STRATEGIES FOR DIAGNOSIS AND STAGING OPEN PROBLEMS

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 (ChildPugh 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.
Per vedere questa immagine
occorre QuickTime™ e un
decompressore Motion JPEG A.
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
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 %
CIRROSI
VIRUS
HCC
Flogosi cronica
Necrosi
Rigenerazione
epatocitaria
Diminuita capacità
riparatrice dei danni
al DNA
HCC
Aumento errori di
replicazione e
trascrizione del DNA
Eterogeneità geografica
Diversi fattori di rischio
Diversi bersagli a livello molecolare
Factors affecting
natural history
Acute hepatitis
Chronic hepatitis
Cirrhosis
6%
Decompensation
Death
HLA type
85%
Male gender
Age on onset
Alcohol
Interferon
20%
Hepatitis B
4% Alcohol
Interferon
HCC
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
(Aizawa, Cancer 2000)
• Male gender
(Zoli, Cancer 1996
Bolondi, Gut 2001
El Serag, J Clin Gastro 2002)
• Child-Pugh
• HBsAg
score
+
(Bolondi, GUT 2001)
(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 GROWTH
IN 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 growth
RAPACCINI 1990
12
10.2 mos
2 benign behaviour
0 neoplastic growth
KONDO 1990
17
> 1 yr
17 benign behaviour
7 neoplastic growth
BOLONDI 1993
12
22.6 mos
5 benign behaviour
PREDICTION OF MALIGNANT EVOLUTION IN
SMALL NODULES (< 1.5 cm) DETECTED AT
IMAGING TECHNIQUES
IMAGING
•Assessment of
vascularity
NEW TISSUE MARKERS
MOLECULAR ANALYSIS
•Markers of
proliferation (AgNORs,
PCNA, Ki67...)
•Enzymatic
cytochemistry
•DNA ploidy
CLINICAL CRITERIA
Volume increase at 4 month
•Assessment of
monoclonality
•Genomic
instability and
LOH
Probably no
consequence on
outcome
Blood supply of liver nodules in cirrhosis
Portal flow
Arterial flow
Large
regenerative
nodule
Dysplastic
nodule
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
Pulse Inversion
Harmonic Imaging
C3-mode
CnTi
ARTERIAL HYPERVASCULARITY IN
SMALL HEPATOCELLULAR CARCINOMA
Perfusional
Angiosonography
with Sonovue
Spiral CT enhanced
artherial phase
HCC
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- Hyperintensity
in the arterial phase
- Iso or Hypointensity in
the portal and late
phases
DIAGNOSIS OF HCC
Cirrhotic patients (US + AFP/6m)
Liver nodule
1-2 cm
> 2 cm
FNAB
No nodule
< 1 cm
US /3m
Increased AFP*
Normal AFP
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
Selection between radical
treatment or palliation
Imaging techniques
insufficient
• 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
Percutaneous
echo-guided
Intra-arterial
Surgical resection
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
NT (n=73)
SURG (n=82)
PEI (n=105)
TACE (n=30)
1 year
2 years
3 years
J Hepatol, 1995
SCREENING FOR HCC IN CIRRHOSIS
ELIGIBILITY FOR CURATIVE TREATMENTS
HCC detected outside
surveillance programme
HCC detected within
surveillance programme
47.5 %
p < 0.01
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
 FROST
 DRUGS
laser, radiofrequency, highly focused ultrasound
cryosurgery
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
Survival (%)
1-yr
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
Surgery
(n=8.010)
(retrospective study)
all clinical stages
>
PEI
(n=4.037)
(Arii et al, Hepatology 2000
Liver Cancer Study Group of Japan)
PEI versus Surgical Resection
(Non-Randomized Studies)
90
100
80
90
80
70
70
60
60
50
50
40
40
30
30
20
20
10
10
0
0
PEI
Resection
p=
N.S.
1-yr
2-yr
3-yr
83
81
66
73
55
44
PEI
Resection
1-yr
3-yr
5-yr
100
96
82
84
59
61
- Same tumor stage
- Poorer liver function in PEI groups
Castells et al, Hepatology
p=
N.S.
Yamamoto et al, Hepatology
2001
Okosa farmaka ouk ihtai, sidheros ihtai,
osa sidheros ouk ihtai, pur 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)
90-115°C
4 to 10 nickel-titanium hooks
with tip thermistors
RF THERMAL ABLATION
COOLED-TIP NEEDLE
(1.2-1.3 mm)
20-25°C
Peristaltic pump
with 0°C saline
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
Overall Survival
100
90
67
%
80
70
60
50
40
30
20
10
0
6
98
PEI
RFTA 100
12
18
24
30
36
96
100
92
98
88
98
80
93
73
81
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
p<00001
2.1
6.4
• 4yr survival
74%
57%
70%
85%
p=0.01
• 4yr Overall recurrence
p=0.005
• 4yr Local progression
1.7%
11%
p=0.003Shiina, 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:
Noduli >3 cm:
Risultati
migliori
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
RF
+++
+++
• Complications
--
-+
• Pts compliance
+
++
• Efficacy
• Physician involvement +++
++
• Cost
+++
+
SURGICAL RESECTION
LIVER TRANSPLANTATION
High rate of complete response in
selected candidates
PERCUTANEOUS TECHNIQUES
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
Child A (293 cases)
5 years survival in
unifocal (<5 cm) HCC
Median:
Child A23 months
Child B (149 cases)
50
%
Child B19 months
0
1
2
3
4
5
years Radiology 1996