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W.Y. LauW.Y. LauDepartment of SurgeryDepartment of Surgery
The Chinese University of Hong The Chinese University of Hong KongKong
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SurgicalSurgical ManagementManagement
Partial hepatectomyPartial hepatectomy Orthotopic liver Orthotopic liver
transplantationtransplantation Debulking surgeryDebulking surgery Tumour downstaging followed Tumour downstaging followed
by salvage liver resectionby salvage liver resection
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Partial Partial HepatectomyHepatectomy
Treatment of choiceTreatment of choice Potential of a “cure”Potential of a “cure” Low operative mortalityLow operative mortality
Approaching 0% for non-cirrhoticApproaching 0% for non-cirrhotic Below 5% for cirrhoticBelow 5% for cirrhotic
10 - 30% resectable at 10 - 30% resectable at diagnosisdiagnosis
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Inducing Compensatory Inducing Compensatory Hypertrophy of Non-involved Hypertrophy of Non-involved
LiverLiver Embolising portal vein supplying lobe Embolising portal vein supplying lobe
of liver containing tumourof liver containing tumour Allowing compensatory hypertrophy Allowing compensatory hypertrophy
of non-involved liverof non-involved liver Making subsequent liver resection Making subsequent liver resection
safersafer
Sugawara et al 2002Sugawara et al 2002Nagino et al 1996Nagino et al 1996
Azoulay et al 1995Azoulay et al 1995
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02S18828
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Survival after Survival after Hepatic Resection for HCCHepatic Resection for HCC
nn 1 yr (%)1 yr (%) 3 yrs (%)3 yrs (%) 5 yrs (%)5 yrs (%)
Nagao 1987Nagao 1987 9898 7373 4242 2525
Lin 1987Lin 1987 352352 3939 1818 --
Chen 1989Chen 1989 120120 -- -- 2626
Tsuzuki 1990Tsuzuki 1990 119119 -- -- 3939
Nagasue 1993Nagasue 1993 229229 8080 5151 2626
Lai 1995Lai 1995 343343 6868 4545 3535
Kawasaki 1995Kawasaki 1995 112112 9292 7979 --
Takenaka 1996Takenaka 1996 280280 8888 7070 5050
Nadig 1997Nadig 1997 7171 -- -- 2020
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““ Curative” Resection Curative” Resection of HCCof HCC
50 - 90% post-operative death due 50 - 90% post-operative death due to recurrent diseaseto recurrent disease
(Friedman 1983, Okuda 1985, Rustgi 1988)(Friedman 1983, Okuda 1985, Rustgi 1988)
Intrahepatic tumour recurrence Intrahepatic tumour recurrence commoncommon
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Neoadjuvant/Adjuvant Neoadjuvant/Adjuvant Therapy for HCCTherapy for HCC
Systematic ReviewSystematic Review RCTRCT Medline 1966 – 2002Medline 1966 – 2002 Follow up longer than 3 Follow up longer than 3
yearsyears 13 studies13 studies
Schwartz et al, 2002Schwartz et al, 2002
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Neoadjuvant/Adjuvant Therapy for Neoadjuvant/Adjuvant Therapy for HCCHCC
RCT
Disease free
Interval
Overall Survival
Yamamoto 1996 Systemic chemotherapy
No change No change
Ono et al 1997 Systemic chemotherapy + TAC
No change No change
Kohno et al 1996 Systemic chemotherapy + TAC
No change No change
Yamasaki et al 1996
TACE No change No change
Kawata et al 1995 Chemoimmunotherapy
No change No change
Wu et al 1995 TACE Worse No change
Lai et al 1998 TACE Worse No change
Izumi et al 1994 TACE Improved No change
Kubo et al 2001 Immunotherapy Improved No change
Takayama et al 2002
Adoptive immunotherapy
Improved No change
Lygidakis et al 1996
TACE + PV embolisation + chemotherapy
Not reported Improved
Muto et al 1999 Oral polyprenoic acid Improved Improved
Lau et al 1999 TARE Improved Improved
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Liver TransplantationLiver Transplantation
Replaces cirrhotic liver with Replaces cirrhotic liver with normal livernormal liver
Prevents the later onset of Prevents the later onset of metachronous tumour in a metachronous tumour in a cirrhotic livercirrhotic liver
Cures portal hypertension Cures portal hypertension and its complicationsand its complications
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Liver Transplantation for Liver Transplantation for HCCHCC
(Milan Criteria) (Milan Criteria)For single tumours < 5 cm, For single tumours < 5 cm,
or multiple tumours < 3 cm and or multiple tumours < 3 cm and < 3 in number, liver < 3 in number, liver transplantation produces results transplantation produces results better than partial hepatectomy.better than partial hepatectomy.
Bismuth 1993; Tan 1995; Mazzaferro 1996Bismuth 1993; Tan 1995; Mazzaferro 1996
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Liver Transplantation Liver Transplantation for HCCfor HCC
Lack of cadaveric donorLack of cadaveric donor Long waitLong wait Tumour progression in spite Tumour progression in spite
of RFA or TACEof RFA or TACE Removal from waiting list at Removal from waiting list at
rate of 2 – 4% per monthrate of 2 – 4% per month
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Living-donor Liver Living-donor Liver Transplant (LDLT)Transplant (LDLT)
Better overall status of recipientBetter overall status of recipient Better liver function of graftBetter liver function of graft Short waiting time eliminating Short waiting time eliminating
need for neoadjuvant therapyneed for neoadjuvant therapy Low drop out rateLow drop out rate Patient not meeting restricted Patient not meeting restricted
listing criteria can be listing criteria can be transplantedtransplanted
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Results of LDLT Results of LDLT exceeding Milan exceeding Milan
CriteriaCriteria
nn5-yr 5-yr
survivalsurvival
Mount Sinai Mount Sinai 20032003 4343 44%44%
UCSF 2001UCSF 2001 7070 25.2%25.2%
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Debulking Surgery Debulking Surgery (Cytoreductive (Cytoreductive
Surgery)Surgery)Multiple and bilobar HCCMultiple and bilobar HCC May represent intrahepatic spread of May represent intrahepatic spread of
disease from one lobe to another disease from one lobe to another oror multifocal HCCmultifocal HCC
In selected patients, resection of main In selected patients, resection of main tumour can be combined with wedge tumour can be combined with wedge excision or local ablative therapy in the excision or local ablative therapy in the other lobe of liverother lobe of liver
Followed by systemic or regional therapies Followed by systemic or regional therapies after surgeryafter surgery
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Debulking Surgery for HCCDebulking Surgery for HCC(resection + local ablative (resection + local ablative
therapy)therapy)Prolongation in Prolongation in
SurvivalSurvival Lau 1994Lau 1994 YesYes Yamamoto 1997Yamamoto 1997 YesYes Adam 1997Adam 1997 YesYes Liu 2003Liu 2003 YesYes
Debulking Surgery + TACEDebulking Surgery + TACE Shimamura et al 1993Shimamura et al 1993 YesYes Clavien et al 2003Clavien et al 2003 YesYes
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Increased Interest in Increased Interest in Debulking Surgery for Debulking Surgery for
unresectable HCCunresectable HCC
Radiofrequency ablationRadiofrequency ablation Combined with liver Combined with liver
resectionresection Alone with Alone with
open surgeryopen surgery laparoscopic surgerylaparoscopic surgery percutaneouslypercutaneously
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Salvage Surgery Salvage Surgery
following following
Downstaging of Downstaging of
unresectable HCCunresectable HCC
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Hepatocellular Hepatocellular CarcinomaCarcinoma
Generally accepted principle Generally accepted principle Cure only possibleCure only possible Complete extirpation of Complete extirpation of
tumourtumour Single or combined Single or combined
modalities of treatmentmodalities of treatment
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Hepatocellular Hepatocellular CarcinomaCarcinoma
Cure is rarely Cure is rarely possiblepossible
When unresectableWhen unresectable
Dismal prognosisDismal prognosis
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Hepatocellular Hepatocellular CarcinomaCarcinoma
Unresectable because of local Unresectable because of local extent or distant metastasesextent or distant metastases
Unsuitable for liver transplantationUnsuitable for liver transplantation Unsuitable for local ablative Unsuitable for local ablative
therapytherapy Treatment is palliativeTreatment is palliative Aims to relief symptoms, if Aims to relief symptoms, if
possible, prolong survivalpossible, prolong survival
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Downstaging vs Downstaging vs Neoadjuvant TherapyNeoadjuvant Therapy
DownstagingDownstaging Tumour unresectableTumour unresectable
Local extent of disease or distant Local extent of disease or distant metastasesmetastases
Procedure improve on stage of Procedure improve on stage of diseasedisease
Neoadjuvant TherapyNeoadjuvant Therapy Tumour resectableTumour resectable Procedure given to improve on Procedure given to improve on
results of liver resectionresults of liver resection
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Downstaging of HCC followed by Downstaging of HCC followed by Salvage Liver ResectionSalvage Liver Resection
Transarterial chemoembolization
Fan et al 1998Harda et al 1996
Combined systemic chemotherapy + external radiation
Sitzmann & Abrams 1993
HA ligation or HA infusion Tang et al 2004
HA ligation + HA infusion Tang et al 2004
HAL + HAI + radioimmunotherapy + fractionated regional radiotherapy
Tang et al 1995Tang et al 2004
Yttrium 90 microspheres Lau et al 1997Lau et al 2004
Systemic chemoimmunotherapy
Lau et al 2000Lau et al 2004
Systemic chemotherapy Lau et al 2004
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Systemic PIAF
YttriumSystemic
Doxorubicin
n 128 71 76
Salvage Surgery
36*(28.1%)
4(5.6%)
9**(11.8%)
* 4 patients received additional yttrium.
** 1 patient received additional yttrium.
Lau et al. Ann Surg 2004
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Reasons for HCC not Reasons for HCC not Resectable Before Resectable Before
DownstagingDownstagingnn
Extensive intrahepatic Extensive intrahepatic diseasedisease 3434 69.4%69.4%
Main portal vein Main portal vein tumour thrombustumour thrombus 77 14.3%14.3%
Extrahepatic spreadExtrahepatic spread 88 16.3%16.3%
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Overall Survival (n = 49)Overall Survival (n = 49)
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Downstaging of HCC Downstaging of HCC followed by Salvage followed by Salvage
SurgerySurgery
Possible in a small Possible in a small proportion of patients, 5 to proportion of patients, 5 to 28.1%28.1%
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5-Year Survival after HCC 5-Year Survival after HCC Downstaging + Salvage Downstaging + Salvage
ResectionResection 32.2% to 69.7%32.2% to 69.7%
Fan et al 1998Fan et al 1998Sitzmann & Abrams 1993Sitzmann & Abrams 1993
Tang et al 1995Tang et al 1995Tang et al 2004Tang et al 2004
Lau et al 1997Lau et al 1997Lau et al 2000Lau et al 2000Lau et al 2004Lau et al 2004
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Salvage liver resection is Salvage liver resection is necessary after HCC necessary after HCC
downstagingdownstaging Complete histological response happen Complete histological response happen
in the minorityin the minority
Serum AFP not useful as 10 out of 14 Serum AFP not useful as 10 out of 14 patients with viable HCC had normal AFPpatients with viable HCC had normal AFP
Tang et al 1995Tang et al 1995
Degree of necrosis cannot predict degree Degree of necrosis cannot predict degree of viable residual tumourof viable residual tumour
Lau et al 2004Lau et al 2004
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Salvage Liver Resection Salvage Liver Resection following Downstaging of following Downstaging of
HCCHCC
Favourable long-term overall Favourable long-term overall survivalsurvival
In a previously dismal In a previously dismal situationsituation
Gives great hope to patients Gives great hope to patients with unresectable HCCwith unresectable HCC
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Limitation of Salvage Liver Limitation of Salvage Liver Resection following Resection following Downstaging of HCCDownstaging of HCC
Only a small proportion of Only a small proportion of patients will respond well patients will respond well enoughenough
Responders cannot be Responders cannot be predictedpredicted
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How to Choose the How to Choose the Downstaging Downstaging
ProcedureProcedure Patient’s general conditionPatient’s general condition Stage of HCCStage of HCC Presence of tumour thrombus in MPVPresence of tumour thrombus in MPV Liver functionLiver function Patient’s choicePatient’s choice Availability of expertise and Availability of expertise and
treatment protocols in different treatment protocols in different centerscenters
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ConclusionsConclusions Surgery plays an important role Surgery plays an important role
in the management of HCCin the management of HCC
Curative treatment of HCC has Curative treatment of HCC has gradually changed from surgery gradually changed from surgery to multidisciplinary approachto multidisciplinary approach
In a proportion of patients In a proportion of patients presenting with unresectable presenting with unresectable tumour, cure is still possibletumour, cure is still possible
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Non-Surgical Treatment Non-Surgical Treatment of Hepatocellular of Hepatocellular
CarcinomaCarcinoma Local Ablative Local Ablative
TherapyTherapy
Regional TherapyRegional Therapy
Systemic TherapySystemic Therapy
Supportive TherapySupportive Therapy
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Local Ablative TherapyLocal Ablative Therapy
A.A. Injection of Injection of Cytotoxic agentsCytotoxic agents1)1) ChemicalsChemicals
a.a. EthanolEthanol
b.b. Acetic acidAcetic acid
2)2) Radioactive isotopesRadioactive isotopes
3)3) Hyperthermic Hyperthermic agentsagentsa.a. SalineSaline
b.b. WaterWater
c.c. Cytotoxic drugsCytotoxic drugs
4)4) Chemotherapeutic Chemotherapeutic agentsagents
B.B. Application of an Application of an energy sourceenergy source1)1) Thermal ablationThermal ablation
a.a. RadiofrequencyRadiofrequency
b.b. MicrowaveMicrowave
c.c. Interstitial laser Interstitial laser photo coagulationphoto coagulation
d.d. High intensity High intensity focused focused ultrasoundultrasound
2)2) CryoablationCryoablation
3)3) Conformal Conformal radiotherapyradiotherapy
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Advantages of Local Ablative Advantages of Local Ablative TherapyTherapy
Minimal invasive approachMinimal invasive approach Little damage to surrounding Little damage to surrounding
liver parenchymaliver parenchyma Little systemic side effectsLittle systemic side effects SafeSafe
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Percutaneous Ethanol Percutaneous Ethanol Injection Therapy (PEI)Injection Therapy (PEI)
First introduced by Suguira et First introduced by Suguira et al in 1983al in 1983
AdvantagesAdvantages InexpensiveInexpensive Easy to performEasy to perform RepeatableRepeatable
Widespread acceptanceWidespread acceptance
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PEIPEI
IndicationsIndications Small tumors < 5 cmSmall tumors < 5 cm Small in number (<3) Small in number (<3)
Need for repeated punctureNeed for repeated puncture Especially suitable for patients who Especially suitable for patients who
are not surgical candidates because ofare not surgical candidates because of Poor general conditionPoor general condition Poor LFTPoor LFT Recurrence after liver resectionRecurrence after liver resection
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PEIPEI
Absolute contraindicationsAbsolute contraindications Gross ascitesGross ascites Uncorrectable coagulopathyUncorrectable coagulopathy ObstructiveObstructive jaundice jaundice
Risks of post-procedural bleeding and bile Risks of post-procedural bleeding and bile peritonitisperitonitis
Relative contraindicationsRelative contraindications Tumor at, or protruding out of liver surface - Tumor at, or protruding out of liver surface -
increased risks of bleeding and peritoneal increased risks of bleeding and peritoneal seedingseeding
Hiding under diaphragmHiding under diaphragm Near to vital structuresNear to vital structures
technical
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Side Effects – usually Side Effects – usually minimalminimal
SystemicSystemic PainPain FeverFever Transient rise in liver Transient rise in liver
enzymesenzymes
LocalLocal Liver abscessLiver abscess Pleural effusionPleural effusion CholangitisCholangitis Portal vein thrombosisPortal vein thrombosis Seeding on puncture tractSeeding on puncture tract
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Action of Ethanol on Action of Ethanol on TumorTumor
Direct effects on cancer cellsDirect effects on cancer cells DehydrationDehydration Necrosis of cells in contact with Necrosis of cells in contact with
ethanolethanol Indirect effects on supplying Indirect effects on supplying
small vessels to tumorsmall vessels to tumor Vascular thrombosisVascular thrombosis IschemiaIschemia
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PEIPEI
More suitable for HCC than liver metastasesMore suitable for HCC than liver metastases ‘‘soft’ tumor and ‘hard’ surrounding cirrhotic soft’ tumor and ‘hard’ surrounding cirrhotic
liver promotes distribution of ethanol in liver promotes distribution of ethanol in HCCHCC
In contrast to ‘hard’ tumor and ‘soft’ normal In contrast to ‘hard’ tumor and ‘soft’ normal liver in metastatic lesionsliver in metastatic lesions
Vascular tumor in HCC causes more Vascular tumor in HCC causes more necrosis and ischemia than hypovascular necrosis and ischemia than hypovascular tumor in metastasestumor in metastases
Livraghi et al 1995Livraghi et al 1995
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PEI on HCCPEI on HCCNon-randomised studiesNon-randomised studies
3-year survival rates of 46 – 77%3-year survival rates of 46 – 77%
Ebara et al 1986Ebara et al 1986Shiina et al 1993Shiina et al 1993Isobe et al 1994Isobe et al 1994
Castells et al 1993Castells et al 1993Livraghi et al 1992Livraghi et al 1992
Post treatment recurrence within 2 Post treatment recurrence within 2 years of over 50%years of over 50%
Isobe et al 1994Isobe et al 1994Castells et al 1993Castells et al 1993
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PEI versus Partial PEI versus Partial HepatectomyHepatectomy
76 patients, Pugh Child A or B76 patients, Pugh Child A or B 1 to 2 HCC, each < 3 cm1 to 2 HCC, each < 3 cm Randomized to receive PEI or Randomized to receive PEI or
partial hepatectomypartial hepatectomy Follow up 12 to 59 monthsFollow up 12 to 59 months Overall survivalOverall survival
Disease free survivalDisease free survival
Huang et al, Ann Surg 2005Huang et al, Ann Surg 2005
No significant difference
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Percutaneous Percutaneous Radiofrequency Ablation Radiofrequency Ablation
(RFA)(RFA) First described by Rossi in 1993First described by Rossi in 1993 Radiofrequency energy leads to cell Radiofrequency energy leads to cell
death and coagulation necrosisdeath and coagulation necrosis Good results achieved in non-Good results achieved in non-
randomised studiesrandomised studies Complete necrosis rate 90 to 100%Complete necrosis rate 90 to 100% Local recurrence rate 3.6% at median Local recurrence rate 3.6% at median
F.U. of 19mF.U. of 19mRossi et al 1993Rossi et al 1993
Solbiati et al 1997Solbiati et al 1997Nagata et al 1997Nagata et al 1997
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Limitations of Limitations of Effectiveness Effectiveness
of RFA of RFA ‘‘ heat sinks’heat sinks’ Peripheral lesions abutting on Peripheral lesions abutting on
adjacent organsadjacent organs Tissue charring results in Tissue charring results in
increased tissue impedance increased tissue impedance cannot treat large lesionscannot treat large lesions
Size of lesionSize of lesion
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Problems and Solutions Problems and Solutions for RFAfor RFA
‘‘ heat sink’heat sink’ Patient selectionPatient selection
Peripheral lesionsPeripheral lesions Laparoscopic Laparoscopic
approachapproach
Open approachOpen approach
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RFARFATechnical Solutions to Technical Solutions to Treat Larger LesionTreat Larger Lesion
Injecting saline into lesion during PxInjecting saline into lesion during Px Cooled tipCooled tip Complex electrode geometryComplex electrode geometry Monitoring tip impedance and Monitoring tip impedance and
temperature with feedback to adjust temperature with feedback to adjust generator outputgenerator output
Multiple puncture and treatment Multiple puncture and treatment sessionssessions
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RFA versus PEIRFA versus PEI
Livraghi et al 1999Livraghi et al 1999
Izumi et al 2001Izumi et al 2001
RFARFA PEIPEI
Complete necrosisComplete necrosis 100%100%
90%90%94%94%
80%80%
Average sessions (n)Average sessions (n) 1.51.5
1.21.244
4.84.8
Local recurrence rate at 1 Local recurrence rate at 1 yearyear 15%15% 14%14%
Non-randomised studies Non-randomised studies RFA better than PEIRFA better than PEI
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RFA versus PEIRFA versus PEIRandomised studiesRandomised studies
RFA better and PEIRFA better and PEI Lower tumor recurrence rateLower tumor recurrence rate Requires less sessions for complete Requires less sessions for complete
ablationablationLencioni et al 1999Lencioni et al 1999
Shiina et al 2000Shiina et al 2000
Better overall survivalBetter overall survival
RFARFA PEIPEI
1-year1-year 100%100% 96%96%
2-year2-year 98%98% 88%88%
Olschewski et al 2001Olschewski et al 2001
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RFA versus Partial RFA versus Partial HepatectomyHepatectomy
180 patients180 patients Single HCC, < 5 cmSingle HCC, < 5 cm Randomized to received RFA or Randomized to received RFA or
partial hepatectomypartial hepatectomy Overall survivalOverall survival
Disease free survivalDisease free survival
Chen et al, Ann Surg 2006Chen et al, Ann Surg 2006
No significant difference
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Regional Therapy for Regional Therapy for HCCHCC
1)1) Transarterial Chemoembolisation (TACE)Transarterial Chemoembolisation (TACE)
2)2) Transarterial Radioembolisation (TARE)Transarterial Radioembolisation (TARE)
• Yttrium 90Yttrium 90
• Iodine 131Iodine 131
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TACETACE
Criticised because no standard protocol:-Criticised because no standard protocol:-1)1) ChemotherapyChemotherapy
• Choice of chemotherapeutic agentChoice of chemotherapeutic agent• DosageDosage• DilutionDilution• Rate of injectionRate of injection• Time interval between PxTime interval between Px
2)2) EmbolisationEmbolisation• Choice of embolising agentChoice of embolising agent• Degree of embolisationDegree of embolisation• Given together or after the Given together or after the
chemotherapeutic agentchemotherapeutic agent
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TACE for HCCTACE for HCC
Meta-analysis (Mathurin et al 1998)Meta-analysis (Mathurin et al 1998)
Systematic review (Simonetti et al Systematic review (Simonetti et al 1997)1997)
Failed to show any benefit of TACE Failed to show any benefit of TACE over no treatment, or one treatment over no treatment, or one treatment regimen better than another.regimen better than another.
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Recent Studies of L-Recent Studies of L-TACE for HCCTACE for HCC
RCT comparing L-TACE versus RCT comparing L-TACE versus symptomatic treatmentsymptomatic treatment
cisplatin, lipiodol, gel foamcisplatin, lipiodol, gel foam
Lo et al 2002Lo et al 2002
doxorubicin, lipiodol, gel foamdoxorubicin, lipiodol, gel foam
Llovet et al 2002Llovet et al 2002
Showed significant overall survival Showed significant overall survival with treatmentwith treatment
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TACE for HCCTACE for HCC
TACE downstaged HCC from TACE downstaged HCC from unresectable to resectable unresectable to resectable tumor tumor (Fan et al 1998)(Fan et al 1998)
Some RCT show significant Some RCT show significant impact on survival while other impact on survival while other RCT do notRCT do not
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Possible explanation:Possible explanation:
The beneficial effects of TACE on The beneficial effects of TACE on a subgroup is being offset by a subgroup is being offset by toxic effects on another subgrouptoxic effects on another subgroup
TACE for HCC has no effect or TACE for HCC has no effect or harmful effect on patients withharmful effect on patients with Poor LFTPoor LFT Large tumorLarge tumor Portal vein tumor thrombosisPortal vein tumor thrombosis
Patient case selection is Patient case selection is important for TACEimportant for TACE
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Transarterial Transarterial RadioembolisationRadioembolisation
for HCC (TARE)for HCC (TARE)
Lipiodol I-131Lipiodol I-131
Yttrium 90 Yttrium 90 microspheresmicrospheres
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Lipiodol I -131 in HCCLipiodol I -131 in HCC
Activity (MBq)Activity (MBq) nn
Kobayashi Kobayashi 19861986 281 - 592281 - 592 77
Park 1987Park 1987 74 - 444074 - 4440 4747
Bretagne Bretagne 19881988 900 - 2400900 - 2400 1515
Yoo 1989Yoo 1989 Single / Single / fractionatedfractionated 6060
Lui 1990Lui 1990 444 - 6220444 - 6220 1010
Novell 1991Novell 1991 475475
11(Ablation of (Ablation of recurrent recurrent
HCC)HCC)
Yoo 1991Yoo 1991 555 - 2220555 - 2220 2424
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Results of TARE with Results of TARE with LipiodolLipiodol
I-131I-131 Results encouragingResults encouraging SafeSafe More effective in small More effective in small
tumorstumors
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Problems with Lipiodol I-Problems with Lipiodol I-131131
I-131 relative low energy I-131 relative low energy cannot treat big tumorcannot treat big tumor
Radiation protection of Radiation protection of medical personnel difficult medical personnel difficult because of gamma irradiationbecause of gamma irradiation
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Intra-arterial Yttrium-90 Intra-arterial Yttrium-90 Microspheres for Localized Microspheres for Localized
Unresectable HCCUnresectable HCC
Yttrium-90 microspheresYttrium-90 microspheres Biological inertBiological inert 29-35 micron, resin or 29-35 micron, resin or
glass baseglass base Physical half life 64 hoursPhysical half life 64 hours Beta radiation, 936.7KeVBeta radiation, 936.7KeV
(Y-90 microspheres in suspension. x300)
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Yttrium-90 Yttrium-90 microspheresmicrospheres
Concentrated in tumor Concentrated in tumor more than non-tumormore than non-tumor blood supply to tumor is blood supply to tumor is
mainly from the hepatic mainly from the hepatic arteryartery
due to high arterial due to high arterial blood flow to tumorblood flow to tumor
selective selective catheterisation of the catheterisation of the tumor feeding arterytumor feeding artery Lodged within the tumor vascular
bedbecause the size of the microspheres isthe same as the internal diameter oftumor capillaries
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Phase II Study of Yttrium-90 Phase II Study of Yttrium-90 Microspheres Treatment for Microspheres Treatment for
Unresectable HCCUnresectable HCC 71 71 patientspatients Single treatment through Seldinger Single treatment through Seldinger
technique during HAGtechnique during HAG Median dose of Y-90: 3 GBq (range 1 to 5)Median dose of Y-90: 3 GBq (range 1 to 5) Results:Results:
Radiological response rate 26%Radiological response rate 26% Median survival 9.4 monthsMedian survival 9.4 months 4 patients downstaged to become resectable4 patients downstaged to become resectable 2 complete histological response2 complete histological response
Lau et al. Int J Rad Onco Biol Phys, 40:3, 583-592, 1998
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SummarySummary
Intra-arterial yttrium-90 Intra-arterial yttrium-90 microspheres treatment is microspheres treatment is feasible, tolerable, able to convert feasible, tolerable, able to convert localized unresectable to localized unresectable to resectable HCCresectable HCC
Complete pathological remission Complete pathological remission is achievable with yttrium-90 is achievable with yttrium-90 microspheres treatment alonemicrospheres treatment alone
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Systemic TherapySystemic Therapy
ChemotherapyChemotherapy
ImmunotheapyImmunotheapy
Chemo-immunotherapyChemo-immunotherapy
Hormonal TherapyHormonal Therapy
Somatostatin analogueSomatostatin analogue
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New CombinationNew CombinationChemoimmunotherapy for Chemoimmunotherapy for
Unresectable HCCUnresectable HCC Treatment regimen “Treatment regimen “PIAF”PIAF”
CisplatinCisplatin 20mg/m20mg/m22 ivi day 1-4 ivi day 1-4 Interferon alphaInterferon alpha 5MU/m5MU/m22 sc day 1-4 sc day 1-4 AdriamycinAdriamycin 40mg/m40mg/m22 ivi day 1 ivi day 1 5-Fluorouracil5-Fluorouracil 400mg/m400mg/m22 ivi day 1-4 ivi day 1-4
• out-patient treatmentout-patient treatment• repeat every 3 weeks for maximum of 6 cyclesrepeat every 3 weeks for maximum of 6 cycles
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Phase II Study of PIAF for Phase II Study of PIAF for Unresectable HCCUnresectable HCC
50 50 patients with inoperable patients with inoperable or metastatic HCCor metastatic HCC
Objective response rate Objective response rate (radiological) 26%(radiological) 26%
18% patients converted to 18% patients converted to operable stage and operable stage and received resection after received resection after PIAFPIAF
Median survival 8.9 monthsMedian survival 8.9 months
Leung et alClinical Cancer Research
5:1676-1681, 1999
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ToxicityToxicity
ToxicityToxicityNo. of patients (%)No. of patients (%)
grade 3 grade 3
HemoglobinHemoglobin 6 (12%)6 (12%)
LeucocyteLeucocyte 17 (34%)17 (34%)
PlateletPlatelet 11 (22%)11 (22%)
RenalRenal 1 (2%)1 (2%)
Nausea & vomitingNausea & vomiting 6 (12%)6 (12%)
Drug-related feverDrug-related fever 1 (2%)1 (2%)
DiarrheaDiarrhea 4 (8%)4 (8%)
AlopeciaAlopecia 9 (18%)9 (18%)
MucositisMucositis 2 (4%)2 (4%)
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Supportive TherapySupportive Therapy
Pain reliefPain relief Management of Management of
ascitesascites Nutritional supportNutritional support Hospice serviceHospice service
Home basedHome based Hospital basedHospital based
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ConclusionConclusion
Many new non-operative treatment Many new non-operative treatment modalities show very promising modalities show very promising resultsresults
Some unresectable HCC can be Some unresectable HCC can be downstaged to become resectable by downstaged to become resectable by these modalitiesthese modalities
These treatment modalities should be These treatment modalities should be properly evaluated with RCT to properly evaluated with RCT to determine their actual role in the determine their actual role in the management of HCCmanagement of HCC