastro 2008
Llovet et al. J Natl Cancer Inst 2008
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Strategy for staging and treatment assignment(Japanese system)
Kudo et al., Oncology 2007; 72 (suppl.1): 2-15Jap Soc Hepatol Guidelines, Hepatol Res 2008
Sorafenib
b: for C-P class B and Ø 2 cm
c: within Milano criteraia
TACE
TARE
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Resection vs. ablation: the results of 3 RCT
Author Tumor
No. x size
Child-Pugh
Survival DF
survival
Complications
Periop.
mortality
Huang, 2005
Resection (n. 38)
PEI (n. 38)
1-2
3 cm
Hepatitis
19
A/B: 28/0
A/B: 29/3
5-yrs
82%
46%
5-yrs
48%
45%
0
0
Chen, 2006
Resection (n. 90)
RF (n. 71)
Single
5 cm
4-yrs
64%
68%
4-yrs
52%
46%
55%
4%
1%
0
Lu, 2006 (abstr.)
Resection (n. 54)
RF/microw. (n. 51)
Milano-in
3-yrs
86%
87%
3-yrs
82%
51%
11%
8%
Huang G-T et al., Ann Surg 2005Chen M-S et al., Ann Surg 2006Lu MD et al., Zhonghua Yi Xue Za Zhi 2006
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Sorafenib treatment for advanced HCCOverall Survival in the SHARP and Asia-Pacific Trials
Months from Randomization
Su
rviv
al P
rob
abil
ity
Sorafenib (n=299)Median: 10.7 months95% CI: 9.4-13.3
Placebo (n=303)Median: 7.9 months95% CI: 6.8-9.1
HR (S/P): 0.6995% CI: 0.55-0.87P=0.00058
0.25
0.50
0.75
1.00
00
4 8 12 16 20
SHARP1
Sorafenib (n=150)Median: 6.5 months 95% CI: 5.6-7.6
Placebo (n=76)Median: 4.2 months 95% CI: 3.7-5.5
HR (S/P): 0.68 95% CI: 0.50-0.93P=0.014
0.25
0.50
0.75
1.00
00
4 8 12 16 20
Asia-Pacific2
Months from Randomization
Su
rviv
al P
rob
abil
ity
1. Llovet JM, et al. N Engl J Med. 2008;359(4):378-3902. Cheng AL, et al. Lancet Oncol. 2009;10:25-34
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Recidiva HCC dopo terapie potenzialmente radicali
Hasegawa et al., J Hepatol 2008
7185 pazienti, 2000-2003 Resezione, PEI o RFA (HCC: 3 cm x 3)
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8 weeksrandomise
Stratify:- prior curative tx- geographical region- CP status
Sorafenib 400mg bid
Placebo
- RFS
- TTR
- OS- Biomarkers
1:1
Design: double-blind RCT
Resection RFA PEI
• Significant OS benefit in phase III gives rationale to go into adjuvant setting
• Prospective, randomized, double-blind, placebo-controlled, company sponsored phase III study
• Primary endpoint: recurrence-free survival
• Patients: n=1100 (randomised)
• Global trial, significant number of patients from China
Clinicaltrials.gov
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Strategy for staging and treatment assignment(BCLC)
Bruix and Sherman, Hepatology 2005
Sorafenib
El-Seragh et al., Gastro 2008
Sorafenib
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Strategy for staging and treatment assignment(Japanese system)
Kudo et al., Oncology 2007; 72 (suppl.1): 2-15Jap Soc Hepatol Guidelines, Hepatol Res 2008
Sorafenib
b: for C-P class B and Ø 2 cm
c: within Milano criteraia
TACE
TARE
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Key pathways in carcinogenesis and molecularly targeted agents under devolopment in advanced HCC
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Strategy for staging and treatment assignment(BCLC)
Paz. 58 aa, HCC 4.5 cm, no invasione postale, N 0, M 0, senza comorbilità, Child-Pugh C.
Bruix and Sherman, Hepatology 2005
Paz. 58 aa, HCC 4.5 cm, no invasione postale, N 0, M 0, senza comorbilità, Child-Pugh A, varici F1.
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HCC size and microsatellites
Kojiro et al, Semin Liver Dis 1999Maeda et al, Hepatogastroenterology 2000Okusaka et al., Cancer 2002Sasaki et al., Cancer 2005Livraghi, J Hepatol Pancreat Surg 2010
2 cm
0.5 cm
3 cm
2 cm
Microvascular Satellites invasion
1.5 cm 0 0
1.6 - 2 cm 10% 3%
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TACE e HCC
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Worldwide HCC burden
• HCC ranks first among PLC: 75-90%
• 5th most frequent tumor in men, 9th in women
• 3rd cause of death among cancers
• 1st cause of mortality in cirrhotic patients
• Incidence (620.000) annual mortality (595.000)
Ferlay et al. IARC CancerBase no. 5, 2004Parking Bray, CA Cancer J Clin 2005El Serag Rudolph, Gastroenterology 2007