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Milano, 13 ottobre 2014
Epatocarcinoma: nulla di nuovo sotto il sole
Gastro-learning 2014
Prof. Massimo Colombo
Chairman Department of Liver, Kidney, Lung and Bone Marrow Units and Organ TransplantHead Division of Gastroenterology and HepatologyFondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoUniversity of MilanMilan, Italy
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Grant and research support: BMS, Gilead Science
Advisory committees: Merck, Roche, Novartis, Bayer, BMS, Gilead Science, Tibotec, Vertex, Janssen Cilag, Achillion,
Lundbeck, GSK, GenSpera, AbbVie
Speaking and teaching: Tibotec, Roche, Novartis, Bayer, BMS, Gilead Science, Vertex, Merck, Janssen
Financial Disclosures
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Hepatocellular Carcinoma: Distinct Features
4. The sole solid cancer treatable by organ transplantation
1. The tumor develops in the context of well-known environmental risk factors. The dominant role of HBV and HCV.
2. The tumor is strictly associated with chronic liver disease, mainly cirrhosis. Long phase of intrahepatic growth.
3. One of the few cancers not requiring histology for diagnosis in all cases. Radiological diagnosis possible in cirrhotics and HBV patients.
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European Mean Age-standardised 5-year Relative Survival For Adult Patients With Cancer Diagnosed In 2000–2007
De Angelis et al, Lancet Oncology 2014;15:23-34
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Evolving Concepts in the Clinical Management of Hepatocellular Carcinoma
www.aasld.org
2001 EASL
2005 AASLD
2010 APASL
2011 AASLD
2012 EASL
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The Barcelona Clinic Liver Cancer (BCLC) Staging Classification for Hepatocellular Carcinoma
0 Very early
A Early
B Intermediate
C Advanced
D End-stage
BCLC stage
0
0
0
1-2
3-4
Performance status
≤ 2 cm vaguely nodular
Single < 5 cm or 3 nodes< 3 cm each
Large/multinodular
Vascular invasion and/orextrahepatic spread
Any of the above
Tumor volume,numberand invasiveness
A
A & B
A & B
A & B
C
Child-Pugh
Forner et al, Sem liver Dis 2010;30:61-74
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The Barcelona Clinic Liver Cancer (BCLC) Staging Classification for Hepatocellular Carcinoma
0 Very early
A Early
B Intermediate
C Advanced
D End-stage
BCLC stage
0
0
0
1-2
3-4
Performance status
≤ 2 cm vaguely nodular
Single < 5 cm or 3 nodes< 3 cm each
Large/multinodular
Vascular invasion and/orextrahepatic spread
Any of the above
Tumor volume,numberand invasiveness
A
A & B
A & B
A & B
C
Child-Pugh
Forner et al, Sem liver Dis 2010;30:61-74
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Early HCC: Survival after Resection Is Influenced by Portal Hypertension and Bilirubin
Best candidates for resection : Solitary HCC ≤ 5 cm
Child-Pugh A: Low portal hypertension
Normal bilirubin
0
20
40
60
80
100
0 12 24 36 48 60 72 84 96
< 10 mmHg HVPG (n= 35)≥ 10 mmHg HVPG and normal bilirubin (n=15)
≥ 10 mmHg HVPG and Bilirubin >1 mg/dL (n=27)
Log Rank 0.00001
Su
rviv
al (
%)
months
74%
50%
25%
Llovet JM et al, Hepatology 1999;30:1434-40
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Portal Hypertension and Hepatic Resection for Small HCCA Meta-analysis, 5-year Mortality
Berzigotti et al, Hepatology in press
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≤ 3cm 889 97.2 65.1 30.7 6.7 P<0.0001
> 3cm 281 94.8 46.5 18.6 4.6
Radiofrequency Ablation in Child Pugh A CirrhosisThe Importance of Tumor Number and Size
Tumor N Survival (%)
1 yr 5 yr 10 yr Median (yr)
Solitary 685 97.2 64.6 32.0 7.0 P=0.0003
2-3 395 95.7 54.4 19.9 5.6
≥ 4 90 96.5 53.6 17.6 5.3
Shiina et al Am J Gastroenterol 2012;107:569-577
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Local Tumor Progression of 1462 HCCs after RFA as a First Line Therapy
Kim et al, J Hepatol 2013;58:89-97
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RCT of Resection vs Radiofrequency as First Line Treatment of HCC in Compensated Cirrhosis
Outline & outcomes Chen 2006 Huang 2010 Feng 2012
SR RFA SR RFA SR RFA
Number patients 90 71 115 115 84 84
Max tumor size (cm) 5 5 5 5 4 4
Single tumor (%) 100 100 100 100 62 57
Overall Survival (%)
3-yr 73 71 92 70 75 67
4-yr 68 64 83 66 - -
5-yr - - 76 55* - -
*P=0.001
Chen Ann Surg 2006;243:321-8. Huang et al Ann Surg 2010;252:903. Feng J Hepatol 2012;57:794
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Five-year OS: Resection 71.1% vs Ablation 61.1%, P=0.0001
Overall Survival Following Resection vs RFA vs PEI in Very Early HCC
Hasegawa et al, J Hepatol 2013;58:724-729
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Cucchetti et al, J Hepatol 2013;59:300-7
Review Three-yr Survival Following Resection or RFA of HCC in Child Pugh A Cirrhosis
Radiofrequency more cost-effective than resection
in very early HCC and 2-3 nodules ≤ 3 cm
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STORM RCT of Adjuvant Sorafenib after Curative Resection or Ablation
Outcomes Sorafenib Placebo Hazard ratio (95% CI) P-value
Recurrence free survival, mos 33.4 33.8 0.940 (0.780-1.134) 0.26
Time to progression, mos 38.6 35.8 0.891 (0.735-1.081) 0.12
Overall survival, mos NR NR 0.995 (0.761-1.300) 0.48
Tx-related Adverse events, %
All grade 98 90
Serious 40 42
Bruix et al, ASCO 2014 Chicago
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Selection Criteria In Liver Transplantation For HCC
Bruix J et al, Gut. 2014;63:844-55 TTV, total tumor volume
Criteria Definition
Milan (MC) Single nodule ≤ 5 cmUp to 3 nodules ≤ 3 cmNo macrovascular invasion
UCSF Single ≤ 6.5 cmUp to three nodules ≤ 4.5 cmSum of tumor diameter ≤ 8 cm
Up-to-7 Sum of size (cm) and number of HCC nodules ≤ 7No mVI
TTV+AFP Any nodule up to TTV ≤115 cm3AFP ≤400 ng/mL
Milan + AFP Score system based on number of nodules, size of the largestnodule, AFP at listing (<100; 100–1000; >1000 ng/mL)
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Predicting Survival after Liver Transplantation in Patients with HCC beyond Milan Criteria
Mazzaferro V et al, Lancet Oncol 2009;10:35-43
No. of Patients
(n=1556)
Milan in
(n=444)
Milan out
(n=1112)
P-value
No. tumors
Median (range)
3 (1-20) 1 (1-3) 4 (1-20) <0.0001
Max tumor size, mm
Median (range)
35 (1-200) 20 (1-50) 40 (4-200) <0.0001
Vascular invasion, n
No
Yes
977 (66.2%)
498 (33.8%)
361 (89.1%)
44 (10.9%)
616 (57.6%)
454 (42.4%)
<0.0001
Overall survival
(95% CI) at 10 years
46.8% (43.0-50.5) 69.6% (63.7-74.8) 38.7% (34.2-43.1) <0.0001
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The Founders of BCLC: Staging and Treatment Strategy
Forner et al, Lancet 2012;379:1245-55
Very early (0) Early (A) Intermediate (B) Advanced (C) Terminal(D)
Potential candidate forliver transplantation
Single Three nodules ≤3 cm
Portal pressure, bilirubin
No Yes Normal Increased Associated diseases
No Yes
Ablation OLTResection Ablation TACE
Sorafenib BSC
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TACE/RFA Down-Staging of HCC Prior to Liver Transplantation. An ITT Analysis
Yao et al, Hepatology 2008;48:819-827
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Salvage Liver Transplantation After Primary Hepatic Resection for HCC, Milan (±)
Chan et al, J Gastroenterol Hepatol 2014;29:31-34
A review of 16 comparative/cohort studies
N=319 Patients SLT Complications Biliary 8%
Tumor size 2.5-3.4 cm Infection 11%
Micro vs macrovascular: 28% vs 4% Bleeding 8%
18-29% Major hepatectomy (0-6% deaths) Vascular 7%
27-80% Tumor recurrence Deaths 6%
16-65% Salvage Liver Transplantation (SLT) Five-yr survival 62% (41-89)
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The Barcelona Clinic Liver Cancer (BCLC) Staging Classification for Hepatocellular Carcinoma
0 Very early
A Early
B Intermediate
C Advanced
D End-stage
BCLC stage
0
0
0
1-2
3-4
Performance status
≤ 2 cm vaguely nodular
Single < 5 cm or 3 nodes< 3 cm each
Large/multinodular
Vascular invasion and/orextrahepatic spread
Any of the above
Tumor volume,numberand invasiveness
A
A & B
A & B
A & B
C
Child-Pugh
Forner et al, Sem liver Dis 2010;30:61-74
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Intermediate HCC: The Outcome of Chemoembolization
Bruix J et al, Gastroenterology 2004;127:S179-88
Lin , Gastroenterology 1988 63
GRETCH, NEJM 1995 96
Llovet, Lancet 2002 112
Pelletier, J Hepatol 1998 70
Bruix , Hepatology 1998 80
Overall 503
Heterogeneity: Q:7.73 P=0.14
Author,Journal year Patients
Lo, Hepatology 2002 79
Favors treatment Favors control
1010.10.01 1000.5 2
p=0.017
Random effects model (DerSimonian & Laird).
OR (95% IC)
Improved survival: from 16 to 20 months
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Survival of Patients with Hepatocellular Carcinoma Treated by TACE Using DC-beads
Burrel et al, J Hepatol 2012;56:1330-5
Overall survival BCLC-A Overall survival BCLC-B
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Uncontrolled Studies: Y-90 Radioembolization (RE) in HCC BCLC B Patients
Adapted from Sangro et al, J Hepatol 2012;56:464-7
Salem 2011
Wang 2008
Chen 2009
Hilgard 2010
Salem 2010
Sangro 2011
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Transarterial Chemoembolization in Combination withLocal Therapies for HCC: A Meta-Analysis
Yao et al, PlosOne 2013 e68453
Three-yr survival
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The Barcelona Clinic Liver Cancer (BCLC) Staging Classification for Hepatocellular Carcinoma
0 Very early
A Early
B Intermediate
C Advanced
D End-stage
BCLC stage
0
0
0
1-2
3-4
Performance status
≤ 2 cm vaguely nodular
Single < 5 cm or 3 nodes< 3 cm each
Large/multinodular
Vascular invasion and/orextrahepatic spread
Any of the above
Tumor volume,numberand invasiveness
A
A & B
A & B
A & B
C
Child-Pugh
Forner et al, Sem liver Dis 2010;30:61-74
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Randomized Controlled Trials of Sorafenib in Advanced Hepatocellular Carcinoma
Study Characteristics SHARP Study1 Asia Study2
Median age 65 yrs 51 yrs
BCLC-B stage 18% 4%
Previous treatments 67% na
HBV etiology of cirrhosis 19% 71%
TTP (control) 5.5 mo (2.8 mo) 2.8 mo (1.4 mo)
Median survival (control) 10.7 mo (7.9 mo) 6.5 mo (4.2 mo)
Grade 3/4 toxicity 30% 24%
1. Llovet JM, et al. N Eng J Med. 2008;359(4):378-390; 2. Cheng A et al. Lancet Oncol. 2009;10(1):25-34.
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Overall Survival According to the Prevalent Dose of Sorafenib in the SOFIA Study (296 Patients)
Iavarone M et al. Hepatology 2011;54:2055-63
Total patients: 296
•97 (40%) discontinued without
previous dose reduction
•122 with half dose for <70% of the
treatment period
•77 patients with half dose for ≥70%
of the treatment period
Predictors of mortality HR (95% CI)
ECOG Performance Status 1.9 (1.5 – 2.5)
Macroscopic vascular
invasion
1.9 (1.4 – 2.6)
Extrahepatic spread 1.4 (1.1 – 1.9)
Early radiological progression 1.4 (1.1 – 2.1)
Full dosing 1.8 (1.4-2.4)
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Cost-effectiveness Analyses of Sorafenib Therapy for HCC
Cammà et al, Hepatology. 2013;57:1046-54
Treatment StrategiesCosts in 2012
euros QALY
ICER/QALY base-case analysis (2012 euros)
Best supportive care 4,142 - -
BCLC B+C Full dose 16,081 0.16 69,344
Dose-adjusted 19,944 0.44 34,534
BCLC B Full dose 24,224 0.32 57,385
Dose-adjusted 26,914 0.38 54,881
BCLC C Full dose 14,841 0.16 65,551
Dose-adjusted 16,625 0.44 27,916
Willingness to pay for 1 ICER/Quality = 34,000€
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Reasons for withdrawing from recommendations
Total (No.370)
BCLC A (No. 251)
BCLC B (No. 66)
BCLC C (No. 53)
Impaired liver function 17 (5%) 0 7 (11%) 10 (19%)
Strategic localization and/or vascular invasion
53 (14%) 19 (8%) 21 (32%) 7 (13%)
Co-morbidities 33 (9%) 28 (11%) 2 (3%) 9 (17%)
Sangiovanni et al submitted
Multimodal Treatment of HCC: How Field Practice Complies with AASLD Recommendations
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Multimodal Treatment of HCC: How Field Practice Complies with AASLD Recommendations
Sangiovanni et al submitted
A (AASLD+)
B (AASLD-)
p = 0.0042
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TREATMENT
Total
(No. 370)
BCLC A
(No. 251)
BCLC B
(No. 66)
BCLC C
(No. 53)
OLT 29 (8%) 26 (10%) 3 (4%) 0
Resection 59 (16%) 52 (21%) 6 (9%) 1 (2%)
Local ablation 146 (40%) 126 (50%) 13 (21%) 7 (13%)
Chemoembolization 90 (24%) 45 (18%) 36 (54%) 9 (17%)
Sorafenib 34 (9%) 1 (0.5%) 6 (9%) 27 (51%)
Best supportive care 12 (3%) 1 (0.5%) 2 (3%) 9 (17%)
Sangiovanni et al submitted
Multimodality Treatment of HCC: How Field Practice Complies with AASLD Recommendations
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Reig M et al, Hepatology. 2013;58:2023-31.
Post-progression Survival of Patients with Advanced HCC. Rationale for Second Line Trial Design
BCLCp C1: Patients BCLC-C under sorafenib treatment with progression due to growth of existing nodules or new intra-hepatic sites.BCLCp C2: Patients BCLC-C under sorafenib treatment with progression due to new extra-hepatic lesion and/or vascular invasion.
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Association of Multidisciplinary (MDC) HCC Clinic with Clinical Outcome
105 patients diagnosed after the MDC clinic (2010)vs209 patients diagnosed in the 3 previous years
1. Received treatment 56% vs 44% P=0.04
2. Time to treatment (mo.) 2.2 vs 4.7 P=0.001
3. Survival time (mo.) 15.2 vs 4.7 P=0.002
4. One-year survival 64% vs 47% P=0.001*
*after excluding BCLC-D patients
Yopp et al, Journal of Clinical Oncology 2013;31 suppl:332