pierre goffette, md interventional radiology cliniques universitaires saint-luc université...
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Pierre GOFFETTE, MDPierre GOFFETTE, MD Interventional Radiology
Cliniques Universitaires Saint-LucUniversité catholique de Louvain
Brussels
TACE with DC beads as a pretransplant TACE with DC beads as a pretransplant treatment for HCCtreatment for HCC
Results with anatomopathological dataResults with anatomopathological data
Florence ET/ECIO 2008- Terumo/Biocompatible symposium
Bruix J.,Llovet J.M.: Prognostic Prediction and Treatment Strategy in Hepatocellular Carcinoma
Liver Transplantation for HCCLiver Transplantation for HCC5 year survival5 year survival
• Within Milan criteriaWithin Milan criteria >75%>75% Comparable to overall LTComparable to overall LT Waiting time < 6 MoWaiting time < 6 Mo Drop out % 10-20%Drop out % 10-20% No role for pre-LT adjuvant therapy(?)No role for pre-LT adjuvant therapy(?)
• Expanded criteriaExpanded criteria (USCF-Mount Sinaï)(USCF-Mount Sinaï) 25-44%25-44% (Single tum < 6.5cm or 3 tum < 4.5cm)(Single tum < 6.5cm or 3 tum < 4.5cm)
Belghiti J. Annals Surg Oncology 2008 Belghiti J. Annals Surg Oncology 2008
Liver Transplantation for HCCLiver Transplantation for HCC
• Main IssuesMain Issues Dropout rate 30-50% Dropout rate 30-50% (WT > 6 Mo)(WT > 6 Mo) Pts beyond inclusion criteria (interm/adv)Pts beyond inclusion criteria (interm/adv)
• Rationale for TACERationale for TACE Bridge therapyBridge therapy
Control tumor + prevent progression, vasc. invasionControl tumor + prevent progression, vasc. invasion Neoadjuvant therapy to improve survivalNeoadjuvant therapy to improve survival
DownstagingDownstaging (to fullfil Milan criteria)(to fullfil Milan criteria)
Majno P. Ann Surg 1997, Graziadei I. Liver transpl. 2003 Majno P. Ann Surg 1997, Graziadei I. Liver transpl. 2003 Otto G. Liver Transpl. 2006Otto G. Liver Transpl. 2006
TACE before LTTACE before LTControversial UsefulnessControversial Usefulness
• Early stagesEarly stages Effective to prevent tumoral progressionEffective to prevent tumoral progression No influence on post-LT (disease-free) survivalNo influence on post-LT (disease-free) survival
Majno P. Ann Surg 1997, Oldhafer K. J. Hepatol 1998 , Graziadei I. L. Majno P. Ann Surg 1997, Oldhafer K. J. Hepatol 1998 , Graziadei I. L. transpl 2003, Maddala Y. L. transpl 2004, Decaens T. L. Transpl 2005transpl 2003, Maddala Y. L. transpl 2004, Decaens T. L. Transpl 2005Llovet J. Sem. Liver Dis 2006, Lesurtel M. Am J Transplantation 2006Llovet J. Sem. Liver Dis 2006, Lesurtel M. Am J Transplantation 2006
• Intermediate/Advanced stagesIntermediate/Advanced stages Effective downstaging ( > 50% red.) Effective downstaging ( > 50% red.) 35-45%35-45% Higher post-LT recurrence rateHigher post-LT recurrence rate Lower 5 yr survival (41 vs 83%)Lower 5 yr survival (41 vs 83%)
Majno, 1999Majno, 1999
HEPATOCELLULARCAHEPATOCELLULARCA
TACE before LTTACE before LT
DC Bead™ hydrogel microspheres are biocompatible, hydrophilic, non resorbable, and precisely calibrated spheres, able to load the doxorubicine.
Precise and controlled release of the chemotherapeutic agent into the tumor bed.
Drug Eluting BeadsDrug Eluting Beads(DC Beads, Biocompatible UK)
available sizesavailable sizes
RATIONALE TO USERATIONALE TO USE
Delivery of large amounts of drugs to tumors for a Delivery of large amounts of drugs to tumors for a prolonged timeprolonged time
Enhanced local tumor concentrationEnhanced local tumor concentration
Without incresead local toxicityWithout incresead local toxicity
Decreased serum level of chemotherapeutic agentDecreased serum level of chemotherapeutic agent
• 27 patients Child-Pugh A27 patients Child-Pugh A
• Response rate (CT at 6 month): 75%Response rate (CT at 6 month): 75%
• Liver abscesses 2, death 1Liver abscesses 2, death 1
• Median follow-up 28 monthsMedian follow-up 28 months
survival 1 year 92%survival 1 year 92% 2 year 89%2 year 89%
J Hepatology, 2007
J Hepatology, 2007
Serum doxorubicin pic value (5 min)Serum doxorubicin pic value (5 min) Conventional TACE : 890ng/mlConventional TACE : 890ng/ml
Precision TACE : 90ng/mlPrecision TACE : 90ng/ml
Brussels ExperienceBrussels ExperienceDrug Eluting Beads for HCC before LTDrug Eluting Beads for HCC before LT
• 88 withinwithin the Milan criteria• 1010 outsideoutside the Milan criteria
Diameter > 5cm Diameter > 5cm 11 > 3 tum < 3cm > 3 tum < 3cm 11 Multiple tum > 3cmMultiple tum > 3cm 88
Downstaging after TACE ?Downstaging after TACE ?
** overall 73 HCC pts treated by DC beads overall 73 HCC pts treated by DC beads over a 22 month periodover a 22 month period
Single center study: Single center study: 18*patients18*patients
LIVER TRANSPLANT CANDIDATES WITH HCCLIVER TRANSPLANT CANDIDATES WITH HCC CHARACTERISTICSCHARACTERISTICS
Sex, M/F 15/315/3
Age, years 47-73(58)47-73(58)
Etiology of CirrhosisEtiology of Cirrhosis
Ethyl
HCV (+ethyl 1)
HAV/HBV
NASH
Primary biliary cirrhosis
Non-cirrhotic HCC
99
33
22
22
1 1
11
Serum α-fetoprotein (ηg/mL) 4949 (4,5-3487)
Child-Pugh classification (A/B) 8/108/10
Child-Pugh score Mean 7,27,2 (5-9)
Materials and MethodsMaterials and MethodsHCC CharacteristicsHCC Characteristics
• DistributionDistribution Unilobar Unilobar 1010 Bilobar Bilobar 88
• Number of nodulesNumber of nodules 11(4Pts), (4Pts), 22(7Pts), (7Pts), 33(4Pts), (4Pts), >3>3(3 pts)(3 pts)
• SizeSize: mean 5.5 cm5.5 cm (range 2.1-8.1)
• Partial intrahepatic PV thrombosisPV thrombosis 1
Materials and MethodsMaterials and MethodsDC Beads TACE protocolDC Beads TACE protocol
Lobar(21%)-Segmental/Subsegmental(79%) injection
Standardized DC Beads doses and sizes: - 4ml (2 vials) of4ml (2 vials) of 300-500 µm300-500 µm particles loaded with particles loaded with
25mg/ml doxorubicin:25mg/ml doxorubicin:100 mg Doxo/session100 mg Doxo/session - Dilution with 4ml of 320mg% Iodine (ratio 1/1)Dilution with 4ml of 320mg% Iodine (ratio 1/1)
Additional unloaded particles (300-500,500-700µ) if persitent flow
Prophylactic antibiotherapy
• Sequential TACE at 3-5 Mo interval (max 4)
• Alternate TACE if bi-lobar lesions
• Progressive arterial feeders occlusion (3 Pts) Tace through collaterals (phrenic, int. mam art.)Tace through collaterals (phrenic, int. mam art.)
• End-points End-points
Primary: Tumor response and DownstagingPrimary: Tumor response and Downstaging Secondary: HCC recurrence after LTSecondary: HCC recurrence after LT
Materials and MethodsMaterials and MethodsDC Beads TACE protocolDC Beads TACE protocol
Procedural ResultsProcedural Results42 sessions in 18 patients42 sessions in 18 patients
• Mean number of sessionsMean number of sessions 2.82.8 1(3pts), 2(6pts), 3(8pts), 4(1pt)
• Serious adverse eventSerious adverse event 22 Cholecystitis
• 30-day mortality 30-day mortality 00
• Transient impaired liver functionTransient impaired liver function 1111
No liver abcessNo liver abcess
CT/MRI Follow-upCT/MRI Follow-up EASL response after EASL response after firstfirst TACE TACE
• Complete Complete 11 (5,5%)(5,5%)
• Partial Partial 14 14 (78%)(78%) Residual peripheral enhancement 7Residual peripheral enhancement 7 Persistent enhanced nodulesPersistent enhanced nodules 77
• Stable Disease Stable Disease 33• Progressive disease Progressive disease 00
• Objective responseObjective response 15 15 (83%)(83%)
CT/MRI Follow-upCT/MRI Follow-up EASL response after EASL response after lastlast TACE TACE
• Complete Complete 66 (33%)(33%)
• Partial Partial 10 10 (55%)(55%) Residual peripheral enhancement Residual peripheral enhancement 66 Persistent enhanced nodulesPersistent enhanced nodules 44
• Stable Disease Stable Disease 11• Progressive disease Progressive disease 11
• Objective responseObjective response 16 16 (89%)(89%)
46 yr old male: Bilobar HCC ( >7cm seg IV)46 yr old male: Bilobar HCC ( >7cm seg IV)Downstaging before LTDownstaging before LT
First TACE session left lobeFirst TACE session left lobe
46 yr old male: Bilobar HCC ( >7cm seg IV)46 yr old male: Bilobar HCC ( >7cm seg IV)Downstaging before LTDownstaging before LT
Repeated controls CT after first sessionRepeated controls CT after first session
Second TACE (right lobe) and control CT……waiting listSecond TACE (right lobe) and control CT……waiting list
Patients beyond Milan criteriaPatients beyond Milan criteriaDownstaging (10 Pts)Downstaging (10 Pts)
• Sufficient for active LT listing 8 (80%)Sufficient for active LT listing 8 (80%) Partial response 7, complete 1Partial response 7, complete 1
transplanted transplanted 55
• Inadequate 2 (20%)Inadequate 2 (20%) stable disease 1stable disease 1
transplanted transplanted 11 (compassionate) (compassionate)
progressive disease 1progressive disease 1
TACE 1
66 yr old male: 6.5 cm right HCC, 1.8 cm left HCC66 yr old male: 6.5 cm right HCC, 1.8 cm left HCC
Three selective TACE – LT 8 Mo laterThree selective TACE – LT 8 Mo later
TACE 2
TACE 3
66 yr old male: 6.5 cm right HCC, 1.8 cm left HCC66 yr old male: 6.5 cm right HCC, 1.8 cm left HCC
Three selective TACE – LT 8 Mo laterThree selective TACE – LT 8 Mo later
Clinical Outcome (N=18 Pts)Clinical Outcome (N=18 Pts)
• Transplanted patients 12Transplanted patients 12 Delay: med 8.5 Mo (3-16)Delay: med 8.5 Mo (3-16) Biliary complications: 3Biliary complications: 3 Follow-up: med 8 monthFollow-up: med 8 month
1 recurrence at 4 mo ( < 50% nec)1 recurrence at 4 mo ( < 50% nec)
• Patients on waiting list Patients on waiting list 5 5 1 death (pneumonia)1 death (pneumonia)
• Drop out 1Drop out 1
Operative DataOperative DataDrawbacks?Drawbacks?
• Complicated arterial anastomosis 7Complicated arterial anastomosis 7 Proper Hep. art. occlusion 4 Proper Hep. art. occlusion 4 Pedicular inflammation 3Pedicular inflammation 3 Early arterial occlusion…redo-OLT in 1Early arterial occlusion…redo-OLT in 1
• Difficult biliary anastomosis 3Difficult biliary anastomosis 3
Known Doxorubicin-related complications!Known Doxorubicin-related complications!
Explanted SpecimenExplanted Specimenafter LT(12) / Necropsy(1)after LT(12) / Necropsy(1)
PATHOLOGIC ASSESSMENT
All patientsAll patients
(n=13)(n=13)
DownstagedDownstagedPts (n=6)Pts (n=6)
RecurrenceRecurrenceAfter LTAfter LT
(n=12)(n=12)
OBJECTIVERESPONSE
CompleteCompletenecrosisnecrosis 6 (46%)6 (46%) 22 0/60/6
Partial Partial necrosis necrosis 75% -99%75% -99% 6 6 (46%)(46%) 33 0/50/5
NO RESPONSE
IncompleteIncomplete
Necrosis <70%Necrosis <70%1 (8%)1 (8%) 11 1/11/1
• Complete necrosis of large tumors (> 5 cm)Complete necrosis of large tumors (> 5 cm)• µ-vascular permeation in 1 patientµ-vascular permeation in 1 patient• No inflammatory changes No inflammatory changes • Imaging for residual viable tumoral nodules Imaging for residual viable tumoral nodules
False (+)False (+) > Atypical regenerative nodule (2 Pts) > Atypical regenerative nodule (2 Pts)
False (-)False (-) > untreated hypovascular tumor > untreated hypovascular tumor > very small viable nodules (delayed LT)> very small viable nodules (delayed LT)
Explanted SpecimenExplanted SpecimenHistological dataHistological data
52 yr old male, ethyl cirrhosis52 yr old male, ethyl cirrhosis5.2 cm right HCC - 2 cm left HCC5.2 cm right HCC - 2 cm left HCC
3 selective TACE – LT 2 Mo later3 selective TACE – LT 2 Mo later
52 yr old male, ethyl cirrhosis52 yr old male, ethyl cirrhosis5.2 cm right HCC (satellite nodules)-2 cm left HCC5.2 cm right HCC (satellite nodules)-2 cm left HCC
MRI: Partial necrosisMRI: Partial necrosisLT: Remaining viable nodule-µvasc. permeationLT: Remaining viable nodule-µvasc. permeation
56 yr old male: 2 HCC nodules seg III-IV56 yr old male: 2 HCC nodules seg III-IV
Three TACE
Liver specimen:Liver specimen:
No viable tumoral cellsNo viable tumoral cells
Cyst-like tumoral necrosisCyst-like tumoral necrosis
CONCLUSIONSCONCLUSIONS• Higher anti-tumoral response % if compared with
conventional TACE• Complete necrosis could be achieved even in
large HCC• TACE-related surgical complications mainly due
to Doxorubicin• Effective downstatging of most patients with
intermediate-advanced HCC• TACE with DCbeads could reduce the dropout %• Large prospective studies are needed
Drug Eluting Beads vs Microspheres before LTDrug Eluting Beads vs Microspheres before LTNicolini A.F. March 2008-SIR Annual meetingNicolini A.F. March 2008-SIR Annual meeting
TAETAE8 Pts/11 HCC8 Pts/11 HCC
DC BeadsDC Beads8 Pts/9 HCC8 Pts/9 HCC
Delay Emb-LTDelay Emb-LT 10 Mo10 Mo 8 Mo8 Mo
EASL CREASL CR
OROR
0%0%
62%62%
71%71%
85%85%
SpecimenSpecimen Nec compl.Nec compl.
>70%>70% < 50%< 50%
3(27%)(27%)
62
7(78%)(78%)
2-