Gastrolearning II modulo/13a lezione Epatocarcinoma: nulla di nuovo sotto il sole Relatore: Prof. Massimo Colombo (Milano) Discussants: Prof. F. Farinati (Padova), Prof.ssa E. Villa (Modena), Prof. A. Grieco (Roma).

1. Gastro-learning 2014
Milano, 13 ottobre 2014
Epatocarcinoma: nulla di nuovo sotto il sole
Prof. Massimo Colombo
Chairman Department of Liver, Kidney, Lung and Bone Marrow Units and Organ
Transplant
Head Division of Gastroenterology and Hepatology
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico
University of Milan
Milan, Italy

2. Financial Disclosures
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

3. Hepatocellular Carcinoma: Distinct Features
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.
4. The sole solid cancer treatable by organ transplantation

4. 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

5. Evolving Concepts in the Clinical Management
of Hepatocellular Carcinoma
www.aasld.org
2001 EASL
2005 AASLD
2010 APASL
2011 AASLD
2012 EASL

6. The Barcelona Clinic Liver Cancer (BCLC) Staging
Classification for Hepatocellular Carcinoma
BCLC stage
0 Very early
A Early
B Intermediate
C Advanced
D End-stage
Performance
status
0
0
0
1-2
3-4
Tumor volume,number
and invasiveness
≤ 2 cm vaguely nodular
Single < 5 cm or 3 nodes
< 3 cm each
Large/multinodular
Vascular invasion and/or
extrahepatic spread
Any of the above
Child-Pugh
A
A & B
A & B
A & B
C
Forner et al, Sem liver Dis 2010;30:61-74

7. The Barcelona Clinic Liver Cancer (BCLC) Staging
Classification for Hepatocellular Carcinoma
BCLC stage
0 Very early
A Early
B Intermediate
C Advanced
D End-stage
Performance
status
0
0
0
1-2
3-4
Tumor volume,number
and invasiveness
≤ 2 cm vaguely nodular
Single < 5 cm or 3 nodes
< 3 cm each
Large/multinodular
Vascular invasion and/or
extrahepatic spread
Any of the above
Child-Pugh
A
A & B
A & B
A & B
C
Forner et al, Sem liver Dis 2010;30:61-74

8. 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
100
80
74%
50%
25%
Survival (%) months
60
40
20
0
Log Rank 0.00001
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)
Llovet JM et al, Hepatology 1999;30:1434-40

9. Portal Hypertension and Hepatic Resection for Small HCC
A Meta-analysis, 5-year Mortality
Berzigotti et al, Hepatology in press

10. Radiofrequency Ablation in Child Pugh A Cirrhosis
The 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
≤ 3cm 889 97.2 65.1 30.7 6.7 P<0.0001
> 3cm 281 94.8 46.5 18.6 4.6
Shiina et al Am J Gastroenterol 2012;107:569-577

11. Local Tumor Progression of 1462 HCCs after RFA
as a First Line Therapy
Kim et al, J Hepatol 2013;58:89-97

12. 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

13. Overall Survival Following Resection vs RFA vs PEI
in Very Early HCC
Five-year OS: Resection 71.1% vs Ablation 61.1%, P=0.0001
Hasegawa et al, J Hepatol 2013;58:724-729

14. 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 ≤
Cucchetti et al, J Hepatol 2013;59:300-7

15. 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

16. Selection Criteria In Liver Transplantation For HCC
Criteria Definition
Milan (MC) Single nodule ≤ 5 cm
Up to 3 nodules ≤ 3 cm
No macrovascular invasion
UCSF Single ≤ 6.5 cm
Up to three nodules ≤ 4.5 cm
Sum of tumor diameter ≤ 8 cm
Up-to-7 Sum of size (cm) and number of HCC nodules ≤ 7
No mVI
TTV+AFP Any nodule up to TTV ≤115 cm3
AFP ≤400 ng/mL
Milan + AFP Score system based on number of nodules, size of the largest
nodule, AFP at listing (<100; 100–1000; >1000 ng/mL)
Bruix J et al, Gut. 2014;63:844-55 TTV, total tumor volume

17. Predicting Survival after Liver Transplantation in
Patients with HCC beyond Milan Criteria
No. of Patients
(n=1556)
Mazzaferro V et al, Lancet Oncol 2009;10:35-43
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

18. The Founders of BCLC: Staging and Treatment Strategy
Very early (0) Early (A) Intermediate (B) Advanced (C) Terminal(D)
Potential candidate for
liver transplantation
Single Three nodules ≤3 cm
Portal pressure, bilirubin
No Yes Normal Increased Associated diseases
Forner et al, Lancet 2012;379:1245-55
No Yes
Ablation Resection OLT Ablation TAC
E
Sorafenib BSC

19. TACE/RFA Down-Staging of HCC Prior to Liver
Transplantation. An ITT Analysis
Yao et al, Hepatology 2008;48:819-827

20. Salvage Liver Transplantation After Primary Hepatic
Resection for HCC, Milan (±)
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)
Chan et al, J Gastroenterol Hepatol 2014;29:31-34

21. The Barcelona Clinic Liver Cancer (BCLC) Staging
Classification for Hepatocellular Carcinoma
BCLC stage
0 Very early
A Early
B Intermediate
C Advanced
D End-stage
Performance
status
0
0
0
1-2
3-4
Tumor volume,number
and invasiveness
≤ 2 cm vaguely nodular
Single < 5 cm or 3 nodes
< 3 cm each
Large/multinodular
Vascular invasion and/or
extrahepatic spread
Any of the above
Child-Pugh
A
A & B
A & B
A & B
C
Forner et al, Sem liver Dis 2010;30:61-74

22. Intermediate HCC: The Outcome of Chemoembolization
Author,Journal year Patients
Lin , Gastroenterology 1988 63
GRETCH, NEJM 1995 96
Bruix , Hepatology 1998 80
Pelletier, J Hepatol 1998 70
Lo, Hepatology 2002 79
Llovet, Lancet 2002 112
Overall 503
Heterogeneity: Q:7.73 P=0.14
Bruix J et al, Gastroenterology 2004;127:S179-88
Random effects model (DerSimonian & Laird).
OR (95% IC)
0.01 0.1 0.5 1 2 10 100
p=0.017
Favors treatment Favors control
Improved survival: from 16 to 20 months

23. Survival of Patients with Hepatocellular Carcinoma Treated
by TACE Using DC-beads
Overall survival BCLC-A Overall survival BCLC-B
Burrel et al, J Hepatol 2012;56:1330-5

24. 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

25. Transarterial Chemoembolization in Combination with
Local Therapies for HCC: A Meta-Analysis
Three-yr survival
Yao et al, PlosOne 2013 e68453

26. The Barcelona Clinic Liver Cancer (BCLC) Staging
Classification for Hepatocellular Carcinoma
BCLC stage
0 Very early
A Early
B Intermediate
C Advanced
D End-stage
Performance
status
0
0
0
1-2
3-4
Tumor volume,number
and invasiveness
≤ 2 cm vaguely nodular
Single < 5 cm or 3 nodes
< 3 cm each
Large/multinodular
Vascular invasion and/or
extrahepatic spread
Any of the above
Child-Pugh
A
A & B
A & B
A & B
C
Forner et al, Sem liver Dis 2010;30:61-74

27. 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.

28. Overall Survival According to the Prevalent Dose of
Sorafenib in the SOFIA Study (296 Patients)
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
Iavarone M et al. Hepatology 2011;54:2055-63
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)

29. Cost-effectiveness Analyses of Sorafenib Therapy for HCC
Treatment Strategies
Cammà et al, Hepatology. 2013;57:1046-54
Costs in 2012
euros QAL
Y
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€

30. Multimodal Treatment of HCC: How Field Practice Complies
with AASLD Recommendations
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

31. Multimodal Treatment of HCC: How Field Practice Complies
with AASLD Recommendations
Sangiovanni et al submitted
A (AASLD+)
B (AASLD-)
p = 0.0042

32. Multimodality Treatment of HCC: How Field Practice
Complies with AASLD Recommendations
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

33. 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.
Reig M et al, Hepatology. 2013;58:2023-31.

34. Association of Multidisciplinary (MDC) HCC Clinic
with Clinical Outcome
105 patients diagnosed after the MDC clinic (2010)
vs
209 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