natural history and staging system for hcc
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Natural History and Staging System for HCC. Child–Pugh scoring system. Pugh RN, et al. Br J Surg. 1973 ;60: 646-649; Riley TR et al. Am Fam Physician 2001; 64: 1555-60. Natural history and prognostic indicators for survival in Cirrhotic Patients. - PowerPoint PPT PresentationTRANSCRIPT
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Natural History andStaging System for HCC
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Child–Pugh scoring system
Points
1 2 3
Encephalopathy (grade) None 1–2 3–4
Ascites None Slight Moderate
Albumin (g/dL) >3.5 2.8–3.5 <2.8
Prothrombin time prolonged (sec) or INR
<4<1.7
4–61.7-2.3
>6>2.3
Bilirubin (mg/dL) <2 2–3 >3
for primary biliary cirrhosis <4 4–10 >10
Pugh RN, et al. Br J Surg. 1973 ;60: 646-649; Riley TR et al. Am Fam Physician 2001; 64: 1555-60
Class A: 5–6 points
Class B: 7–9 points
Class C: 10–15 points
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Median survival
Compensated cirrhosis: > 12 years
Decompensated cirrhosis: ~ 2 years
Natural history and prognostic indicators for survival in Cirrhotic Patients
Markedly longer survival in patients with compensated cirrhosis vs those with decompensated cirrhosis
1 year risk
D’Amico G, et al. J Hepatology. 2006;44:217-231
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Compensated cirrhosis: absence of jaundice, ascites, portal-systemic encephalopathy or variceal bleeding
Natural history and prognostic indicators for survival in Cirrhotic Patients
Pro
bab
ilit
y o
f su
rviv
al (
%)
Months
Compensated cirrhosisn=806
Decompensated cirrhosisn=843
100
75
50
25
00 12 24 36 48 60 72 84 96 108 120
100
80
60
40
20
0
100
80
60
40
20
Child–Pugh A
1 yr 2 yr 1 yr 2 yr 1 yr 2 yr
Child–Pugh B Child–Pugh C
Compensated
1 yr 2 yr
Decompensated
1 yr 2 yr
Su
rviv
al
(%)
Su
rviv
al
(%)
D’Amico G, et al. J Hepatology. 2006;44:217-231
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Liver cirrhosis: Prognosis by stage
1. de Franchis R [Editor]. Portal Hypertension V: Proceedings of the Fifth Baveno International Consensus Workshop, 5th Ed. 2010
Classification system proposed at the Baveno V workshop1
Compensated Decompensated
No varices
STAGE 1
DEATH
STAGE 2 STAGE 3 STAGE 4 STAGE 5
STAGE 6 ?
Varices Bleeding AscitesAscites
Bleeding
SepsisRenal failure
4–6%
8–12%
10–20%
5–8%
3–5%1%
10–15%
7–10%
~30%
26%
6–15%
N%= expected 1-year outcome rates
No varices
STAGE 1
DEATH
STAGE 2 STAGE 3 STAGE 4 STAGE 5
Varices Bleeding AscitesAscites
Bleeding
SepsisRenal failure
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Survival rates among untreated patients with unresectable HCC
Meta-analysis of patients included in the placebo or no-treatment arms of 30 randomized controlled trials (n=1927)
1. Cabibbo G et al. Hepatology 2010:51:1274-1283; 2. Cabibbo G et al. Hep Med Evidence Res2010:2;163-73.
Survival rates highly heterogeneous
Shorter survival for:– Impaired PS– CP-B or -C– Presence of PVT
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The TNM staging system
Stage Tumor Node Metastases
I T1 N0 M0
II T2 N0 M0
IIIA T3 N0 M0
IIIB T4 N0 M0
IIIC Any T N1 M0
IV Any T Any N M1M = metastases; N = node; T = tumor.
1.Bruix J, Sherman M. Hepatology. 2011;53:1020-2. 2. Pons F, et al. HPB (Oxford). 2005;7:35-41. 3. Kee K, et al. Int J Cancer. 2007;120:2650-
2655.
Advantage of TMN in HCC
• The TNM system and the simplified TNM system are used in many cancers, and therefore there is familiarity with the system1
• Commonly used in the USA in HCC patients1
• Widely tested in the surgical HCC population2
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Disadvantages of the TNM in HCC
• There is lack of homogeneity in outcomes for patients within certain current TNM categories1
• Poor stratification of survival at intermediate stages2
• Requires evidence of microvascular invasion, something that is not available except from surgical specimens3
• Use is limited as it is based on pathological findings and does not consider liver function or tumors < 5 cm4
• Changes to the TNM system have been proposed by several authors, but it still lacks adequate prognostic accuracy1,2,4
The TNM staging system
1. Wildi S, et al. Br J Surg. 2004;91:400-8. 2. Marrero JA, et al. Hepatology. 2005;41:707-16.
3. Bruix J, Sherman M. Hepatology. 2011;53:1020-2.4. Pons F, et al. HPB (Oxford). 2005;7:35-41.
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CLIP staging system for HCC
Median survivalCombined score 0: 35.7 months
Combined score 2: 8.5 months
Combined score 4-6: 3.2 months
Modified from The CLIP investigators. Hepatology 2000; 31: 840-845
Variable 0 1 2
Child-Pugh score A B C
Tumor morphologyUninodular and extension ≤ 50%
Multinodular and extension ≤ 50%
Massive or extension > 50%
AFP (ng/dL) < 400 ≥ 400
Portal vein thrombosis No Yes
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0 2 4 6 8 10
Survival period (year)
Su
rviv
al r
ate
(%)
(n = 722)
6
5
4 3
21
0
CLIP 0 (n = 229)
CLIP 1 (n = 241)
CLIP 2 (n = 136)
CLIP 3 (n = 70)
CLIP 4 (n = 31)
CLIP 5 (n = 8)
CLIP 6 (n = 7)
p < 0.0001
p < 0.01
p < 0.0001
NS
NS
NS
Survival according to the CLIP scoring system
Kudo M, et al. J Gastroenterol. 2003;38:207-15.
• Survival at 3, 5, and 10 years, respectively, for each CLIP group was
− 86%, 72%, and 23% for CLIP 0
− 70%, 47%, and 19% for CLIP 1
− 53%, 37%, and 8% for CLIP 2
− 20%, 7%, and 0% for CLIP 3
− 15%, 15%, and 15% for CLIP 4
− 0%, 0%, and 0% for CLIP 5/6
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The Barcelona Clinic Liver Cancer (BCLC) staging classification for HCC
Llovet JM et al. J Gastroenterol 2005; 40: 225-235
BCLC stagePerformance
statusTumor volume,
number and invasiveness Child-Pugh
0 Very early 0Single < 2 cm
Carcinoma in situA
A Early 0 Single or 3 nodules < 3 cm A – B
B Intermediate 0 Multinodular A – B
C Advanced 1 – 2 Portal invasion N1M1 A – B
D Terminal > 2 Any of above C
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Months
%
Survival
A
B
C
D
Log-rank PA vs B P=0.0002B vs C P<0.0001C vs D P=0.057
Prognosis of newly diagnosed HCC patients (1999 2005) by BCLC class
Cammà et al. Aliment Pharmacol Ther 2008; 28: 62-75
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Staging systems for HCC
Marrero JA et al. Hepatology 2005; 41: 707-716
Staging SystemHepatic function AFP PS Tumor staging
BCLC CTP No YesTumor size, No. of nodules
and PVT
OkudaAscitesAlbuminBilirubin
No NoTumor greater or less
than 50% of cross-sectional area of liver
TNM No No NoNo. of nodules, tumor size,
presence of PVT and metastasis
CLIP CTP< 400 or
≥ 400 ng/mLNo
No. of nodules, tumor greater or less than 50%
area of liver, PVT
CUPIAscites
Bilirubin, AP< 500 or
≥ 500 ng/mLSymptoms TNM
JIS CTP No No TNM
GRETCHBilirubin
AP< 35 or
≥ 35 μg/mLYes PVT
AFP: alpha fetoprotein; AP: alcaline phosphatase; CTP: Child-Turcotte-Pugh; PS: performance status; PVT: portal vein thrombosis
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Staging of HCC: Several different systems are available
AFP, alpha-fetoprotein; AP, alkaline phosphatase; BCLC, Barcelona Clinic Liver Cancer; CLIP, Cancer of the Lliver Italian Program; CUPI, Chinese University Prognostic Index; GRETCH, Groupe d'Etude et de Traitement du Carcinome Hépatocellulaire; HCC, hepatocellular carcinoma; Histol., histological; JIS, Japan Integrated Stage; TNM, tumor nodes metastases.1. American Cancer Society. Available at: http://www.cancer.org/docroot/CRI/content/CRI_2_4_3X_How_is_liver_cancer_staged_25.asp; 2. Schafer DF, et al. Lancet 1999;353:1253-7; 3. Makuuchi M, et al. World J Gastroenterol 2006;12:828-9; 4. CLIP. Hepatology 1998;28:751-5; 5. Chevret S, et al. J Hepatol 1999;31:133-41; 6. Llovet JM, et al. Semin Liver Dis 1999;19:329-38; 7. Leung T, et al. Cancer 2002;94:1760-9.
System
Tumour Spread Liver Symptoms
Tumour features
Histol. grade
AFP Vascular invasion
Metastases Child-Pugh
Bilirubin AP Ascites Cancer symptoms
TNM1 Okuda2 JIS3 CLIP4 GRETCH5 BCLC6 CUPI7
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HCC staging is complex and multifaceted
Staging is used for prognosisand to guide treatment1
Staging HCC1
• Most patients have underlyingliver disease
• Key prognostic indicatorsare not clearly defined
• Prognostic indicators vary during the course of disease
Factors affecting staging2,3
• Tumour stage
• Liver function
• Health status
• Impact of treatment
BCLC, Barcelona Clinic Liver Cancer; CLIP, cancer of the liver Italian program; CUPI, Chinese University Prognostic Index; ECOG PS, Eastern Cooperative Oncology Group performance status; GRETCH, Groupe d'Etude et de Traitement du Carcinome Hépatocellulaire; HCC, hepatocellular carcinoma; JIS, Japan Integrated Stage; TNM, tumor nodes metastases.
1. Llovet JM, et al. Lancet 2003;362:1907–17; 2. Marrero JA, et al. Clin Liver Dis 2006;10:339–51; 3. Marrero JA, et al. Hepatology 2005;41:707–16; 4. Llovet JM, et al. Semin Liver Dis 1999;19:329–38; 5. Leung T, et al. Cancer 2002;94:1760–1769; 6. Chevret S, et al. J Hepatol 1999;31:133–41; 7. Schafer DF, et al. Lancet 1999;353:1253–7; 8. CLIP. Hepatology 1998;28:751–5; 9. Makuuchi M, et al. World J Gastroenterol 2006;12:828–9.
Patient
TumourLiver
ECOGPS
Child-Pugh
TNM
BCLC4
Okuda7
CLIP8
JIS9
CUPI5
GRETCH6
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Cillo U, et al. J Hepatol. 2006;44:723-31.
Prospective validation of the BCLC staging system
The BCLC staging system gives a more precise prognostic stratification in a study group treated mainly with radical therapies
Univariate model(All patients n = 195)
Linear trend2 test
LHR 2 test(p value)
AIC
Okuda 3.98 8.87 (0.0118) 933.06
CLIP 4.17 7.83 (0.0979) 938.10
UNOS-TNM 20.03 28.31 (0.0000) 915.62
JIS 12.45 15.77 (0.0013) 928.16
BCLC 43.01 57.94 (0.0000) 885.98
Multivariate modelAll patients (n = 195)
Log-likelihoodLHR 2 test
(p value)AIC
Full model 434.80 – 899.60
Removing Okuda 436.29 2.97 (0.2258) 898.58
Removing CLIP 436.36 3.11 (0.5385) 894.72
Removing UNOS-TNM 437.47 5.32 (0.1494) 898.94
Removing JIS 435.43 1.26 (0.7386) 896.86
Removing BCLC 449.92 48.90 (0.0000) 923.84
Assessment of BCLC discrimination in the 195 HCC patients
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RFA Sorafenib
Stage 0PST 0, Child–Pugh A
Very early stage (0)
single <2cmCarcinoma in situ
Early stage (A)1 HCC or 3 nodules
<3cm, PST 0
Advanced stage (C)
Portal invasion, N1, M1, PST 1–2
End stage (D)
Liver transplantation TACEResection Symptomatictreatment Curative treatments Palliative treatments
Associated diseases
YesNo
3 nodules ≤3cm
Increased
Normal
1 HCC
Portal pressure/bilirubin
Stage DPST >2, Child–Pugh C
HCC
Intermediate stage (B)Multinodular,
PST 0
Stage A–CPST 0–2, Child–Pugh A–B
AASLD PRACTICE GUIDELINES 2011: Staging and treatment of HCC
Llovet JM, et al. J Natl Cancer Inst. 2008; 100: 698–711
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HCC presentation and survival by BCLC stage in untreated patients from randomized trials
HCC
Stage A–COkuda 1–2, PS 0–2, Child-Pugh A–B
Stage 0PS 0, Child-Pugh A
Stage DPS >2,
Child-Pugh C
Very early stage (0)Single <2 cm
carcinoma in situ
Early stage (A)1–3 nodules <3 cm,
PS 0
Intermediate stage (B)Multinodular,
PS 0
Advanced stage (C)Portal invasion, N1, M1, PS 1–2
End stage (D)
1. Lencioni R et al. Radiol 2005; 234:961–967; 2. Llovet JM, et al. J Natl Cancer Inst 2008;100:698–7; 3. Bruix B, Llovet J. Hepatology 2002;35:51924; 4. Cottone M et al. Gastroenterology 1989; 96:1566-71; 5. Cabibbo G et al. Hepatology 2010:51:1274-1283.
BCLC stage 0-A BCLC stage B BCLC stage C BCLC stage D
30% of pts at presentation3 50% of pts at presentation3 20% of pts3
Asymptomatic HCC: 96% 1-year survival4
50% 1-year survival5
25% 1-year survival5
11% 1-year survival5
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Tumour doubling in untreated nodules
59 small HCCs in 39 patients:
• No correlation to initial tumour size
• No significant relation to cirrhosis severity (trend to faster DT if more severe)
• Serial tumour volume measurements over time identified different growth patterns
Almost constant growth rate (n=8)
Declining growth rate over time (n=9)
Months
Ch
an
ge
in
tu
mo
ur
vo
lum
e
No or very slow initial growth (DT > 200 days); subsequent increasing growth rate (n=10)
Barbare L et al. Hepatology 1992;16:132-7.
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•T1: Resection
Ablation
•T2: Transplant
• 5-yr survival rates 50 – 70%
• HCCs detected in T1 & T2 stages show much better survival• Sensitive imaging modalities to detect HCCs in its early stages
El-Serag HB, et al. Gastroenterology 2008; 134:1752-1763.
Clinical Importance of Early Detection & Precise staging of HCC
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Common worldwide, although disease aetiology varies Often occurs in conjunction with liver cirrhosis Liver function of prognostic importance in cirrhotic patients
• CP-A survival > CP-B survival > CP-C survival Multitude of staging systems exist
• Tumour characteristics alone are unlikely to adequately predict prognosis
• Integrated staging systems are mandatory BCLC staging system links integrated staging and treatment strategy The natural history of intermediate/advanced stage HCC is dismal and prognosis
for patients still remains very poor
• In fact, surgical or locoregional treatments of large tumour burden may further worsen liver function, which might be compromised already
There is a pressing need for improved management strategies to improve survival
The natural history of HCC – a summary
HCC, hepatocellular carcinoma; CP, Child-Pugh.