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L’imaging del fegato nella patologia di confine benigno-maligno e nella diagnostica pre- e post-interventiva
Chirurgia Epatobiliare e Centro Trapianto di Fegato
Azienda Università degli Studi di Padova
cillo@unipd.it
Prof. Umberto Cillo, MD, FEBS
Camposampiero, 11 Ottobre 2013
Indicazioni e controindicazioni alla terapia chirurgica
ed al trapianto
HCCResection and/or Transplantation
ResectionAblation
Transplantation
TACE Sorafenib
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)
LIVER RESECTION
HCCResection and/or Transplantation
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 OSfor patients with HCC
within the Milan criteriaand with good liver function
Outcomes have tended toimprove in more recent years
Liver resection &
LARGE HCC
HCCResection and/or Transplantation
“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
Postoperative mortality and OS ratesafter major hepatectomy
improved over time
Factors associated with worse survival atmultivariate 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 hepatectomyis justified by the significant improvement in outcomes
over the past three decades
Liver function
Tumor extension
Location
Extensionof hepatectomy for oncolgical
radicality
HCC: Resectability
Functional reserve
Liver resection &
Portal Hypertenison
HCCResection and/or Transplantation
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%
Liver resection for HCCClinically Relevant Portal Hypertension
Liver resection &
Hepatic Function
HCCResection and/or Transplantation
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 patients11 (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 andp.o. liver failure
(AUC 0.9295% CI 0.87-0.96)
MELD andp.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
Liver resection &
Multifocality
HCCResection and/or Transplantation
126 Multiple HCC vs308 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
Shi J, et al. Ann Surg Oncol 2010; 17: 2073
Several papers on resection of BCLC C tumors
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 resultsand justifying an update
of the EASL/AASLD therapeutic guidelines in this sense
Torzilli et al, Ann Surg 2013;257: 929–937
LAPAROSCOPICLIVER
RESECTION
HCCResection and/or Transplantation
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 2009No reccomendations on laparoscopy
Poon D, et al. Lancet Oncol 2009
AASLD 2010No reccomendations on laparoscopy
Bruix J, et al. Hepatology 2010
Rahbari NN, et al. Ann Surg 2011
US National Conference 2010No reccomendations on laparoscopy
Pomfret EA, et al. Liver Transplant 2010
Systematic Review 2011No reccomendations on laparoscopy
HCC Consensus Gruop 2012No reccomendations on laparoscopy
Laparoscopy and HCC: high potential, poor evidence
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
Belli G et al, Surg Endosc (2009) 23:1807–1811
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 timeReduced blood loss Reduced transfusion requirements
Cillo U. unpublished data
Laparoscopic Liver Resection: Padova Experience
From March 2004 to October 2013
Total hepatic resection 1238
Total VLS hepatic resection 144 (11.6%)
converted to “open” 29 (20.1%)
VLS hepatic resection for HCC 97 (67.4%)
Hepatobiliary Surgery and Liver Transplant UnitUniversity 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%)
Hepatobiliary Surgery and Liver Transplant UnitUniversity of Padova
Chief: Prof. Umberto CILLO
Cillo U. unpublished data
Laparoscopic Liver Resection: Padova Experience
Courtesy by Luca Aldrighetti
Laparoscopic Approach
1677 CASES
Evolution in liver surgery
HCCResection and/or Transplantation
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, 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
Improvement in Surgical outcome reflects…
….evolution in surgical planning
Evolution in surgical planning
U. CilloCasistica personale
Evolution in surgical planning
U. CilloCasistica personale
Technical evolution:Intra-operative Ultrasound
Technical evolution
Intraoperative Ultrasound (IOUS)
&
Contrast EnhancedUltrasound (CEUS)
Technical evolution:Intra-operative Ultrasound
U. CilloCasistica personale
Prospective - 161 patients•61 study group: underwent ERAS-protocol•100 control group: underwent traditional protocol
ERAS-group56/61 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 daysControl-group: 8.0 days (P < 0·001)
Rates of readmissionERAS-group: 13%Control-group: 10% (P = NS)
Morbidity and MortalityERAS-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
Glasgow et al, Arch Surg 1999; 134: 30-35 Yasunaga- Hepatology Research 2012; 42: 1073–1080
Improvement in Surgical outcome reflects...Centre Volume
HCCResection and/or Transplantation
LIVERTRANSPLANTATION
The Milan Criteria paradigm:DFS orientedSingle nodule < 5cm 2 or 3 nodules < 3cm
No macroscopic vascular invasionNo metastases
Mazzaferro V, et al. NEJM 1996; 334: 693
• The Milan criteria paradigm:Sustainable?
The Milan Criteria paradigm: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 2007http://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
• The Milan criteria paradigm:Sustainable?
Accurate?
The Milan Criteria paradigm:DFS oriented
FONTE DATI: Dati Reports CIRFONTE DATI: Dati Reports CIR
RESOURCES: Fixed pool of donor organs
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
Dimensioni mm
N. N
oduli
2
4
6
8
10
12
14
20 40 60 80 100 120
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
5-y
r surv
ival
Mu
ltip
le H
CC
> 1
cm
Mazzaferro. Lancet Oncol 2009
Indivualized survival prediction
The Metroticket model
Minimum5-yrpost-LT survival threshold: 50%
OLTxMilan criteria
Up-to-7criteria
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
MC are not accurate predictors of post-LT outcome (UTILITY)
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
MC are not accurate predictors of post-LT outcome (UTILITY)
• The Milan criteria paradigm:Sustainable?
Accurate?
Fair?
The Milan Criteria paradigm: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
MC are not accurate predictors of 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 EXCEPTIONSOrganized 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 = STAGEI. T1 1 nodule 1.9 cmII. T2 1 nodule 2-5 cm; 2-3 nodules all 3 cmIII. T3 1 nodule > 5 cm; 2-3 nodules 1 > 3 cmIV. T4a ≥ 4 nodules, any size;
T4b any T with gross vascular invasionN1, M1 Metastases
THIRD CRITERION = TIMEWaiting list time with HCC
FIRST CRITERION = RESPONSE TO THERAPY
I. Stable / Progression* = 6II. Untreatable (location, severity of cirrhosis) = 5III. Partial** = 4IV. Recurrent new tumor (> 6 mo last therapy) awaiting therapy = 3V. New tumor awaiting therapy = 2VI. 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
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
• The Milan criteria paradigm:Sustainable?
Accurate?
Fair?
Need for a Paradigm Shift ?
The Milan Criteria paradigm: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 yrsTACE (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
Unadjusted model Adjusted model
11.2
17.7
24.9
34.6
11.213.5
17.4
28.5
BCLC predicts the Transplant Benefit5-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)
Need for a Paradigm shift?
Study period: 1998-2006Study group: 4482 HCC patients with HCC on the US - WLResults: 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. Gastroenterology 2008; 134: 1342
Rahbari NN, et al. Ann Surg 2011
Resection might compete with CLTxas 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
Sur
viva
l
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
Need for a Paradigm shift?Intention to treat survival
HCC liver resection at Padua University
-Period: 2000-2010
- 342 patients with cirrhosis underwent resection for HCC
LT, ITT survivalLR for HCC with PHT
5 yr surv = 56%LR for multiple HCC
5 yr surv = 58%
RF for unresectable HCC5 yr surv = 50%
Laparoscopic RFfor 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
Liver Transplantation(CLT/LDLT)
Consider ResectionConsider AblationConsider Liver Transplant
Consider ResectionConsider AblationConsider Liver Transplant
Multidiscipl.Setting only
PROPOSAL FOR GUIDELINES IMPROVEMENT 2.
Liver Transpl 2012
LT as second line therapy after resection
Milan In
Yes No
Liver Transplantation(CLT/LDLT)
Consider ResectionConsider AblationConsider Liver Transplant
Consider ResectionConsider AblationConsider Liver Transplant
Multidiscipl.Setting only*
Due to high benefit consider downstaging in “early B”
Due to high benefit consider downstaging in “early B”
PROPOSAL FOR GUIDELINES IMPROVEMENT 3.
*including Tx specialists and considering organ availability CLT/LDLT
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
Parzialmente d’accordo
Disaccordo 6,4%
0,0%
93,6%
Turin 18 October 2012
Successful downstaging of HCC to within the Milan criteria is feasible in a proportionof patients. Absolute and disease-free survival rates in patients transplanted following downstaging arecomparable 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
From 2003 to 2006177 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 patients67% Downstaged HCC patients
1 Year Disease Free Survival80% in Milan-in HCC patients78% in Downstaged HCC patients
3 Years Disease Free Survival71% in Milan-in HCC patients71% in Downstaged HCC patients
Actuarial intention-to-treat survival62.8% in Milan-in HCC patients56.3% 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
Parzialmente d’accordo
Disaccordo 0,0%
4,3%
95,7%
PARTECIPANTIGIURIA
Turin 18 October 2012
c-K
IT
SCF
Cell membrane
IGF1
IGF2
RAS
RAF
Akt
PTEN
IGFBP3
PROLIFERATIONCELL 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
Her
2/n
eu
MEK
IGF
R
XL-228
EGFE
GF
R
VEGF
VE
GF
R
PDGF
PD
GF
R
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/
• 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 2013