1. 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

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

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

4. 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

6. 02S18828

7. Survival after Hepatic Resection for HCC
n 1 yr (%) 3 yrs (%) 5 yrs (%)
Nagao
Lin
Chen
Tsuzuki
Nagasue
Lai
Kawasaki
Takenaka
Nadig

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

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

10. 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

11. 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

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

14. 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

15. 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

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

17. 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

19. 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

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

21. Salvage Surgery following Downstaging of unresectable HCC

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

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

24. 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

25. 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

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
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. * 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

28. 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%

29. Overall Survival (n = 49)

30. Downstaging of HCC followed by Salvage Surgery
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%
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
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

33. 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

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

35. 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

36. 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

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

38. 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

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

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

41. 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

42. 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

43. 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

44. 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

45. 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

46. 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

47. 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

48. 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

49. 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

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

51. 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

52. 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

53. 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

54. 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

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

56. 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

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
cisplatin, lipiodol, gel foam
Lo et al 2002
doxorubicin, lipiodol, gel foam
Llovet et al 2002
Showed significant overall survival with treatment

59. 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

60. 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

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

62. 1 (Ablation of recurrent HCC)
Lipiodol I -131 in HCC
Activity (MBq) n
Kobayashi 1986 7
Park 1987 47
Bretagne 1988 15
Yoo 1989
Single / fractionated 60
Lui 1990 10
Novell 1991
475
1 (Ablation of recurrent HCC)
Yoo 1991 24

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

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

65. 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)

66. 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

67. 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, , 1998

68. 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

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

70. 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

71. 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: , 1999

72. 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%)

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

74. 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