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.