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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
Strategy for staging and treatment assignment(BCLC)
Bruix and Sherman, Hepatology 2005
C
Trapianto: - Chi trapiantare? - Resezione o trapianto HCC suscettibile di entrambi?
Bruix and Sherman, Hepatology 2005
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
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)
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
Resezione: - Chi resecare?
Bruix and Sherman, Hepatology 2005
Resection for HCCOnly single? Only without PHT?
Ishizawa et al., Gastro 2008
Resection for HCC The Bologna-Torino experience
466 resections
Resection for HCC The Bologna-Torino model
0 - 3.3% 0 – 2.5%0Mortalità
Bilirubin
Creatinine
INR
MELD
Percutaneous ablation: for whom?
• PEI is ineffective against: - satellites - microvascular invasion• PEI-induced necrosis is not predictable
Bruix and Sherman, Hepatology 2005
Percutaneous ablation: for whom?
59%
Ethanol injection
HCC size and microsatellites
2 cm
0.5 cm
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
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)
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
Survival of patients with single HCC 2 cm treated by RF (218 patients)
Livraghi et al., Hepatology 2008
Survival of patients with singleHCC <2 cm treated by ablation
Analysis by surgical candidacy (100 vs 118)
Livraghi et al., Hepatology 2008
Terapie ablative percutanee:
Termoblazione o alcolizzazione?
Strategy for staging and treatment assignment(BCLC)
Bruix and Sherman, Hepatology 2005
C
Dynamic imaging techniques: arterial phase
TC
MRI
Conventional TACE
+ Embolic Embolic agentagent =
• Gelatine sponge
• PVA
• Microspheres
• N-isobutilcyanoacrialate
Gelatine sponge
TACE
Pre- TACE
Post-TACE
Cortesia dott.ssa R. Golfieri
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
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)
• 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)
Lewis et al J. Vasc. Interv. Radiol. 2006; 17(8):1335 -43
CONVENTIONAL TACE
DC Bead TACE
DRUG-ELUTING BEADS: DC BeadsTM (DEB-TACE)
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
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
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
RCT with DC Beads vs. TACE(Precision-Italy)
117 pazienti arruolati
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
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
01/06 02/0605/0608/06
“Radiation segmentectomy”
TAR(adio)E
90Y-Radioembolization
Cortesia dott.ssa R. Golfieri
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
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
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
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
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
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)
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
Strategy for staging and treatment assignment(BCLC)
Bruix and Sherman, Hepatology 2005
Sorafenib
El-Seragh et al., Gastro 2008
Sorafenib
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
Key pathways in carcinogenesis and molecularly targeted agents under devolopment in advanced HCC
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.
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%
TACE e HCC
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