Paziente maschio di 74 anniStoria di ipertensione arteriosa.Giunge alla nostra osservazione nel giugno 2002 per ictus

ischemico. In tale occasione viene diagnostica epatopatia cronica HCV-relata in fase cirrotica ben compensata (Child-Pugh A5).

Inizia follow up ecografico e clinico semestrale.

Ottobre 2002, sfumata area iperecogena di 10 mm nel VI segmento sottocapsulare.

Lieve splenomegalia (area 54 cmq) Vene epatiche con flusso appiattito. Vena porta con velocità di 19 cm/sec, RI splenico 0.70)

Storia clinica

1. Viene rivisto a 4 mesi circa (febbraio 2003). Si conferma il piccolo nodulo di 11 mm. Si consiglia TC. Viene eseguita e risulta negativa. Si programma uno stretto follow up.

2. Maggio 2003Permane immodificata la lesione debolmente iperecogena di 11 mm nel VI segmento. Non ulteriori lesioni focali.

3. Ottobre 2003In sede centroepatica, strettamente adiacente al ramo portale posteriore destro, è presente un'area ipoecogena di 17 mm con scarsi segnali vascolari al suo interno.Permane invariata la lesione focale debolmente iperecogena di 11 mm al 6° segmento. Si procede ad angioecografia perfusionale.

Per vedere questa immagineoccorre QuickTime™ e un

decompressore Motion JPEG A.

Fase arteriosa Fase portaleTC spirale trifasica

(26.11.2003)

Fase portale

TC spirale trifasica (26.11.2003)

?

CLINICA, DIAGNOSTICA E

TERAPIA

DELL’EPATOCARCINOMA

Luigi Bolondi

Cattedra di Clinica Medica

Dipartimento di Medicina Interna e

Gastroenterologia

Università di Bologna - Policlinico S. Orsola

Malpighi

“

INCIDENCE OF HCC IN LIVER CIRRHOSIS

annual incidence

Oka et al, 1990 6.5 %

Colombo et al, 1991 3 %

Pateron et al, 1994 5.8 %

Benvegnu et al, 1994 3 %

Cottone et al, 1994 1.5-10 %

Solmi et al, 1996 1.4 %

Bolondi et al, 2001 4.1 %

CIRROSIVIRUS

HCC

HCC

Flogosi cronicaNecrosiRigenerazioneepatocitaria

Diminuita capacità riparatrice dei danni al DNA

Aumento errori di replicazione e trascrizione del DNA

Eterogeneità geograficaDiversi fattori di rischioDiversi bersagli a livello molecolare

Acute hepatitis

Chronic hepatitis

Cirrhosis

Decompensation HCC

Death

85%

20%

6% 4%

3,6% Di Bisceglie, Hepatology, 2000

Factors affecting natural history

HLA type

Male genderAge on onsetAlcoholInterferon

Hepatitis BAlcoholInterferon

Transplantation

INCIDENCE OF HCCDURING THE SURVEILLANCE PROGRAMME

OF LIVER CIRRHOSIS(1989-1997)

313 patients with a follow-up of 56 31 months

74 nodules (23,6 %)

13 cases non HCC 61 HCC (19,5 %)

Bolondi et al. Gut 2001

SCREENING FOR HCC IN CIRRHOSISANALYSIS OF SURVIVAL BENEFIT

Significant longer survivals for screened vs non screened

p = 0.009 (Wong, Liver Transpl 2000)p < 0.0001 (Yuen, Hepatology 2000)p < 0.02 (Bolondi, Gut 2001)p < 0.001 (Trevisani, Am J Gastro 2002)

No Significant difference *(Sarasin, Am J Med 1996)

* transplantation not included in the model

Tailoring screening onRISK FACTORS FOR HCC IN CIRRHOSIS

• Age (Aizawa, Cancer 2000)

• Male gender (Zoli, Cancer 1996Bolondi, Gut 2001El Serag, J Clin Gastro 2002)

• Child-Pugh score (Bolondi, GUT 2001)

• HBsAg + (Solmi, Am J Gastro 1996)Tsukuma, N Engl J Med 1993)

• HCV+ (Velazquez, Hepatology 2003)

• HBV + HCV (Parkin, IARC 1992)

• HCV + alcol (Benvegnù, Gut 2001)

• AFP (Bolondi, Gut 2001)

DEVELOPEMENT OF NEOPLASTIC GROWTHIN MACROREGENERATIVE NODULES

ARAKAWA 1986 RECOGNITION OF EARLY MALIGNANT FOCI IN 5 ADENOMATOUS HYPERPLASTIC NODULES

N°nodules mean follow-up 9 neoplastic growth

TAKAYAMA 1990 18 1-5 yrs 9 benign behaviour

10 neoplastic growthRAPACCINI 1990 12 10.2 mos

2 benign behaviour

0 neoplastic growthKONDO 1990 17 > 1 yr

17 benign behaviour

7 neoplastic growthBOLONDI 1993 12 22.6 mos

5 benign behaviour

PREDICTION OF MALIGNANT EVOLUTION IN PREDICTION OF MALIGNANT EVOLUTION IN SMALL NODULES (< 1.5 cm) DETECTED AT SMALL NODULES (< 1.5 cm) DETECTED AT

IMAGING TECHNIQUESIMAGING TECHNIQUES

IMAGING NEW TISSUE MARKERS MOLECULAR ANALYSIS

•Assessment of vascularity

•Markers of proliferation (AgNORs, PCNA, Ki67...)

•Enzymatic cytochemistry

•DNA ploidy

•Assessment of monoclonality

•Genomic instability and LOH

CLINICAL CRITERIA

Volume increase at 4 month

Probably no consequence on outcome

Large Large regenerative regenerative

nodulenoduleDysplastic Dysplastic

nodulenoduleBorderline Borderline

lesionlesion HCCHCC

Portal flowPortal flowArterial flowArterial flow

Blood supply of liver nodules in cirrhosis

CHARACTERIZATION OF LIVER MASSES: ASSESSMENT OF VASCULARITY BY IMAGING TECHNIQUES

DOPPLERQUANTITATIVE QUALITATIVE

SPECTRAL ANALYSIS

COLOR and POWER mapping

+ mdc

SPIRAL CT

Contrast-enhanced NMR

CONTRAST-ENHANCED USStimulated Acoustic Emission Harmonic Imaging

Pulse Inversion C3-mode CnTi

ARTERIAL HYPERVASCULARITY INSMALL HEPATOCELLULAR CARCINOMA

Perfusional Angiosonography

with Sonovue

Spiral CT enhanced artherial phase

Per vedere questa immagineoccorre QuickTime™ e un

decompressore Video.

HCC

Per vedere questa immagineoccorre QuickTime™ e un

decompressore Motion JPEG A.

- Hyperintensity in the arterial phase- Iso or Hypointensity in the portal and late phases

DIAGNOSIS OF HCCCirrhotic patients (US + AFP/6m)

Liver nodule No nodule

Normal AFPIncreased AFP*

Spiral CT

Surveillance US + AFP/6m

1-2 cm > 2 cm < 1 cm

US /3m

No HCC

AFP > 400 ng/mlDoppler/CT/MRI/An

HCC

FNAB

* AFP level >200ng/dl Bruix, J Hepatol ,2001

STAGING:STAGING:OPEN PROBLEMS AND AREAS FOR FUTURE RESEARCHES OPEN PROBLEMS AND AREAS FOR FUTURE RESEARCHES

• Multinodularity

• Vascular invasion Selection between radical

treatment or palliation

Imaging techniques insufficient

• Selection between OLT and ablation/destruction therapies• Need for adjuvant therapy

• Recurrence potential

Tissue and molecular markers

(Currently not done)

Local therapy Surgical resection

TransplantPercutaneousecho-guided

Intra-arterial

Systemic chemotherapy or hormonal therapy

THERAPEUTIC OPTIONS FOR HCC

0102030405060708090

100

1 year 2 years 3 years

NT (n=73)SURG (n=82)PEI (n=105)TACE (n=30)

EFFECT OF TREATMENT ON SURVIVAL OF 1108 PTS WITH HCCMulticentric Italian Study Group on HCC

SURVIVAL OF SINGLE HCC <5 cm Child A

J Hepatol, 1995

SCREENING FOR HCC IN CIRRHOSIS

ELIGIBILITY FOR CURATIVE TREATMENTS

HCC detected within surveillance programme

HCC detected outside surveillance programme

47.5 % 31.7 %p < 0.01

(Bolondi, Gut 2001)

• High rate of exclusion criteria from surgical resection

(5-9% of pts arising from screening are

candidate to surgery)

• High recurrence rate after surgical resection

3 year recurrence 72% Ikeda et al, 1993

5 year recurrence 83% Ng et al, 1995

100% Belghiti et al, 1991

91% Gouillat et al, 1999

Rationale for the use of local treatments

HEAT laser, radiofrequency, highly focused ultrasound

FROST cryosurgery

DRUGS alcohol injection

RADIOACTIVITY implantation of radioactive seeds

INTERSTITIAL TUMOR ABLATION

Survival Outcomes in PEI-Treated Pts(Retrospective Studies)

Author and yearShiina S et al, AJR 1993

Livraghi T et al, Radiology 1995 Child A, single < 5 cm Child B, single < 5 cm

Lencioni R et al, Cancer 1995 Child A, single / multiple < 3 cm Child B, single / multiple < 3 cm

85

98 93

100 91

62

7963

8753

No. of Pts

98

293149

6441

Survival (%)

3-yr 5-yr1-yr

52

4729

5513

SURVIVAL AFTER SURGICAL AND NONSURGICAL TREATMENT FOR HCC

HCC < 2 cm clinical stage I

5 cm > HCC > 2 cm all clinical stages

Surgery > PEI (n=8.010) (n=4.037)

(retrospective study)(Arii et al, Hepatology 2000Liver Cancer Study Group of Japan)

0

10

20

30

40

50

60

70

80

90

PEI 83 66 55Resection 81 73 44

1-yr 2-yr 3-yr

Castells et al, Hepatology 1993

p = N.S.

0

10

20

30

40

50

60

70

80

90

100

PEI 100 82 59Resection 96 84 61

1-yr 3-yr 5-yr

Yamamoto et al, Hepatology 2001

p = N.S. - Same tumor stage

- Poorer liver function in PEI groups

PEI versus Surgical Resection

(Non-Randomized Studies)

oss

Quae maedicamenta non sanant, ferrum sanat,quae ferrum non sanat, ignis sanat,quae vero ignis non sanat, insanabilia reputari oportet

Ippocrate, Aforisma 7, 87

RF THERMAL ABLATIONRF THERMAL ABLATION

EXPANDABLE NEEDLE (1.9 mm)EXPANDABLE NEEDLE (1.9 mm)

4 to 10 nickel-titanium hooks 4 to 10 nickel-titanium hooks with tip thermistorswith tip thermistors

90-115°C90-115°C

RF THERMAL ABLATIONRF THERMAL ABLATION

COOLED-TIP NEEDLE COOLED-TIP NEEDLE (1.2-1.3 mm)(1.2-1.3 mm)

20-25°C20-25°CPeristaltic Peristaltic

pump with 0°C pump with 0°C saline solutionsaline solution

RF Ablation of HCC: Local Effect

(histologic assessment after OLT)

24 pts, 47 HCC lesions (0.4 – 5.5 cm; mean, 2.3 cm)- Complete necrosis on histology: 35 / 47 (74%)

Lu DSK et al, Radiology 2005

0

10

20

30

40

50

60

70

80

90

100

PEI 98 96 92 88 80 73RFTA 100 100 98 98 93 81

6 12 18 24 30 36

PEI series (n = 184) - Lencioni R et al, Eur Radiol 1997

Overall Survival

67%

Lin SM et alGastroenterology 2004

50%

74%

RANDOMIZED COMPARISON OF RF THERMAL ABLATION vs PEI

232 patients with up to 3 HCC < 3 cm eachRF PEI

----------------------------------------------------------------• Treatment sessions 2.1 6.4 p<00001• 4yr survival 74% 57%p=0.01• 4yr Overall recurrence 70% 85% p=0.005• 4yr Local progression 1.7% 11% p=0.003 Shiina, Gastroenterology 2005

COMPARING THE OUTCOMES OF RF ABLATION AND SURGERY IN PTS WITH SINGLE SMALL HCC AND

WELL-PRESERVED HEPATIC FUNCTION

Hong SN et al, J Clin Gastroenterol 2005

Barcelona 2005 - PERCUTANEOUS ABLATIONSummary and conclusions

• RF thermal ablation has emerged as the most valid alternative to PEI. According to various studies, its failure in achieving local control is lower than PEI. Data on survival are still preliminary and are influenced by different patient selection

• The complication rate of RF was initially considered higher but recent reports do not confirm this finding

• In HCCs of 3 to 5 cm the efficacy of a percutaneous treatment in achieving local control is questionable

• Individual factors play an important role in treatment selection

• Other techniques such as microwave or Laser have a minor impact

• PEI can probably maintain a place in the treatment of very small nodules (<2 cm) or in difficult locations (perivascular)

multifocal HCC

PROBLEMS IN EVALUATION RCTs ON TRANSARTERIAL CHEMOEMBOLIZATION

• Small sample size

• Differences in treatment procedures (chemoterapeutic agent - Cysplatin, Mytomicin, Doxorubicin - , embolization, number and interval of procedures)

• Patients selection and stratification

TERAPIA DELL’ HCC UNIFOCALEIN FEGATO CIRROTICO

CONCETTI CHIAVE

Pz con nodulo singolo < 5 cm (e buon compenso epatico)

ottimi candidati alle terapie locoregionali percutanee:

l’alcolizzazione è la tecnica di scelta

Pz in classe Child-Pugh Aa basso rischio operatorio e

nodulo unico

candidati aresezione anatomica

Noduli >3 cm:

Se non resecabili, si può associare

PEI + TACE

Noduli < 3 cm:

Risultati migliori

TERAPIA DELL’HCC UNIFOCALEIN FEGATO CIRROTICO

CONCETTI CHIAVE

Pz < 65 aa con nodulo singolo in classe Child-Pugh B e C

Considerare indicazione a trapianto di fegato

La TACE può essere utile nei pz in lista d’attesa per contrastare la crescita e la diffusione della neoplasia (?)

BARCELONA RECOMMENDATIONS

CURATIVE TREATMENTS CURATIVE TREATMENTS PEI vs SURGICAL RESECTION PEI vs SURGICAL RESECTION

Recurrence rate after percutaneous treatments is as frequent as after surgical Recurrence rate after percutaneous treatments is as frequent as after surgical

resection (>50% at 3 years and > 70% at 5 years) resection (>50% at 3 years and > 70% at 5 years)

The are no RCTs comparing surgical resection and PEI. While some series report The are no RCTs comparing surgical resection and PEI. While some series report

that survival after PEI is lower than after surgical resection, some cohort studies that survival after PEI is lower than after surgical resection, some cohort studies

have failed to detect significant differenceshave failed to detect significant differences

PEI can be recommended for well compensated patients when surgery is PEI can be recommended for well compensated patients when surgery is

precludedprecluded

J Hepatol 2001 J Hepatol 2001

TERAPIA DELL’HCC MULTIFOCALEIN FEGATO CIRROTICO

CONCETTI CHIAVE

Pz con HCC bifocale nello stesso segmento

Candidabili a resezione epatica con gli stessi criteri

dell’HCC singolo

Pz fino a 3 noduli <3 cm,età <65 aa

Candidabili atrapianto di fegato

CHEMIOEMBOLIZZAZIONE TRANSARTERIOSA:• è stato il trattamento più impiegato nel trattamento dei pz con HCC multifocale• mancano chiare dimostrazioni di efficacia sulla sopravvivenza

TERAPIE INTERSTIZIALI:• l’ efficacia in pz con HCC multifocale non è sufficientemente nota

BARCELONA RECOMMENDATIONS

TREATMENT OF INTERMEDIATE – ADVANCED HCCTREATMENT OF INTERMEDIATE – ADVANCED HCC

Six RCTs, comparing arterial embolisation alone or associated with chemotherapy Six RCTs, comparing arterial embolisation alone or associated with chemotherapy

have failed to identify a survival benefit, even in those patients with local have failed to identify a survival benefit, even in those patients with local

response to treatment response to treatment

Additional large RCTs are needed to clarify wheter differences in the selection of Additional large RCTs are needed to clarify wheter differences in the selection of

patients or in treatment schedules may result in a therapeutic benefit at least in a patients or in treatment schedules may result in a therapeutic benefit at least in a

subgroup of HCC subgroup of HCC (Recent demonstration of advantages of TACE emerging from a (Recent demonstration of advantages of TACE emerging from a

metanalysis of puvblished RCTs and 2 new RCTs)metanalysis of puvblished RCTs and 2 new RCTs)

None of the available options including tamoxifen, antiandrogens, Interferon and None of the available options including tamoxifen, antiandrogens, Interferon and

chemotherapeutic agents, offers an unequivocal survival benefitchemotherapeutic agents, offers an unequivocal survival benefit

J Hepatol 2001 J Hepatol 2001

DIVISIONE DI MEDICINA INTERNA

Centro per lo studio dei tumori del fegato

UNIVERSITA’ DI BOLOGNAPOLICLINICO S.ORSOLA MALPIGHI

Luigi Bolondi

Gianni Zironi

Laura Gramantieri

Patrizia Pini

Fabio PiscagliaValeria CamaggiElena SilvagniNatascia CelliSimona Leoni

NON-SURGICAL ABLATION OF SMALL HCCNON-SURGICAL ABLATION OF SMALL HCC

PEI RF

• Efficacy +++ +++

• Complications - - - +

• Pts compliance + ++

• Physician involvement +++ ++

• Cost + +++

SURGICAL RESECTIONSURGICAL RESECTION

LIVER TRANSPLANTATIONLIVER TRANSPLANTATION

PERCUTANEOUS TECHNIQUESPERCUTANEOUS TECHNIQUES

CURATIVE/EFFECTIVE TREATMENTSCURATIVE/EFFECTIVE TREATMENTS

High rate of complete response in High rate of complete response in selected candidatesselected candidates

Assumed to improve the natural history, prolonging Assumed to improve the natural history, prolonging the survival of patients with single < 5 cm HCC or 3 the survival of patients with single < 5 cm HCC or 3

nodules < 3 cmnodules < 3 cm

EASL Conference J Hepatol 2001

0

50

100

1 2 3 4 5years

Child A (293 cases)

Child B (149 cases)

5 years survival in unifocal (<5 cm) HCC

Median:

Child A23 months

Child B19 months

%

Multicentric Italian Study on PEI in HCC(746 cases)

(Bologna, Brescia, Clusone, Napoli Cotugno, Napoli Policlinico, Padova, Roma, Torino, Vimercate)

Radiology 1996