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