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

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Presentation on theme: "W.Y. Lau Department of Surgery The Chinese University of Hong Kong."— Presentation transcript:

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

2 Surgical Management Partial hepatectomy Partial hepatectomy Orthotopic liver transplantation Orthotopic liver transplantation Debulking surgery Debulking surgery Tumour downstaging followed by salvage liver resection Tumour downstaging followed by salvage liver resection

3 Partial Hepatectomy Treatment of choice Treatment of choice Potential of a cure Potential of a cure Low operative mortality Low operative mortality Approaching 0% for non-cirrhotic Approaching 0% for non-cirrhotic Below 5% for cirrhotic Below 5% for cirrhotic % resectable at diagnosis % resectable at diagnosis

4 Inducing Compensatory Hypertrophy of Non-involved Liver Embolising portal vein supplying lobe of liver containing tumour Embolising portal vein supplying lobe of liver containing tumour Allowing compensatory hypertrophy of non-involved liver Allowing compensatory hypertrophy of non-involved liver Making subsequent liver resection safer Making subsequent liver resection safer Sugawara et al 2002 Nagino et al 1996 Azoulay et al 1995

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6 02S18828

7 Survival after Hepatic Resection for HCC n1 yr (%)3 yrs (%)5 yrs (%) Nagao Lin Chen Tsuzuki Nagasue Lai Kawasaki Takenaka Nadig

8 Curative Resection of HCC Curative Resection of HCC % post-operative death due to recurrent disease % post-operative death due to recurrent disease (Friedman 1983, Okuda 1985, Rustgi 1988) Intrahepatic tumour recurrence common Intrahepatic tumour recurrence common

9 Neoadjuvant/Adjuvant Therapy for HCC Systematic Review Systematic Review RCT RCT Medline 1966 – 2002 Medline 1966 – 2002 Follow up longer than 3 years Follow up longer than 3 years 13 studies 13 studies Schwartz et al, 2002

10 Neoadjuvant/Adjuvant Therapy for HCC RCT Disease free Interval Overall Survival Yamamoto 1996Systemic chemotherapyNo change Ono et al 1997Systemic chemotherapy + TAC No change Kohno et al 1996Systemic chemotherapy + TAC No change Yamasaki et al 1996TACENo change Kawata et al 1995ChemoimmunotherapyNo change Wu et al 1995TACEWorseNo change Lai et al 1998TACEWorseNo change Izumi et al 1994TACEImprovedNo change Kubo et al 2001ImmunotherapyImprovedNo change Takayama et al 2002Adoptive immunotherapyImprovedNo change Lygidakis et al 1996TACE + PV embolisation + chemotherapy Not reportedImproved Muto et al 1999Oral polyprenoic acidImproved Lau et al 1999TAREImproved

11 Liver Transplantation Replaces cirrhotic liver with normal liver Replaces cirrhotic liver with normal liver Prevents the later onset of metachronous tumour in a cirrhotic liver Prevents the later onset of metachronous tumour in a cirrhotic liver Cures portal hypertension and its complications Cures portal hypertension and its complications

12 Liver Transplantation for HCC (Milan Criteria) For single tumours < 5 cm, or multiple tumours < 3 cm and < 3 in number, liver transplantation produces results better than partial hepatectomy. Bismuth 1993; Tan 1995; Mazzaferro 1996

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14 Liver Transplantation for HCC Lack of cadaveric donor Lack of cadaveric donor Long wait Long wait Tumour progression in spite of RFA or TACE Tumour progression in spite of RFA or TACE Removal from waiting list at rate of 2 – 4% per month Removal from waiting list at rate of 2 – 4% per month

15 Living-donor Liver Transplant (LDLT) Better overall status of recipient Better overall status of recipient Better liver function of graft Better liver function of graft Short waiting time eliminating need for neoadjuvant therapy Short waiting time eliminating need for neoadjuvant therapy Low drop out rate Low drop out rate Patient not meeting restricted listing criteria can be transplanted Patient not meeting restricted listing criteria can be transplanted

16 Results of LDLT exceeding Milan Criteria n 5-yr survival Mount Sinai % UCSF %

17 Debulking Surgery (Cytoreductive Surgery) Multiple and bilobar HCC May represent intrahepatic spread of disease from one lobe to another or multifocal HCC May represent intrahepatic spread of disease from one lobe to another or multifocal HCC In selected patients, resection of main tumour can be combined with wedge excision or local ablative therapy in the other lobe of liver In selected patients, resection of main tumour can be combined with wedge excision or local ablative therapy in the other lobe of liver Followed by systemic or regional therapies after surgery Followed by systemic or regional therapies after surgery

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19 Debulking Surgery for HCC (resection + local ablative therapy) Prolongation in Survival Lau 1994Yes Lau 1994Yes Yamamoto 1997Yes Yamamoto 1997Yes Adam 1997Yes Adam 1997Yes Liu 2003Yes Liu 2003Yes Debulking Surgery + TACE Shimamura et al 1993Yes Shimamura et al 1993Yes Clavien et al 2003Yes Clavien et al 2003Yes

20 Increased Interest in Debulking Surgery for unresectable HCC Radiofrequency ablation Combined with liver resection Combined with liver resection Alone with Alone with open surgery open surgery laparoscopic surgery laparoscopic surgery percutaneously percutaneously

21 Salvage Surgery following Downstaging of unresectable HCC

22 Hepatocellular Carcinoma Generally accepted principle Generally accepted principle Cure only possible Cure only possible Complete extirpation of tumour Complete extirpation of tumour Single or combined modalities of treatment Single or combined modalities of treatment

23 Hepatocellular Carcinoma Cure is rarely possible Cure is rarely possible When unresectable When unresectable Dismal prognosis Dismal prognosis

24 Hepatocellular Carcinoma Unresectable because of local extent or distant metastases Unresectable because of local extent or distant metastases Unsuitable for liver transplantation Unsuitable for liver transplantation Unsuitable for local ablative therapy Unsuitable for local ablative therapy Treatment is palliative Treatment is palliative Aims to relief symptoms, if possible, prolong survival Aims to relief symptoms, if possible, prolong survival

25 Downstaging vs Neoadjuvant Therapy Downstaging Tumour unresectable Tumour unresectable Local extent of disease or distant metastases Local extent of disease or distant metastases Procedure improve on stage of disease Procedure improve on stage of disease Neoadjuvant Therapy Tumour resectable Tumour resectable Procedure given to improve on results of liver resection Procedure given to improve on results of liver resection

26 Downstaging of HCC followed by Salvage Liver Resection Transarterial chemoembolization Fan et al 1998 Harda 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 1995 Tang et al 2004 Yttrium 90 microspheres Lau et al 1997 Lau et al 2004 Systemic chemoimmunotherapy Lau et al 2000 Lau et al 2004 Systemic chemotherapy Lau et al 2004

27 Systemic PIAF Yttrium Systemic Doxorubicin n 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

28 Reasons for HCC not Resectable Before Downstaging n Extensive intrahepatic disease % Main portal vein tumour thrombus 714.3% Extrahepatic spread 816.3%

29 Overall Survival (n = 49)

30 Downstaging of HCC followed by Salvage Surgery Possible in a small proportion of patients, 5 to 28.1% Possible in a small proportion of patients, 5 to 28.1%

31 5-Year Survival after HCC Downstaging + Salvage Resection 32.2% to 69.7% 32.2% to 69.7% Fan et al 1998 Sitzmann & Abrams 1993 Tang et al 1995 Tang et al 2004 Lau et al 1997 Lau et al 2000 Lau et al 2004

32 Salvage liver resection is necessary after HCC downstaging Complete histological response happen in the minority Complete histological response happen in the minority Serum AFP not useful as 10 out of 14 patients with viable HCC had normal AFP Serum AFP not useful as 10 out of 14 patients with viable HCC had normal AFP Tang et al 1995 Degree of necrosis cannot predict degree of viable residual tumour Degree of necrosis cannot predict degree of viable residual tumour Lau et al 2004

33 Salvage Liver Resection following Downstaging of HCC Favourable long-term overall survival Favourable long-term overall survival In a previously dismal situation In a previously dismal situation Gives great hope to patients with unresectable HCC Gives great hope to patients with unresectable HCC

34 Limitation of Salvage Liver Resection following Downstaging of HCC Only a small proportion of patients will respond well enough Only a small proportion of patients will respond well enough Responders cannot be predicted Responders cannot be predicted

35 How to Choose the Downstaging Procedure Patient s general condition Patient s general condition Stage of HCC Stage of HCC Presence of tumour thrombus in MPV Presence of tumour thrombus in MPV Liver function Liver function Patient s choice Patient s choice Availability of expertise and treatment protocols in different centers Availability of expertise and treatment protocols in different centers

36 Conclusions Surgery plays an important role in the management of HCC Surgery plays an important role in the management of HCC Curative treatment of HCC has gradually changed from surgery to multidisciplinary approach Curative treatment of HCC has gradually changed from surgery to multidisciplinary approach In a proportion of patients presenting with unresectable tumour, cure is still possible In a proportion of patients presenting with unresectable tumour, cure is still possible

37 Non-Surgical Treatment of Hepatocellular Carcinoma Local Ablative Therapy Local Ablative Therapy Regional Therapy Regional Therapy Systemic Therapy Systemic Therapy Supportive Therapy Supportive Therapy

38 Local Ablative Therapy A.Injection of Cytotoxic agents 1)Chemicals a.Ethanol b.Acetic acid 2)Radioactive isotopes 3)Hyperthermic agents a.Saline b.Water c.Cytotoxic drugs 4)Chemotherapeutic agents B.Application of an energy source 1)Thermal ablation a.Radiofrequency b.Microwave c.Interstitial laser photo coagulation d.High intensity focused ultrasound 2)Cryoablation 3)Conformal radiotherapy

39 Advantages of Local Ablative Therapy Minimal invasive approach Minimal invasive approach Little damage to surrounding liver parenchyma Little damage to surrounding liver parenchyma Little systemic side effects Little systemic side effects Safe Safe

40 Percutaneous Ethanol Injection Therapy (PEI) First introduced by Suguira et al in 1983 First introduced by Suguira et al in 1983 Advantages Advantages Inexpensive Inexpensive Easy to perform Easy to perform Repeatable Repeatable Widespread acceptance Widespread acceptance

41 PEI Indications Small tumors < 5 cm Small tumors < 5 cm Small in number (<3) Small in number (<3) Need for repeated puncture Need for repeated puncture Especially suitable for patients who are not surgical candidates because of Especially suitable for patients who are not surgical candidates because of Poor general condition Poor general condition Poor LFT Poor LFT Recurrence after liver resection Recurrence after liver resection

42 PEI Absolute contraindications Gross ascites Gross ascites Uncorrectable coagulopathy Uncorrectable coagulopathy Obstructive jaundice Obstructive jaundice Risks of post-procedural bleeding and bile peritonitis Relative contraindications Tumor at, or protruding out of liver surface - increased risks of bleeding and peritoneal seeding Tumor at, or protruding out of liver surface - increased risks of bleeding and peritoneal seeding Hiding under diaphragm Hiding under diaphragm Near to vital structures Near to vital structures technical

43 Side Effects – usually minimal Systemic Pain Pain Fever Fever Transient rise in liver enzymes Transient rise in liver enzymesLocal Liver abscess Liver abscess Pleural effusion Pleural effusion Cholangitis Cholangitis Portal vein thrombosis Portal vein thrombosis Seeding on puncture tract Seeding on puncture tract

44 Action of Ethanol on Tumor Direct effects on cancer cells Direct effects on cancer cells Dehydration Dehydration Necrosis of cells in contact with ethanol Necrosis of cells in contact with ethanol Indirect effects on supplying small vessels to tumor Indirect effects on supplying small vessels to tumor Vascular thrombosis Vascular thrombosis Ischemia Ischemia

45 PEI More suitable for HCC than liver metastases More suitable for HCC than liver metastases soft tumor and hard surrounding cirrhotic liver promotes distribution of ethanol in HCC soft tumor and hard surrounding cirrhotic liver promotes distribution of ethanol in HCC In contrast to hard tumor and soft normal liver in metastatic lesions In contrast to hard tumor and soft normal liver in metastatic lesions Vascular tumor in HCC causes more necrosis and ischemia than hypovascular tumor in metastases Vascular tumor in HCC causes more necrosis and ischemia than hypovascular tumor in metastases Livraghi et al 1995

46 PEI on HCC Non-randomised studies 3-year survival rates of 46 – 77% 3-year survival rates of 46 – 77% Ebara et al 1986 Shiina et al 1993 Isobe et al 1994 Castells et al 1993 Livraghi et al 1992 Post treatment recurrence within 2 years of over 50% Post treatment recurrence within 2 years of over 50% Isobe et al 1994 Castells et al 1993

47 PEI versus Partial Hepatectomy 76 patients, Pugh Child A or B 76 patients, Pugh Child A or B 1 to 2 HCC, each < 3 cm 1 to 2 HCC, each < 3 cm Randomized to receive PEI or partial hepatectomy Randomized to receive PEI or partial hepatectomy Follow up 12 to 59 months Follow up 12 to 59 months Overall survival Disease free survival Overall survival Disease free survival Huang et al, Ann Surg 2005 No significant difference

48 Percutaneous Radiofrequency Ablation (RFA) First described by Rossi in 1993 First described by Rossi in 1993 Radiofrequency energy leads to cell death and coagulation necrosis Radiofrequency energy leads to cell death and coagulation necrosis Good results achieved in non-randomised studies Good results achieved in non-randomised studies Complete necrosis rate 90 to 100% Complete necrosis rate 90 to 100% Local recurrence rate 3.6% at median F.U. of 19m Local recurrence rate 3.6% at median F.U. of 19m Rossi et al 1993 Solbiati et al 1997 Nagata et al 1997

49 Limitations of Effectiveness of RFA heat sinks heat sinks Peripheral lesions abutting on adjacent organs Peripheral lesions abutting on adjacent organs Tissue charring results in increased tissue impedance cannot treat large lesions Tissue charring results in increased tissue impedance cannot treat large lesions Size of lesion Size of lesion

50 Problems and Solutions for RFA heat sink heat sink Patient selection Patient selection Peripheral lesions Peripheral lesions Laparoscopic approach Laparoscopic approach Open approach Open approach

51 RFA Technical Solutions to Treat Larger Lesion Injecting saline into lesion during Px Injecting saline into lesion during Px Cooled tip Cooled tip Complex electrode geometry Complex electrode geometry Monitoring tip impedance and temperature with feedback to adjust generator output Monitoring tip impedance and temperature with feedback to adjust generator output Multiple puncture and treatment sessions Multiple puncture and treatment sessions

52 RFA versus PEI Livraghi et al 1999 Izumi et al 2001 RFAPEI Complete necrosis 100%90%94%80% Average sessions (n) Local recurrence rate at 1 year 15%14% Non-randomised studies RFA better than PEI

53 RFA versus PEI Randomised studies RFA better and PEI Lower tumor recurrence rate Lower tumor recurrence rate Requires less sessions for complete ablation Requires less sessions for complete ablation Lencioni et al 1999 Shiina et al 2000 Better overall survival Better overall survival RFAPEI 1-year100%96% 2-year98%88% Olschewski et al 2001

54 RFA versus Partial Hepatectomy 180 patients 180 patients Single HCC, < 5 cm Single HCC, < 5 cm Randomized to received RFA or partial hepatectomy Randomized to received RFA or partial hepatectomy Overall survival Disease free survival Overall survival Disease free survival Chen et al, Ann Surg 2006 No significant difference

55 Regional Therapy for HCC 1)Transarterial Chemoembolisation (TACE) 2)Transarterial Radioembolisation (TARE) Yttrium 90Yttrium 90 Iodine 131Iodine 131

56 TACE Criticised because no standard protocol:- 1)Chemotherapy Choice of chemotherapeutic agentChoice of chemotherapeutic agent DosageDosage DilutionDilution Rate of injectionRate of injection Time interval between PxTime interval between Px 2)Embolisation Choice of embolising agentChoice of embolising agent Degree of embolisationDegree of embolisation Given together or after the chemotherapeutic agentGiven together or after the chemotherapeutic agent

57 TACE for HCC Meta-analysis (Mathurin et al 1998) Systematic review (Simonetti et al 1997) Failed to show any benefit of TACE over no treatment, or one treatment regimen better than another.

58 Recent Studies of L-TACE for HCC RCT comparing L-TACE versus symptomatic treatment RCT comparing L-TACE versus symptomatic treatment cisplatin, lipiodol, gel foam Lo et al 2002 doxorubicin, lipiodol, gel foam Llovet et al 2002 Showed significant overall survival with treatment Showed significant overall survival with treatment

59 TACE for HCC TACE downstaged HCC from unresectable to resectable tumor (Fan et al 1998) TACE downstaged HCC from unresectable to resectable tumor (Fan et al 1998) Some RCT show significant impact on survival while other RCT do not Some RCT show significant impact on survival while other RCT do not

60 Possible explanation: Possible explanation: The beneficial effects of TACE on a subgroup is being offset by toxic effects on another subgroup TACE for HCC has no effect or harmful effect on patients with TACE for HCC has no effect or harmful effect on patients with Poor LFT Poor LFT Large tumor Large tumor Portal vein tumor thrombosis Portal vein tumor thrombosis Patient case selection is important for TACE Patient case selection is important for TACE

61 Transarterial Radioembolisation for HCC (TARE) Lipiodol I-131 Lipiodol I-131 Yttrium 90 microspheres Yttrium 90 microspheres

62 Lipiodol I -131 in HCC Activity (MBq) n Kobayashi Park Bretagne Yoo 1989 Single / fractionated 60 Lui Novell (Ablation of recurrent HCC) Yoo

63 Results of TARE with Lipiodol I-131 Results encouraging Results encouraging Safe Safe More effective in small tumors More effective in small tumors

64 Problems with Lipiodol I-131 I-131 relative low energy cannot treat big tumor I-131 relative low energy cannot treat big tumor Radiation protection of medical personnel difficult because of gamma irradiation Radiation protection of medical personnel difficult because of gamma irradiation

65 Intra-arterial Yttrium-90 Microspheres for Localized Unresectable HCC Yttrium-90 microspheres Yttrium-90 microspheres Biological inert Biological inert micron, resin or glass base micron, resin or glass base Physical half life 64 hours Physical half life 64 hours Beta radiation, 936.7KeV Beta radiation, 936.7KeV (Y-90 microspheres in suspension. x300)

66 Yttrium-90 microspheres Concentrated in tumor more than non-tumor Concentrated in tumor more than non-tumor blood supply to tumor is mainly from the hepatic artery blood supply to tumor is mainly from the hepatic artery due to high arterial blood flow to tumor due to high arterial blood flow to tumor selective catheterisation of the tumor feeding artery selective catheterisation of the tumor feeding artery Lodged within the tumor vascular bed because the size of the microspheres is the same as the internal diameter of tumor capillaries

67 Phase II Study of Yttrium-90 Microspheres Treatment for Unresectable HCC 71 patients 71 patients Single treatment through Seldinger technique during HAG Single treatment through Seldinger technique 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 months Median survival 9.4 months 4 patients downstaged to become resectable 4 patients downstaged to become resectable 2 complete histological response 2 complete histological response Lau et al. Int J Rad Onco Biol Phys, 40:3, , 1998

68 Summary Intra-arterial yttrium-90 microspheres treatment is feasible, tolerable, able to convert localized unresectable to resectable HCC Intra-arterial yttrium-90 microspheres treatment is feasible, tolerable, able to convert localized unresectable to resectable HCC Complete pathological remission is achievable with yttrium-90 microspheres treatment alone Complete pathological remission is achievable with yttrium-90 microspheres treatment alone

69 Systemic Therapy Chemotherapy Chemotherapy Immunotheapy Immunotheapy Chemo-immunotherapy Chemo-immunotherapy Hormonal Therapy Hormonal Therapy Somatostatin analogue Somatostatin analogue

70 New Combination Chemoimmunotherapy for Unresectable HCC Treatment regimen PIAF Treatment regimen PIAF Cisplatin20mg/m 2 ivi day 1-4 Cisplatin20mg/m 2 ivi day 1-4 Interferon alpha5MU/m 2 sc day 1-4 Interferon alpha5MU/m 2 sc day 1-4 Adriamycin40mg/m 2 ivi day 1 Adriamycin40mg/m 2 ivi day 1 5-Fluorouracil400mg/m 2 ivi day Fluorouracil400mg/m 2 ivi day 1-4 out-patient treatment out-patient treatment repeat every 3 weeks for maximum of 6 cycles repeat every 3 weeks for maximum of 6 cycles

71 Phase II Study of PIAF for Unresectable HCC 50 patients with inoperable or metastatic HCC 50 patients with inoperable or metastatic HCC Objective response rate (radiological) 26% Objective response rate (radiological) 26% 18% patients converted to operable stage and received resection after PIAF 18% patients converted to operable stage and received resection after PIAF Median survival 8.9 months Median survival 8.9 months Leung et al Clinical Cancer Research 5: , 1999

72 Toxicity Toxicity No. of patients (%) grade 3 Hemoglobin 6 (12%) Leucocyte 17 (34%) Platelet 11 (22%) Renal 1 (2%) Nausea & vomiting 6 (12%) Drug-related fever 1 (2%) Diarrhea 4 (8%) Alopecia 9 (18%) Mucositis 2 (4%)

73 Supportive Therapy Pain relief Pain relief Management of ascites Management of ascites Nutritional support Nutritional support Hospice service Hospice service Home based Home based Hospital based Hospital based

74 Conclusion Many new non-operative treatment modalities show very promising results Many new non-operative treatment modalities show very promising results Some unresectable HCC can be downstaged to become resectable by these modalities Some unresectable HCC can be downstaged to become resectable by these modalities These treatment modalities should be properly evaluated with RCT to determine their actual role in the management of HCC These treatment modalities should be properly evaluated with RCT to determine their actual role in the management of HCC


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