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

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

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.

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

Evolving Concepts in the Clinical Management of Hepatocellular Carcinoma

www.aasld.org

2001 EASL

2005 AASLD

2010 APASL

2011 AASLD

2012 EASL

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

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

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

Portal Hypertension and Hepatic Resection for Small HCCA Meta-analysis, 5-year Mortality

Berzigotti et al, Hepatology in press

≤ 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

Local Tumor Progression of 1462 HCCs after RFA as a First Line Therapy

Kim et al, J Hepatol 2013;58:89-97

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

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

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

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

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)

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

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

TACE/RFA Down-Staging of HCC Prior to Liver Transplantation. An ITT Analysis

Yao et al, Hepatology 2008;48:819-827

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)

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

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

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

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

Transarterial Chemoembolization in Combination withLocal Therapies for HCC: A Meta-Analysis

Yao et al, PlosOne 2013 e68453

Three-yr survival

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

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.

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)

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€

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

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

Sangiovanni et al submitted

A (AASLD+)

B (AASLD-)

p = 0.0042

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

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.

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