W.Y. Lau Department of Surgery The Chinese University of Hong Kong.

W.Y. LauW.Y. LauDepartment of SurgeryDepartment of Surgery

The Chinese University of Hong The Chinese University of Hong KongKong

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

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

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

02S18828

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

““ 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

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

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

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

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

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

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

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%

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

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

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

Salvage Surgery Salvage Surgery

following following

Downstaging of Downstaging of

unresectable HCCunresectable HCC

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

Hepatocellular Hepatocellular CarcinomaCarcinoma

Cure is rarely Cure is rarely possiblepossible

When unresectableWhen unresectable

Dismal prognosisDismal prognosis

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

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

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

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

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%

Overall Survival (n = 49)Overall Survival (n = 49)

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%

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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.

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

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

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

Transarterial Transarterial RadioembolisationRadioembolisation

for HCC (TARE)for HCC (TARE)

Lipiodol I-131Lipiodol I-131

Yttrium 90 Yttrium 90 microspheresmicrospheres

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

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

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

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)

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

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

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

Systemic TherapySystemic Therapy

ChemotherapyChemotherapy

ImmunotheapyImmunotheapy

Chemo-immunotherapyChemo-immunotherapy

Hormonal TherapyHormonal Therapy

Somatostatin analogueSomatostatin analogue

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

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

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%)

Supportive TherapySupportive Therapy

Pain reliefPain relief Management of Management of

ascitesascites Nutritional supportNutritional support Hospice serviceHospice service

Home basedHome based Hospital basedHospital based

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