Epatocarcinoma: trapianto o resezione? A chi e perche? - Gastrolearning®

Progetto GASTROLEARNING
www.gastrolearning.it
Chirurgia Epatobiliare e
Centro Trapianto di Fegato
Azienda Università degli Studi di Padova
cillo@unipd.it
Prof. Umberto Cillo, MD, FEBS
Padova, 03 Giugno 2013
EPATOCARCINOMA:
TRAPIANTO O RESEZIONE?
a chi e perchè

HCC
Resection vs Transplantation
Resection
Ablation
Transplantation
TACE Sorafenib

Haynes RB, et al. BMJ 2002; 324: 1350
An updated model
for EBM
clinical decisions
Limits of a specific therapy

Flather M, et al. Clin Trials 2006; 3: 508-512
RCT are not useful to measure the effectiveness
of complex – multifaceted therapies like organ transplantation
Research evidence &
treatment decision for HCC patients

Variation in choice of therapy by nonclinical factors,
after adjustment for clinical factors
Nathan et al, Ann Surg Oncol. 2013 Feb;20(2):448-56

TRANSPLANTATION
- Indicated within Milan criteria
- LDLT is an alternative if wating time >6 month
- LDLT is a suitable setting for extended indications
RESECTION
-“Single tumors (no size limit), normal bilirubin with either
HPVG<10mmHg or PLT<100.000
- In multiple tumors within Milan criteria (not trasplantable)
resection has to be considered (and validated)

HCC
LIVER
RESECTION

AASLD 2005, 2010; EASL 2012 recommendations
AASLD 2005 = AASLD 2010
= EASL 2012
Treatment decision for HCC patients

Lim et al, British Journal of Surgery 2012; 99: 1622–1629
152 studies reviewed
Median 5-year overall survival rate: 67% (range 27-81)
Median disease-free survival rate: 37% (range 21 – 57)
Operative mortality rate 0.7% (range 0-5)
Surgical resection offers good OS
for patients with HCC
within the Milan criteria
and with good liver function
Outcomes have tended to
improve in more recent years

Liver resection
&
LARGE HCC
HCC

AUTHOR, YEAR N° OF PATIENTS 5-year survival
Kelvin, 2005 380 39%
Pawlik, 2005 300 (tumor > 10 cm) 27%
Cillo, 2007 48 35%
Minagawa, 2007
2312 (5-10 cm)
843 (> 10 cm)
43%
38%
Shah, 2007 24 (>10 cm) 54%
Young, 2007 42 (> 10 cm) 45%
Cho, 2007 62 (5-10 cm) 52%
Wang, 2008 243 50%
Torzilli, 2008 24 80% (3-year)
Choi GH, 2009 50 (> 10 cm) 40%
Yang LY, 2009 260 38%
Delis SG, 2009 66 (> 5 cm) 32%
Schiffman SC, 2010* 78 (> 5 cm) 20%
Single tumor > 5 cm
is an INDICATION to resection
if technically feasible
Liver resection for HCC
Extension of resection (Size)

“Single tumors > 5 cm are still considered for surgical resection as first
option, because if modern MRI is applied in pre-operative staging, the
fact that solitary large tumors remain single and with no
macrovascular involvement – which might be common in HBV-related
HCC – reflects a more benign biological behavior”
Early HCC (= BCLC stage A)
• Single tumor >2 cm
• 3 nodules <3 cm of diameter
• ECOG-0
• Child–Pugh class A or B

Andreou et al, J Gastrointest Surg (2013) 17:66–77
1115 patients/539  Major hepatectomy
Median tumor size was 10 cm (range: 1–27 cm)
22% bilateral lesions
The TNM-Stage distribution:
29% Stage I
31%Stage II
38 % Stage III
2 % Stage IV
35% Chronic Liver disease
60% Microvascular invasion
90-day p.o. mortality rate was 4%
Median follow-up: 63 months
5-year OS 40 %
Patients treated with right hepatectomy (n=332) and those requiring extended
hepatectomy (n=207) had similar 90-day postoperative mortality rates
(4 % and 4 %, respectively, p=0.976) and 5-year overall survival rates
(42 % and 36 %, respectively, p=0.523)

Andreou et al, J Gastrointest Surg (2013) 17:66–77
Postoperative mortality and OS rates
after major hepatectomy
improved over time
Factors associated with worse survival at
multivariate analysis:
-AFP level >1,000 ng/mL
-Tumor size >5 cm
-Presence of major vascular invasion
-Presence of extrahepatic metastases
-Positive surgical margins
-Earlier time period
Expansion of surgical indications to include major hepatectomy
is justified by the significant improvement in outcomes
over the past three decades

Liver
function
Tumor
extension
Location
Extension
of hepatectomy
for oncolgical
radicality
HCC: Resectability
Functional
reserve

Liver resection
&
Portal Hypertenison
HCC

Bruix et al, Gastroenterology 1996 Oct;111(4):1018-22.Bruix et al, Gastroenterology 1996 Oct;111(4):1018-22.
29 HCC (all except one < 5 cm)
CPT-A
At multivariate analysis
only HVPG was significant
(P = 0.0001; OR 1.90; 95% CI 1.12-3.22).
Preoperative HVPG of decompensated patient was
higher (13.9±2.4 vs. 7.4±3.5 mmHg respectively)
P < 0.001

Ishizawa T, et al. Gastroenterology 2008; 134: 1908
PH is not an absolute contraindication
to liver resection
Need for RCT versus ablation
136 PTH patients vs. 250 no PTH undergoing to resection
CPT-A patients 5-yr survival
• PTH 56%
• No PTH 71%
Clinically Relevant Portal Hypertension

No CRPH, Normal bilirubin
CRPH and/or abnormal bilirubin
Gis`ele N’Kontchou, et al. Hepatology 2009; 50
5-year survival & prognosis factors
in 235 consecutive cirrhotic patients
• CPT-A: 205
• CPT-B: 30
who received RFA as first-line treatment
for up to three HCC<5 cm
307 tumors
mean diameter: 29 mm
53 multinodular forms
Clinically Relevant Portal Hypertension

241 cirrhotic patients with HCC
89 patients: with portal hypertension (PH)
152 patients without portal hypertension (NPH)
Preoperative mean MELD:
PH  9.5 ± 7.8
NPH  8.4 ± 1.3; P 0.001
After one-to-one matching:
PH (n=78) and NPH (n=78) had the same preoperative characteristics and showed the
same intraoperative course, postoperative occurrence of liver failure, morbidity, length of in-
hospital stay and survival rates (P =ns in all cases).
The only predictors of postoperative liver failure
were MELD score (P 0.001) and extent of hepatectomy (P 0.005)
Cucchetti et al, Ann Surg 2009;250: 922–928
Overall survival curves of resected patients
with and without PH (P =0.453)
Faced with the same MELD score
and extent of hepatectomy
presence of PH should not be considered
as a contraindication
for hepatic resection in cirrhotic patients

Liver resection
&
Hepatic Function
HCC

Cucchetti et al, Liver Transplantation 12:966-971, 2006
Role of MELD score in predeicting
p.o. liver failure and morbidity
after hepatectomy for HCC in cirrhotics
154 HCC-resected cirrhotic patients
11 (7.1%) p.o. liver failure (death or LT)
46 (29.9%) developed ≥ 1 po complication
At ROC analysis:
• MELD ≥ 11 High risk for p.o. liver failure
• MELD ≥ 9 Major risk for p.o. complications
MELD and
p.o. liver failure
(AUC 0.92
95% CI 0.87-0.96)
MELD and
p.o. complication
after hepatic
resection
in cirrhotics
(AUC 0.85,
95% CI 0.78-
0.89).
MELD score should be used
to select the best candidates
for hepatectomy

Selection of HCC patients for resection is based on
planned extension of hepatectomy and liver functional reserve
Cescon M, et al. Arch Surg 2009http://www.webaisf.org/
Liver resection for HCC in cirrhosis

Liver resection
&
Multifocality
HCC

126 Multiple HCC vs
308 single HCC undergoing to resection
Child A patients 5-yr survival
•Multiple 58%
•Single 68%
Ishizawa T, et al. Gastroenterology 2008; 134: 1908
Multiple tumors
are not a contraindication
to liver resection

Lin CT et al. World J Surg 2010; 34: 2155
Hepatic resection combined
with intraoperative local ablation therapy
is effective for multinodular HCCs

AUTHOR, YEAR N° OF PATIENTS Survival
Kumada K, 1990 13 Median: 12months
Wu CC, 2000 112 5yr: 28%
Minagawa M, 2001 18 5yr: 42%
Pawlik TM, 2005 102
5yr: 10%
Median: 11months
Le Treut YP, 2006 26
5yr: 13%
Median: 9 months
Ikai I, 2006 78
3yr: 22%
Median: 9 months
Chen XP, 2006 286 5yr: 18%
Minagawa M, 2007 1517 5yr: 20-40%
Liang LJ, 2008 86 Median=11months
Inoue Y, 2009 49 5yr: 40%
Kondo K, 2009 48 5yr: 30%
Ban D, 2009 45 5 yr: 21%
Several papers on resection of BCLC C tumors
Tumor Thrombectomy
In selected cases with tumor thrombus (child A,
PST=0, no main trunc) surgery is an INDICATION
(sorafenib as only alternative)

Shi J, et al. Ann Surg Oncol 2010; 17: 2073
Several papers on resection of BCLC C tumors

Peng ZW, et al. Cancer 2012;118:4725-36
Type I Type I
Type II Type II

The impact of multinodularity on HCC outcomes.
Patients with multiple neoplasms at the time of surgery
had a lesser overall survival rate and greater recurrence rate
Chang WT, et al. Surgery 2012;152:809-20

Wang et al, Digestive and Liver Disease 45 (2013) 510– 515
SR- Median survival: 11 months
Supportive-care- Median survival : 3.9 months (HR, 0.45; 95% CI, p < 0.001)
Patients who underwent surgical resection had the longest survival
compared to patients undergoing other treatments (33.4 months versus 8.1 months, p < 0.001).

2046 consecutive patients resected for HCC
(10 centers)
• BCLC-0/A: 1012 patients (50%)
• BCLC-B: 737 patients (36%)
• BCLC-C: 297 patients (14%)
Overall Survival (P = 0.000)
BCLC 0/A
(50%; 1012)
BCLC B
(36%; 737)
BCLC C
(14%; 297)
1 year 95% 88% 76%
3 years 80% 71% 49%
5 years 61% 57% 38%
BCLC 0-A
BCLC B
BCLC C
Torzilli et al, Ann Surg 2013;257: 929–937

2046 consecutive patients resected for HCC
(10 centers)
• BCLC-0/A: 1012 patients (50%)
• BCLC-B: 737 patients (36%)
• BCLC-C: 297 patients (14%)
BCLC 0-A
BCLC B
BCLC C
Disease Free Survival (P = 0.000)
BCLC 0/A
(50%; 1012)
BCLC B
(36%; 737)
BCLC C
(14%; 297)
1 year 77% 63% 46%
3 years 41% 38% 28%
5 years 21% 27% 18%
Resection is in current practice widely applied
among patients with multinodular, large, and macrovascular invasive HCC
with acceptable short- and long-term results
and justifying an update
of the EASL/AASLD therapeutic guidelines in this sense
Torzilli et al, Ann Surg 2013;257: 929–937

HCC staging and treatment algorithm
JSH guidelines 2011
Kudo et al., JSH Practice Guidelines,
Dig Dis 2011; 29: 3339
HCC

HCC
LAPAROSCOPIC
LIVER
RESECTION

Bruix J, Sherman. Hepatology 2010
Laparoscopy and HCC:
high potential, poor evidence
Laparoscopic approach is an orphan procedureLaparoscopic approach is an orphan procedure
Asian Oncology Summit 2009
No reccomendations on laparoscopy
Poon D, et al. Lancet Oncol 2009
AASLD 2010
Bruix J, et al. Hepatology 2010
Rahbari NN, et al. Ann Surg 2011
US National Conference 2010
Pomfret EA, et al. Liver Transplant 2010
Systematic Review 2011
HCC Consensus Gruop 2012

Laparoscopy and HCC:
high potential, poor evidence

1. Same oncological radicality?
1. Lower surgical stress
(decompensated cirrhosis)
1. Potential for redo and salvage
surgery (Open resection, OLTx)
1. Multimodal therapy
VLS
R
esection
Ablation
Stadiation
Potential
forredo
Laparoscopic Approach
Multimodal Treatment
Laparoscopic approach advantages:
RESECTION

3 European centers Between 1998 and 2008
163 LLR for HCC
Median surgical duration: 180 minutes
Median operative blood loss: was 250 mL
9.8% patients received blood transfusion
9.2% Conversion to open surgery
Median tumor size: 3.6 cm
Median surgical margin: 12 mm
Liver-specific complications: 11.6%
General complications: 10.4%
Hospital stay: 7 days
Overall
Survival
Recurrence
Free Survival
1 yr 92.6% 77.5%
3 ys 68.7% 47.1%
5 ys 64.9% 32.2%
Overall Survival
Disease Free
Survival
Dagher et al, J Am Coll Surg 2010;211:16–23

Levels of evidence 2b - 4
MARGINS+RECURRENCE
P>0.05
P>0.05
Same oncological radicality
Li N et al, Hepatology Research 2012; 42: 51–59

MORBIDITYHOSPITALSTAY
P<0.01
P<0.01
Li N et al, Hepatology Research 2012; 42: 51–59
Levels of evidence 2b - 4 Lower Morbidity and Hospital Stay

Liver Resection:
Laparoscopic Surgery
• 10 non-randomized controlled studies that reported 494 patients
• 213 underwent laparoscopic liver resection (LLR)
• 281 underwent open liver resection (OLR)

Blood transfusion requirement:
Patients in LLR had a lower rate of blood transfusion requirement
(five trials reported this data, OR: 0.39, 95% CI: 0.18 to 0.86)

LLR for HCC is superior to the OLR in terms of its perioperative results
and does not compromise the oncological outcomes

Yoon et al, Surg Endosc (2012) 26:3133–3140

Belli G et al, Surg Endosc (2009) 23:1807–1811
Recurrence of cancer and the need for several surgical treatments are the Achilles’ heel of HCC
treatment
15 patients submitted to laparoscopic reintervention
(hepatic resection or radiofrequency ablation)
for a recurrence of HCC after a previous OLR o LLR
Overall postoperative mortality : 0%
Overall postoperative morbidity : 26.65
No patients had a severe postoperative complication.
1/15 moderate ascites
1/15 atelectasis requiring physiotherapy
1/15 pneumonia, which was treated with antibiotics.
OLR:
More intra-abdominal adhesions
Longer operative time
Laparoscopic redo surgery
for recurrent HCC in cirrhotic patients
is a safe and feasible procedure

Belli G et al, Surg Endosc (2009) 23:1807–1811

Laurent et al, J Hepatobiliary Pancreat Surg (2009) 16:310–314
24 LT:
12 following prior LLR
12 following prior OLR
19/24 Salvage LT
5/24 Neoadjuvant procedure (bridge resection)

Laurent et al, J Hepatobiliary Pancreat Surg (2009) 16:310–314
Initial LLR facilitates subsequent LT
compared with OLR
Median duration of hepatectomy
• LLR: 2.5 hours
• OLR: 4.5 hours
Median duration of LT:
• LLR: 6.2 hours
• OLR: 8.3 hours
Reduced operative time
Reduced blood loss
Reduced transfusion requirements

Cillo U. unpublished data
Laparoscopic Liver Resection:
Padova Experience
From March 2004 to October 2012
Total hepatic resection 1113
Total VLS hepatic resection 129 (11.5%)
converted to “open” 27 (20.9%)
VLS hepatic resection for HCC 87 (67.4%)
Hepatobiliary Surgery and Liver Transplant Unit
University of Padova
Chief: Prof. Umberto CILLO

Main indications
Malignant
HCC
colo-rectal mets
non colo-rectal mets
CCA
104 (80.6%)
87 (83.7%)
7 (6.7%)
5 (4.8%)
5 (4.8%)
Benign
Angioma
Adenoma
FNC
25 (19.4%)
10 (40%)
8 (32%)
7 (28%)
Padova Experience

Surgical Procedures
Left Hepatectomy 7 (5.4%)
Left Lobectomy 24 (18.6%)
Segmentectomy
S1
S2
S3
S4
S5
S6
S7
S8
98 (76%)
1 (1%)
19 (19.3%)
24 (24.5%)
10 (10.2%)
8 (8.2%)
30 (30.6%)
2 (2%)
4 (4.1%)
Padova Experience

Complications
(Prof. Umberto CILLO)
Ascites 2 42 (32.6%)
Fever 2 35 (27.1%)
Hemoperitoneum 3-b 4 (3.1%)
Pleural effusion 2 4 (3.1%)
Biliary leak 2 3 (2.3%)
Intestinal perforation 3-b 2 (1.6%)
Wound infection 2 2 (1.6%)
BPCO 2 1 (0.8%)
Padova Experience

Courtesy by Luca Aldrighetti
Laparoscopic Approach
1677 CASES

Evolution in liver surgery
HCC
How to recognize a high specialty center?
- Preoperative planning
- I.O. US
- I.O. Technique
- VLS approach available/ablation
- P.O. fast track
- High resection numbers
- LT availability

Improvement in Surgical
outcome reflects…
….evolution in anatomical knowledge
Etruscan Liver
I-II century BC
Couinaud’s liver segmentation
XX century AC - 1957
Virtual liver
XXI century AC
Jin et al, Liver Transplantation 14:1180-1184, 2008

outcome reflects…
….evolution in anatomical knowledge
Etruscan Liver
I-II century BC
Couinaud’s liver segmentation
XX century AC - 1957
Virtual liver
XXI century AC
Jin et al, Liver Transplantation 14:1180-1184, 2008Jin et al, Liver Transplantation 14:1180-1184, 2008

Provides essential information about:
- tumor extension
- vessel involvement
- choice of resection plane
- total liver remnant volume
outcome reflects…
….evolution in surgical planning

Evolution in surgical planning
U. Cillo
Casistica personale

Technical evolution:
Intra-operative Ultrasound

Technical evolution
Intraoperative
Ultrasound (IOUS)
&
Contrast Enhanced
Ultrasound (CEUS)

Intra-operative Ultrasound
U. Cillo
Casistica personale

outcome reflects…
….evolution in surgical technology
CUSA:
Cavitron Ultrasonic
Surgical Aspirator

CUSA dissection
U. Cillo
Casistica personale

Three major
Liver Resection Schools

Prospective - 161 patients
•61 study group: underwent ERAS-protocol
•100 control group: underwent traditional protocol
ERAS-group
56/61 patients (92%) tolerated fluids within 4 h
and a normal diet on day 1 after surgery
Median hospital stay (including readmissions,)
ERAS-group: 6.0 days
Control-group: 8.0 days (P < 0·001)
Rates of readmission
ERAS-group: 13%
Control-group: 10% (P = NS)
Morbidity and Mortality
ERAS-group: 41% and 0%
Control-group: 31% and 2.0% (P = NS)
The ERAS fast-track protocol is safe and effective
for patients undergoing liver resection.
Van Dam et al, British Journal of Surgery 2008; 95: 969–975

Fattori di rischio per una
degenza complicata
Totale pazienti N= 341
Variabile
Chi-
quadrato
Odds
ratio
Intervallo di
confidenza al
95%
p
Child-Pugh B-C 4,18 2,74 1,08 7,66 0,0409
Ipertensione clinicamente
significativa
6,91 2,47 1,27 4,94 0,0086
BCLC B-C-D 0,32 1,21 0,63 2,34 0,5702
Margini positivi 0,72 1,45 0,62 3,51 0,3971
Satellitosi 1,75 3,00 0,62 3,51 0,1859
Res ep magg> 2S 0,80 2,08 0,49 14,35 0,3704
Durata intervento >200 min 8,87 2,64 1,40 5,05 0,0029
Perdite intraop/100 3,97 1,87 1,01 3,47 0,0464
RISULTATI 3

Glasgow et al, Arch Surg 1999; 134: 30-35 Yasunaga- Hepatology Research 2012; 42: 1073–1080
outcome reflects...Centre Volume

HCC
LIVER
TRANSPLANTATION

The Milan Criteria paradigm:
DFS oriented
Single nodule < 5cm
2 or 3 nodules < 3cm
No macroscopic vascular invasion
No metastases
Mazzaferro V, et al. NEJM 1996; 334: 693

• The Milan criteria paradigm:
Sustainable?
DFS oriented

PatientPatient Organ
•8447 due to benign chronic liver disease
•9725 deaths due to liver cancer •1041 Liver transplants
• 6% of total deaths
http://www.istat.it/dati/dataset/20100129_00/
Liver related deaths in Italy for 2007
http://www.trapianti.salute.gov.it/cnt/
The central axiom of LT:
disparity demand/resources
Available resources may potantially satisfy
6% of whole demand and 20% of transplantable patients

Sustainable?
Accurate?
DFS oriented

FONTE DATI: Dati Reports CIRFONTE DATI: Dati Reports CIR
RESOURCES: Fixed pool of donor organs

Altekruse SF, et al. Hepatology 2011
Among 21,390 HCC cases diagnosed examined during 1998-2008 there were 4,727
(22%) with reported first course invasive liver surgery, local tumor destruction, or both.
Incidence rates
of localized stage HCC
increased faster
than rates of regional
and distant stage HCC
combined
(8% versus 4% per year)
Rising incidence of early-HCC
Increasing proportion of LT for HCC
Reason 2: Epidemiologic
RESOURCES:
Competition between different disease

The Milan Criteria paradigm
(YES or NO philosophy): DFS oriented
Single nodule < 5cm, 2 or 3
nodules < 3cm, no macroscopic
vascular invasion, no metastases
Mazzaferro V, et al. NEJM
1996; 334: 693
5-yrsurvival
MultipleHCC>1cm
Mazzaferro. Lancet Oncol 2009
Indivualized survival prediction
The Metroticket model
Vascular invasion
Minimum
5-yr
post-LT survival
threshold: 50%
OLTx
Milan
criteria
Up-to-7
criteria
MC are not accurate predictors of
post-LT outcome (UTILITY)
The dichotomous Milan criteria

• Total tumor volume > 115 cm3
as significant predictor of post-LT recurrence
• 115 cm3
= 1 nodule < 6cm, 3 < 4.2 cm, but it is not influenced by nodules < 1-2 cm
• Radiologic TTV staging is more accurate than Milan and UCSF ones
Toso C, et al. Liver Transpl 2008; 14: 1107

Progression of Alphafetoprotein Before Liver Transplantation
for HCC in Cirrhotic Patients: A Critical Factor
Progression group (26)
No progression group (127)
Vibert A, et al. Am J Transpl 2010; 10: 129
ROLE OF DINAMIC CHANGES IN TUMOR BIOLOGY

18F-FDG Uptake is the best
predictor of microscopic
vascular invasion
Kornberg A, et al. Liver Transpl 2012. In press
91 patients underwent LT for HCC after PET evaluation.
Patients with 18F-FDG non-avid HCC beyond the Milan criteria on clinical
staging may achieve excellent recurrence-free long-term survival after LT.

Overall survival Disease-free survival
Cillo U et al. Ann Surg 2004;239:150–159;
DuBay D et al. Ann Surg. 2011;253:166–72
Pre-transplant tumor biopsy
Predictors of biologic
aggressiveness

Barry CT et al. Am J Transplant 2012:428–37
Micro RNA Expression Profiles as Adjunctive Data to Assess the Risk of Hepatocellular
Carcinoma Recurrence After Liver Transplantation: a microarray study on 64 LT patients
Predictors of biologic
aggressiveness

Sustainable?
Accurate?
Fair?
DFS oriented

Urgency
Utility
Outcome
without LT
Urgency
Utility
Outcome
with OLTx
Urgency Utility
Non HCC Pts (Cirrhosis)
(no superior MELD limit)
HCC PATIENTS
(5yr surv > 70%)
Equity
MELD – HCC inequity

NEED
Utility
Outcome
without LT
Outcome
with OLTx
outcome without LT (URGENCY)
Available alternative
therapies??

• 20% transplanted HCC are T1
• 50% transplanted T1-T2 HCC have
MELD < 11
Diffuse use of LT in pts with therapeutic
alternatives (resection/ablation)
Angelico M, Cillo U, et al. DLD 2011.

OTHER EXCEPTIONS
Organized in WL according to joint clinical evaluation expressed in the weakly
multidisciplinary meeting.
Modified RECIST criteria
EXCLUSION CRITERIA
• Gross vascular invasion
or metastases (T4b and /or
N1, M1)
• Poorly differentiated HCC at
biopsy
SECOND CRITERION = STAGE
I. T1 1 nodule ≤ 1.9 cm
II. T2 1 nodule 2-5 cm; 2-3 nodules all ≤ 3 cm
III. T3 1 nodule > 5 cm; 2-3 nodules 1 > 3 cm
IV. T4a ≥ 4 nodules, any size;
T4b any T with gross vascular invasion
N1, M1 Metastases
THIRD CRITERION = TIME
Waiting list time with HCC
FIRST CRITERION = RESPONSE TO THERAPY
I. Stable / Progression* = 6
II. Untreatable (location, severity of cirrhosis)
= 5
III. Partial** = 4
IV. Recurrent new tumor (> 6 mo last therapy) awaiting therapy = 3
V. New tumor awaiting therapy
= 2
VI. Complete (total tumor necrosis)
= 1
* > 50% pre therapy vital tumor; ↑ n° nodules; ↓ AFP < 50% pre therapy level (if >
200ng/ml)
** < 50% pre therapy vital tumor; ↓ AFP > 50% pre therapy level (if > 200ng/ml)
Priority in waiting list given
according to response to therapy
Cillo U, et al. Am J Transpl 2007

Cox regression model for the progression
outside the Milan criteria or death.
De Giorgio M, et al. Liver Transplant 2010
HCC persistence or recurrence after bridging
therapy helps predicting transplant list dropout and
generate a more equitable exception policy.
HCC persistence or recurrence after bridging
therapy helps predicting transplant list dropout and
generate a more equitable exception policy.
Response to therapy as priority
criterion
Level of evidence 2b; Grade of reccomendation = BLevel of evidence 2b; Grade of reccomendation = B

Freeman R, et al. Am J Transpl 2006; 6: 1416
Multivariable analysis with
competing risks showed that
MELD score and AFP, were most
influential in predicting dropout for
HCC patients.
Washburn K, et al. Am J Transpl 2010; 10: 1652
Cox Model Competing risk Model
outcome without LT (URGENCY)

Il paziente con epatocarcinoma T1 e MELD minore di 15 non
deve essere inserito in lista per trapianto tranne che in ben
motivate eccezioni (E2R1).
STATEMENT 5.d
12,5%
12,5%
75,0%D’accordo
Parzialmente d’accordo
Disaccordo
4,7%
9,3%
86,0%
PARTECIPANTIGIURIA
Turin 18 October 2012

Sustainable?
Accurate?
Fair?
Need for a Paradigm Shift ?
DFS oriented

Paradigm shift?
“We can’t solve problems
by using the same kind of thinking
we used when we created them” Albert Einstein (1879-1955)
Need for changes
in allocation
principles and LT
endpoints

Merion RM, et al. Transpl Int 2011; 25: 965
The benefit of LT is better appreciated in terms of gain of LE
(linked to recipient age and alternative treatment) than in terms of survival
Benefit and liver transplantation

Man, 40 years old, HBV with 2 HCC nodules, the largest
nodule 6 cm in size , Child B (MILAN OUT, UCSF OUT)
Clinical scenario 1
OLT (5 yr surv.=60%) LE=10 yrs (LDLT?)
TACE (5 yr surv. = 10%) LE = 2 yrs
Gain in LE = 8 yrs
yrs1 2 3 4 5
1 3 5 6 8
%
yrs2 4 7 9
OLT (5 yr surv.=70%) LE=14 yrs
Resection (5 yr surv.=60%) LE = 10 yrs
Man, 65 years old, HCV, with 1 HCC nodule (4 cm in size), Child A
Clinical scenario 2
Gain in LE = 4 yrs/ 8 yrs
TACE (5 yr surv. = 10%) LE = 2 yrs
Balancing allocation principles:
the transplant benefit
The benefit of LT is better appreciated in terms of gain of LE
(linked to recipient age and alternative treatment) than in terms of survival
INDIVIDUAL BENEFIT

3-year (%) 5-year(%)
Post-transplantation survival 79.1 70.3
Post-surgical resection survival, median (range) 73 (62 to 92) 59 (51 to 80)
Post-RFA survival, median (range) 69 (50 to 95) 51 (37 to 65)
Survival benefit of transplantation over surgical resection,
median (range) 6 (-13 to 17) 11 (-10 to 19)
Survival benefit of transplantation over RFA, median
(range) 10 (-16 to 29) 19 (5 to 33)
3-year (%) 5-year(%)
Post-transplantation survival 79.1 70.3
Post-surgical resection survival, median (range) 73 (62 to 92) 59 (51 to 80)
Post-RFA survival, median (range) 69 (50 to 95) 51 (37 to 65)
Survival benefit of transplantation over surgical resection,
median (range) 6 (-13 to 17) 11 (-10 to 19)
Survival benefit of transplantation over RFA, median
(range) 10 (-16 to 29) 19 (5 to 33)
Ioannou G, et al. Am J Transpl 2012
Liver transplantation in patients with stage II HCC and Child A
cirrhosis results in a low survival benefit
and may not constitute optimal use of scarce liver donor organs
Transplant benefit in early HCC

Fast track — Articles
DOI:10.1016/S1470-2045(11)70144-9www.thelancet.com/oncology
Submitted April 19, 2011 Published Online June 17, 2011

Unadjusted model Adjusted model
11.2
17.7
24.9
34.6
11.2
13.5
17.4
28.5
BCLC predicts the Transplant Benefit
5-year transplant benefit model
Monte Carlo simulation: we obtained a list of
1000 outcomes for each BCLC stage
Vitale A, et al. Lancet Oncol 2011

PROPOSAL FOR GUIDELINES IMPROVEMENT 1.
Milan In
Yes No
Liver Transplantation
(CLT/LDLT)

Tumor Liver function Alternative
therapy
available
Downstaging Bridging Priority Post-LT
AASLD Milan § § - After 6mo - No
evidence
EASL Milan* § Resection No evidence After 6mo - -
ESMO Milan § Resection - After mo - -
Asian Milan Child C
Child AB if
recurrent HCC
Resection/a
blation
- - - -
Japan Milan Child C
Child AB if
recurrent HCC
Resection/a
blation
- - - -
AISF Milan** § § Yes After 6mo Response
to therapy
Size
AFP
mTOR
* Up-to-7 criteria should be validated prospectively
**possibility to use expanded criteria in selected centers with well estabilished protocols
§ Impaired liver function and alternative therapy only suggested in the comments/algorithm, no in reccomendations
SUMMARY OF AVAILABLE GUIDELINES FOR HCC LT

Need for a Paradigm shift?
Study period: 1998-2006
Study group: 4482 HCC patients with HCC on the US - WL
Results: 65% underwent LT, and 18% were dropouts.
5-year intent-to-treat survival = 50%
Pelletier SJ, et al. Liver Transpl 2009; 15: 859
50%
70%
Ioannou, et al. Gastroenterology2008; 134: 1342

Rahbari NN, et al. Ann Surg 2011
Resection might compete with CLTx
as first line therapy

0,0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1,0
Survival
0 12 24 36 48 60
months
BCLC 0, A1
BCLC 0, A1 (85)
BCLC A2, A3, A4 (152)
BCLC B, C, D (104)
Hazard ratio 95% Confidence
interval
BCLC A2-A3- A4
vs 0- A1
1,192515 0,786156 1,845475
BCLC B-C-D vs A2,A3, A4 1,852244 1,300711 2,637639
Intention to treat survival
HCC liver resection at
Padua University
-Period: 2000-2010
- 342 patients with cirrhosis
underwent resection for HCC

Koniaris LG, et al. Ann Surg 2011
413 patients with HCC underwent:
- Surgical resection (n = 106)
- Transplantation (n = 270)
or
- Listed without receiving
transplantation (n = 37)
Among known HCC patients
with preserved liver function
resection was associated
with superior patient survival
versus transplantation
Intention to treat survival

LT, ITT survival
LR for HCC with PHT
5 yr surv = 56%
LR for multiple HCC
5 yr surv = 58%
RF for unresectable HCC
5 yr surv = 50%
Laparoscopic RF
for HCC
unsuitable for resection
or ablation
5 yr surv = 40%
Alternative therapies and
Benefit for BCLC A2, A3, A4
Livraghi T, Hepatology 2009 Cillo U, Plos One 2013
Pelletier SJ, Liver Transpl 2009 Ishizawa T, et al. Gastroenterology 2008

Milan In
Yes No
(CLT/LDLT)
Consider Resection
Consider Ablation
Consider Liver Transplant
Consider Resection
Consider Ablation
Multidiscipl.
Setting only

Fuks et al, Hepatology 2012;55:132-140
LT as second line therapy after resection

Liver Transpl 2012
LT as second line therapy after resection

• 24 patients had undergone LT (21 for HCC
recurrence and three for liver failure).
• No HCC recurrence occurred after LT.
• The probability rates for 5-year overall and
tumor-free survival were 74% and 69%,
respectively.
• Conclusions: First line RFA followed by
salvage LT allows survival figures that are at
least as good as a first-line LT, while limiting
the number of grafts
RF ablation and salvage LT
N’Kontchou G, et al. J Hepatol 2012
LT as second line therapy
after ablation

Milan In
Yes No
(CLT/LDLT)
Consider Resection
Consider Ablation
Consider Resection
Consider Ablation
Multidiscipl.
Setting only*
Due to high benefit
consider downstaging
in “early B”
Due to high benefit
consider downstaging
in “early B”
*including Tx specialists and considering organ availability CLT/LDLT

STATEMENT 2.c HCC
0,0%
6,3%
93,8%
PARTECIPANTIGIURIA
D’accordo
Disaccordo
0,0%
12,5%
87,5%

Authors n Selection criteria Rec Survival
* 4-yr survival
Mazzaferro, NEJM 1996 48 Single < 5cm 8% 74%*
3 nodules < 3cm
Bismuth, Semin Liver Dis 1999 45 Single< 3cm 11% 74%
3 nodules < 3cm
Jonas, Hepatology 2001 120 Single< 5cm 16% 71%
3 nodules < 3cm
Yao, Hepatology 2001 70 Single<6.5cm 11% 75%
3 nodules < 4.5 cm
Total diameter<8cm
Cillo, Ann Surg 2004 48 G1-G2, no macrov.
Inv. (38% Milan out) 6% 73%
5-yrsurvival
MultipleHCC>1cm
Mazzaferro. Lancet Oncol 2009
Indivualized survival prediction
The Metroticket model
Vascular invasion
Minimum
5-yr
post-LT survival
threshold: 50%
In the Italian proposal there is no discrimination for HCC patients (futile LT = <50%
5yr PT survival)
= no absolute limits in size and number of nodules
Transplant benefit in intermediate HCC

STATEMENT 3. Obiettivo: Minima soglia di sopravvivenza
(Minima utilità)
La soglia ad oggi accettabile di sopravvivenza stimata dopo
trapianto è pari a 50% a 5 anni indipendentemente
dall’indicazione al trapianto di fegato (E3R2)
0,0%
6,7%
93,3%
PARTECIPANTIGIURIA
D’accordo
Disaccordo
6,4%
0,0%
93,6%

Criteria to establish a reliable selection policy:
1.Defined entry criteria
• Size/number or total tumour volume of
HCC
• Biological/pathological and molecular
markers
1.Defined end-points of successful downstaging
• Radiological
• Degree of necrosis
• Decrease in size
• Biological: alpha-fetoprotein (AFP)
1.Defined time between downstaging and listing
for LT
Toso C et al, J. Of Hepatology, 2010 vol.52; 930-936

Successful downstaging of
HCC to within the Milan
criteria is feasible in a
proportion
of patients. Absolute and
disease-free survival rates
in patients transplanted
following downstaging are
comparable to those in
patients within the Milan
criteria.
Systematic review of downstaging HCC
before LT in patients outside the Milan crit.
Downstaging for HCC beyond MC
A. N. Gordon-Weeks, et al. Br J Surg 2011

Ravaioli et al, American Journal of Transplantation 2008; 8: 2547–2557

From 2003 to 2006
177 HCC patients outside conventional criteria:
• single HCC 5–6 cm
• 2 HCCs ≤ 5 cm
• < 6 HCCs ≤ 4 cm (sum diameter ≤ 12 cm)
Within Milan criteria after down-staging
Transplantation rate:
68% Milan-in HCC patients
67% Downstaged HCC patients
1 Year Disease Free Survival
80% in Milan-in HCC patients
78% in Downstaged HCC patients
3 Years Disease Free Survival
71% in Milan-in HCC patients
71% in Downstaged HCC patients
Actuarial intention-to-treat survival
62.8% in Milan-in HCC patients
56.3% in Downstaged HCC patients
Ravaioli et al, American Journal of Transplantation 2008; 8: 2547–2557
Patient survival after liver transplantation;
CC: conventional criteria, BCDS: downstaged patients
Intention-to-treat
survival
P=NS

L’HCC oltre T2 dovrebbe essere rivalutato per indicazione e
priorità al trapianto considerando le strategie di downstaging
nell’ambito di protocolli dichiarati (E2 R2).
STATEMENT 5.f
0,0%
6,7%
93,3%
D’accordo
Disaccordo
0,0%
4,3%
95,7%
PARTECIPANTIGIURIA

c-KIT
SCF
Cell
membrane
IGF1
IGF2
RAS
RAF
Akt
PTEN
IGFBP3
PROLIFERATION
CELL SURVIVAL
Sorafenib
Gefitinib
Erlotinib
ERK
PROTEIN
TRANSLATION
Cetuximab
Mdm2 FKHR BAD
Sunitinib
Sorafenib
Bevacizumab
Targeted therapies
in phase II or III in
HCC
Everolimus
Rapamycin
Targeted therapies
under preclinical
evalution
AEE788
mTOR
PI3K
XL-765
Lapatinib
Her2/neu
MEK
IGFR
XL-228
EGFEGFR
VEGF
VEGFR
PDGF
PDGFR
Molecular targeted therapies and HCC

“The central focus must be
on increasing value for patients
— the health outcomes achieved per dollar spent.
Good outcomes that are achieved efficiently are the goal,
not the false “savings” from cost shifting
nd restricted services”.
From a “COST SHIFTING” system
To
a “VALUE – BASED SYSTEM”
From a “COST SHIFTING” system
To
a “VALUE – BASED SYSTEM”
A Strategy for Health Care Reform
- Toward a Value-Based System
Porter ME. N Engl J Med 2009; 361: 109-112

P4P
“Pay For Performance”
The health care
system tends to pay for quantity of
services not quality. Experts have
recommended that hospitals and
doctors be paid based on delivering
high
quality care, or what is called "pay for
performance." The President’s
Budget will link a portion of Medicare
payments for acute in-patient hospital
services to hospitals’ performance on
specific quality measures. This
program will improve the quality of
care delivered to Medicare
beneficiaries,
and the higher quality will save over
$12 billion over 10 years.
http://www.whitehouse.gov/omb/fy2010_key_healthcare/

HCC: Resection vs. Transplantation
Summary of surgical therapies
Tumor/Patient
Characteristics
Consider 2° line Therapy
Single HCC
• > 2 cm any size
• CPT-A-B
RESECTION
(OLTx-LDLT?)
OLTx
Multiple HCC
•Portal Hypertension
•Hyperbilirubinemia
OLTx (LDLT)
RESECTION
ABLATION
BCLC-B
DOWNSTAGING
(RESECTION/ABLATION/TACE)
and OLTx
BCLC-C
Type 1-2
RESECTION
BCLC-D • Milan in OLTx -

• M ultidisciplinarietà
• A lta specialità
• N umerosità di casi assistiti
• T rapianto
• R ete gestionale
• A llocazione equa delle risorse (con rispetto delle
gerarchie terapeutiche: trattamenti potenzialmente radicali>altro)
TERAPIA CHIRURGICA
DELL’HCC 2012

Liang W et al, Liver Transplantation 2012, in press
Meta-analysis
Recurrence Rate

Donor
harm
Recipient
Tx benefit
Waiting List
benefit/harm
The Ethical Dimensions of Equipoise in LDLT
Lee HS. Dig Dis 2007; 25: 296 Miller C. Transpl Rev 2008; 22: 206
RECIPIENT TX BENEFIT > (DONOR HARM + WL HARM)
LDLT
Recipient
Tx benefit
Cadaveric LT
Waiting List
benefit/harm

Bhangui P, et al. Hepatology 2011; 53: 1579
Recipient benefit
LDLT for patients more in need
(high transplant benefit)
Cohort study on 183 consecutive HCC patients undergoing LDLT (36) or
DDLT (147): INTENTION TO TREAT ANALYSIS
LDLT had a trend for lower post-LT outcome (selection
bias)
but a lower dropout rates than DLDT (0% vs. 18%)
HCC
PATIENTS

Within MC Beyond MC
Mizuno S, et al. Transplantation 2010; 89: 650
Prospective comparison of the survival rates between HCC patients who
underwent LDLT (n=29) and those who did not undergo LDLT (n=27).
*Period necessary to
develop macrovascular
invasion or metastases
*Period necessary to
develop macrovascular
invasion or metastases
*
Recipient benefit
LDLT for patients more in need
(high transplant benefit) HCC
PATIENTS

LDLT represents an acceptable option
when compared to DDLT for HCC patients
especially those within Milan criteria
Comparative studies of LDLT vs. DDLT for HCC
7 studies (1310 participants)
Patient survival: COMPARABLE
•1-year: OR = 1.03 (95% CI = 0.62-1.73)
•3-years: OR = 1.07 (95% CI = 0.77-1.48)
•5-years: OR = 0.64, (95% CI = 0.33-1.24)
Recurrence-free survival: COMPARABLE
•1-year: OR = 0.86 (95% CI = 0.54-1.38)
•3-years: OR = 1.04 (95% CI = 0.69-1.58)
•5-years: OR = 1.11 (95% CI = 0.70-1.77)
Recurrence-rates: NO SIGNIFICANT DIFFERENCES
•1-year: OR = 1.55, (95% CI 0.36-6.58)
•3-years: OR = 2.57 (95% CI 0.53-12.41)
•5-years: OR = 1.21, 95% CI 0.44-3.32).
Subgroup analysis: similar outcomes
for patients with HCC meeting Milan criteria

Meta-analysis
Patient survival

Meta-analysis
Recurrence free
survival

Grant et al, Liver Transplantation, Vol 17, No 10, Suppl 2 (October), 2011: pp S133-S138
Theoretical reasons for the potential higher
rates of HCC recurrence after LDLT:
•Stimulation of residual cancer cells by GF in
the regenerating liver
•Relatively brief waiting time for LDLT (LT for
patients whit aggressive or rapidly progressive
HCC
•More limited oncological clearance with the
IVC–sparing technique
•Presence of programmatic biases:
Centers unknowingly offer LDLT to patients
with a higher risk of HCC recurrence.
Is it ehical to offer a potentially risky
procedures to a potential
Low transplant benefit population?
In selected conditions yes
but still waiting for evidences

Anti-IL-2Rα
MMF
AZA
SIR-EVR
TAC
CsA
mAbs
pAbs
STER
Halloran et al, NEJM 2004; 351: 2715
Molecular targets of IS

mTORi-based IS may be associated
with increased survival after
liver transplant for HCC
Multivariate analysis of a registry population of adult liver transplant recipients
Results corrected for MELD, year of transplant, primary liver disease (non HCC),
age at transplant and, when applicable, TTV, AFP and pre-transplant HCC treatment
Toso C et al.Hepatology 2010;51:1237–43

Possible mechanisms:
1. Inhibit mTOR which is the downstream
effector of PI3k/Akt pathway, which can
serve as an oncogenic event when
overactive
1. Delay cancer progression by anti-
angiogenesis
1. Disregulate the oxygen supply to cancer
cells
Anti-neoplastic effects
of mTORi
Guba M et al. Nat Med 2002;8:128–35;
Lang SA et al. Int J Cancer 2007;120:1803–10;
Lang SA et al. Hepatology 2009;49:523–32;
Cohen A, Hall MN. Cell 2009;136:399–400;
Nicklin P et al. Cell 2009;136:521–34;
Rao RR et al. Immunity 2010;32:67–78;
Koehl GE et al. Transplant Rev 2005;19:20–31

mTOR has been implicated
in cancer progression in HCC
40–50% of patients with HCC demonstrate mTOR activation
mTOR activation (indicated by pRPS6 staining)
associated with recurrence in surgically resected patients
Trieber G. Expert Rev Anticancer Ther 2009;9:247–61;
Villanueva A et al. Gastroenterology 2008;135:1972–83

mTORi mediated growth inhibition
of HCC cells: preclinical data
Tumour volume and mice survival in xenografts treated with EGFRi and everolimus
Villanueva A et al. Gastroenterology 2008;135:1972–83;
Schumacher G et al. World J Gastroenterol 2005;11:1420–5

Menon et al, Aliment Pharmacol Ther 2013; 37: 411–419
Recurrence rate
SRL group (4.9–12.9%) < CNIs (17.3–38.7%)
RFS SIR RFS CNI
93–96% 1 year 70–78%
82–86% 3 years 64–65%
79–80% 5-years 54–60%
OS SIR OS CNI
94–95% 1 year 79–83%
85% 3 years 66%
80% 5-years 59–62%
In the Sirolimus-group:
1. Lower recurrence (OR = 0.30, 95% CI = 0.16–0.55, P < 0.001)
1. Lower recurrence-related mortality (OR = 0.29, 95% CI = 0.12–0.70, P = 0.005)
1. Lower overall mortality (OR = 0.35, 95% CI = 0.20–0.61, P < 0.001)

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