L’imaging del fegato nella patologia di confine benigno-maligno e nella diagnostica pre- e post-interventiva Chirurgia Epatobiliare e Centro Trapianto

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

[email protected]

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


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


“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


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


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


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


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


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


Technical evolution:Intra-operative Ultrasound

Technical evolution

Intraoperative Ultrasound (IOUS)

&

Contrast EnhancedUltrasound (CEUS)

Technical evolution:Intra-operative Ultrasound


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


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


Accurate?


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


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



Accurate?

Fair?


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


Accurate?

Fair?

Need for a Paradigm Shift ?


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


Consider ResectionConsider AblationConsider Liver Transplant


Multidiscipl.Setting only


Liver Transpl 2012

LT as second line therapy after resection

Milan In

Yes No




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 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%


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


Disaccordo 0,0%

4,3%

95,7%

PARTECIPANTIGIURIA


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

Documents

L’imaging del fegato nella patologia di confine benigno-maligno e nella diagnostica pre- e post-interventiva Chirurgia Epatobiliare e Centro Trapianto