Early stage HCC management

BCLC Staging and Treatment Schedule

Adapted from Llovet JM et al. J Natl Cancer Inst 2008;100: 698 – 711

HCC

Stage 0PST 0, Child-Pugh A

Stage A-CPST 0-2, Child-Pugh A-B

Stage DPST>2, Child-Pugh C

Early stage (A)Single or 3 nodules

< 3 cm, PS 0

Intermediate stage (B)Multinodular, Ps 0

Advanced stage (C)Portal invasion,N1, M1, PS 1-2

Terminalstage (D)

Very early stage (O)Single < 2 cm

Carcinoma in situ

Single 3 modules 3 cm

Portalpressure/bilirubin

Normal No Yes

AssociateddiseasesIncreased

Resection Liver Transplantation(CLT/LDLT) PEI/RF Chemoembolization Sorafenib

Curative Treatments (30%)5-yr survival: 50-70%

Randomized controlled trials (50%)3 yr survival: 20-40%

Symptomatic ttc (20%)1 yr survival: 10-20%

ttc: treatment

Levels of evidence in the assessment of benefits in HCC treatment

Llovet JM et al J Natl Cancer Inst 2008;100: 698 – 711

Treatments assessed Benefit EvidenceSurgical treatmentsSurgical resection Adjuvant therapiesLiver transplantation Neoadjuvant therapies

Increased survivalUncertainIncreased survivalTreatment response

3iiA1iiA3iiA2iiDiii

Locoregional treatmentsPercutaneous ablation Ethanol injection Radiofrequency ablationChemoembolizationArterial chemotherapyInternal radiation (I131, Y90)

Increased survival

Better local controlIncreased survivalTreatment responseTreatment response

3iiA

1iiD1iiA3iiDiii3iiDiii

Systemic treatmentsSorafenibTamoxifenSystemic chemotherapyInterferon

Increased survivalNo benefitNo benefitNo benefit

1iA1iA1iiA1iiA

Classification of evidence adapted from the National Cancer Institute (from Llovet JM, et al. J Natl Cancer Inst 2008;100:698-711)

Level 1 = Randomized, controlled trial, meta-analysis (double-blinded, 1i; non-blinded, 1ii)Level 2 = Non-randomized controlled trialLevel 3 = Case series (population-based, 3i; non-population-based, consecutive; 3ii; non-population-based, non-consecutive, 3iii)Endpoints: A = Survival, B = Cause-specific mortality, C = quality of life, D = indirect surrogates (DFS, PFS, tumor response)

Surgical resection

Surgical Resection

Optimal candidates:

BCLC stage 0 or A– Child-Pugh A

– Performance status 0

– Single tumors (< 3 cm)

– Normal portal pressure

– Normal bilirubin

Excellent functional reserve

5-year survival 60-70%

High recurrence rate

50% at 3 years

70% at 5 years

Bruix J et al. J Hepatol 2001; 35: 421-430; Llovet JM. J Gastroenterol 2005; 40: 225-235

Resection in Child A Patients offers good survival

Poon RT et al. Ann Surg 2002; 235(3): 373-82.

70%

Hazard ratio

95% CI

Microscopic vascular invasion

2.36 1.62 – 3.45

Serum AFP value ≥ 32 ng/ml

1.83 1.25 – 2.68

Non anatomical resection

1.65 1.13 – 2.40

Factors contributing to early phase (<2 years) recurrence

Risk Factors Contributing to HCC Early Phase Intrahepatic Recurrence after Hepatectomy

Imamura H et al. J Hepatol 2003; 38: 200-207

Yamamoto M et al. Ann Surg. 2004; 239(3): 395-9

The survival rate of patients with early HCC undergoing Liver Resection decreases 5 years after surgery. This phenomenon is explained by occurrence of second primary HCCs that should be prevented

Early HCC Small advanced HCC

Is resection only a palliation?186 patients with HCC 2 cm treated with curative hepatectomy

Liver transplantation

Liver Transplantation

Illustration Copyright © 2007 Nucleus Medical Art,All rights reserved. www.nucleusinc.com.

5-year survival 70% Recurrence rate < 15%

Bruix J, Sherman M. Hepatology 2005; 42: 1208-1236; Llovet JM. J Gastroenterol 2005; 40: 225-235;Mazzaferro V et al. N Engl J Med 1996; 334: 693-699

Optimal candidates:

• BCLC Stage A disease

• No vascular invasion

• No metastases

• Fulfill the Milan criteria

– Solitary tumor < 5 cm or

– ≤ 3 nodules < 3 cm

Advantage Removal of the diseased liver together with the tumor

Disadvantage Long waiting lists

Mazzaferro V et al. N Engl J Med. 1996; 334(11): 693-9

MILAN Criteria

• Unresectable HCC single nodule <5cm or

<3nodules <3cm

• No vascular invasion or node mets

Ove

rall

Sur

viva

l %

Mazzaferro V et al. N Engl J Med. 1996; 334(11): 693-9

Survival of patients with single HCC < 5 cm or 3 < 3 cm (n= 48)

0

20

40

60

80

100

0 12 24 36 48 months

75%

Liver Transplantation

…The 5-year survival of liver transplantation for HCC has improved

with time (1987-2001). It is possible that the published criteria for

patient selection may have contributed to the better outcome.

Yoo HY et al. J Clin Oncol. 2003; 21(23): 4329-35

Liver Transplantation

Non surgical treatments

Non Surgical Treatments:Percutaneous Ablation

Radiofrequency ablation (RFA)

Percutaneous ethanol injection (PEI)

Optimal candidates:

Child-Pugh A

Single tumors < 3 cm in diameter

Llovet JM. J Gastroenterol. 2005; 40(3): 225-35; Bruix J et al. Hepatology 2005; 42(5): 1208-36; Bruix J et al. J Hepatol. 2001; 35(3): 421-30

Illustration Copyright © 2007 Nucleus Medical Art,All rights reserved. www.nucleusinc.com.

Non Surgical Treatments:Percutaneous Ablation

Radiofrequency ablation (RFA)

Percutaneous ethanol injection (PEI)

Optimal candidates:

Child-Pugh A

Single tumors < 3 cm in diameter

PEI

5-year survival 40-50%

High recurrence rate

50% at 3 years70% at 5 years

Llovet JM. J Gastroenterol. 2005; 40(3): 225-35; Bruix J et al. Hepatology 2005; 42(5): 1208-36; Bruix J et al. J Hepatol. 2001; 35(3): 421-30

Recurrence rates

Recurrence of HCC after curative treatment

PEI/RFALiver

transplantationResection

Very early stage (0)Single <2 cm

carcinoma in situ

Early stage (A)1–3 nodules <3 cm,

PS 0

Single 3 nodules ≤3 cm

Portal pressure/bilirubin

Increased Associated diseases

Normal No Yes

Potentially curative treatment

5-year recurrence

Possible causes contributing to recurrence

HCC stage

>70% >70%<15%

Proliferation of residual microscopic diseaseNeovascularization

Mazzaferro V et al. N Engl J Med 1996;334:693–9; Zavaglia C et al. Am J Gastroenterol 2005;100:2708–16; Cherqui D et al. Ann Surg 2009;250:738–46; Imamura H et al. J Hepatol 2003;38:200–07; Forner A & Bruix J. Hepatology 2008;44:5–7;

Qin LX & Tang ZY. Curr Cancer Ther Rev 2005;1:71–80; Poon R et al. J Clin Oncol 2002;20:1775–85

Poon et al, 2002Llovet et al, 1999

After resection

After ablation

Shiina et al, 2005

100

60

40

20

0

80

0 12 24 32 6048 72

Pro

ba

bil

ity

(%

)

Months

Magnitude of the problem: the unmet need of prevention of recurrence

Llovet J et al. Hepatology 1999;29:62–7; Poon R et al. Ann Surg 2002;235:373–82;Lencioni R et al. Radiology 2005;234:961–7; Shiina S et al. Gastroenterology 2005; 129:122–30

Lencioni et al, 2005

Months

Predictors of EARLY recurrence Predictors of LATE recurrence

• Microscopic vascular invasion

• Serum AFP value ≥32 ng/mL

• Non-anatomical resection

• Grade of hepatitis activity

• Aetiology of hepatitis

• Age

Patterns of HCC recurrence

Imamura H et al. J Hepatol 2003;38: 200–07;Mazzaferro V et al. Hepatology 2006;44:1543–54; Cucchetti A et al. Ann Surg Oncol 2009;16:413–22

Patients who developed recurrence Patients who did not develop recurrence

AFP-expressing tumour cells are disseminated mostly post-operatively This may potentially be the source of recurrence or metastasis

Haematogenous dissemination of tumour cells after resection of HCC

Wong GL et al. Clin Cancer Res 1999;5:4021–7

Micrometastases could spread via invasion of portal vein branchesat an early stage even when the tumour is solitary and small

Micrometastases/microsatellites could spread via invasion of portal vein branches at an early stage

Sasaki A et al. Cancer 2005;103:299–306; Shi M et al. World J Surg 2004;28:376–81

Size of main tumour (mm)

Dis

tan

ce o

f m

icro

sate

llit

e (m

m)

50

0 10 20 30 40 60

40

30

20

10

–10

N=100y = –0.344 + 0.24x

r2 = 0.084P<0.001

Distance of spread (cm)

Nu

mb

er o

f m

icro

met

asta

ses

(n)

80

0.00

Micrometastases in proximal area

70

60

40

20

0

50

30

10

0.25

0.50

0.75

1.00

1.25

1.50

1.75

2.00

2.25

2.50

2.75

3.00

3.25

3.50

Micrometastases in distal area

0

50

LOW RISK <2 risk factors

HIGH RISK ≥2 risk factors

Risk factors for and incidence of late recurrence after surgery overlapwith those associated with HCC first occurrence in cirrhosis

(Resected patients)

(HCC occurrence)

Late recurrence of HCC after surgery

Cucchetti A et al. Ann Surg Oncol 2009;16:413–22

Strong predictors of HCC recurrence after curative resection:

• Microvascular invasion

• Grade of differentiation

• Microsatellites

Microvascular invasionGrade of differentation

Microsatellites

Prognostic factors associated with risk of recurrence

Lauwers GY et al (The International Cooperative Study Group on Hepatocellular Carcinoma). Am J Surg Pathol 2002;26:25–34; Bruix J & Sherman M. Hepatology 2005;42:1208–36

Nuclear grade 1

Nuclear grade 2

Nuclear grade 3

Incidence of mVI and G3 tumours are parallel and increasesignificantly with size-and-number features of HCC

1083 pts

Mazzaferro V et al. Lancet Oncol 2009;10:35–43

Morphology: pathology correlation

The metroticket experience: 1556 HCCs studied with explant pathology

17%

Microvascular invasion and outcome

Roayaie S et al. Gastroenterology 2009;137:850–5

The degree of mVI predicts outcome after resection and could be usefulto select patients for salvage transplant or to enrol patients in trialsevaluating new molecular targeted therapies

Immunoreactivity for anti-smooth muscle actin antibody to asses presence of muscle in the wall

Can mVI invasion be predicted by imaging?

Kim H et al. Eur Radiol 2009;19:1744–51

NMR findings of circumferential peritumoural enhancement showedstatistical correlation with microscopic vascular invasion

Wedge-shaped peritumoural enhancement is triangular enhancement with the base headed way from the tumour

Irregular circumferential peritumoural enhancement: (polygonal shape parallelto the tumour border)

• S1 tumours exhibited more vascular invasion and satellite lesion• These results may suggest that the S1 subclass is associated with

a more invasive/disseminative phenotype

Integrative transcriptome analysis reveals common molecular subclasses of human HCC

Hoshida Y et al. Cancer Res 2009;69:7385–92

A reproducible gene signature correlated with survival in liver tissue adjacent to the tumour

Molecular markers of late recurrence

Hoshida Y et al. N Engl J Med 2008 359:1995–2004

AExpression pattern of 186 gene-survival-signature

BOS accordingto the level of expression of the 186 genes among 225 tissue validation samples

COS according to the level of expression of the 186 genes among 168 pts with longer duration of follow-up

DProbability of late-recurrence according to the expression of the late-recurrence gene signature

Taub R et al. Nat Rev Mol Cell Biol 2004;5:836–47

Liver regeneration pathways after resectionare partially shared by HCC cell proliferation

A Growth factor-dependent

B Cytokine-dependent

Hepatocyte

Hepatocyte

TGF uPA/plasminogen

HGF

MetStellate cell

Pro-HGF

P13KAKTS6 kinaseTGF

AP1JNKpERKC/EBPIGFBP1

PAI

SCF

STAT3

SOCS3

Endothelial cell

VEGF

TOR?

Hepatocyte

Cyclin E

P27

Cyclin D

IL-6

TNF

Kupffer cell

LPS

C3a

C5a

ICAM

A: Growth factor-dependent

• HGF activate hepatocyte regeneration throughdownstream pathways (PI3K, pERK, AKT)

• VEGF activate proliferation of endothelial cells

B: Cytokine-dependent

• IL-6 and TNFα are crucial priming stimuli activating STAT 3, MAPK and pERK

Adjuvant systemic strategies

ChemotherapyChemotherapy

Adjuvant immunotherapyAdjuvant immunotherapy

Vitamin chemopreventionVitamin chemoprevention

Novel agentsNovel agents

- HCFU- UFT- Epirubicin + cisplatin- Capecitabine…..

- Adoptive immunotherapy- Tumour vaccines- Interferon

- Vitamin A- Vitamin K…..

Recurrent HCC after curative treatment: adjuvant strategies

Chemotherapy

No evidence of benefit from adjuvant chemotherapy compared to surgery alone in improving survival rates after curative tumour resection

The potential benefits of CT on tumour recurrence should be weighed against the risk of adverse reactions in patients with an underlying liver dysfunction

Samuel M et al. Cochrane Database Syst Rev 2009;CD001199

Chemotherapy: RCT using UFT (uracil + tegafur)

• No evidence to support potential benefit of adjuvant UFT, an oral agent which combines uracil and 5FU prodrug

• Such treatment may even worsen OS

Hasegawa K et al. Hepatology 2006;44:891–5

Control

Years

Pat

ien

ts (

%)

100

0

80

60

40

20

0

1 2 3 4 5 6 7 8

79 53 38 32 20 18 9UFT

Patients at risk

80 58 43 29 19 13 4

A. Recurrence-free survival

UFT

Control

Years

Pat

ien

ts (

%)

100

0

80

60

40

20

0

1 2 3 4 5 6 7 8

79 79 78 72 54 35 19 7UFT

Patients at risk

80 80 79 75 56 40 21 8Control

B. Overall survival

UFT

Control

Autologous lymphocytes activated with recombinantinterleukin-2 and antibody to CD3

Adjuvant immunotherapy: adoptive immunotherapy

• Safe, feasible and lowers tumour recurrence

• No significant difference in OSTakayama T et al. Lancet 2000;356:802–7

Time after hepatectomy (years)

Rec

urr

ence

-fre

e (%

)

100

80

60

40

20

0

P=0.008

0 1 2 3 4 5 6 7

Immunotherapy

Control

Adjuvant immunotherapy: role of IFN

Clavien PA. Ann Surg 2007;245:843–5

IFN may prevent late recurrence after HCC resection in specific subgroups of HCV cirrhosis

Mazzaferro V et al. Hepatology 2006;44:1543–54

HCV pure patients

Oral polyprenoic acid prevents late recurrence

after surgical resection or PEI

Muto Y et al. N Engl J Med 1996;334:1561–7;Takai K et al. Intervirology 2005;48:39–45

Vitamin chemoprevention of recurrence: retinoids

Level II clinical evidence does not support the use of systemic adjuvant therapy, tested for resectable HCC

Based on the current evidence, there is no role for the aforementioned adjuvant strategies therapy in the management of HCC

Adjuvant systemic strategies

ChemotherapyChemotherapy

Adjuvant immunotherapyAdjuvant immunotherapy

Vitamin chemopreventionVitamin chemoprevention

- HCFU- UFT- Epirubicin + cisplatin-Capecitabine…..

- Adoptive immunotherapy- Tumour vaccines- Interferon

- Vitamin A- Vitamin K…..

Recurrent HCC after curative treatment: adjuvant strategies