Storia clinica Paziente maschio di 74 anni Storia 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)

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

3. Ottobre 2003 In 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.

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TC spirale trifasica (26.11.2003) Fase arteriosa Fase portale

?

TC spirale trifasica (26.11.2003) Fase portale

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 Oka et al, 1990 Colombo et al, 1991 Pateron et al, 1994 Benvegnu et al, 1994 Cottone et al, 1994 Solmi et al, 1996 Bolondi et al, 2001 annual incidence 6.5 % 3 % 5.8 % 3 % 1.5-10 % 1.4 % 4.1 %

VIRUS CIRROSI HCC Flogosi cronica Necrosi Rigenerazione epatocitaria Diminuita capacità riparatrice dei danni al DNA Aumento errori di replicazione e trascrizione del DNA Eterogeneità geografica Diversi fattori di rischio Diversi bersagli a livello molecolare HCC

Acute hepatitis Factors affecting natural history Chronic hepatitis 85% HLA type 6% Cirrhosis Decompensation Death 20% Male gender Age on onset Alcohol Interferon HCC 4% Hepatitis B Alcohol Interferon 3,6% Transplantation Di Bisceglie, Hepatology, 2000

INCIDENCE OF HCC DURING 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 CIRRHOSIS ANALYSIS OF SURVIVAL BENEFIT Significant longer survivals for screened vs non screened p = 0.009

p < 0.0001

p < 0.02

p < 0.001

(Wong, Liver Transpl 2000) (Yuen, Hepatology 2000) (Bolondi, Gut 2001) (Trevisani, Am J Gastro 2002) No Significant difference * (Sarasin, Am J Med 1996) * transplantation not included in the model

Tailoring screening on RISK FACTORS FOR HCC IN CIRRHOSIS

•

Age

•

Male gender ( Aizawa, Cancer 2000 ) ( Zoli, Cancer 1996 Bolondi, Gut 2001 El Serag, J Clin Gastro 2002)

•

Child-Pugh score

•

HBsAg + (Bolondi, GUT 2001) (Solmi, Am J Gastro 1996) Tsukuma, N Engl J Med 1993)

•

HCV+

•

HBV + HCV

•

HCV + alcol

•

AFP (Velazquez, Hepatology 2003) (Parkin, IARC 1992) (Benvegnù, Gut 2001) (Bolondi, Gut 2001)

DEVELOPEMENT OF NEOPLASTIC GROWTH IN MACROREGENERATIVE NODULES

ARAKAWA 1986 TAKAYAMA 1990 RAPACCINI 1990 KONDO 1990 BOLONDI 1993 RECOGNITION OF EARLY MALIGNANT FOCI IN 5 ADENOMATOUS HYPERPLASTIC NODULES N°nodules 18 12 17 12 mean follow-up 1-5 yrs 10.2 mos > 1 yr 22.6 mos 9 neoplastic growth 9 benign behaviour 10 neoplastic growth 2 benign behaviour 0 neoplastic growth 17 benign behaviour 7 neoplastic growth 5 benign behaviour

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

Blood supply of liver nodules in cirrhosis Portal flow Large regenerative nodule Dysplastic nodule Arterial flow Borderline lesion

HCC

CHARACTERIZATION OF LIVER MASSES: ASSESSMENT OF VASCULARITY BY IMAGING TECHNIQUES DOPPLER QUANTITATIVE QUALITATIVE SPECTRAL ANALYSIS COLOR and POWER mapping + mdc SPIRAL CT Contrast-enhanced NMR CONTRAST-ENHANCED US Stimulated Acoustic Emission Harmonic Imaging Pulse Inversion C 3 -mode CnTi

ARTERIAL HYPERVASCULARITY IN SMALL HEPATOCELLULAR CARCINOMA

Perfusional Angiosonography with Sonovue Spiral CT enhanced artherial phase

HCC

Per vedere questa immagine occorre QuickTime™ e un decompressore Video.

Per vedere questa immagine occorre QuickTime™ e un decompressore Motion JPEG A.

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

DIAGNOSIS OF HCC

Cirrhotic patients (US + AFP/6m) Liver nodule No nodule 1-2 cm FNAB > 2 cm < 1 cm Increased AFP* Normal AFP US /3m Spiral CT AFP > 400 ng/ml Doppler/CT/MRI/An HCC

* AFP level >200ng/dl

No HCC Surveillance US + AFP/6m

Bruix, J Hepatol ,2001

STAGING:

OPEN PROBLEMS AND AREAS FOR FUTURE RESEARCHES

•

Multinodularity

•

Vascular invasion

Imaging techniques insufficient

Selection between radical treatment or palliation

•

Recurrence potential

Tissue and molecular markers (Currently not done)

•

Selection between OLT and

•

ablation/destruction therapies Need for adjuvant therapy

THERAPEUTIC OPTIONS FOR HCC

Local therapy Surgical resection Percutaneous echo-guided Intra-arterial Transplant Systemic chemotherapy or hormonal therapy

EFFECT OF TREATMENT ON SURVIVAL OF 1108 PTS WITH HCC

Multicentric Italian Study Group on HCC

SURVIVAL OF SINGLE HCC <5 cm Child A

100 90 80 70 60 50 40 30 20 10 0 1 year 2 years NT (n=73) SURG (n=82) PEI (n=105) TACE (n=30) 3 years

J Hepatol, 1995

SCREENING FOR HCC IN CIRRHOSIS

ELIGIBILITY FOR CURATIVE TREATMENTS HCC detected within surveillance programme

47.5 %

p < 0.01

HCC detected outside surveillance programme

31.7 % (Bolondi, Gut 2001)

Rationale for the use of local treatments

•

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

INTERSTITIAL TUMOR ABLATION  HEAT laser, radiofrequency, highly focused ultrasound  FROST cryosurgery  DRUGS alcohol injection  RADIOACTIVITY implantation of radioactive seeds

Survival Outcomes in PEI-Treated Pts

(Retrospective Studies)

Author and year

Shiina 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 No. of Pts 1-yr Survival (%) 3-yr 5-yr 98 85 62 52 293 149 98 93 79 63 47 29 64 41 100 91 87 53 55 13

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 2000 Liver Cancer Study Group of Japan)

PEI

versus

Surgical Resection

(Non-Randomized Studies)

90 80 30 20 10 70 60 50 40 0

PEI Resection 1-yr 83 81 2-yr 66 73 3-yr 55 44

100 40 30 20 10 0 90 80 70 60 50

PEI Resection 1-yr 100 96 3-yr 82 84 5-yr 59 61

p = N.S.

- Same tumor stage - Poorer liver function in PEI groups Castells et al, Hepatology 1993

p = N.S.

Yamamoto et al, Hepatology 2001

Okosa farmaka ouk ihtai, sidher osa sidhero

s os

ouk ihtai, pur ihtai, ihtai, osa dh pur ouk ihtai tauta crh nomizein aniata 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 ABLATION EXPANDABLE NEEDLE (1.9 mm) 4 to 10 nickel-titanium hooks with tip thermistors 90-115°C

RF THERMAL ABLATION COOLED-TIP NEEDLE (1.2-1.3 mm) Peristaltic pump with 0°C saline solution 20-25°C

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

Overall Survival

100 90 80 70 60 50 40 30 20 10 0

6 PEI 98 RFTA 100 12 96 100 18 92 98 24 88 98 30 80 93 36 73 81

67 % PEI series (n = 184) - Lencioni R et al, Eur Radiol 1997

74 % 50 % Lin SM et al Gastroenterology 2004

RANDOMIZED COMPARISON OF RF THERMAL ABLATION vs PEI

232 patients with up to 3 HCC < 3 cm each

•

RF PEI --------------------------------------------------------------- Treatment sessions 2.1 6.4

p<00001

•

4yr survival 74% 57% p=0.01

•

4yr Overall recurrence p=0.005

70% 85%

•

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 ABLATION

•

Summary 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 UNIFOCALE IN FEGATO CIRROTICO CONCETTI CHIAVE Pz in classe Child-Pugh A a basso rischio operatorio e nodulo unico candidati a resezione anatomica Pz con nodulo singolo < 5 cm (e buon compenso epatico) ottimi candidati alle terapie locoregionali percutanee: l’alcolizzazione è la tecnica di scelta Noduli < 3 cm: Risultati migliori Noduli >3 cm: Se non resecabili, si può associare PEI + TACE

TERAPIA DELL’HCC UNIFOCALE IN 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 PEI vs SURGICAL RESECTION Recurrence rate after percutaneous treatments is as frequent as after surgical resection (>50% at 3 years and > 70% at 5 years) 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 have failed to detect significant differences PEI can be recommended for well compensated patients when surgery is precluded J Hepatol 2001

TERAPIA DELL’HCC MULTIFOCALE IN FEGATO CIRROTICO CONCETTI CHIAVE Pz fino a 3 noduli <3 cm, età <65 aa Pz con HCC bifocale nello stesso segmento Candidabili a trapianto di fegato Candidabili a resezione epatica con gli stessi criteri dell’HCC singolo 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 HCC Six RCTs, comparing arterial embolisation alone or associated with chemotherapy have failed to identify a survival benefit, even in those patients with local response to treatment 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 subgroup of HCC

(Recent demonstration of advantages of TACE emerging from a metanalysis of puvblished RCTs and 2 new RCTs)

None of the available options including tamoxifen, antiandrogens, Interferon and chemotherapeutic agents, offers an unequivocal survival benefit J Hepatol 2001

DIVISIONE DI MEDICINA INTERNA

UNIVERSITA’ DI BOLOGNA POLICLINICO S.ORSOLA MALPIGHI

Luigi Bolondi

Centro per lo studio dei tumori del fegato

Gianni Zironi Laura Gramantieri Patrizia Pini Fabio Piscaglia Valeria Camaggi Elena Silvagni Natascia Celli Simona Leoni

NON-SURGICAL ABLATION OF SMALL HCC

PEI • Efficacy • Complications +++ - • Pts compliance + • Physician involvement +++ • Cost + RF +++ - + ++ ++ +++

SURGICAL RESECTION LIVER TRANSPLANTATION PERCUTANEOUS TECHNIQUES

High rate of complete response in selected candidates

CURATIVE/EFFECTIVE TREATMENTS

Assumed to improve the natural history, prolonging the survival of patients with single < 5 cm HCC or 3 nodules < 3 cm EASL Conference J Hepatol 2001

Multicentric Italian Study on PEI in HCC (746 cases)

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

100 5 years survival in unifocal (<5 cm) HCC Child A (293 cases) Child B (149 cases)

Median: Child A  23 months Child B  19 months

50

%

0 1 2 3 4 5 years

Radiology 1996