Transcript

Carcinoma hepatocelular: Estadioinicial

Alejandro Forner

BCLC Group. Liver Unit. Hospital Clínic. CIBERedh. University of Barcelona

VI CURSO DE RESIDENTES AEEHBarcelona, 10-­‐11 Noviembre 2017

Question #1

Respecto al hepatocarcinomaen estadio inicial, señale usted la respuesta incorrecta:

1.-­‐ Es posible su diagnóstico mediante técnicas de imagen sin necesidad de realizar una biopsia

2.-­‐ Con los tratamientos disponibles es posible obtener una supervivencia a 5 años superior al 50%

3.-­‐ Es aceptable una mortalidad intraoperatoriadel 5% en aquellos pacientes afectos de CHC inicial tratados mediante resección quirúrgica

4.-­‐ La función hepática es un parámetro fundamental para elegir la mejor opción terapéutica.

Early stage (A)Single or 3 nodules < 3cm

Preserved liver function*, PS 0

Portal pressure Bilirubin

Solitary 3 nodules ≤3cm

Associated diseasesIncreased

No Yes

Potential candidate for liver transplantation

No Yes

Normal

Effective treatmentswith impact on survival

Intermediate stage (B)Multinodular

Preserved liver function*, PS 0

Advanced stage (C)Portal invasion

Extrahepatic spreadPreserved liver function*, PS 1-­‐2

HCC

Terminal stage (D)End-­‐stage liver function**

PS 3-­‐4

Very early stage (0) Single< 2cm

Preserved liver function*, PS 0

Treatm

ent

Prognosis

*This term includes a heterogeneous group of patients with different degree of liver function reserve that has to be carefully evaluated. For most treatment options, compensated liver disease (Child-­‐Pugh A without ascites) is requested to obtain optimal outcomes. The sole option that may be applied irrespective of liver function is liver transplant. Most of them are compensated and fitting into the Chilld-­‐Pugh stage A.**Patients with end stage cirrhosis due to heavily impaired liver function (Child-­‐Pugh C or earlier stages with predictors of poor prognosis, high MELD score) should be considered for liver transplantation. In them HCC may become a contraindication if exceeding the enlistment criteria. ***Currently sorafenibfollowed by regorafenib has been shown to be effective. lenvatinib has been shown to be non-­‐inferior to sorafenib, but no effective second line option after lenvatinib has beenexplored.

Chemoembolization Systemictherapy***TransplantResectionAblation Ablation

BSC

>5 years >2.5 years >1 year 3 months

Survival

BCLC Staging and Treatment Strategy, 2017

Forner A, Reig ME, Bruix J. Lancet. 2017. Accepted.

>5 years

Early stage (A)Single or 3 nodules < 3cm

Preserved liver function*, PS 0

Portal pressure Bilirubin

Solitary 3 nodules ≤3cm

Associated diseasesIncreased

No Yes

Potential candidate for liver transplantation

No Yes

Normal

Effective treatmentswith impact on survival

HCC

Very early stage (0) Single< 2cm

Preserved liver function*, PS 0

Treatm

ent

Prognosis

*This term includes a heterogeneous group of patients with different degree of liver function reserve that has to be carefully evaluated. For most treatment options, compensated liver disease (Child-­‐Pugh A without ascites) is requested to obtain optimal outcomes. The sole option that may be applied irrespective of liver function is liver transplant. Most of them are compensated and fitting into the Chilld-­‐Pugh stage A.**Patients with end stage cirrhosis due to heavily impaired liver function (Child-­‐Pugh C or earlier stages with predictors of poor prognosis, high MELD score) should be considered for liver transplantation. In them HCC may become a contraindication if exceeding the enlistment criteria. ***Currently sorafenibfollowed by regorafenib has been shown to be effective. lenvatinib has been shown to be non-­‐inferior to sorafenib, but no effective second line option after lenvatinib has beenexplored.

TransplantResectionAblation Ablation

Survival

Forner A, Reig ME, Bruix J. Lancet. 2017. Accepted.

Natural history: Unknown

Survival: 12-­‐65% at 3 years

BCLC Staging and Treatment Strategy, 2017

EASL–EORTC Clinical Practice Guidelines. J Hepatol. 2012:56(4);908-­‐43

3

2

1

2 (weak) 1 (strong)

Grade of recommendation

Levels of evidence

Sorafenib

Chemoembolization

RF<5cmRF/PEI<2cm

OLT-­‐MilanResectionLDLT

C B AC B A

REOLT-­‐Extended

Adjuvant therapy in waiting listAdjuvant therapy after resection

Down-­‐stagingExternal/palliative radiotherapy

EASL-­‐EORTC recommendations for treatment

>5 years

Portal pressure Bilirubin

Potential candidate for liver transplantation

No Yes

Normal

Effective treatmentswith impact on survival

HCC

Very early stage (0) Single< 2cm

Preserved liver function*, PS 0

Treatm

ent

Prognosis

*This term includes a heterogeneous group of patients with different degree of liver function reserve that has to be carefully evaluated. For most treatment options, compensated liver disease (Child-­‐Pugh A without ascites) is requested to obtain optimal outcomes. The sole option that may be applied irrespective of liver function is liver transplant. Most of them are compensated and fitting into the Chilld-­‐Pugh stage A.**Patients with end stage cirrhosis due to heavily impaired liver function (Child-­‐Pugh C or earlier stages with predictors of poor prognosis, high MELD score) should be considered for liver transplantation. In them HCC may become a contraindication if exceeding the enlistment criteria. ***Currently sorafenibfollowed by regorafenib has been shown to be effective. lenvatinib has been shown to be non-­‐inferior to sorafenib, but no effective second line option after lenvatinib has beenexplored.

ResectionAblation

Survival

Forner A, Reig ME, Bruix J. Lancet. 2017. Accepted.

BCLC Staging and Treatment Strategy, 2017

Tumor cell invasion into the portal veinand minute intrahepatic metastases in the vicinity of the tumor are observed in 27% and 10% of distinctly nodular smallHCCs, respectively, but not observed in

indistinctly nodular small HCCs

Prognostic scoring systems for HCCVery early HCC

KojiroM, Roskams T. Semin Liver Dis. 2005;25:133-­‐142.Hasegawa K et al. J Hepatol 2013;58:724-­‐729.

Patients CP-­‐A (n=785) 5-­‐year survival: 83.9%

Single tu

mor < 2cm

CP-­‐A and platelet >150,000/mm3 (n=66)

5-­‐year survival: 81%

Roayaie S. et al. Hepatology 2013:57(4):1426-­‐35.

Overall Survival Rate (%)Study No. of patients 1 year 3 year 5 year

Lencioni et al. 2005Child-­‐Pugh A 144 100% 76% 51%Child-­‐Pugh B 43 89% 46% 31%

Tateishi et al. 2005Child-­‐Pugh A 221 96% 83% 63%Child-­‐Pugh B 98 90% 65% 31%

Choi et al. 2007Child-­‐Pugh A 359 NA 78% 64%Child-­‐Pugh B 160 NA 49% 38%

Hasegawa et al. 2013 5548 NA 81% 61%N’Kontchou et al. 2009

BCLC resectable 67 NA 82% 76%BCLC unresectable 168 NA 49% 27%

Lencioni R. et al Radiology 2005:234(3);;961-­967.Tateishi R. et al. Cancer 2005:103(6);;1201-­1209.

Choi D. et al. Eur Radiol 2007:17(3);;684-­92.Hasegawa K et al. J Hepatol 2013;;58:724-­729.

N’Kontchou G. et al. Hepatology 2009:50(5):1475-­1483.

Percutaneous ablation: RadiofrequencyLong-­‐term outcome after radiofrequency

Is resection still the treatment of choice in early/very early HCC?

Resection vs. ablation in very early HCCFirst line treatment for early/very early stage HCC

Croswell and Kramer. J Hepatol:2009 Apr;50(4):817-­‐26

Chen MS et al. Ann Surg 2006;243:321-­‐28 Huang J et al. Ann Surg 2010;252:903-­‐912

Feng K et al. J Hepatol. 2012 Oct;57(4):794-­‐802

RFA non inferior to resection RFA is inferior to resection

The pyramid of evidence

None of these studies are designed for evaluating both options in very early HCC

Ng KKC et al. Br J Surg. 2017 Nov 1. in press.

Croswell and Kramer. J Hepatol:2009 Apr;50(4):817-­‐26

The pyramid of evidence

• Population are not comparable:ü RFA patients are usually older, had lower platelet count,

belonged to more frequently to Child-­‐Pugh class B ü Surgical patients have usually bigger tumors

• Associated comorbidities are not registered

• Tumor staging is more accurate in patients treated by resection

Results can be biased by covariate distribution

Drawbacks of observational retrospective studies

Croswell and Kramer. J Hepatol:2009 Apr;50(4):817-­‐26

Systematic reviews

Cost-­‐effective analysis

The pyramid of evidence

Cho YK et al. Hepatology 2010;;51(4):1284-­1290.

• Group I: Hepatic resection (HR)• Group II: RFA and HR in case of local

failure• Group III: RFA

Expected overall survival:• Group I: 7.577 years, 5-­‐yr survival: 62.5%• Group II: 7.564 years, 5-­‐yr survival: 62.3%• Group III: 7.356 years, 5-­‐yr survival: 60.3%

Conclusion: “Considering that RFA is much less invasive as compared with HR, this study highly suggests that RFA may deserve to be considered as a primary treatment for very early stage HCC”

Resection vs. Radiofrequency in very early HCCA Markov Model Analysis

Cuchetti A et al. J Hepatol. 2013 Aug;59(2):300-­‐7.

17 studies: RFA (n= 3996) and resection (n= 4424)

Resection vs. Radiofrequency in very early HCCMeta-­‐analysis and Cost-­‐effectiveness analysis

< 20 mm 20-­‐30 mm 30-­‐50 mm

Margin no needed Margin may benefit

Margin may not benefit

Ablation = Resection Ablation < Resection Ablation <<<Resection (but might no be enough…LT)

Rodriguez-­‐Lope C, et al. J Hepatol. 2012;56 Suppl 1:S75-­‐87.

Resection vs. Radiofrequency in very early HCCResection and ablation: the benefit of margin

>5 years

Portal pressure Bilirubin

Potential candidate for liver transplantation

No Yes

Normal

Effective treatmentswith impact on survival

HCC

Very early stage (0) Single< 2cm

Preserved liver function*, PS 0

Treatm

ent

Prognosis

*This term includes a heterogeneous group of patients with different degree of liver function reserve that has to be carefully evaluated. For most treatment options, compensated liver disease (Child-­‐Pugh A without ascites) is requested to obtain optimal outcomes. The sole option that may be applied irrespective of liver function is liver transplant. Most of them are compensated and fitting into the Chilld-­‐Pugh stage A.**Patients with end stage cirrhosis due to heavily impaired liver function (Child-­‐Pugh C or earlier stages with predictors of poor prognosis, high MELD score) should be considered for liver transplantation. In them HCC may become a contraindication if exceeding the enlistment criteria. ***Currently sorafenibfollowed by regorafenib has been shown to be effective. lenvatinib has been shown to be non-­‐inferior to sorafenib, but no effective second line option after lenvatinib has beenexplored.

ResectionAblation

Survival

Forner A, Reig ME, Bruix J. Lancet. 2017. Submitted.

BCLC Staging and Treatment Strategy, 2017

>5 years

Portal pressure Bilirubin

Potential candidate for liver transplantation

Yes

Normal

Effective treatmentswith impact on survival

HCC

Very early stage (0) Single< 2cm

Preserved liver function*, PS 0

Treatm

ent

Prognosis

*This term includes a heterogeneous group of patients with different degree of liver function reserve that has to be carefully evaluated. For most treatment options, compensated liver disease (Child-­‐Pugh A without ascites) is requested to obtain optimal outcomes. The sole option that may be applied irrespective of liver function is liver transplant. Most of them are compensated and fitting into the Chilld-­‐Pugh stage A.**Patients with end stage cirrhosis due to heavily impaired liver function (Child-­‐Pugh C or earlier stages with predictors of poor prognosis, high MELD score) should be considered for liver transplantation. In them HCC may become a contraindication if exceeding the enlistment criteria. ***Currently sorafenibfollowed by regorafenib has been shown to be effective. lenvatinib has been shown to be non-­‐inferior to sorafenib, but no effective second line option after lenvatinib has beenexplored.

Resection

Survival

Forner A, Reig ME, Bruix J. Lancet. 2017. Submitted.

Consider the inclusion in waiting list if the explant shows satellites and/or microvascular invasion

BCLC Staging and Treatment Strategy, 2017

>5 years

Potential candidate for liver transplantation

No

Effective treatmentswith impact on survival

HCC

Very early stage (0) Single< 2cm

Preserved liver function*, PS 0

Treatm

ent

Prognosis

*This term includes a heterogeneous group of patients with different degree of liver function reserve that has to be carefully evaluated. For most treatment options, compensated liver disease (Child-­‐Pugh A without ascites) is requested to obtain optimal outcomes. The sole option that may be applied irrespective of liver function is liver transplant. Most of them are compensated and fitting into the Chilld-­‐Pugh stage A.**Patients with end stage cirrhosis due to heavily impaired liver function (Child-­‐Pugh C or earlier stages with predictors of poor prognosis, high MELD score) should be considered for liver transplantation. In them HCC may become a contraindication if exceeding the enlistment criteria. ***Currently sorafenibfollowed by regorafenib has been shown to be effective. lenvatinib has been shown to be non-­‐inferior to sorafenib, but no effective second line option after lenvatinib has beenexplored.

Ablation

Survival

Forner A, Reig ME, Bruix J. Lancet. 2017. Submitted.

In case of failure, consider resection

BCLC Staging and Treatment Strategy, 2017

>5 years

Early stage (A)Single or 3 nodules < 3cm

Preserved liver function*, PS 0

Portal pressure Bilirubin

Solitary

Potential candidate for liver transplantation

Yes

Normal

Effective treatmentswith impact on survival

HCC

Very early stage (0) Single< 2cm

Preserved liver function*, PS 0

Treatm

ent

Prognosis

*This term includes a heterogeneous group of patients with different degree of liver function reserve that has to be carefully evaluated. For most treatment options, compensated liver disease (Child-­‐Pugh A without ascites) is requested to obtain optimal outcomes. The sole option that may be applied irrespective of liver function is liver transplant. Most of them are compensated and fitting into the Chilld-­‐Pugh stage A.**Patients with end stage cirrhosis due to heavily impaired liver function (Child-­‐Pugh C or earlier stages with predictors of poor prognosis, high MELD score) should be considered for liver transplantation. In them HCC may become a contraindication if exceeding the enlistment criteria. ***Currently sorafenibfollowed by regorafenib has been shown to be effective. lenvatinib has been shown to be non-­‐inferior to sorafenib, but no effective second line option after lenvatinib has beenexplored.

Resection

Survival

Forner A, Reig ME, Bruix J. Lancet. 2017. Submitted.

BCLC Staging and Treatment Strategy, 2017

Best candidates: -­‐ Solitary HCC-­‐ Child-­‐Pugh A: No portal hypertension (HVPG < 10 mmHg)

Normal Bilirubin (< 1 mg/dl)

0

20

40

60

80

100

0 12 24 36 48 60 72 84 96

No portal hypertension and normal bilirubin (n= 35)Portal hypertension and normal bilirubin (n=15)Portal hypertension and Bilirubin >1 mg/dL (n=27)

Log Rank 0.00001

Survival (%

)

months

74%

50%

25%

Llovet JM, et al. Hepatology. 1999;30:1434-­‐40.

Curative treatments: Surgical ResectionPrognosis of HCC suitable to resection

5-­years survival:CP A, No PHT: 71%CP A, PHT: 56% Ishizawa T, et al. Gastroenterology. 2008;;134:1908-­16.

Cuchetti A, et al. Clin CancerRes:18(6);;4397-­4405.

5-­‐years survival:Overall: 57.7%CP A, No PHT: 63.8%

CP A, Single: 68%

CP A, Multiple: 58%

Curative treatments: Surgical ResectionPrognosis of HCC suitable to resection

Berzigotti A, Reig M, et al, Hepatology. 2015 Feb;61(2):526-­‐36.

Metanalysis of the impact of CSPH on postoperative outcomes

Panel A: 3-­year mortality Panel B: 5-­year mortality

Panel C: clinical decompensation

Curative treatments: Surgical Resection

Surgical resection and ablation

Hasegawa K et al. J Hepatol 2013;;58:724-­729.

Curative treatments: Surgical ResectionRecurrence after surgical resection/ablation

Author, year Vascular invasion Satellites Poor-­‐diff. Multifocal Size Cirrhosis AFP Others

Imamura, 2003 X X Hepatitis activity X Non-­‐anatomical

resection

Ishizawa, 2008 X X Child B

Schiffman SC, 2010 X X

Fuks, 2012 X X X > 3 cm X

Hasegawa, 2013 X > 2 cmLiver

damage, platelets

X Age, gender, HCV+, DCP

Park SK, 2013 X UICC stageBCLC stage

Li SH, 2013 X X Non-­‐anatomicalresection

Yin, 2013 X X X BCLC stage > 3 cmAge, capsule, GGT,

HBV DNA, antivirial

Curative treatments: Surgical ResectionPredictive factors for recurrence

Curative treatments: Surgical Resection

True recurrence

-­‐ Chemoembolization-­‐ Chemotherapy-­‐ Internal radiation I131

-­‐ Adoptive immunotherapy-­‐ PI-­‐88

De novo HCC50-­‐70% 30-­‐50%

Recurrence of HCC (50-­‐70% at 5 years)

Llovet et al. Semin Liver Dis. 2005;25:181-­‐200.

Mazzaferroet al. Semin Liver Dis 2014;34:415–426.

Curative treatments: Surgical ResectionRecurrence after surgical resection

Chemoprevention-­‐ Retinoids-­‐ Interferon

Bruix J. et al. Lancet Oncol. 2015 Oct;;16(13):1344-­54.

STORM trial (Sorafenib vs. Placebo): RFS Prevention of recurrence in early HCC

Ferrer-­Fàbrega J, Forner A, et al. Hepatology. 2016 Mar;;63(3):839–49.

Liver transplantation ab initioPrevention of recurrence in early HCC

1995-­‐2012: Liver Resection HCC (n=164; 96 low risk and 68 high risk)

Suitable for both Liver Resection and Liver Transplantation

YESn= 85 (51.8%)

NOn= 79 (48.2%)

Age: n=57Bridge resection to LT: n=1Tumor beyond Milan Criteria: n=21

HIGH RISK of RECURRENCEn= 37 (43.5%)

LOW RISK of RECURRENCEn= 48 (56.5%)

No Liver Transplantationn= 15

Liver Transplantationn= 17

No Recurrencen= 22

Recurrencen= 26

No Liver Transplantationn= 15

Liver Transplantationn= 11

No Enlistmentn= 5

Waiting list: n=2Recurrence beyond MC: n=9Excluded for medical reasons: n=4

Recurrence prior-­‐LT (n=7)Explant tumor foci: n=6Recurrence on the liver graft: n=2

No Recurrence prior-­‐LT (n=10)Explant tumor foci: n=3Recurrence on the liver graft: n=0

Explant tumor foci: n=10Recurrence on the liver graft: n=2

Declined to be enlist: n=2 Excluded for advanced age: n=3Waiting list: n=1Excluded for medical reasons: n=2Recurrence beyond MC: n=5Re-­‐resection: n=2

Lost of follow-­‐up: n=1Refused to be enlist: n=4

Ferrer-­Fàbrega J, Forner A, et al. Hepatology. 2016 Mar;;63(3):839–49.

Liver transplantation ab initioPrevention of recurrence in early HCC

1995-­‐2012: Liver Resection HCC (n=164; 96 low risk and 68 high risk)

Suitable for both Liver Resection and Liver Transplantation

YESn= 85 (51.8%)

HIGH RISK of RECURRENCEn= 37 (43.5%)

No Liver Transplantationn= 15

Liver Transplantationn= 17

No Enlistmentn= 5

Waiting list: n=2Recurrence beyond MC: n=9Excluded for medical reasons: n=4

Recurrence prior-­‐LT (n=7)Explant tumor foci: n=6Recurrence on the liver graft: n=2

No Recurrence prior-­‐LT (n=10)Explant tumor foci: n=3Recurrence on the liver graft: n=0

Lost of follow-­‐up: n=1Refused to be enlist: n=4

Ferrer-­Fàbrega J, Forner A, et al. Hepatology. 2016 Mar;;63(3):839–49.

Liver transplantation ab initioPrevention of recurrence in early HCC

1995-­‐2012: Liver Resection HCC (n=164; 96 low risk and 68 high risk)

Suitable for both Liver Resection and Liver Transplantation

YESn= 85 (51.8%)

HIGH RISK of RECURRENCEn= 37 (43.5%)

No Liver Transplantationn= 15

Liver Transplantationn= 17

No Enlistmentn= 5

Waiting list: n=2Recurrence beyond MC: n=9Excluded for medical reasons: n=4

Recurrence prior-­‐LT (n=7)Explant tumor foci: n=6Recurrence on the liver graft: n=2

No Recurrence prior-­‐LT (n=10)Explant tumor foci: n=3Recurrence on the liver graft: n=0

Lost of follow-­‐up: n=1Refused to be enlist: n=4

Ferrer-­Fàbrega J, Forner A, et al. Hepatology. 2016 Mar;;63(3):839–49.

Liver transplantation ab initioPrevention of recurrence in early HCC

1995-­‐2012: Liver Resection HCC (n=164; 96 low risk and 68 high risk)

Suitable for both Liver Resection and Liver Transplantation

YESn= 85 (51.8%)

HIGH RISK of RECURRENCEn= 37 (43.5%)

No Liver Transplantationn= 15

Liver Transplantationn= 17

No Enlistmentn= 5

Waiting list: n=2Recurrence beyond MC: n=9Excluded for medical reasons: n=4

Recurrence prior-­‐LT (n=7)Explant tumor foci: n=6Recurrence on the liver graft: n=2

No Recurrence prior-­‐LT (n=10)Explant tumor foci: n=3Recurrence on the liver graft: n=0

Lost of follow-­‐up: n=1Refused to be enlist: n=4

Ferrer-­Fàbrega J, Forner A, et al. Hepatology. 2016 Mar;;63(3):839–49.

Liver transplantation ab initioPrevention of recurrence in early HCC

1995-­‐2012: Liver Resection HCC (n=164; 96 low risk and 68 high risk)

Suitable for both Liver Resection and Liver Transplantation

YESn= 85 (51.8%)

NOn= 79 (48.2%)

Age: n=57Bridge resection to LT: n=1Tumor beyond Milan Criteria: n=21

HIGH RISK of RECURRENCEn= 37 (43.5%)

LOW RISK of RECURRENCEn= 48 (56.5%)

Liver Transplantationn= 17

Recurrencen= 26

Liver Transplantationn= 11

Recurrence prior-­‐LT (n=7)Explant tumor foci: n=6Recurrence on the liver graft: n=2

No Recurrence prior-­‐LT (n=10)Explant tumor foci: n=3Recurrence on the liver graft: n=0

Explant tumor foci: n=10Recurrence on the liver graft: n=2

Survival of those patients finally transplanted (n=28) from the moment of livertransplantation: 5-­‐year survival of 81.4% vs. 71.4%, respectively; p=0.773

Question #2

Señale la opción correcta respecto al trasplante hepático en pacientes afectos de CHC

1.-­‐ El CHC es una indicación infrecuente de trasplante hepático en nuestro medio.

2.-­‐ Los criterios de Milán son los únicos criterios utilizados para indicar trasplante hepático en estos pacientes.

3.-­‐ Está recomendado realizar tratamiento puente en lista si el tiempo de espera para recibir un trasplante hepático es superior a 6 meses.

4.-­‐ Los pacientes trasplantados con un CHC deben recibir inmunosupresión con inhibidores del mTOR.

>5 years

Early stage (A)Single or 3 nodules < 3cm

Preserved liver function*, PS 0

Portal pressure Bilirubin

Solitary 3 nodules ≤3cm

Associated diseasesIncreased

No

Potential candidate for liver transplantation

Yes

Effective treatmentswith impact on survival

HCC

Very early stage (0) Single< 2cm

Preserved liver function*, PS 0

Treatm

ent

Prognosis

*This term includes a heterogeneous group of patients with different degree of liver function reserve that has to be carefully evaluated. For most treatment options, compensated liver disease (Child-­‐Pugh A without ascites) is requested to obtain optimal outcomes. The sole option that may be applied irrespective of liver function is liver transplant. Most of them are compensated and fitting into the Chilld-­‐Pugh stage A.**Patients with end stage cirrhosis due to heavily impaired liver function (Child-­‐Pugh C or earlier stages with predictors of poor prognosis, high MELD score) should be considered for liver transplantation. In them HCC may become a contraindication if exceeding the enlistment criteria. ***Currently sorafenibfollowed by regorafenib has been shown to be effective. lenvatinib has been shown to be non-­‐inferior to sorafenib, but no effective second line option after lenvatinib has beenexplored.

Transplant

Survival

Forner A, Reig ME, Bruix J. Lancet. 2017. Submitted.

BCLC Staging and Treatment Strategy, 2017

Authors, year n Selection criteria Recurrence Survival at 5y

Mazzaferro, 1996 48 Milan 8% 74%*

Jonas, 2001 120 Milan 15% 71%

Cillo, 2004 30 Milan 6.7% 72%

Herrero, 2008 47 Milan 8.5% 70%

Mazzaferro, 2009 444 Milan 5.5% 73.3%

* Survival at 4 years~ 5-­‐y recurrence rate¬ 100-­‐(5-­‐y RFS)

Mazzaferro V et al. N Engl J Med. 1996;334:693-­‐9Jonas S et al. Hepatology. 2001;33:1080-­‐6

Cillo U et al. Ann Surg. 2004;239:150-­‐9Herrero JI et al. Liver Transpl. 2008;14:272-­‐8

Mazzaferro V et al. Lancet Oncol. 2009;10:35-­‐43Kulik LM et al. Am J Transplant. 2012;12(11):2997-­‐3007

Outcomes applying restrictive selection criteria

Curative treatments: Liver Transplantation

TRANSPLANTEDENLISTED

DROPOUT

time

Prognosis of patients with HCC waiting for OLT

Intention to treat Per protocol

-­‐Time-­‐Size-­‐AFP-­‐Liver function / MELD

Yao FY, et al. Liver Transplantation. 2003;9(7):684-­‐92.Freeman RB, et al. Am J Transplant. 2006;6(6):1416-­‐21.Washburn K, et al. Am J Transplant. 2010;10(7):1643-­‐8.

Curative treatments: Liver Transplantation

• Expanding criteria: Where are the limits?

Expanding criteria for LT

Curative treatments: Liver Transplantation

35–50 %50–75 %75–80 %Survival at 5 years

0

1

2

3

4

5

6

0 1 2 3 4 5 6 7 8 9 10

Number of nodules

Size (cm)

Llovet JM, et al. Semin Liver Dis. 2005;25:181-200.

Beyond Milan Criteria…..chaos!

35–50 %50–75 %75–80 %

0

1

2

3

4

5

6

0 1 2 3 4 5 6 7 8 9 10

Llovet JM, et al. Semin Liver Dis. 2005;25:181-200.

Beyond Milan Criteria…..chaos!

Survival at 5 years

Number of nodules

Size (cm)

35–50 %50–75 %75–80 %

0

1

2

3

4

5

6

0 1 2 3 4 5 6 7 8 9 10

Llovet JM, et al. Semin Liver Dis. 2005;25:181-200.

The longer the trip, the higher the price

“Metroticket”

Survival at 5 years

Number of nodules

Size (cm)

Beyond Milan Criteria…..chaos!

Expanded criteria5 year survival

Author (year) Criteria Patients Survival

Yao, 2001 Post-­‐LT, explantOne tumor < 6.5 cm or3 tumors < 4.5 cm

70 75%

Duffy, 2007 Post-­‐LT, radiology/explantOne tumor < 6.5 cm or3 tumores < 4.5 cm

208 64-­‐81%

Onaca, 2007Post-­‐LT, explantOne tumor < 6 cm or4 tumors < 5 cm

758 60%

Lee, 2008 Pre-­‐LT, radiologyMain nodule < 6 cmLess than 5 nodules

186 76%

Toso, 2008 Post-­‐LT, expantTotal tumoral volume<115 cm3

274 74%

Herrero, 2008 Pre-­‐LT, radiologyOne tumor < 6 cm or 3 tumors< 5 cm

85 70%

Yao F et al. Hepatology. 2001:33(6);1394-­‐1405.Duffy JA et al. Ann Surg. 2007:246(3):502-­‐511.

Onaca N et al. Liver Transpl. 2007:13(3):391-­‐399.Lee S et al. Liver Transpl. 2008:14(7):935-­‐945.

Toso C. et al. Liver Transpl. 2008:14(8):1107-­‐1115.Herrero JI et al. Liver Transpl. 2008:14(3):272-­‐278.

Beyond Milan Criteria

There is not an uniformcriteria for reporting results

0

1

2

3

4

5

6

7

8

9

10

0 1 2 3 4 5 6 7 8 9 10Size (cm)

No

du

les

Milan criteria

Survival 70%

Majno P, MazzaferroV. Liver Transpl. 2006;12:896-­‐8.

Beyond Milan Criteria…..chaos!

5 year survival

Author (year) Criteria Patients Survival

Yao, 2001 Post-­‐LT, explantOne tumor < 6.5 cm or3 tumors < 4.5 cm

70 75%

Duffy, 2007 Post-­‐LT, radiology/explantOne tumor < 6.5 cm or3 tumores < 4.5 cm

208 64-­‐81%

Onaca, 2007Post-­‐LT, explantOne tumor < 6 cm or4 tumors < 5 cm

758 60%

Lee, 2008 Pre-­‐LT, radiologyMain nodule < 6 cmLess than 5 nodules

186 76%

Toso, 2008 Post-­‐LT, expantTotal tumoral volume<115 cm3

274 74%

Herrero, 2008 Pre-­‐LT, radiologyOne tumor < 6 cm or 3 tumors< 5 cm

85 70%

Yao F et al. Hepatology. 2001:33(6);1394-­‐1405.Duffy JA et al. Ann Surg. 2007:246(3):502-­‐511.

Onaca N et al. Liver Transpl. 2007:13(3):391-­‐399.Lee S et al. Liver Transpl. 2008:14(7):935-­‐945.

Toso C. et al. Liver Transpl. 2008:14(8):1107-­‐1115.Herrero JI et al. Liver Transpl. 2008:14(3):272-­‐278.

5 year survival exceedingMilancriteria

Patients Survival

N/A N/A

82 N/A

130 N/A

N/A N/A

N/A N/A

26 66%

Beyond Milan CriteriaExpanded criteria

Median follow-­‐up: 53 months

The survival is similar to Milan criteria using“up-­‐to-­‐7” (6+1; 5+2...) without vascular invasión

10.9% 29.1% 50.4%

Up to seven criteria

MazzaferroV, et al. Lancet Oncol. 2009;10:35-­‐43.

Metroticket analysis

Marcadores biológicos en la selección de candidatos

Sapisochin G et al. Hepatology. 2016 Dec;64(6):2077-­‐2088.

• Toronto criteria: No limits in size/number nodules• Excluded if: Vascular or extrahepatic invasionor poor differentiatedHCC

(FNB of the main nodule)• 243 HCC patients evaluated: 33 excluded of LT due to tumor progression in

theWL and 210 finally transplanted

Differentiation degree as selection criteriaBeyond Milan Criteria

Duvoux C et al. Gastroenterology. 2012:143:986-­‐994.

AFP levels as selection criteria for LTBeyond Milan Criteria

Piñero F et al. Liver Int. 2016 Nov;36(11):1657-­‐1667.

AFP levels as selection criteria for LTBeyond Milan Criteria

Notarpaolo A, et al. J Hepatol. 2017;66:552–9.

Majno P et al. Ann Surg. 1997:226(6):688-­‐701.Yao FY et al. Liver Transpl. 2005:11(12):1505-­‐1514.Otto G et al. Liver Transpl. 2006:12(8):1260-­‐1267.

Yao FY et al. Hepatology. 2015:61(6):1968-­‐77.

Survival

Author (year) Baseline stage Downstaging criteria Patients:Included/Transplanted

5-yearsurvival

Majno,1997 Post-LT,explantOnetumor< 6.5cmor3tumors< 4.5cm

Necrosis>50% 54/28downstaged 71%(recurrence-free

survival)

Yao,2005 Pre-LT,radiology

1lesion 5-8cmor 2-3

nodules <5cmor 4-5

nodules <3cmwith sumof

all diameters <8cm

USCFcriteria

atleast 3months

30/21 82%2years

(follow-uponly16

months!)

Otto,2006 Post-LT,explant

Any HCCstageMilan criteria 62/34 51.9%(intention to

treat)

Yao,2015

Pre-LT,radiology

Same asYao 2005Milan criteria 118/64

56.1%(intention totreat)

DownstagingBeyond Milan Criteria

• There is not an homogeneous defintion of succesful downstaging

• Downstagingmight allow to select tumors biologically less aggressive

• Up to now, there is not any RCT or controlled cohort study that has demonstrated its efficay

Clavien PA et al. Lancet Oncol. 2012:Jan;13(1):e11-­‐22.

5-­‐year survival 5-­‐year survivalExceeding Milan criteria

Author (year) Criteria Patients Survival Patients Survival

Yao, 2001 Post-­‐LT, explantOne tumor < 6.5 cm or3 tumors < 4.5 cm

70 75% N/A N/A

Duffy, 2007 Post-­‐LT, radiology/explantOne tumor < 6.5 cm or3 tumores < 4.5 cm

208 64-­‐81% 82 N/A

Onaca, 2007Post-­‐LT, explantOne tumor < 6 cm or4 tumors < 5 cm

758 60% 130 N/A

Lee, 2008 Pre-­‐LT, radiologyMain nodule < 6 cmLess than 5 nodules

186 76% N/A N/A

Toso, 2008 Post-­‐LT, explantTotal tumoral volume<115 cm3

274 74% N/A N/A

Herrero, 2008 Pre-­‐LT, radiologyOne tumor < 6 cm or 3 tumors< 5 cm

85 70% 26 66%

Mazzaferro, 2009 Post-­‐LT, explant“Up-­‐to-­‐seven” criteria

727 74% 283 71.2%

Yao F et al. Hepatology. 2001:33(6);1394-1405.Duffy JA et al. Ann Surg. 2007:246(3):502-511.Onaca N et al. Liver Transpl. 2007:13(3):391-399.Lee S et al. Liver Transpl. 2008:14(7):935-945.

Toso C. et al. Liver Transpl. 2008:14(8):1107-1115.Herrero JI et al. Liver Transpl. 2008:14(3):272-278.Mazzaferro V, et al. Lancet Oncol. 2009;10:35-43.

Expanded criteria

Beyond Milan Criteria

Trasplante hepático en pacientes con CHC

• Expanding criteria: Where are the limits?

• The problemof the waiting list

Expanding criteria for LT

Curative treatments: Liver Transplantation

Toso C, et al. Clinical Transplant. 2010; 24:695-­‐700.

Increase of HCC patients if expanded criteria are adoptedBeyond Milan Criteria

Navasa M and Bruix J. Hepatology. 2010;51;12-­‐15.

Selection-­‐inclusion

K-­‐in

NO-­‐MELD DISEASES (HCC) (2)

MELD DISEASES (1)

K2out

K2in

K1in

K1out

Drop-­‐out (toxic clearance)

Drop-­‐out (toxic clearance)

LIVER TRANSPLANTATION5-­‐year survival>50%

K-­‐out

Increase of HCC patients if expanded criteria are adoptedBeyond Milan Criteria

Navasa M and Bruix J. Hepatology. 2010;51;12-­‐15.

Selection-­‐inclusion

K-­‐in

NO-­‐MELD DISEASES (HCC) (2)

MELD DISEASES (1)

K2out

K2in

K1in

K1out

Drop-­‐out (toxic clearance)

Drop-­‐out (toxic clearance)

LIVER TRANSPLANTATION5-­‐year survival>50%

K-­‐out

NO-­‐MELD DISEASES (HCC) (2)

Increase of HCC patients if expanded criteria are adoptedBeyond Milan Criteria

Volk M et al. Am J Transplant 2008;8:839-­‐846.

Cost-­‐efficacy studyusinga Markov model for evaluating the benefit in survival of adoptingan expandingcriteria compared to the harm of other patients in thewaiting list

Impact of the waiting list if expanded criteria are adoptedBeyond Milan Criteria

Main indication of LT in Cataluña 2008-­‐2015Curative treatments: Liver Transplantation

Source: OCATT reports

MazzaferroV. Hepatology 2016; 63: 1707–17.

Adapt the selection and prioritation of HCC patientsBeyond Milan Criteria: An adaptative Approach

>5 years

Early stage (A)Single or 3 nodules < 3cm

Preserved liver function*, PS 0

Portal pressure Bilirubin

Solitary 3 nodules ≤3cm

Associated diseasesIncreased

Yes

Potential candidate for liver transplantation

No Yes

Effective treatmentswith impact on survival

HCC

Very early stage (0) Single< 2cm

Preserved liver function*, PS 0

Treatm

ent

Prognosis

*This term includes a heterogeneous group of patients with different degree of liver function reserve that has to be carefully evaluated. For most treatment options, compensated liver disease (Child-­‐Pugh A without ascites) is requested to obtain optimal outcomes. The sole option that may be applied irrespective of liver function is liver transplant. Most of them are compensated and fitting into the Chilld-­‐Pugh stage A.**Patients with end stage cirrhosis due to heavily impaired liver function (Child-­‐Pugh C or earlier stages with predictors of poor prognosis, high MELD score) should be considered for liver transplantation. In them HCC may become a contraindication if exceeding the enlistment criteria. ***Currently sorafenibfollowed by regorafenib has been shown to be effective. lenvatinib has been shown to be non-­‐inferior to sorafenib, but no effective second line option after lenvatinib has beenexplored.

Ablation Ablation

Survival

Forner A, Reig ME, Bruix J. Lancet. 2017. Adapted.

BCLC Staging and Treatment Strategy, 2017

Radiofrequency in (very) early HCCSystematic reviews and Meta-­‐analysis

Cho et al. Hepatology 2009;49(2):453-­‐9.Germani et al. J Hepatol. 2010:52(3):380-­‐8.

TUMOR BURDEN:

• Size• Number of nodules• Explant findings

LIVER FUNCTION:

• Child-­Pugh• Decompensation• Bilirubin• Portal hypertension

OTHER FACTORS:

• Age, associated comorbidities,…• Technical issues• Local resources/expertise

Early HCC: Resection, transplant or ablationHCC: A multidimensional disease

Question #3

Visitamos un paciente varón de 55 años, con cirrosis hepática por VHC y consumo de enol, con antecedentes de hemorragia digestiva alta por varices esofágicas hace 4 años y ascitis de debut durante el ingreso. El paciente inicio abstinencia de alcohol y hace dos años realizó tratamiento con DAAscon RVS. Actualmente presenta una función hepática conservada, con TP 95%, albúmina 40 g/L, bilirrubina 0.6 mg/dL. En la ecografía de cribado se identifica un nódulo 25 mm en el segmento lateral del LHI. Se realiza RM que objetiva el nódulo de 28 mm, que capta contraste y lava en fases venosas. La AFP es de 3 ng/mL. Respecto a este paciente, señale la respuesta incorrecta:1.-­‐ La cirugía hepática está contraindicada por presencia de hipertensión portal.2.-­‐ El diagnóstico de CHC es certero y no es necesario realizar una biopsia hepática.3.-­‐ Es un paciente que podría necesitar un trasplante hepático como tratamiento de su CHC.4.-­‐ Todas las opciones son correctas.

Question #4

¿Cuál de las siguientes afirmaciones es incorrecta?

1.-­‐ La hipertensión portal es un parámetro fundamental a la hora de valorar la resección quirúrgica.

2.-­‐ La radiofrecuencia es la técnica ablativa de elección que ha demostrado superioridad respecto a la PEI.

3.-­‐ El trasplante hepático está limitado por la falta de órganos.

4.-­‐ La incidencia acumulada de recurrencia tumoral tras una resección quirúrgica exitosa es de 20% a los 5 años.

Evidence-­‐based treatment of early HCCTake home message

•Ablation might be considered first line treatment in HCC

•The ideal candidate for surgical resection are those patients with solitary HCC and well preserved liver function

•Portal hypertension impacts on survival

•Patients with multinodular disease and/or impaired liver function are best treated with liver transplantation

•There is life beyond Milan criteria:

-­‐ We have to surpass the criteria based exclusively on size and number of nodules-­‐ The application of expanding criteria is feasible if the local dynamic of the WL allows

it without harming the other patients (end-­‐stage liver disease patients and HCC patients within MC)

Barcelona-­‐Clínic Liver Cancer (BCLC) Group

Radiology: C. Brú, R. Vilana, L. Bianchi, C. Ayuso, J. Rimola, A. Darnell, M. Burrel,

M. Barrufet, A. García-­‐Criado, E. Belmonte, C. Caparroz.

Translational research lab:

JM. Llovet, A. Moeini, R.Pinyol,

L. Bassaganyas, J. Peix, R. Montal,

I. Martínez, L.Cabellos,

Oncology: J. Maurel

ResearchNurses: N. LlarchG Iserte

Adm. Support: N. PérezA. Farré

Study Coordinator C. Tedesco

www.bclc.cat

Hepatology: J. Bruix, A. Forner, M. Reig, A. Díaz-­‐González, M. Sanduzzi-­‐Zamparelli, L. Gomez

Surgery: J. Fuster, J. Ferrer Pathology: M. Solé, A. Díaz

@BCLC_groupwww.bclc.cat

Statistician: V. Sapena

Global BCLC lab: L. Boix, AC. Rhodes, J Corominas, C. Millán, E. Samper


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