early stage hcc management. bclc staging and treatment schedule adapted from llovet jm et al. j natl...
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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