IL CARCINOMA EPATOCELLULARE

IL CARCINOMA EPATOCELLULARE

Paolo Caraceni

III Workshop Nazionale

Terapie Innovative delle Epatiti Virali Croniche

Firenze, 14-15 Gennaio 2013

2010

2012

Patients with hepatocellular carcinoma (HCC) should be managed with a

multidisciplinary approach framed in a network where all the diagnostic techniques

and therapeutic resources are available in order to provide the optimal level of care.

Given this assumption as the pre-requisite to adequately approach all patients with

known or suspected HCC, the following recommendations of the Italian Association for

the Study of the Liver (AISF) aim at providing:

1. homogeneous and efficacious diagnostic and staging work-up

2. the best treatment choice tailored to patient status and tumor stage at diagnosis.

Position Paper AISF

The Multidisciplinary Approach to HCC

Dig Liv Dis, 2013 in press

• Surveillance

• Recall procedures

• Staging

• Treatments - Surgical

- Ablation techniques

- Transcatheter arterial techniques

- Systemic

- Adjuvant

- Combined

Position Paper


Adjuvant therapy after resection

OLT-extended

Neoadjuvant therapy in waiting list

LDLT

Downstaging

Internal radiation Y90

Resection

Levels of

evidence

(NCI)

Grade of recommendation

(GRADE)

1

2

3

2 (weak) 1 (strong)

RF (<5 cm),

RF/PEI (<2 cm)

Chemoembolization

External/palliative radiotherapy

Sorafenib

A C B A C B

OLT-Milan

Levels of evidence and grade of recommendation

EASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol 2012 ;56 :908-43

Surveillance

Position Paper


Patients candidates to surveillance

• Cirrhotic patients, Child-Pugh class A and B (2b,B)

• Cirrhotic patients, Child-Pugh class C awaiting liver transplantation (5,D)

• Non cirrhotic patients with chronic hepatitis B or inactive hepatitis B carriers with

viremia > 2000 UI/ml (3b,B for Western patients; 1b, A for Oriental patients)

• Non cirrhotic patients with chronic hepatitis C and liver fibrosis ≥ F3 Metavir (o ≥10

Kpa at transient elastography [Fibroscan®]) (5,D for Western patients; 3b,B for

Oriental patients

• Patients with chronic HCV and HBV hepatitis successfully treated (negative viremia),

but corresponding in any of the previous categories at risk prior to starting antiviral

treatment (5,D)

Surveillance is recommended for all the above patients if they do not have

contraindications to radical or effective palliative treatments.

Baseline HBV-DNA level and

risk of HCC in chronic hepatitis B

<10˙000 c/mL

1˙000˙000 c/mL

>1˙000˙000 c/mL

100˙000 c/mL

At entry:

- HBeAg neg.

- Normal ALT

- No cirrhosis

HBV-DNA (c/mL) Annual incidence of HCC (%)

<10,000 0.11

10,000-99,9999 0.29

100,0000-999,9999 0.96

≥1 Million 1.15

HCC risk in non-cirrhotic populations

Masuzaki et al., Hepatology 2009

Liver stiffness

(kPa)

Hazard Ratio Annual incidence

of HCC (%)

≤10 1 0.1

10.1 - 15 16.7 2.9

15.1 – 20 20.9 5.0

20.1 – 25 25.6 8.3

>25 45.5 14.4

Cirrhosis: 15-17 kPa

Prospective study with elastography (Fibroscan) 866 patients anti-HCV+

Patients at risk of HCC development should be enrolled in surveillance programs for early

tumor detection (1a-A). Candidates to liver transplantation should be screened regardless of the

Child-Pugh class, in order to detect tumors exceeding conventional criteria and modify priority

in the waiting list (5-D).

Surveillance should be based on periodic liver ultrasound (2a-B) performed by an experienced

operator (5-D). In the presence of conditions clearly limiting the accuracy of ultrasound, CT scan

or MRI may be proposed as supplementary imaging techniques (5-D). In patients awaiting liver

transplantation and presenting a coarse liver echo-pattern, surveillance should be carried out

with CT or MRI (5-D).

The measurement of alpha-fetoprotein is not indicated as a surveillance tool as its use, alone or in

combination with ultrasound, does not improve the cost/efficacy ratio of surveillance (2b-B).

A surveillance interval of 6 months is recommended (2a-B). Shortening the interval to 3 months,

even in patients at higher risk of developing HCC (5-D), is not associated with any prognostic

improvement and may worsen the cost/efficacy ratio of surveillance (1b-A).

Position Paper


Recall procedures

Position Paper


* One imaging technique only recommended in centers of excellence with high-end radiological equipment.

** HCC radiological hallmark: arterial hypervascularity and venous/late phase washout

Mass/nodule on US

< 1 cm 1-2 cm > 2 cm

4-phase CT or Dynamic

Contrast enhanced MRI

4-phase CT/Dynamic

Contrast enhanced MRI

Repeat US at 4 mo

Growing/Changing

Character Stable

1 or 2 positive techniques*:

HCC radiological Hallmarks**

1 positive technique:

HCC radiological Hallmarks**

Yes No

HCC Biopsy

Investigate

according to size

Inconclusive

Yes No

HCC Biopsy

Diagnostic recall policy


Aspetto tipico (wash-in e wash-out)

Nuovo nodulo in cirrosi

NO Sì

Altra metodica contrastografica

Aspetto atipico Aspetto tipico

Biopsia

Aumento (Ø > 1 cm)

NO Sì

Ecografia/3 mesi

Ø < 1 cm

TC, RM, CEUS

Ø > 1 cm

Aumento (Ø > 1 cm)

Ecografia/3 mesi (per 12 mesi)

NO

Ecografia/6 mesi

Sì

Altra diagnosi

HCC

Non diagnostica

Algoritmo diagnostico: politica del richiamo

Staging

Position Paper


Portal pressure/

bilirubin

HCC

PEI/RFA Sorafenib

Stage 0

PST 0, Child–Pugh A

Very early stage (0)

1 HCC < 2 cm

Carcinoma in situ

Early stage (A)

1 HCC or 3 nodules

< 3 cm, PST 0

End stage (D)

Liver transplantation TACE Resection

Curative treatments (30%)

5-year survival (40–70%)

Target: 20%

OS: 20 mo (45-14)

Associated diseases

Yes No

3 nodules ≤ 3 cm

Increased

Normal

1 HCC

Stage D

PST > 2, Child–Pugh C

Intermediate stage (B)

Multinodular,

PST 0

Advanced stage (C)

Portal invasion,

N1, M1, PST 1–2

Stage A–C

PST 0–2, Child–Pugh A–B

Target: 40%

OS: 11 mo (6-14)

Best supportive

care

Target: 10%

OS: <3 mo

BCLC staging system


The BCLC is the only staging system that proposes a therapeutic algorithm for

HCC. However, the AISF expert panel points out that BCLC treatment allocation

should be considered as a general frame indicating the most beneficial treatment

option available for the group of patients included in each stage of the disease.

The definitive therapeutic choice should be personalized at the individual level,

taking into account several clinical variables and regional organizational setting

that may lead to combined/sequential treatments (5-D). Inclusion of patients into

therapeutic trials is suggested in the case of contra-indications to conventional

treatment or treatment failures (5-D).

Position Paper


Performance Status

(Eastern Cooperative Oncology Group)

Grade ECOG

0 Fully active, able to carry on all pre-disease performance without restriction

1 Restricted in physically strenuous activity but ambulatory and able to carry

out work of a light or sedentary nature, e.g., light house work, office work

2 Ambulatory and capable of all selfcare but unable to carry out any work

activities. Up and about more than 50% of waking hours

3 Capable of only limited selfcare, confined to bed or chair more than 50% of

waking hours

4 Completely disabled. Cannot carry on any selfcare. Totally confined to bed or

chair

5 Dead

Oken, et al., Am J Clin Oncol 5:649-655, 1982

Portal pressure/

bilirubin

HCC

PEI/RFA Sorafenib

Stage 0



1 HCC < 2 cm

Carcinoma in situ

Early stage (A)

1 HCC or 3 nodules

< 3 cm, PST 0

End stage (D)




Target: 20%

OS: 20 mo (45-14)

Associated diseases

Yes No

3 nodules ≤ 3 cm

Increased

Normal

1 HCC

Stage D



Multinodular,

PST 0

Advanced stage (C)

Portal invasion,

N1, M1, PST 1–2

Stage A–C


Target: 40%

OS: 11 mo (6-14)

Best supportive

care

Target: 10%

OS: <3 mo

BCLC staging system


PST 0-1

Paz. 58 aa, Child-Pugh A, PS 0, 2 noduli HCC (3.6 cm e 2.7 cm), no invasione portale,

N 0, M 0, senza comorbilità.

Sorafenib

BCLC staging system

Treatments

Position Paper


Terapia dell’HCC iniziale

BCLC 0-A

Portal pressure/

bilirubin

HCC

PEI/RFA Sorafenib

Stage 0



1 HCC < 2 cm

Carcinoma in situ

Early stage (A)

1 HCC or 3 nodules

< 3 cm, PST 0

End stage (D)




Target: 20%

OS: 20 mo (45-14)

Associated diseases

Yes No

3 nodules ≤ 3 cm

Increased

Normal

1 HCC

Stage D



Multinodular,

PST 0

Advanced stage (C)

Portal invasion,

N1, M1, PST 1–2

Stage A–C


Target: 40%

OS: 11 mo (6-14)

Best supportive

care

Target: 10%

OS: <3 mo

BCLC staging system


RF results in Child-Pugh A patients

with a single HCC 2 cm

Livraghi et al., Hepatology 2008

Mortality 0

Major complications 1.8%

(1 seeding case)

Complete radiological necrosis

- 1st course 86%

- 2nd course 12%

- Total 98%

Sustained complete response 97%

(median follow-up 31 mo)

Treatment failure 3%

232 pts

218 pts

6 pts (2.6%)

unfeasibility

Survival of patients with single HCC <2 cm

treated by ablation

Analysis by surgical candidacy (100 vs 118)

Livraghi et al., Hepatology 2008

Results of RFand resection in patients with

very early HCC (single <2 cm)

Propensity analysis (resection 52 vs RF 9152)

Wang JH et al., J Hepatol 2012

One-to-one near-neighbor matching for:

sex, age, HBsAg, anti-HCV, platelet, Child-Pugh, AFP, ALT, BMI, hypertension, diabetes.

• Negligible mortality

• Lower liver mutilation

• Lower costs

• Shorter hospital stay

• Easy repeatibility

Portal pressure/

bilirubin

HCC

PEI/RFA Sorafenib

Stage 0



1 HCC < 2 cm

Carcinoma in situ

Early stage (A)

1 HCC or 3 nodules

< 3 cm, PST 0

End stage (D)




Target: 20%

OS: 20 mo (45-14)

Associated diseases

Yes No

3 nodules ≤ 3 cm

Increased

Normal

1 HCC

Stage D



Multinodular,

PST 0

Advanced stage (C)

Portal invasion,

N1, M1, PST 1–2

Stage A–C


Target: 40%

OS: 11 mo (6-14)

Best supportive

care

Target: 10%

OS: <3 mo

BCLC staging system


Ishizawa et al., Gastro 2008

CPA = Child Pugh Class A; CPB = Child Pugh Class B; PHT = Portal Hypertension

Resection for HCC Single nodule vs Multiple nodules

Resection for HCC Portal Hypertension

P=0.008

241 pts.

156 pts.

MELD score

9 - 10

Serum sodium level

Cirrhotic patients eligible

for liver resection

≥ 140 mEq/L < 140 mEq/L

Segmentectomy

or

bisegmentectomy

Segmentectomy

or limited

resection

Major

hepatectomy

(up to 4 segments)

Risk of

IPLF>15% in

all types of

hepatectomy

> 10 < 9

0 - 3.3% 0 - 2.5% 0 Mortality

Simple algorithm based on pre-operative variables to determine the

extent of safe hepatectomy in cirrhotic patients with HCC

Cescon et al., Arch Surg 2009

For patients with solitary HCC and preserved liver function without evidence of portal

hypertension, liver resection is a first choice treatment. This is particularly true for HCC 2-5 cm,

whereas for smaller HCC (< 2 cm) the clinical outcome of surgery is comparable to

radiofrequency thermal ablation (RFTA) if this can be safely and effectively performed. As the

only available radical treatment for single HCC > 5 cm is surgical resection, the feasibility of this

option should be always assessed also in these patients, preferably in a multidisciplinary setting

(3b-B).

In the presence of portal hypertension, hyperbilirubinemia, multinodularity, patients must be

evaluated by a multidisciplinary team with great expertise, and the surgical option must be

accurately weighed against the risk of decompensation after surgery (4-C).

Position Paper


For HCC 2 cm, in the setting of a multi-disciplinary evaluation, RFTA can be considered the

first-line treatment when performed in expert centers (3b-B).

For HCC of 2.1-3 cm, the choice between surgery and RFTA should be made on a case-by-case

after a multi-disciplinary evaluation (5-D)

Patients with nodules > 3 cm should be treated with surgery, when feasible (5-D).

In case of failure of percutaneous ablation, patients should be reassessed by a multidisciplinary

team for the most appropriate treatment modality, at first considering surgery if feasible.

When technically feasible, RFTA should be preferred to PEI due to better efficacy and

predictability of treatment result (2a-B).

In non-resectable cases where RFTA is not feasible (due to insufficient ultrasound visibility or

proximity to hollow organs or coagulopathy), video-laparoscopic RFTA, performed in expert

centers, should be considered (5-D).

Position Paper


Portal pressure/

bilirubin

HCC

PEI/RFA Sorafenib

Stage 0



1 HCC < 2 cm

Carcinoma in situ

Early stage (A)

1 HCC or 3 nodules

< 3 cm, PST 0

End stage (D)




Target: 20%

OS: 20 mo (45-14)

Associated diseases

Yes No

3 nodules ≤ 3 cm

Increased

Normal

1 HCC

Stage D



Multinodular,

PST 0

Advanced stage (C)

Portal invasion,

N1, M1, PST 1–2

Stage A–C


Target: 40%

OS: 11 mo (6-14)

Best supportive

care

Target: 10%

OS: <3 mo

BCLC staging system


Mazzaferro et al., Lancet Oncol 2009

1556 pts. from 36 centres (1122 Milano-out at pathology examination)

5-year overall-survival

Liver transplantation for HCC outside Milan criteria

1 5 15 10 85 20 25 30 35 50 45 40 55 60 65 75 70 80

Size of the largest tumor (mm)

Down-staging:

5.1-6 cm

3.1-5 cm “Milano-in” after down-staging

≤ 4 cm each, sum Ø 12 cm

0

20

40

60

80

100

0 12 24 36

Actu

aria

l su

rviv

al

(%)

Milano-in Down-staging

Post-Tx (88 vs 32 pts)

0

20

40

60

80

100

0 12 24 36

Actu

aria

l su

rv

iva

l (%

)

Milano-in Down-staging

Intention-to-treat (129 vs 48 pts)

Ravaioli et al., Am J Transplant 2008


Down-staging: Bologna criteria

Down-staging:

8 cm

5 cm each, sum Ø 8 cm

≤ 3 cm each, sum Ø 12 cm

Yao et al., Hepatology 2008

Inizio down-staging


Down-staging: UCSF criteria

LT is a well established treatment for HCC patients, and the Milan criteria represent the

benchmark for patient selection (1a-A).

LT listing should be considered even in patients with intermediate stage HCC (BCLC B) slightly

beyond Milan criteria. These patients should be (re)-evaluated at transplant centers adopting

"expanded criteria" or "down-staging" protocols (4-C). Tumor vascular invasion and metastases

always are absolute contraindications to LT (4-C). Due to the limited accuracy of the available

indicators of recurrence, patients with non conventional criteria should be considered eligible for

LT only in centers with well-established interventional algorithms or in the context of clinical

trials (5-D).

Position Paper


Terapia dello stadio intermedio

(BCLC B)

Portal pressure/

bilirubin

HCC

PEI/RFA Sorafenib

Stage 0



1 HCC < 2 cm

Carcinoma in situ

Early stage (A)

1 HCC or 3 nodules

< 3 cm, PST 0

End stage (D)




Target: 20%

OS: 20 mo (45-14)

Associated diseases

Yes No

3 nodules ≤ 3 cm

Increased

Normal

1 HCC

Stage D



Multinodular,

PST 0

Advanced stage (C)

Portal invasion,

N1, M1, PST 1–2

Stage A–C


Target: 40%

OS: 11 mo (6-14)

Best supportive

care

Target: 10%

OS: <3 mo

BCLC staging system


Recommendation Contraindications and

specifications

BCLC stage B pts not eligible for surgery or ablation (1a-A).

Best candidates are asymptomatic (PS 0) Child-Pugh class A pts (1b-A);

Child-Pugh score of B7 or PS 1 can be considered (5-D)

Jaundice, untreatable

ascites, portal or main

branch thrombosis and

HCC >10 cm

TACE can be utilized in pts with early stage HCC if surgical or ablative

techniques are not applicable (technical reasons and/or comorbidities)

TACE should be performed with a selective or super-selective

(segmental or sub-segmental) technique to optimize risk/benefit ratio and

increase likelihood of complete response (2b-B)

For bi-lobar HCCs not

treatable with a super-

selective approach,

treating a single lobe per

session should be

considered (5-D)

Peripheral, segmental or intra-tumoral thrombosis is not an absolute

contraindication to TACE, and should be used in association with a

systemic treatment (5-D)

Should be considered in

the frame of controlled

clinical studies

Position Paper


Conventional RECIST:

longest overall tumor diameter

mRECIST:

longest viable tumor diameter

RECIST vs mRECIST criteria

Prognostic power of the response to TACE

according to the criteria utilized

EASL1 RECIST1 mRECIST1

Survival similar with EASL and mRECIST, and better in pts. with an overall

response, assessed at an early time point (median 64 days)1:

Responder Non-responders P

• EASL: 22.0 months 12.7 months 0.019

• mRECIST: 20.7 months 13.3 months 0.009

• RECIST 1.1: 12.4 months 16.8 months n.s

1. Shim et al. Radiology 2012;262(2):708-18; 2. Llovet JM, Ducreux M, et al. J Hepatol. 2012;56:908-943

Response to TACE should be evaluated using the modified RECIST criteria (5-D).

Results of conventional TACE should be preferentially evaluated using MRI if available (4-C),

while CT and MRI are equivalent in evaluating results of DEB-TACE (5-D). CEUS can be used

to ascertain disease persistence in patients in which the targets are one or two lesions.

The first radiologic assessment of TACE results should be performed at 1 month, and thereafter

repeated at 3-4 month intervals (5-D).

Position Paper


Proposed algorithm for TACE

Second TACE

New lesion Growth of

existing lesion

Raoul J-L et al. Cancer Treat Rev 2011;37:212–20

No PVT

No EHS

Child-Pugh A or

B7

First TACE

CT or MRI

CT or MRI

Liver deterioration or

major complications

Disease control

(CR or PR or SD)

Disease

progression

Follow-up /

3 months

Consider retreatment

with TACE

Consider

Sorafenib

Patient / disease characteristics

Acceptable?

Acceptable?

Why?

HCC CANDIDATO A TACE - No trombosi portale (ammessa trombosi di ramo segmentario)

- No malattia extraepatica

- Classe di Child Pugh A o B7

Deterioramento epatico,

complicazioni maggiori * CR ***

RM o TC

trimestrale

Recidiva di malattia *** PR ***

Risoluzione No

Palliazione Sì

Progressione di malattia

(DP) o non risposta al

trattamento (SD) ***

Nuova

lesione

Crescita lesioni

trattate o SD***

Considera

SORAFENIB

Considera nuovo trattamento

(cTACE o DEB-TACE)

Trattamento cTACE o DEB-TACE

RM o TC

(dopo 1 mese)

Trattamento cTACE o DEB-TACE

RM o TC

(dopo 1 mese)

Position Paper


Per-nodule response rate to 1st TACE

Role of tumour size

• Retrospective cohort study: 271 patients eligible to TACE with 635 treated nodules

• cTACE* performed ‘on demand’ upon demonstration of viable tumour (non-CR)

• Tumour assessment according to mRECIST (after 1 month and then every 3–4 months)

• Mean follow-up: 12 months (range 1-51)

Golfieri R et al. submitted for publication

≤2 cm (N=386) 2.1-5 cm (N=211) >5 cm (N=36)

N. nodes % N. nodes % N. nodes %

Tumour response

CR 263 68 134 64 9 25

PR 123 32 77 36 27 75

Local Recurrence Rate 52 20 36 27 6 57

Only 25% of large (>5 cm) nodules achieve CR and, in these nodules,

local relapse is very frequent.

Wang W et al., Liver International 2010; 30: 741-749

Survival

1 year: 512 pts → OR = 3.26 (95% CI = 1.23-8.69)

2 years: 437 pts → OR = 4.53 (95% CI = 2.62-7.82)

3 years: 425 pts → OR = 3.50 (95% CI = 1.75-7.02)

Comparison Trials

• TACE + PEI vs. TACE 4

• TACE + RF vs. RF 2

• TACE + PEI vs. PEI 1

• TACE + RF vs. TACE 1

• TACE + PEI vs. TACE o PEI 1

• TACE + RF vs. TACE o RF 1

Recurrence rate

Combined locoregional treatments

In non-surgical cases, a combined/sequential approach (TACE plus PEI, RFTA, or

microwave ablation) should be considered, on an individual basis, for multinodular

HCCs and for each nodule >3 cm, after a multidisciplinary assessment (2b-B).

Position Paper


Terapia dello stadio avanzato

(BCLC C)

Portal pressure/

bilirubin

HCC

PEI/RFA Sorafenib

Stage 0



1 HCC < 2 cm

Carcinoma in situ

Early stage (A)

1 HCC or 3 nodules

< 3 cm, PST 0

End stage (D)




Target: 20%

OS: 20 mo (45-14)

Associated diseases

Yes No

3 nodules ≤ 3 cm

Increased

Normal

1 HCC

Stage D



Multinodular,

PST 0

Advanced stage (C)

Portal invasion,

N1, M1, PST 1–2

Stage A–C


Target: 40%

OS: 11 mo (6-14)

Best supportive

care

Target: 10%

OS: <3 mo

BCLC staging system


n = 107

n = 245

n = 150

n = 45

n = 183

Sorafenib ASIA-PACIFIC (Cheng, Lancet Oncol. 2009)

Sorafenib SHARP (Llovet, NEJM. 2009)

TARE (Sangro, Hepatology. 2011)

TARE EHD+ (Salem, Gastro. 2011)

TARE EHD– (Salem, Gastro. 2011)

Sangro B, et al. J Hepatol 2012; 56:464-73

Advanced stage

Radioembolization for HCC

Position Paper


Systemic chemotherapy with conventional agents, octreotide, interferon, tamoxifen, and anti-

androgenic drugs has no role in HCC treatment (1b-A).

Full dose sorafenib is the recommended treatment for HCC patients with preserved liver function

who are not amenable to surgery and loco-regional treatments or in whom TACE failed,

according to the Italian National Health Service rules (1b-A). In patients intolerant to full dose

sorafenib, the tolerance to a reduced dose (400 mg/day) is to be pursued before definitively

suspending the treatment (2b-B).

TARE may be indicated in patients with large masses and/or portal thrombosis/invasion, but it

should be utilized in the context of prospective studies aimed at ascertaining its cost-effectiveness

profile (5, D).

www.webaisf.org, March 2013

Raccomandazioni AISF per la gestione integrata

del paziente con epatocarcinoma

http://www.webaisf.org/

11th AISF PRE-MEETING

THE MULTIDISCIPLINARY APPROACH TO THE

TREATMENT OF HEPATOCELLULAR CARCINOMA

Roma, February 20, 2013

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IL CARCINOMA EPATOCELLULARE