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

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

Partial Hepatectomy Treatment of choice Potential of a “cure” Low operative mortality Approaching 0% for non-cirrhotic Below 5% for cirrhotic 10 - 30% resectable at diagnosis

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

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Survival after Hepatic Resection for HCC n 1 yr (%) 3 yrs (%) 5 yrs (%) Nagao 1987 98 73 42 25 Lin 1987 352 39 18 - Chen 1989 120 - - 26 Tsuzuki 1990 119 - - 39 Nagasue 1993 229 80 51 26 Lai 1995 343 68 45 35 Kawasaki 1995 112 92 79 - Takenaka 1996 280 88 70 50 Nadig 1997 71 - - 20

“Curative” Resection of HCC 50 - 90% post-operative death due to recurrent disease (Friedman 1983, Okuda 1985, Rustgi 1988) Intrahepatic tumour recurrence common

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

Neoadjuvant/Adjuvant Therapy for HCC RCT Disease free Interval Overall Survival Yamamoto 1996 Systemic chemotherapy No change Ono et al 1997 Systemic chemotherapy + TAC Kohno et al 1996 Yamasaki et al 1996 TACE Kawata et al 1995 Chemoimmunotherapy Wu et al 1995 Worse Lai et al 1998 Izumi et al 1994 Improved Kubo et al 2001 Immunotherapy Takayama et al 2002 Adoptive immunotherapy Lygidakis et al 1996 TACE + PV embolisation + chemotherapy Not reported Muto et al 1999 Oral polyprenoic acid Lau et al 1999 TARE

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

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

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

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

Results of LDLT exceeding Milan Criteria 5-yr survival Mount Sinai 2003 43 44% UCSF 2001 70 25.2%

Debulking Surgery (Cytoreductive Surgery) Multiple and bilobar 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 Followed by systemic or regional therapies after surgery

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

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

Salvage Surgery following Downstaging of unresectable HCC

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

Hepatocellular Carcinoma Cure is rarely possible When unresectable Dismal prognosis

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

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

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 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

* 4 patients received additional yttrium. Systemic PIAF Yttrium Systemic 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 Resectable Before Downstaging Extensive intrahepatic disease 34 69.4% Main portal vein tumour thrombus 7 14.3% Extrahepatic spread 8 16.3%

Overall Survival (n = 49)

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

5-Year Survival after HCC Downstaging + Salvage Resection 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

Salvage liver resection is necessary after HCC downstaging Complete histological response happen in the minority 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 Lau et al 2004

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

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

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

Conclusions Surgery plays an important role in the management of HCC 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

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

Local Ablative Therapy Injection of Cytotoxic agents Chemicals Ethanol Acetic acid Radioactive isotopes Hyperthermic agents Saline Water Cytotoxic drugs Chemotherapeutic agents Application of an energy source Thermal ablation Radiofrequency Microwave Interstitial laser photo coagulation High intensity focused ultrasound Cryoablation Conformal radiotherapy

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

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

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

PEI Absolute contraindications Gross ascites Uncorrectable coagulopathy 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 Hiding under diaphragm Near to vital structures technical

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

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

PEI More suitable for HCC than liver metastases ‘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 Vascular tumor in HCC causes more necrosis and ischemia than hypovascular tumor in metastases Livraghi et al 1995

PEI on HCC Non-randomised studies 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% Isobe et al 1994 Castells et al 1993

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

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

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

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

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

RFA versus PEI Non-randomised studies RFA better than PEI RFA PEI Complete necrosis 100% 90% 94% 80% Average sessions (n) 1.5 1.2 4 4.8 Local recurrence rate at 1 year 15% 14% Livraghi et al 1999 Izumi et al 2001

RFA versus PEI Randomised studies RFA better and PEI Lower tumor recurrence rate Requires less sessions for complete ablation Lencioni et al 1999 Shiina et al 2000 Better overall survival RFA PEI 1-year 100% 96% 2-year 98% 88% Olschewski et al 2001

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

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

TACE Criticised because no standard protocol:- Chemotherapy Choice of chemotherapeutic agent Dosage Dilution Rate of injection Time interval between Px Embolisation Choice of embolising agent Degree of embolisation Given together or after the chemotherapeutic agent

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.

Recent Studies of L-TACE for HCC 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

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

Patient case selection is important for TACE 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 Poor LFT Large tumor Portal vein tumor thrombosis Patient case selection is important for TACE

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

1 (Ablation of recurrent HCC) Lipiodol I -131 in HCC Activity (MBq) n Kobayashi 1986 281 - 592 7 Park 1987 74 - 4440 47 Bretagne 1988 900 - 2400 15 Yoo 1989 Single / fractionated 60 Lui 1990 444 - 6220 10 Novell 1991 475 1 (Ablation of recurrent HCC) Yoo 1991 555 - 2220 24

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

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

Intra-arterial Yttrium-90 Microspheres for Localized Unresectable HCC Biological inert 29-35 micron, resin or glass base Physical half life 64 hours Beta radiation, 936.7KeV (Y-90 microspheres in suspension. x300)

Yttrium-90 microspheres Concentrated in tumor more than non-tumor blood supply to tumor is mainly from the hepatic artery due to high arterial blood flow to tumor 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

Phase II Study of Yttrium-90 Microspheres Treatment for Unresectable HCC 71 patients Single treatment through Seldinger technique during HAG Median dose of Y-90: 3 GBq (range 1 to 5) Results: Radiological response rate 26% Median survival 9.4 months 4 patients downstaged to become resectable 2 complete histological response Lau et al. Int J Rad Onco Biol Phys, 40:3, 583-592, 1998

Summary 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

Systemic Therapy Chemotherapy Immunotheapy Chemo-immunotherapy Hormonal Therapy Somatostatin analogue

New Combination Chemoimmunotherapy for Unresectable HCC Treatment regimen “PIAF” Cisplatin 20mg/m2 ivi day 1-4 Interferon alpha 5MU/m2 sc day 1-4 Adriamycin 40mg/m2 ivi day 1 5-Fluorouracil 400mg/m2 ivi day 1-4 out-patient treatment repeat every 3 weeks for maximum of 6 cycles

Phase II Study of PIAF for Unresectable HCC 50 patients with inoperable or metastatic HCC Objective response rate (radiological) 26% 18% patients converted to operable stage and received resection after PIAF Median survival 8.9 months Leung et al Clinical Cancer Research 5:1676-1681, 1999

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

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

Conclusion Many new non-operative treatment modalities show very promising results 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