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.
• 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