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LIVER RESECTION VERSUS LIVER RESECTION VERSUS TRANSPLANTATION FOR TRANSPLANTATION FOR HEPATOCELLULAR CARCINOMA HEPATOCELLULAR CARCINOMA LIVER RESECTION VERSUS LIVER RESECTION VERSUS TRANSPLANTATION FOR TRANSPLANTATION FOR HEPATOCELLULAR CARCINOMA HEPATOCELLULAR CARCINOMA L. DE CARLIS L. DE CARLIS DEPT. OF SURGERY AND ABDOMINAL DEPT. OF SURGERY AND ABDOMINAL ORGAN TRANSPLANTATION ORGAN TRANSPLANTATION NIGUARDA HOSPITAL - MILAN (ITALY) NIGUARDA HOSPITAL - MILAN (ITALY) L. DE CARLIS L. DE CARLIS DEPT. OF SURGERY AND ABDOMINAL DEPT. OF SURGERY AND ABDOMINAL ORGAN TRANSPLANTATION ORGAN TRANSPLANTATION NIGUARDA HOSPITAL - MILAN (ITALY) NIGUARDA HOSPITAL - MILAN (ITALY)
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LIVER RESECTION VERSUS LIVER RESECTION VERSUS TRANSPLANTATION FOR TRANSPLANTATION FOR
HEPATOCELLULAR CARCINOMAHEPATOCELLULAR CARCINOMA
LIVER RESECTION VERSUS LIVER RESECTION VERSUS TRANSPLANTATION FOR TRANSPLANTATION FOR
HEPATOCELLULAR CARCINOMAHEPATOCELLULAR CARCINOMA
L. DE CARLISL. DE CARLIS
DEPT. OF SURGERY AND ABDOMINAL DEPT. OF SURGERY AND ABDOMINAL ORGAN TRANSPLANTATIONORGAN TRANSPLANTATION
NIGUARDA HOSPITAL - MILAN (ITALY)NIGUARDA HOSPITAL - MILAN (ITALY)
L. DE CARLISL. DE CARLIS
DEPT. OF SURGERY AND ABDOMINAL DEPT. OF SURGERY AND ABDOMINAL ORGAN TRANSPLANTATIONORGAN TRANSPLANTATION
NIGUARDA HOSPITAL - MILAN (ITALY)NIGUARDA HOSPITAL - MILAN (ITALY)
SURGICAL TREATMENT OF HCCSURGICAL TREATMENT OF HCCSURGICAL TREATMENT OF HCCSURGICAL TREATMENT OF HCC
• Due to its direct link with liver cirrhosis, the Due to its direct link with liver cirrhosis, the surgical therapy of HCC remains controversial.surgical therapy of HCC remains controversial.
• Liver resection (LR) is limited by the severity of Liver resection (LR) is limited by the severity of cirrhosis and tumor recurrence is a frequent cirrhosis and tumor recurrence is a frequent event in the cirrhotic liver remnant, which event in the cirrhotic liver remnant, which maintains its oncogenic potential.maintains its oncogenic potential.
• Liver transplantation (LTx) is the only option to Liver transplantation (LTx) is the only option to treat tumor and cirrhosis at the same time but treat tumor and cirrhosis at the same time but mortality and morbidity are higher and waiting mortality and morbidity are higher and waiting lists are crowded.lists are crowded.
• Due to its direct link with liver cirrhosis, the Due to its direct link with liver cirrhosis, the surgical therapy of HCC remains controversial.surgical therapy of HCC remains controversial.
• Liver resection (LR) is limited by the severity of Liver resection (LR) is limited by the severity of cirrhosis and tumor recurrence is a frequent cirrhosis and tumor recurrence is a frequent event in the cirrhotic liver remnant, which event in the cirrhotic liver remnant, which maintains its oncogenic potential.maintains its oncogenic potential.
• Liver transplantation (LTx) is the only option to Liver transplantation (LTx) is the only option to treat tumor and cirrhosis at the same time but treat tumor and cirrhosis at the same time but mortality and morbidity are higher and waiting mortality and morbidity are higher and waiting lists are crowded.lists are crowded.
• Absence of randomized controlled Absence of randomized controlled trialstrials
• Absence of randomized controlled Absence of randomized controlled trialstrials
• Treatment of HCC is not yet well Treatment of HCC is not yet well codifiedcodified
• Treatment of HCC is not yet well Treatment of HCC is not yet well codifiedcodified
Aim of the studyAim of the studyAim of the studyAim of the study
• Compare 2 large series of pts with HCC Compare 2 large series of pts with HCC treated with LR or OLTxtreated with LR or OLTx
• Determine tumor and patients chara-Determine tumor and patients chara-cteristic on survival and recurrencecteristic on survival and recurrence
• Verify whether these parameters can Verify whether these parameters can identify the most appropriate treatment identify the most appropriate treatment optionoption
• Compare 2 large series of pts with HCC Compare 2 large series of pts with HCC treated with LR or OLTxtreated with LR or OLTx
• Determine tumor and patients chara-Determine tumor and patients chara-cteristic on survival and recurrencecteristic on survival and recurrence
• Verify whether these parameters can Verify whether these parameters can identify the most appropriate treatment identify the most appropriate treatment optionoption
LR and LTx for HCCLR and LTx for HCC((casistics 1985-2003)casistics 1985-2003)
LR and LTx for HCCLR and LTx for HCC((casistics 1985-2003)casistics 1985-2003)
• Liver ResectionLiver Resection 282282
• Liver Transplantation Liver Transplantation 187/654187/654 (28,5%)(28,5%)
• Liver ResectionLiver Resection 282282
• Liver Transplantation Liver Transplantation 187/654187/654 (28,5%)(28,5%)
LR and OLTx for HCCLR and OLTx for HCCanalysis 1985-1999analysis 1985-1999
LR and OLTx for HCCLR and OLTx for HCCanalysis 1985-1999analysis 1985-1999
• Liver ResectionLiver Resection 154154
• Liver Transplantation Liver Transplantation 121121
• Liver ResectionLiver Resection 154154
• Liver Transplantation Liver Transplantation 121121
LTx - Indication (121 pts)LTx - Indication (121 pts)LTx - Indication (121 pts)LTx - Indication (121 pts)• Unresectable single nodule <5 Unresectable single nodule <5
cm or 1-3 nodules cm or 1-3 nodules ≤≤ 3 cm 3 cm• Child B9 to C ptsChild B9 to C pts
28 pts with incidental HCC28 pts with incidental HCCMedian diameter of the nodules Median diameter of the nodules →→ 3.7 cm 3.7 cm (±2.5)(±2.5)
• Unresectable single nodule <5 Unresectable single nodule <5 cm or 1-3 nodules cm or 1-3 nodules ≤≤ 3 cm 3 cm
• Child B9 to C ptsChild B9 to C pts
28 pts with incidental HCC28 pts with incidental HCCMedian diameter of the nodules Median diameter of the nodules →→ 3.7 cm 3.7 cm (±2.5)(±2.5)
LR - Indication (154 pts)LR - Indication (154 pts)LR - Indication (154 pts)LR - Indication (154 pts)
• Child A-(B) ptsChild A-(B) pts• Absence of portal hypertensionAbsence of portal hypertension• Single or multiple nodules in Single or multiple nodules in
resectable positionresectable position✓ Major liver resectionsMajor liver resections 27 pts 27 pts✓ Segmentectomies 90 ptsSegmentectomies 90 pts✓ Wedge resectionWedge resection 27 pts 27 pts✓ Multiple proceduresMultiple procedures 10 pts 10 pts
• Child A-(B) ptsChild A-(B) pts• Absence of portal hypertensionAbsence of portal hypertension• Single or multiple nodules in Single or multiple nodules in
resectable positionresectable position✓ Major liver resectionsMajor liver resections 27 pts 27 pts✓ Segmentectomies 90 ptsSegmentectomies 90 pts✓ Wedge resectionWedge resection 27 pts 27 pts✓ Multiple proceduresMultiple procedures 10 pts 10 pts
Patients characteristicsPatients characteristicsPatients characteristicsPatients characteristicsp
Age NSGender NSEthiology of liver disease NSChild classification <0.05pTNM <0.05Tumor size <0.05Number of nodules NSVascular infiltration NSPresence of capsule NSαFP / Histologic Grade NS
Perioperative mortality *Perioperative mortality *Perioperative mortality *Perioperative mortality *
• LTxLTx 22/12122/121 (18.1%)(18.1%)
• LRLR 7/154 7/154 (4.5%)(4.5%)
* (1996-2001 OLTx = 9% - LR * (1996-2001 OLTx = 9% - LR ~~ 0) 0)
• LTxLTx 22/12122/121 (18.1%)(18.1%)
• LRLR 7/154 7/154 (4.5%)(4.5%)
* (1996-2001 OLTx = 9% - LR * (1996-2001 OLTx = 9% - LR ~~ 0) 0)
Causes of perioperative deathsCauses of perioperative deaths LTx (22 pts) LTx (22 pts)
Causes of perioperative deathsCauses of perioperative deaths LTx (22 pts) LTx (22 pts)
• SepsisSepsis 55• MOFMOF 44• Vascular complicationVascular complication 44• Haemorrhagic shockHaemorrhagic shock 33• Graft-non-functionGraft-non-function 22• Cerebrovascular accidentsCerebrovascular accidents 22• Myocardial infarctionMyocardial infarction 11• Irreversible rejectionIrreversible rejection 11
• SepsisSepsis 55• MOFMOF 44• Vascular complicationVascular complication 44• Haemorrhagic shockHaemorrhagic shock 33• Graft-non-functionGraft-non-function 22• Cerebrovascular accidentsCerebrovascular accidents 22• Myocardial infarctionMyocardial infarction 11• Irreversible rejectionIrreversible rejection 11
Causes of perioperative deathsCauses of perioperative deaths LR (7 pts) LR (7 pts)
Causes of perioperative deathsCauses of perioperative deaths LR (7 pts) LR (7 pts)
• Hepatic FailureHepatic Failure 55
• Haemorrhagic shockHaemorrhagic shock 11
• Cerebrovascular accidentsCerebrovascular accidents 11
• Hepatic FailureHepatic Failure 55
• Haemorrhagic shockHaemorrhagic shock 11
• Cerebrovascular accidentsCerebrovascular accidents 11
Late MortalityLate MortalityLate MortalityLate MortalityTumor UnrelatedTumor Unrelated• LTxLTx 1212• LRLR 2121Tumor RelatedTumor Related• LTxLTx 1010• LRLR 5555 (p<0.0001)(p<0.0001)
Tumor UnrelatedTumor Unrelated• LTxLTx 1212• LRLR 2121Tumor RelatedTumor Related• LTxLTx 1010• LRLR 5555 (p<0.0001)(p<0.0001)
Data at the end of follow-upData at the end of follow-upData at the end of follow-upData at the end of follow-upOverall RecurrenceOverall Recurrence• LTxLTx 11 11 (9%)(9%)
• LRLR 74 74 (47.4%)(47.4%)
Pts Survival With RecurrencePts Survival With Recurrence• LTxLTx 1* 1* (9%)(9%)
• LRLR 19 19 (25.6%)(25.6%)
Overall RecurrenceOverall Recurrence• LTxLTx 11 11 (9%)(9%)
• LRLR 74 74 (47.4%)(47.4%)
Pts Survival With RecurrencePts Survival With Recurrence• LTxLTx 1* 1* (9%)(9%)
• LRLR 19 19 (25.6%)(25.6%)
* 8,3 yrs* 8,3 yrs
Final results of statistical analysis IFinal results of statistical analysis I Univariate AnalysisUnivariate Analysis
Final results of statistical analysis IFinal results of statistical analysis I Univariate AnalysisUnivariate Analysis
• Capsule, Vascular Invasion, pTNM, Capsule, Vascular Invasion, pTNM, ααFP, FP, seem important factors for 5 yrs survival and seem important factors for 5 yrs survival and recurrence rate in both groupsrecurrence rate in both groups
• in in LR LR number of nodules and age were number of nodules and age were significant for recurrence and 5 yrs survival significant for recurrence and 5 yrs survival while Child and size only for survival while Child and size only for survival
• in in LTxLTx size of tumor was significant for size of tumor was significant for recurrence and survival while viral cirrhosis recurrence and survival while viral cirrhosis for survivalfor survival
• Capsule, Vascular Invasion, pTNM, Capsule, Vascular Invasion, pTNM, ααFP, FP, seem important factors for 5 yrs survival and seem important factors for 5 yrs survival and recurrence rate in both groupsrecurrence rate in both groups
• in in LR LR number of nodules and age were number of nodules and age were significant for recurrence and 5 yrs survival significant for recurrence and 5 yrs survival while Child and size only for survival while Child and size only for survival
• in in LTxLTx size of tumor was significant for size of tumor was significant for recurrence and survival while viral cirrhosis recurrence and survival while viral cirrhosis for survivalfor survival
Final results of statistical analysis IIFinal results of statistical analysis IIMultivariate AnalysisMultivariate Analysis
Final results of statistical analysis IIFinal results of statistical analysis IIMultivariate AnalysisMultivariate Analysis
• At multivariate analysis only At multivariate analysis only ααFP, FP, histological grade and vascular invasion histological grade and vascular invasion were indipendent variables for tumor were indipendent variables for tumor recurrence in both groupsrecurrence in both groups
• In In LRLR pTNM, pTNM, ααFP, Child and age were FP, Child and age were indipendent variables for 5 yrs survivalindipendent variables for 5 yrs survival
• In In LTxLTx capsula, capsula, ααFP, viral cirrhosis were FP, viral cirrhosis were indipendent variables for 5 yrs survivalindipendent variables for 5 yrs survival
• At multivariate analysis only At multivariate analysis only ααFP, FP, histological grade and vascular invasion histological grade and vascular invasion were indipendent variables for tumor were indipendent variables for tumor recurrence in both groupsrecurrence in both groups
• In In LRLR pTNM, pTNM, ααFP, Child and age were FP, Child and age were indipendent variables for 5 yrs survivalindipendent variables for 5 yrs survival
• In In LTxLTx capsula, capsula, ααFP, viral cirrhosis were FP, viral cirrhosis were indipendent variables for 5 yrs survivalindipendent variables for 5 yrs survival
Multivariate AnalysisMultivariate AnalysisMultivariate AnalysisMultivariate Analysis VariableVariable Risk RatioRisk Ratio Confidence Interval 95%Confidence Interval 95% PP
SURVIVALSURVIVAL
LTxLTxCapsuleCapsule 2.452.45 0.99 , 6.130.99 , 6.13 0.050.05AFPAFP 2.322.32 1.11 , 4.861.11 , 4.86 0.020.02Viral CirrhosisViral Cirrhosis 2.262.26 1.11 , 4.611.11 , 4.61 0.020.02Histologic GradeHistologic Grade 2.222.22 1.07 , 5.001.07 , 5.00 0.030.03
LRLR
ChildChild 2.892.89 1.82 , 4.611.82 , 4.61 0.0010.001AgeAge 1.791.79 0.98 , 3.260.98 , 3.26 0.050.05PTNMPTNM 2.792.79 1.73 , 4.501.73 , 4.50 0.00010.0001
AFPAFP 2.202.20 1.34 , 3.621.34 , 3.62 0.00010.0001
FREEDOM FREEDOM FROMFROM
RECURRENCERECURRENCE
LTxLTxVascular InfiltrationVascular Infiltration 11.1111.11 2.86 , 43.222.86 , 43.22 0.00050.0005
AFPAFP 2.682.68 2.13 , 8.582.13 , 8.58 0.00010.0001
Histologic GradeHistologic Grade 2.992.99 2.46 , 9.752.46 , 9.75 0.00020.0002
LRLRVascular InfiltrationVascular Infiltration 2.522.52 1.59 , 4.011.59 , 4.01 0.00010.0001
AFPAFP 3.993.99 2.38 , 6.692.38 , 6.69 0.00010.0001
Histologic GradeHistologic Grade 2.792.79 1.26 , 5.391.26 , 5.39 0.0010.001
SURVIVALSURVIVALSURVIVALSURVIVAL
0 1000 2000 3000 4000 50000.0
0.2
0.4
0.6
0.8
1.0LR (n= 154)
LTx (n=121)
p=0.08
Days After Transplantation
Surv
ival
Dis
trib
utio
nFu
nctio
n
DISEASE FREE SURVIVALDISEASE FREE SURVIVALDISEASE FREE SURVIVALDISEASE FREE SURVIVAL(perioperative mortality censored)(perioperative mortality censored)(perioperative mortality censored)(perioperative mortality censored)
0 1000 2000 3000 4000 50000.0
0.2
0.4
0.6
0.8
1.0LTx (n=99)LR (n=147)
p<.0001
Days After Transplantation
Rec
urre
nce-
Free
Surv
ival
Dis
tr.F
unct
.
pT 1/2pT 1/2pT 1/2pT 1/2
0 1000 2000 3000 4000 50000.0
0.2
0.4
0.6
0.8
1.0 LR pT 1/2LTx pT 1/2
p=0.3
Days After Transplantation
Surv
ival
Dis
tr.F
unct
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SMALL TUMOR (< 5 cm)SMALL TUMOR (< 5 cm)SMALL TUMOR (< 5 cm)SMALL TUMOR (< 5 cm)
0 1000 2000 3000 4000 50000.0
0.2
0.4
0.6
0.8
1.0LR < 5cmLTx< 5cm
p=0.4
Days After Transplantation
Surv
ival
Dis
tr.F
unct
.
SMALL, ENCAPSULATED WITH SMALL, ENCAPSULATED WITH LOW LOW ααFP LEVELSFP LEVELS
SMALL, ENCAPSULATED WITH SMALL, ENCAPSULATED WITH LOW LOW ααFP LEVELSFP LEVELS
0 1000 2000 3000 4000 50000.0
0.2
0.4
0.6
0.8
1.0LR (n=32)LT (n=26)
p=0.3
Days After Transplantation
Surv
ival
Dis
tr.F
unct
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The best options for small The best options for small HCCHCC
The best options for small The best options for small HCCHCC
• Liver resection Liver resection
• Liver transplantationLiver transplantation
✓ The same 3-5 years survivalThe same 3-5 years survival
✓ HCC recurrence > in liver resectionHCC recurrence > in liver resection
• Liver resection Liver resection
• Liver transplantationLiver transplantation
✓ The same 3-5 years survivalThe same 3-5 years survival
✓ HCC recurrence > in liver resectionHCC recurrence > in liver resection
Conclusions IConclusions IConclusions IConclusions I• LTxLTx appears to offer a better recurrence appears to offer a better recurrence
freedom than freedom than LRLR in patients with HCC. in patients with HCC. Nevertheless, many patients still live a long Nevertheless, many patients still live a long time after recurrence and mortality is often time after recurrence and mortality is often related to the progression of cirrhosisrelated to the progression of cirrhosis
• Shortage of organs limits the possibility of Shortage of organs limits the possibility of offering this option to every pts with HCCoffering this option to every pts with HCC
• A strict selection should be made to A strict selection should be made to optimise organ allocationoptimise organ allocation
• LTxLTx appears to offer a better recurrence appears to offer a better recurrence freedom than freedom than LRLR in patients with HCC. in patients with HCC. Nevertheless, many patients still live a long Nevertheless, many patients still live a long time after recurrence and mortality is often time after recurrence and mortality is often related to the progression of cirrhosisrelated to the progression of cirrhosis
• Shortage of organs limits the possibility of Shortage of organs limits the possibility of offering this option to every pts with HCCoffering this option to every pts with HCC
• A strict selection should be made to A strict selection should be made to optimise organ allocationoptimise organ allocation
ConclusionsConclusions II IIConclusionsConclusions II II• LR should be considered a good therapeutic LR should be considered a good therapeutic
alternative in pts who do not fulfill LTx criteriaalternative in pts who do not fulfill LTx criteria
• The HCCs most suitable for The HCCs most suitable for LRLR are the same are the same tumors that should have the best results when tumors that should have the best results when treated by treated by LTxLTx, i.e. small, encapsulated tumors , i.e. small, encapsulated tumors with low AFP levels. with low AFP levels.
• In these cases other risk factors should be In these cases other risk factors should be considered like the etiology of the disease, the considered like the etiology of the disease, the age of the patients, the severity of the cirrhosis age of the patients, the severity of the cirrhosis and, when available, the grade of the neoplasm. and, when available, the grade of the neoplasm.
• LR should be considered a good therapeutic LR should be considered a good therapeutic alternative in pts who do not fulfill LTx criteriaalternative in pts who do not fulfill LTx criteria
• The HCCs most suitable for The HCCs most suitable for LRLR are the same are the same tumors that should have the best results when tumors that should have the best results when treated by treated by LTxLTx, i.e. small, encapsulated tumors , i.e. small, encapsulated tumors with low AFP levels. with low AFP levels.
• In these cases other risk factors should be In these cases other risk factors should be considered like the etiology of the disease, the considered like the etiology of the disease, the age of the patients, the severity of the cirrhosis age of the patients, the severity of the cirrhosis and, when available, the grade of the neoplasm. and, when available, the grade of the neoplasm.
Conclusions IIIConclusions IIIConclusions IIIConclusions III• Size and multifocality are not ‘per se’ signs of an Size and multifocality are not ‘per se’ signs of an
aggressive behavior of the tumor.aggressive behavior of the tumor.
• AFP, vascular invasion, histological grade and an AFP, vascular invasion, histological grade and an aggressive behavior during the waiting period, aggressive behavior during the waiting period, more likely reflect the risk of recurrence of the more likely reflect the risk of recurrence of the disease.disease.
• Criteria for transplantation may undoubtedly be Criteria for transplantation may undoubtedly be widened by including larger tumors in young widened by including larger tumors in young patients, but the length of the waiting time and patients, but the length of the waiting time and the appropriateness of the organ allocation limit the appropriateness of the organ allocation limit this procedure only to selected cases. this procedure only to selected cases.
• Size and multifocality are not ‘per se’ signs of an Size and multifocality are not ‘per se’ signs of an aggressive behavior of the tumor.aggressive behavior of the tumor.
• AFP, vascular invasion, histological grade and an AFP, vascular invasion, histological grade and an aggressive behavior during the waiting period, aggressive behavior during the waiting period, more likely reflect the risk of recurrence of the more likely reflect the risk of recurrence of the disease.disease.
• Criteria for transplantation may undoubtedly be Criteria for transplantation may undoubtedly be widened by including larger tumors in young widened by including larger tumors in young patients, but the length of the waiting time and patients, but the length of the waiting time and the appropriateness of the organ allocation limit the appropriateness of the organ allocation limit this procedure only to selected cases. this procedure only to selected cases.
Open ProblemsOpen ProblemsOpen ProblemsOpen Problems• ExpandingExpanding indication for resectable HCC? indication for resectable HCC?
• Expanding selection criteria for LTx ?Expanding selection criteria for LTx ?
• LTx after downstaging the tumor ?LTx after downstaging the tumor ?
““Nowadays the main problem of LTx is not the Nowadays the main problem of LTx is not the definition of the best selection criteria, but the definition of the best selection criteria, but the low applicability of the treatment because of the low applicability of the treatment because of the lack of donors”lack of donors”(Lowet. Hepatology 1999; 30, 6, 1434)(Lowet. Hepatology 1999; 30, 6, 1434)
• ExpandingExpanding indication for resectable HCC? indication for resectable HCC?
• Expanding selection criteria for LTx ?Expanding selection criteria for LTx ?
• LTx after downstaging the tumor ?LTx after downstaging the tumor ?
““Nowadays the main problem of LTx is not the Nowadays the main problem of LTx is not the definition of the best selection criteria, but the definition of the best selection criteria, but the low applicability of the treatment because of the low applicability of the treatment because of the lack of donors”lack of donors”(Lowet. Hepatology 1999; 30, 6, 1434)(Lowet. Hepatology 1999; 30, 6, 1434)
Transplantation of a right lobe from a living donor.Transplantation of a right lobe from a living donor.
