Highlights in the management of gastrointestinal cancer

Roma, 21 Maggio, 2010

Treatment algorithm for

hepatocellular carcinoma

Franco Trevisani

Semeiotica Medica

Dipartimento di Medicina Clinica

Alma Mater Studiorum - Università di Bologna

Strategy for staging and treatment assignment(BCLC)

Bruix and Sherman, Hepatology 2005

C

Trapianto: - Chi trapiantare? - Resezione o trapianto HCC suscettibile di entrambi?

Bruix and Sherman, Hepatology 2005

Linee guida: rapidi cambiamenti delle evidenze.Chi trapiantare?

Toso et al., Hepatology 2009

Scientific Registry of Transplant Recipients (USA) 2003-07: 6478 OLT

% Milano-out

Total tumor volume

Mazzaferro et al., Lancet Oncol 2009

1556 pts. from 36 centres (1122 Milano-out at pathology examination)5-year overall-survival

Chi trapiantare?Il sistema “metro ticket”

10 20 30 40 50 60 70 80 90 100

Size of the largest (mm)

Linee guida: rapidi cambiamenti delle evidenze. Criteri down-staging di Bologna

0

20

40

60

80

100

0 12 24 36

Act

uari

al s

urvi

val (

%)

Milano-in Down-staging

Post-Tx (88 vs. 32 pts)

0

20

40

60

80

100

0 12 24 36

Act

uari

al s

urvi

val (

%)

Milano-in Down-staging

Intention-to-treat (129 vs. 48 pts)

Down-staging:- 5.1-6 cm - 3.1-5 cm “Milano-in” dopo down-staging- ≤4 cm ciascuno, somma Ø 12 cm- AFP <400 ng/mL

Ravaioli et al., Am J Transplant 2008

Resezione: - Chi resecare?

Bruix and Sherman, Hepatology 2005

Resection for HCCOnly single? Only without PHT?

Ishizawa et al., Gastro 2008

Resection for HCC The Bologna-Torino experience

466 resections

Resection for HCC The Bologna-Torino model

0 - 3.3% 0 – 2.5%0Mortalità

Bilirubin

Creatinine

INR

MELD

Percutaneous ablation: for whom?

• PEI is ineffective against: - satellites - microvascular invasion• PEI-induced necrosis is not predictable

Bruix and Sherman, Hepatology 2005

Percutaneous ablation: for whom?

59%

Ethanol injection

HCC size and microsatellites

2 cm

0.5 cm

PEI and RF outcome: the results of 5 RCT

Author Tumor

number x size

Initial CR (%)

Treatment failure (%) (§)

3-year survival

(%)

P value

Lencioni, 2003

PEI (n. 50)

RF (n. 52)

1 x 5 cm

or

3 x 3 cm

92

98

34

8

73

81

NS

Lin, 2004

PEI (n. 52)

RF (n. 52)

1-3 x 3 cm

91

96

45

17

50

74

0.014

Shiina, 2005

PEI (n. 114)

RF (n. 118)

1-3 x 3 cm

100

100

11

2

63

80

0.02

Lin, 2005

PEI (n. 62)

RF (n. 62)

1-3 x 3 cm

89

97

42

16

51

74

0.031

Brunello, 2008

PEI (n. 69)

RF (n. 70)

1-3 x 3 cm

66

96

64

34

57

59

NS

(§): incomplete initial response and/or local recurrence

RF vs. PEI(meta-analisi di RCT)

Cho et al., Hepatology 2009

Sopravvivenza a 3 anni

RF PEI

Odds ratio 0.48 (95%CI: 0.34-0-67)

RF results in Child-Pugh A patients with asingle 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 RF (218 patients)

Livraghi et al., Hepatology 2008

Survival of patients with singleHCC <2 cm treated by ablation

Analysis by surgical candidacy (100 vs 118)

Livraghi et al., Hepatology 2008

Terapie ablative percutanee:

Termoblazione o alcolizzazione?

Strategy for staging and treatment assignment(BCLC)

Bruix and Sherman, Hepatology 2005

C

Dynamic imaging techniques: arterial phase

TC

MRI

Conventional TACE

+ Embolic Embolic agentagent =

• Gelatine sponge

• PVA

• Microspheres

• N-isobutilcyanoacrialate

Gelatine sponge

TACE

Pre- TACE

Post-TACE

Cortesia dott.ssa R. Golfieri

1. Proper patient selection2. Proper tumor selection3. Proper technical procedure4. Proper timing of treatments

Tumor Progression Treatment-inducedliver failure

Potential factors determining the results of TACE

Trevisani et al., J Clin Gastroenterol 2001

TACE for intermediate-advanced HCC

Llovet, Hepatology 2002

Overall 2-year mortality OR (95% C.I.)

- Embolization 0.59 (0.29-1.20)

- Chemoembolization 0.42 (0.20-0.88)

• DC Bead (Biocompatibles, UK) sulphonate-modified compressible hydrogel PVA microspheres designed to release chemotherapy at a slow rate

• Designed to be loaded with Doxorubicin: recommended dose of 25 mg/ml (maximum 37.5 mg/ml)

• Bead sizes 100-300 µm, 300-500 µm, 500-700 µm, 700-900 µm

DRUG-ELUTING BEADS: DC BeadsTM (DEB-TACE)

Lewis et al J. Vasc. Interv. Radiol. 2006; 17(8):1335 -43

CONVENTIONAL TACE

DC Bead TACE

DRUG-ELUTING BEADS: DC BeadsTM (DEB-TACE)

0

10

20

30

40

50

60

70

80

0 100 200 300 400

Time (hrs)

[Do

x]

(ng

/mL

)

DEB

TACE

0

10

20

30

40

50

60

70

80

90

100

DEB TACE

Procedure

[Do

x]

in t

um

ou

r @

72

h(n

mo

les

/g t

iss

ue

)

• Doxorubicin in the tumor: more and longer

– Doxorubicin presence in the tumor peaks at 3 days and remains in the tumor for 14 days

– 4 times more Doxorubicin in the tumor compared to conventional TACE

DRUG-ELUTING BEADS: DC BeadsTM (DEB-TACE)

Area under the curveDEB-TACE

TACE

RCT with DC Beads vs. TACE(Precision V study)

- 212 pz. arruolati: C-P A/B, ECOG 0/1, lobi 1/2, precedente tx.- Procedure bimestrali- End points:

1. risposta tumorale (criteri EASL) a 6 mesi 2. effetti avversi severi

P=0.11

Lammer et al., J Cardiovasc Intervent Radiol 2010

RCT with DC Beads vs. TACE(Precision V study)

Picco ALT P<0.001

FEVs P=0.018

EA doxo-dipendenti P=0.0001 Alopecia 1% v. 20%

Lammer et al., J Cardiovasc Intervent Radiol 2010

- 212 pz. arruolati: C-P A/B, ECOG 0/1, lobi 1/2, precedente tx.- Procedure bimestrali- End points:

1. risposta tumorale (criteri EASL) a 6 mesi 2. effetti avversi severi

RCT with DC Beads vs. TACE(Precision-Italy)

117 pazienti arruolati

YTTRIUM-90 microspheres:

20-40 μm particles emitting

β-radiation, delivered via the

hepatic arterial route.

Average penetration range in tissue: 2.5 mm (maximum 11 mm).

TAR(adio)E

90Y-Radioembolization

Hypovascular-infiltrative HCCs

Very large HCCs ± Portal invasion

ECOG 2 No extrahepatic spread Child-Pugh class A-B Bilirubin <2 mg (risk of further liver deterioration)

>2 mg: TACE preferable!!

PATIENT SELECTION for 90Y vs. TACE in intermediate-advanced HCC

01/06 02/0605/0608/06

“Radiation segmentectomy”

TAR(adio)E

90Y-Radioembolization

Cortesia dott.ssa R. Golfieri

HCC: response (WHO modified-EASL)HCC: response (WHO modified-EASL)

1 month

17 pts

3 months

14 pts

6 months

7 pts

9 months

5 pts

>12 months

4 pts

CR 8 (47%) 6 (43%) 5 (71%) 2 (40%) 2 (50%)

PR 6 (35%) 4 (29%) 1 (14.5%) - -

SD 3 (18%) 2 (14%)

DP in target lesions

0 0 0 0 0

DP new lesions 0 2 (14%)

(1 retreat.)

1 (14.5%)

(1 retreat.)

3 (60%) 2 (50%)

Deaths (liver failure)

0 1 2 3 3

Mean dose: 1350 MBq (range: 740-2010) Mean follow-up: 9.6 months

17 pts (19 treatments)17 pts (19 treatments)

Cortesia dott.ssa R. Golfieri

Strategy for staging and treatment assignment(BCLC)

Bruix and Sherman, Hepatology 2005

Sorafenib

El-Seragh et al., Gastro 2008

Llovet et al. J Natl Cancer Inst 2008

Strategy for staging and treatment assignment(Japanese system)

Kudo et al., Oncology 2007; 72 (suppl.1): 2-15Jap Soc Hepatol Guidelines, Hepatol Res 2008

Sorafenib

b: for C-P class B and Ø 2 cm

c: within Milano criteraia

TACE

TARE

Resection vs. ablation: the results of 3 RCT

Author Tumor

No. x size

Child-Pugh

Survival DF

survival

Complications

Periop.

mortality

Huang, 2005

Resection (n. 38)

PEI (n. 38)

1-2

3 cm

Hepatitis

19

A/B: 28/0

A/B: 29/3

5-yrs

82%

46%

5-yrs

48%

45%

0

0

Chen, 2006

Resection (n. 90)

RF (n. 71)

Single

5 cm

4-yrs

64%

68%

4-yrs

52%

46%

55%

4%

1%

0

Lu, 2006 (abstr.)

Resection (n. 54)

RF/microw. (n. 51)

Milano-in

3-yrs

86%

87%

3-yrs

82%

51%

11%

8%

Huang G-T et al., Ann Surg 2005Chen M-S et al., Ann Surg 2006Lu MD et al., Zhonghua Yi Xue Za Zhi 2006

Sorafenib treatment for advanced HCCOverall Survival in the SHARP and Asia-Pacific Trials

Months from Randomization

Su

rviv

al P

rob

abil

ity

Sorafenib (n=299)Median: 10.7 months95% CI: 9.4-13.3

Placebo (n=303)Median: 7.9 months95% CI: 6.8-9.1

HR (S/P): 0.6995% CI: 0.55-0.87P=0.00058

0.25

0.50

0.75

1.00

00

4 8 12 16 20

SHARP1

Sorafenib (n=150)Median: 6.5 months 95% CI: 5.6-7.6

Placebo (n=76)Median: 4.2 months 95% CI: 3.7-5.5

HR (S/P): 0.68 95% CI: 0.50-0.93P=0.014

0.25

0.50

0.75

1.00

00

4 8 12 16 20

Asia-Pacific2

Months from Randomization

Su

rviv

al P

rob

abil

ity

1. Llovet JM, et al. N Engl J Med. 2008;359(4):378-3902. Cheng AL, et al. Lancet Oncol. 2009;10:25-34

Recidiva HCC dopo terapie potenzialmente radicali

Hasegawa et al., J Hepatol 2008

7185 pazienti, 2000-2003 Resezione, PEI o RFA (HCC: 3 cm x 3)

8 weeksrandomise

Stratify:- prior curative tx- geographical region- CP status

Sorafenib 400mg bid

Placebo

- RFS

- TTR

- OS- Biomarkers

1:1

Design: double-blind RCT

Resection RFA PEI

• Significant OS benefit in phase III gives rationale to go into adjuvant setting

• Prospective, randomized, double-blind, placebo-controlled, company sponsored phase III study

• Primary endpoint: recurrence-free survival

• Patients: n=1100 (randomised)

• Global trial, significant number of patients from China

Clinicaltrials.gov

Strategy for staging and treatment assignment(BCLC)

Bruix and Sherman, Hepatology 2005

Sorafenib

El-Seragh et al., Gastro 2008

Sorafenib

Strategy for staging and treatment assignment(Japanese system)

Kudo et al., Oncology 2007; 72 (suppl.1): 2-15Jap Soc Hepatol Guidelines, Hepatol Res 2008

Sorafenib

b: for C-P class B and Ø 2 cm

c: within Milano criteraia

TACE

TARE

Key pathways in carcinogenesis and molecularly targeted agents under devolopment in advanced HCC

Strategy for staging and treatment assignment(BCLC)

Paz. 58 aa, HCC 4.5 cm, no invasione postale, N 0, M 0, senza comorbilità, Child-Pugh C.

Bruix and Sherman, Hepatology 2005

Paz. 58 aa, HCC 4.5 cm, no invasione postale, N 0, M 0, senza comorbilità, Child-Pugh A, varici F1.

HCC size and microsatellites

Kojiro et al, Semin Liver Dis 1999Maeda et al, Hepatogastroenterology 2000Okusaka et al., Cancer 2002Sasaki et al., Cancer 2005Livraghi, J Hepatol Pancreat Surg 2010

2 cm

0.5 cm

3 cm

2 cm

Microvascular Satellites invasion

1.5 cm 0 0

1.6 - 2 cm 10% 3%

TACE e HCC

Worldwide HCC burden

• HCC ranks first among PLC: 75-90%

• 5th most frequent tumor in men, 9th in women

• 3rd cause of death among cancers

• 1st cause of mortality in cirrhotic patients

• Incidence (620.000) annual mortality (595.000)

Ferlay et al. IARC CancerBase no. 5, 2004Parking Bray, CA Cancer J Clin 2005El Serag Rudolph, Gastroenterology 2007