Natural History andStaging System for HCC
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
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
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
5
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
6
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
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
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.
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
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
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
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
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
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
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
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
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
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
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.
•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
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.