clinicaloptions.com/oncology a multidisciplinary perspective on the management of hcc 肝癌年報

clinicaloptions.com/oncology

A Multidisciplinary Perspective on the Management of HCC

肝癌年報



Hepatocellular Carcinoma: Overview

Burden of HCC

Surveillance and diagnosis

Staging and treatment algorithms

– Early HCC

– Intermediate HCC

– Advanced HCC

A look to the future



衛生署 2008 & 2010 死亡統計

惡性腫瘤自 1982 年起即高居台灣民眾死因首位，

2008 年死亡人數首次破 14 萬人，標準化死亡率為每 10 萬人口 484.3 人

十大死因：惡性腫瘤為 3萬 8913 人，佔所有死亡人數的 27.3% 、標準化死亡率為每 10 萬人口 133.7 人

2008 年十大癌症順位分別是肺癌占 20% 、肝癌占 19.7% 、結腸直腸癌占 11%、女性乳癌占 4% 、胃癌占 5.9%

衛生署資料顯示， 2010 年死亡人數占率依序為：惡性腫瘤占 28.4% 、心臟疾病占 10.8% 、腦血管疾病占 7.0% 、



肝細胞癌的發生率

在民國 69 年的統計中，男性與女性的每十萬人死亡率分別是 26.10 及 8.14

肝細胞癌的發生率男性是每十萬人有二十五人，在女性是每十萬人有十人。

年發生率在慢性 B 型肝炎的人是 0.826 ％，在大於 35 歲的慢性 B 型肝炎病人是 2.77 ％，在肝硬化的人是 5.6 ％，

在 B 型肝炎病毒表面抗原 (HBsAg) 陰性的肝硬化病人是4.5-6.2 ％，在 HBsAg 陽性的肝硬化病人是 5.7-7.7 ％。

台灣的肝癌死亡率在東部山區有顯著的較高，而在西部山區則較低。最高的死亡率見於澎湖群島



肝癌最盛行的年齡肝癌最盛行的年齡見於 31至 60 歲之間，在民國 50 年代，

最高的發生率是在 41 至 50 歲之間，但在爾後的研究則為50至 60 歲。

肝硬化併發肝癌的平均年齡是 56.7 歲，在非肝硬化者則為52 歲。 HBsAg 陽性的肝癌病人，其平均年齡是 55 歲，而在 HBsAg 陰性且 C 型肝炎病毒抗體陽性的肝癌病人 , 其平均年齡是 65.7 歲。



Malignant TransformationMultistep

Potential Targets

Oxidative stress and

inflammation

Viral oncogenes

Carcinogens

Growth factors Telomere shortening

Cancer stem cells

Loss of cell cycle checkpoints

Antiapoptosis

Angiogenesis

Normal liver

Liver cirrhosis

Hepatitis CHepatitis B

EthanolNASH

Epigenetic alterationsGenetic alterations

HCC[2]

Dysplastic nodules[1]

1. Tornillo L, et al. Lab Invest. 2002;82:547-553. 2. Verslype C, et al. AASLD 2007. Abstract 24.



Surveillance for Hepatoma

Cost-effective

The expected HCC > 1.5% /year in patients with hepatitis C and 0.2% / year in patients with hepatitis B



Patients for Whom HCC Surveillance Is Recommended Asian males HBV carriers older than 40 yrs of age

Asian female HBV carriers older than 50 yrs of age

HBV carrier with HCC family history

African/N American blacks with HBV

Cirrhotic HBV carriers

Hepatitis C with cirrhosis

Stage 4 primary biliary cirrhosis

Genetic hemochromatosis and cirrhosis

Alpha-1 antitrypsin deficiency and cirrhosis

Other cirrhosis

80% of patients with HCC have underlying cirrhosis

Bruix J, et al. AASLD HCC guidelines. July 2010. Simonetti RS, et al. Dig Dis Sci. 1991;36:962-972.



AASLD Surveillance Guidelines

Surveillance recommended in at-risk groups

– Specific hepatitis B carriers

– Non–hepatitis B cirrhosis

HCC surveillance should be performed with ultrasound

Patients should be screened at 6-mo intervals

– Increased surveillance interval in patients at higher risk not needed

Bruix J, et al. AASLD HCC guidelines. July 2010.



Diagnosis of HCC should be based on imaging techniques and/or biopsy



Diagnostic Algorithm for Suspected HCC



Diagnosis of Hepatocellular Carcinoma

The application of dynamic imaging criteria applied only to patients with

cirrhosis of any etiology

chronic hepatitis B who may not have fully developed cirrhosis or have regressed cirrhosis.

High-grade dysplastic nodules or HCC ?? staining for

1.glypican 3

2.heat shock protein 70

3 glutamine synthetase

Positivity for two of these three stains confirms HCC

Bosetti C, Levi F, Boffetta P, Hepatology 2008;48:137–145.



Staging Systems and Treatment Strategies in HCC



Variables used in staging

Tumor factors

- Tumor size

- Portal vein thrombosis

- AFP

Liver function

- Child - Pugh criteria

- MELD - score

Over all heath of the patient

Performance status

Efficacy of treatment



Staging systems for Hepatoma Clinical staging vs Pathological staging

Outcome prediction

- TNM - Okuda

- CLIP

(The Cancer of the Liver Italian Program)

- JIS ( Japanese Integrated score )

Treatment option

- BCLC ( Bacelona Clinic Liver Cancer)



AJCC staging system 2002



The prognostic value of the AJCC staging system (the 2002 edition)

Has been validated in liver transplantation

The most accurate system to stratify post-transplantation outcomes

The AJCC staging is the only one that is validated in patients treated with either hepatic resection or transplantation

Vauthey JN, Ribero D, Abdalla EK, J Am Coll Surg. 2007;204(5):1016.



The prognostic value of the AJCC staging system (the 2002 edition)

Five-year survival rates, based upon the TNM staging system are as follows

Stage I – 55 percent

Stage II – 37 percent

Stage III – 16 percent

Vauthey JN, Lauwers GY, Esnaola NF, J Clin Oncol. 2002;20(6):1527.



Tumor, Node, Metastasis (TNM) staging

Staging of liver cancer includes only HCC; intrahepatic bile duct cancer is staged separately.

The T3 category is split any of which are >5 cm (T3a; stage IIIA) versus tumors of any size that involve a major portal vein or hepatic vein (T3b, stage IIIB).

stage IIIC disease. A T4 primary (direct invasion of an adjacent organ other than the gallbladder or with perforation of the visceral peritoneum) constitutes

Inferior phrenic lymph nodes are no longer classified as a distant metastatic site (stage IVB) but as regional lymph node involvement (N+, stage IVA).



Tumor, Node, Metastasis (TNM) staging

Stage IV include all metastasis

Stage IVa - includes node-positive disease (N1).

Stage IVb- distant metastasis (M1).



TNM-7- 2010Classification for Hepatocellular Carcinoma

TNM-7 Classification for Hepatocellular Carcinoma 2010

T N M

Stage T1 Single, no vascular Invasion 0 0

Stage T2 Single with vascular invasion, or Multiple tumors non> 5cm

0 0

Stage T3a Multiple tumor with any > 5cm 0 0

Stage T3b Any T with major portal vein or hepatic vein

0 0

Stage T3c T4 adjacent organ, No GB ,No perforation of visceral peritoneum

0 0

Stage IVa Any T N1 0

Stage IVb Any T Any N 1



Okuda staging System



The Cancer of the Liver Italian Program score (CLIP)



CLIP in Clinical Practice

THE CANCER OF THE LIVER ITALIAN PROGRAM (CLIP) INVESTIGATORS HEPATOLOGY 1998; 28:751-755.

HEPATOLOGY 2000;31: 840-845.



The French Groupe d'Etude et de Traitement du Carcinome Hepatocellulaire (GETCH)

Multivariate analysis of prognostic factors in 761 patients from 34 countries

Five prognostic factors :

Karnofsky performance status

Serum bilirubin >50 micromol/L (>2.9 mg/dL)

Serum alkaline phosphatase at least twice the upper ≧limit of normal

Serum alpha-fetoprotein >35 ng/mL

Ultrasonographic portal obstruction



JIS (Japanese Integrated Score)



BCLC Staging System

Terminalstage (D)

Okuda 1-2, PS 0-2, Child-Pugh A-B

Multinodular, PS 0 N1, M1, PS 1-2< 3 cm, PS 0

Intermediate stage (B)

Okuda 3, PS > 2,Child-Pugh C

Very early stage (0)Single < 2 cmCarcinoma in situ

Early stage (A)Single or 3 nodules

Advanced stage (C)Portal invasion,

PS 0, Child-Pugh A

HCC

Llovet JM, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. Journal of the National Cancer Institute. 2008;100(10):698-711, by permission of Oxford University Press.

Stage 0 Stage A-C Stage D



Marrero JA, et al. Hepatology. 2005;41:707-716.

Variables Used in HCC Staging Systems

System Tumor Staging Liver Function Health Status

Europe-US

GETCH/

French

PVT; AFP < 35 or > 35 ug/L Bilirubin, alkaline phosphatase

Karnofsky

CLIP Number of nodules, tumor > or < 50% area of liver, and PVT;

AFP< 400 or ≥ 400 ng/mL

CTP No

BCLC Tumor size, number of nodules, and PVT

CTP PST

TNM Number of nodules, tumor size, presence of PVT, and presence of metastasis

No No

Asia

JIS TNM CTP No

Okuda/

Tokyo

Tumor > or < 50% of cross-sectional area of liver

Ascites, albumin, and bilirubin

No

CUPI TNM; AFP< 500 or ≥ 500 ng/mL Bilirubin, ascites, alkaline phosphatase

Symptoms



Comparison of HCC Staging Systems

BCLC system uses key independent predictors of survival

– Performance score, portal vein thrombosis, tumor diameter

Compared with other staging systems in cohort study

– BCLC had best stratification of survival across all stages

– BCLC was only system to have independent predictive value on survival

BCLC is the only staging system that stratifies patients into treatment groups

Marrero JA, et al. Hepatology. 2005;41:707-716.



Liver transplantation RFA/PEI

Curative treatments (30%); 5-yr survival: 40%-70%

TACE

Single

Increased Associateddiseases

Normal No Yes

Sorafenib

Portal pressure/bilirubin

3 nodules ≤ 3 cm

Resection Symptomatic (20%); survival

< 3 mosRCTs (50%); 3-yr survival: 10%-40%

Terminalstage (D)








PS 0, Child-Pugh A

HCC

BCLC Staging and Treatment Strategy




Treatment for Very Early Stage Hepatoma



Treatment for Very Early Stage Hepatoma

Hepatic resection or ablation of HCC lesion < 2cm have the same 5- year survival rates

Decision based on tumor location, hepatic function, functional status, other co-morbidities, local practice

Resection limited to patients with compensated cirrhosis

- bilirubiin < 2mg/dl, No portal hypertension, platelet >105

In studies of Child A resection for tumor <2 cm -

The 5 year survival rates 49-93%, 5 year recurrence 80%

1. Takayama T, Hepatology 1998;28:1241–1246. 2. Ikai I Cancer 2004;101:796– 802 3. Zhou XD Cancer 2001;91:1479–1486. 4. Nathan H Ann Surg 2009; 249:799–805.



Ablation as the first lineapproach for very early HCC

A cohort study of radiofrequency ablation of 218 patients

Complete ablation of lesions < 2 cm - 97% in 31 ms, with a local recurrence rate of less than 1%.

5 year recurrence rate 80%

NO RCT to compare surgery or RFA

Markov Model simulating 10,000 patients -overall survival was nearly identical in RFA and HR

Livraghi T, Meloni F, Di Stasi M, et al. HEPATOLOGY 2008;47:82-89.

Cho YK, Kim JK, Kim WT, et al. Hepatology 2010;51:1284–1290.



Treatment for Early Stage Hepatomas



Resection Option

Portal pressure measurement to predict the outcome has been validated in Japan.

First option for patients who have the optimal profile, as defined by the BCLC staging system.

Advanced liver disease, the mortality is higher – liver transplantation or ablation.



Resection versus Ablation

A RCT comparing Child-Pugh class A cirrhosis who have single HCCs 5 cm or less in diameter

- No statistically significant differences

Nonrandomized investigations –

RFA can achieve similar survival rates as surgical resection in small, solitary tumors at the very early stage of the BCLC classification

The response rates to RFA 70-95% in tumor < 3cm,

In tumors 3 cm response rates 50-70% in > 3 cm. ≧overall 5 year survival 30 - 50 %



Candidates for RFA/PEI

Includes individuals who are not candidates for surgery

Radiofrequency ablation generally preferred over percutaneous ethanol injection

– Necrotic effect more predictable across tumor sizes

– Meta-analyses suggest survival benefit with radiofrequency ablation vs percutaneous ethanol injection




Combining RF ablation with TACE for (3.1–5.0 cm) HCCs

An RCT - evaluating the therapeutic efficacy of Combining RF ablation with TACE

Local tumor progression rate were significantly lower in the TACE and RF ablation–treated group than in the RF ablation–only group (6% vs 39%, P =0.012)

A phase III randomized double-blinded placebo controlled study with thermally sensitive liposomal doxorubicin in combination with RF ablation HCC is ongoing.

Morimoto M , Numata K , Kondou M Cancer 2010 ; 116 ( 23 ): 5452 – 5460 .



Adjuvant Therapy in the Resection Setting

Recurrence following resection

(in one year –metastasis , late recurrence -De no Vo carcinogenesis)

– Approximately 50% at 3 yrs

– Approximately 70% at 5 yrs

Positive results for several types of adjuvant therapy in this setting

– However, no standard-of-care adjuvant therapy for HCC patients undergoing resection

– RCT using Vit K2 , 548 patients- not effective

Sorafenib after resection or ablation - ongoing

Large, randomized, controlled trials of adjuvant therapy following resection

Llovet JM, et al. Hepatology. 1999;30:1434-1440.Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711.



Liver Transplantation for HCC:Milan Criteria (Stage 1 and 2)

5-yr survival with transplantation: ~ 70%

5-yr recurrent rates: < 15%

+Absence of macroscopic vascular invasion,

absence of extrahepatic spread

Single tumor, not > 5 cm Up to 3 tumors, none > 3 cm

Mazzaferro V, et al. N Engl J Med. 1996;334:693-699.Llovet JM. J Gastroenterol Hepatol. 2002;17(suppl 3):S428-S433.



UCSF (University of California, San Francisco criteria)

Solitary tumor < or = 6.5 cm,

Three or fewer nodules with the largest lesion < or = 4.5 cm

Total tumor diameter < or = 8 cm, without gross vascular invasion



Solitary large ( > 5-cm) tumor

Not early-stage disease because they do not qualify for transplantation

No upper limit of size for surgical resection appears in the BCLC flowchart

These patients should not be excluded from surgical referral because their tumors are too large

The results of transarterial therapies as standalone treatments are highly variable

Down staging?

Majno PE , Mentha G , Mazzaferro V ..Hepatology 2010 ; 51 ( 4 ): 1116 – 1118 .



Treatment of Intermediate HCC



Liver transplantation RFA/PEI

Curative treatments (30%); 5-yr survival: 40%-70%

TACE

Single

Increased Associateddiseases

Normal No Yes

Sorafenib

Portal pressure/bilirubin

3 nodules ≤ 3 cm

Resection Symptomatic (20%); survival

< 3 mosRCTs (50%); 3-yr survival: 10%-40%

Terminalstage (D)








PS 0, Child-Pugh A

HCC

Unresectable HCC

BCLC Staging and Treatment Strategy




Llovet JM, et al. Hepatology. 1999;29:62-67.

Natural History of Nonsurgical HCCStudy Design: Control Arm of 2 RCTs

102 untreated cirrhotic patients with unresectable HCC

– Managed with symptomatic treatment

Median survival of 17 months (range: 1-60 months)

– 1-yr survival was 54%





Llovet JM, et al. Hepatology. 2003;37:429-442.

Arterial Embolization for HCCMeta-analysis of 6 RCTs (2-Yr Survival)

Random Effects Model,OR (95% CI)

Author, Journal Yr Patients, n

Lin, Gastroenterology 1988 63

GETCH, NEJM 1995 96

Bruix, Hepatology 1998 80

Pelletier, J Hepatol 1998 73

Lo, Hepatology 2002 79

Llovet, Lancet 2002 112

Overall 503

Median survival: ~ 20 mos

0.01 0.1 0.5 1 2 10 100

Z = -2.3P = .017

Favors Treatment Favors Control



Contraindications to TACE

Extrahepatic tumor spread

Lack of portal blood flow

– Portal vein thrombosis, portosystemic anastomoses or hepatofugal flow

Advanced liver disease (Child-Pugh Class B or C)

Clinical symptoms of end-stage cancer




Survival After Yttrium-90 Resin MicrosphereRadioembolization of HCC

325 patients September 2003 and December 2009

Child-Pugh class A (82.5%), underlying cirrhosis (78.5%)

Common adverse events were: fatigue, nausea/vomiting, and abdominal pain.

Grade 3 or higher increases in bilirubin were reported in 5.8% of patients.

All-cause mortality was 0.6% and 6.8% at 30 and 90 days

Bruno Sangro, Livio Carpanese, Roberto CianniHEPATOLOGY 2011;54:868-878)



Survival After Yttrium-90 Resin MicrosphereRadioembolization of HCC The median overall survival was 12.8 months (10.9-15.7 months)

BCLC A, 24.4 months [18.6-38.1 months]

BCLC B, 16.9 months [12.8-22.8 months]

BCLC C, 10.0 months [7.7-10.9 months

Bruno Sangro, Livio Carpanese, Roberto Cianni HEPATOLOGY 2011;54:868-878

Overall median survival was 7.3 months in patients with BCLC class C without extrahepatic metastases and

10.4 months (95% CI: 7.2, 16.6) in those with Child-Pugh A with portal vein thrombosis

Salem R , Lewandowski RJ , Mulcahy MF , et al . Gastroenterology 2010 ; 138 ( 1 ): 52 – 64 .



Treatment of Advanced HCC



Understanding Survival Outcomes in HCC Patients

HCC

Stage 0PS 0, Child-Pugh A

Stage DOkuda 3, PS > 2, Child-Pugh C

Stage A-COkuda 1-2, PS 0-2, Child-Pugh A-B

Very early stage (0)

Single < 2 cmCarcinoma in situ


< 3 cm, PS 0


Multinodular, PS 0

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

Terminalstage (D)

2010

2012 60% 20% 20%

Median OS > 36 mos Median OS 16 mos

Median OS 6 mos (4-8 mos)

Curative therapiesOS > 60 mos

Sorafenib: 10.7 mosTACE:

OS 20 mos

40% 20% 40%

Natural History

With Therapy

2011 Stage at Diagnosis

Courtesy of Josep M. Llovet, MD.



Llovet JM, et al. N Engl J Med. 2008;359:378-390.

Patients with advanced,

measurable HCC,

ECOG PS 0-2

(N = 602)

Sorafenib 400 mg BID PO(n = 299)

Placebo(n = 303)

Stratification by macroscopic vascular invasion and/or

extrahepatic spread, ECOG PS, geographical region

Primary endpoints: OS, time to symptomatic progressionSecondary endpoints: progression (radiologic, clinical), adverse events

Phase III SHARP Trial: Sorafenib vs Placebo in Advanced HCC



Llovet JM, et al. N Engl J Med. 2008;359:378-390. Copyright © 2008 Massachusetts Medical Society. All rights reserved.

Phase III SHARP Trial: OS (ITT)

Sorafenib (n = 299)Median: 10.7 mos (95% CI: 9.4-13.3)

Placebo (n = 303)Median: 7.9 mos (95% CI: 6.8-9.1)

1.00

0.75

0.50

0.25

0

Su

rviv

al P

rob

abili

ty

HR (S/P): 0.69 (95% CI: 0.55-0.88;P = .00058)

0 808 16 24 32 40 48 56 64 72WksPts at Risk, n

SorafenibPlacebo

299303

274276

241224

205179

161126

10878

6747

3825

127

02

00



Llovet JM, et al. N Engl J Med. 2008;359:378-390. Cheng AL Lancet Oncology 2009; 10: 25-34

Conclusions From Phase III SHARP Trial

Sorafenib is first systemic therapy to prolong survival in HCC patients

– Survival: HR: 0.69; 31% decrease in risk of death

– Time to radiologic progression: 5.5 mos with sorafenib vs 2.8 mos with placebo (P < .001)

– In Asian patients , an identical RCT shows a median survival time of 4.2 months ( placeb) vs 6.5 months

Sorafenib is the new reference standard for systemic therapy of HCC patients



HCC Management

HCC is the intersection of 2 diseases

– Liver disease and cancer

Skilled pathologists needed for diagnosis

Specialists required to deliver treatment options

– Surgeons for resection or transplantation

– Radiologists ( Hepatologist )for ablation and chemoembolization

Hepatologists and oncologists follow treatment strategy and labs

Midlevel providers bring support, particularly for oral therapy



性別分佈 M: F = 2 : 1

─【肝癌性別分佈圖】

, 80男生, 101男生

, 121男生

, 27女生

, 43女生

, 56女生

020406080

100120140160180200

2008 2009 2010 年份

人數

女生男生



年齡分佈 50- 79

─【肝癌年齡層分佈圖】

0

10

20

30

40

50

60

00~19 20~29 30~39 40~49 50~59 60~69 70~79 80以上年齡層

人數

2008

2009

2010



臨床期別分佈 - stage I,II, III 增加

─【肝癌臨床期別分佈】

0

10

20

30

40

50

60

Ⅰ 期 Ⅱ 期 Ⅲ A期 Ⅲ B期 Ⅲ C期 Ⅳ期不詳期別

人數

2008

2009

2010



首次治療方式分佈 ─臨床期別Ⅰ期 - 開刀與局部治療增加

(C220)I【肝癌期治療方式分佈圖】

74 5 6

38

16

11

0

14

18 20

4 3 30

5

10

15

20

25

²手術 ³局部治療栓塞化療放療其他治療方式

人次

2008

2009

2010



AJCC 臨床期別

─ AJCC【肝癌臨床分期】

020406080

100120140160180

AJCC(Ⅰ ~Ⅳ )期

AJCC不適用

AJCC 不詳期別

申報數

2008

2009

2010



期別相關分佈

AJCC 臨床及病理期別為不詳比例年份申報數 AJCC 臨床

與病理期別皆填寫不詳之申報數

％

2008 107 10 9.35

2009 144 0 0

2010 177 0 0

─ AJCC【肝癌臨床及病理期別為不詳比例】

0.00

2.00

4.00

6.00

8.00

10.00

1 年份

百分比

2008

2009

2010

2008 20102009



本院肝癌病患存活率分析結果 ─治療方式 OP與 RFA

●利用生命表法來繪製 OP與 RFA 療法之存活曲線 (N =120)

註 1 ：以生命表法分析。

clinicaloptions.com/oncology a multidisciplinary perspective on the management of hcc 肝癌年報

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