1. Liver Cancer Treatment

2. Liver Cancer Treatment
Surgical Resection
Liver Transplantation
Radiation Therapy
Radiofrequenzy Ablation
Cryosurgery
Local Chemotherapy
Percutaneous Ethanol Injection
Systemic Chemotherapy 

3. Liver Cancer Treatment
Surgical Resection
Liver Transplantation
Radiation Therapy
Radiofrequenzy Ablation
Cryosurgery
Local Chemotherapy
Percutaneous Ethanol Injection
Systemic Chemotherapy 

4. Liver Cancer Treatment
Surgical Resection
Surgical resection may be a curative treatment for HCC
But…
…only 10% - 30% of patients with HCC are eligible for surgical resection because their pre-existing liver disease limits the regenerative capacity of their liver 

5. Liver Cancer Treatment
Surgical Resection
In secondary liver cancer the 5 year survival after resection is between 20 and 40% , compared to 0% without resection.
In HCC survival rates can be up to 75% after 5 years.
The more metastasis in the liver the less likely is the chance for successful surgery. 

6. Liver Cancer Treatment
Surgical Resection
Absolute contraindications to resection of metastatic liver cancer are
Presence of extra hepatic metastasis
Inability to remove all hepatic disease
In resected cancer patients with metastatic disease recurrence has occurred in 50% to 75% of the patients and remains the most important problem. 

7. Liver Cancer Treatment
Anatomic Liver Resections I II
III IV
portal vein VI V
VIII
VII IX
Liver resections are classified either anatomic or nonanatomic. Anatomic resections follow defined anatomic landmarks and involve removal of a lobe, sector or segment. Nonanatomic resections are based principally on tumour location and the parenchymal transection is not along anatomic landmarks. 

8. Liver Cancer Treatment
In summary the limiting factors for a surgical resection of primary and secondary liver tumours are:
Remaining liver function
Number of tumour nodules (usually 3 or less)
Proximity or involvement of major hepatic vascular structures
Number of lobes affected (usually 1 only)
Tumour size (remaining liver function)
In general, non cirrhotic patients with solitary HCCs are ideal candidates for resection and can tolerate up to 80% liver resection without compromising the regenerative capacity of their liver remnant. 

9. Liver Cancer Treatment
Surgical Resection - Complications
Intraoperative complications are:
Blood loss
Postoperative complications are:
Liver failure
Ascites
Pleural effusions
Intraperitoneal infection
Major bile leak
Gastrointestinal bleeding 

10. Liver Cancer Treatment
Surgical Resection
Liver Transplantation
Radiation Therapy
Radiofrequenzy Ablation
Cryosurgery
Local Chemotherapy
Percutaneous Ethanol Injection
Systemic Chemotherapy 

11. Liver Cancer Treatment
Liver Transplantation
Transplantation for hepatic malignancies is indicated in the setting of either unresectable lesion(s), or coexistent cirrhosis resulting in both inadequate hepatic reserve and prohibitive portal hypertension 

12. Liver Cancer Treatment
Liver Transplantation
Limitations:
Not all patients are eligible for transplantation
Availability of donor organs
Patients require lifelong immunosupression
Contraindicated in patients with secondary liver cancer
Some patients have achieved excellent survival in excess of 12 to 20years. These long-term survivors demonstrate the potential for cure of these fatal malignancies.
R.L. Jenkis et al., Cancer Chemother Pharmacol 1989: 23: 

13. Liver Cancer Treatment
Liver Transplantation
Survival data for patients with HCC undergoing liver transplantation:
49% at one year
37% at two years
30% at three years
R.L. Jenkis et al., Cancer Chemother Pharmacol 1989: 23: 

14. Liver Cancer Treatment
Surgical Resection
Liver Transplantation
Radiation Therapy
Radiofrequenzy Ablation
Cryosurgery
Local Chemotherapy
Percutaneous Ethanol Injection
Systemic Chemotherapy 

15. Liver Cancer Treatment
Radiation Therapy
The use of radiotherapy is limited as the liver does not tolerate large doses (above 35Gy).
Nevertheless radiotherapy has a useful role in palliation of pain, nausea and vomiting. 

16. Liver Cancer Treatment
Surgical Resection
Liver Transplantation
Radiation Therapy
Radiofrequenzy Ablation
Cryosurgery
Local Chemotherapy
Percutaneous Ethanol Injection
Systemic Chemotherapy 

17. Liver Cancer Treatment
Radiofrequency Ablation 
The radiofrequency ablation uses heat to destroy an entire tumour with minimal damage to adjacent vital structures.
Radiofrequency is used as a source of thermal energy 

18. Multiple electrode array
Liver Cancer Treatment
Radiofrequency Ablation - Procedure
3 parallel electrodes
Multiple electrode array
Thin needles are placed under imaging guidance into the tumour 

19. Liver Cancer Treatment
Radiofrequency Ablation - Procedure
The needles are connected to a radiofrequency generator and function as an electrode 

20. Liver Cancer Treatment
Radiofrequency Ablation - Procedure
Coagulation necrosis
During the procedure a temperature of 500C to 1000C is maintained throughout the entire target volume
The field of coagulation should include a 0.5 to 1cm margin of normal tissue 

21. Liver Cancer Treatment
Radiofrequency Ablation
Limitations:
Not practicable for multiple lesions
Tumours in vascular environments
Only small tumours suitable (<3-4cm)
Relatively new technique
Limited number of studies published
With an increasing number of lesions the procedure becomes more and more time consuming and has its limitations. As blood flow serves as a heat sink tumours located in vascular environments are less suspectable. In the studies available good results are reported for patients with tumours with a diameter of less than 3cm. Here the response rate is around 50-70%. 

22. abandoned Liver Cancer Treatment Surgical Resection
Liver Transplantation
Radiation Therapy
Radiofrequenzy Ablation
Cryosurgery
Local Chemotherapy
Percutaneous Ethanol Injection
Systemic Chemotherapy
abandoned 

23. abandoned Liver Cancer Treatment
Cryosurgery
abandoned
The cryosurgery uses subzero temperatures to destroy an entire tumour with minimal damage to adjacent vital structures.
The terms cryosurgery, cryoablation and cryotherapy are interchangeable 

24. or abandoned Liver Cancer Treatment Cryosurgery can treat
Cryosurgery versus conventional surgery or
abandoned
Cryosurgery can treat
bilobar disease
as many as 8 or 10 lesions
tumours adjacent to major vessels 

25. abandoned Liver Cancer Treatment
Cryosurgery
In cryosurgery tumour cells are exposed to temperatures below -20°C for at least one minute
abandoned
This is generally lethal to living cells because:
Ice crystals damage cell plasma membrane
Ice crystals create a grinding effect
Small arterioles and venules are destroyed
The grinding effect generally disrupts the tumour. The destruction of small vessels leads to tumour destruction by devascularization. 

26. abandoned Liver Cancer Treatment Procedure:
Cryosurgery
Procedure:
The operative exposure is similar to liver resection
Cryoprobes are placed within the tumour centers
The probes are flushed with cryogen
Tip temperatures of -100°C are achieved
The freeze front is monitored by ultrasound
Aim is to freeze the whole tumour plus 1cm margin
abandoned
The cryoprobes are placed within the tumour under ultrasound guidance. They come in different shapes and sizes (up to a diameter of 10mm) and are connected to a cryogen unit via vacuum insulated coils. The cryogen is either liquid nitrogen or argon gas 

27. abandoned Liver Cancer Treatment Limitations:
Cryosurgery
Limitations:
With this technique, patients with primary and secondary liver cancer can be treated if
abandoned
the tumour size is less than 6cm
less than 50% cumulative liver volume is affected 

28. abandoned Liver Cancer Treatment Outcome:
Cryosurgery
Outcome:
HCC with a tumour size less than 5cm
abandoned
1 year survival 92.2%
3 year survival 75.5%
5 year survival 47.8%
Colorectal metastasis (mean diameter 4.4cm)
Only a few data are available at that stage with only a limited number of patients. The HCC data are based on 167 patients. The outcome for patients with a tumour diameter above 5cm is 66.1%(1 year), 35.4% (3 years) and 24.5% (5 years) respectively. The data of the colorectal metastasis patient survival are based on 116 patients with a 7 year follow up. The mean diameter of the tumour was 4.4cm, the average number of lesions was 3.9 and 80% of the patients had both lobes affected. The perioperative mortality was around 1% in both studies.
1 year survival 82.4%
3 year survival 32.3%
5 year survival 13.4% 

29. Liver Cancer Treatment
Surgical Resection
Liver Transplantation
Radiation Therapy
Radiofrequenzy Ablation
Cryosurgery
Local Chemotherapy
Percutaneous Ethanol Injection
Systemic Chemotherapy 

30. Liver Cancer Treatment
Local Chemotherapy
There are two different approaches to local chemotherapy treatment:
Transcatheter Arterial Chemoembolization (TACE)
Hepatic Artery Infusional Chemotherapy (HAC or HAI) 

31. Liver Cancer Treatment
Local Chemotherapy
There are two different approaches to local chemotherapy treatment:
Transcatheter Arterial Chemoembolization (TACE)
Hepatic Artery Infusional Chemotherapy (HAC or HAI) 

32. Liver Cancer Treatment
Transcatheter Arterial Chemoembolization (TACE)
TACE aims to deliver high doses of a chemotherapeutic drug directly to the tumour and to simultaneously enhance the effect by embolization of the tumour vascularization
The chemotherapeutic drug plus the embolic agent are injected via a hepatic artery catheter 

33. Liver Cancer Treatment
Transcatheter Arterial Chemoembolization (TACE)
The major component is Lipiodol, which is iodized poppy seed oil
Common chemotherapeutic agents are Doxorubicin, Cisplatin and Mitomycin C
Other embolic agents like polyvinyl alcohol (PVA), gel foam, coils and degradable microspheres are also used 

34. Liver Cancer Treatment
Transcatheter Arterial Chemoembolization (TACE)
Proposed effect of Lipiodol:
Enhanced accumulation in and around tumours
May enter tumour cells and induce death
Occlusive to tumour vascularity
Less than 0.2ml/kg of Lipiodol are regarded as a safe dose. If of the whole liver needs to be embolized, 10-20ml are used. The normal dose is around 1ml per cm tumour diameter 

35. Liver Cancer Treatment
Transcatheter Arterial Chemoembolization (TACE)
Advantages versus systemic chemotherapy:
Delivery of higher doses to the tumour
Less systemic side effects
Embolization cuts tumour off essential nutrients
Embolization enhances dwell time of drug 

36. Liver Cancer Treatment
Transcatheter Arterial Chemoembolization (TACE)
Indications:
Unresectable HCC
Unresectable metastasis
Reduction of progression
Downsize tumour before resection
Major Contraindications:
Extrahepatic disease
Poor liver function
Large arteriovenous shunting
Hepatic encephalopathy 

37. Liver Cancer Treatment
Transcatheter Arterial Chemoembolization (TACE)
Patient workup:
Imaging (CT, MRT)
Labs
Angiography
Procedure:
Installation of the highly viscous TACE mixture via a hepatic artery catheter. Almost always a repeated treatment is necessary. 

38. Liver Cancer Treatment
Transcatheter Arterial Chemoembolization (TACE)
Complications:
Post embolization syndrome
Acute progressive hepatic insuffiency (APHI)
Pulmonary oil embolism
Liver abscess
Cholecystitis
Non-target embolization of the gut
Gastrointestinal bleeding
Others
Serious complications are quite common (5-7%) and the 30 day mortality is 4% prior due to post embolization syndrome. 

39. Liver Cancer Treatment
Transcatheter Arterial Chemoembolization (TACE)
Outcome:
HCC
Colorectal metastasis
1 year survival 54-88%
2 year survival 33-64%
3 year survival 18-51%
5 year survival <6%
1 year survival 78%
2 year survival 35%
3 year survival 15%
In general the outcome is hard to quantify in a meta-analysis as many different protocols are used by different groups 

40. Liver Cancer Treatment
Local Chemotherapy
There are two different approaches to local chemotherapy treatment:
Transcatheter Arterial Chemoembolization (TACE)
Hepatic Artery Infusional Chemotherapy (HAC or HAI) 

41. Liver Cancer Treatment
Hepatic Artery Infusional Chemotherapy (HAC/HAI)
Like TACE, HAI (HAC) aims to deliver high doses of a chemotherapeutic drug directly to the tumour
To achieve this, a drug is used which is highly extracted by the liver during the first pass with a short systemic half life time
This is drug is usually Floxuridine(FUDR)
Also 5-Fluorouracil is used. 

42. Liver Cancer Treatment
Hepatic Artery Infusional Chemotherapy (HAC/HAI)
The chemotherapeutic drug is automatically delivered by an implanted pump which pumps it directly into the hepatic artery 

43. Liver Cancer Treatment
Hepatic Artery Infusional Chemotherapy (HAC/HAI)
Complications:
Surgical complications (pump placement)
Acute gastric or duodenal ulcers
Catheter or hepatic artery thrombosis (10%)
Septic complications
Biliary sclerosis (20%)
The operative mortality is around 1%. 

44. Liver Cancer Treatment
Hepatic Artery Infusional Chemotherapy (HAC/HAI)
Outcome:
There are no good survival data available. Nevertheless this technique is regarded as efficient with response rates around 50% (42-62).
One source mentions a 2 year survival rate of 47% 

45. Liver Cancer Treatment
Surgical Resection
Liver Transplantation
Radiation Therapy
Radiofrequenzy Ablation
Cryosurgery
Local Chemotherapy
Percutaneous Ethanol Injection
Systemic Chemotherapy 

46. Liver Cancer Treatment
Percutaneous Ethanol Injection (PEI)
PEI is a local tumour ablative technique depending on the toxic effects of ethanol (alcohol)
Ethanol causes
Protein denaturation
Cellular dehydration 

47. Liver Cancer Treatment
Percutaneous Ethanol Injection (PEI)
Procedure:
Most common is the ‘Multi-Session’ approach in an outpatient setting
In each session 8-10ml ethanol are injected in the tumour under local anesthesia and ultrasound guidance.
Complications are systemic alcohol intoxication, transient pain and fever 

48. Liver Cancer Treatment
Percutaneous Ethanol Injection (PEI)
Outcome:
There are only data for HCC available, these only retrieved from retrospective reviews without control.
HCC
1 year survival 93%
2 year survival 80%
3 year survival 68% 

49. Liver Cancer Treatment
Surgical Resection
Liver Transplantation
Radiation Therapy
Radiofrequenzy Ablation
Cryosurgery
Local Chemotherapy
Percutaneous Ethanol Injection
Systemic Chemotherapy 

50. Liver Cancer Treatment
Systemic Chemotherapy
Systemic chemotherapy is not regarded as an effective treatment, neither in HCC nor in metastatic liver cancer
Liver cancers have been found to be relatively resistant to chemotherapeutic drugs at systemic doses and the reported response rate is less than 30%
The chemotherapy regimen in secondary liver cancer is therefore determined by the type of the primary cancer and only palliative with regard to the liver. 

51. Liver Cancer Treatment
Management of unresectable metastatic colorectal cancer (mCRC) - principles:
Palliation and control of symptoms
Control of tumour growth
Lengthen progression-free and overall survival 

52. Liver Cancer Treatment
Chemotherapeutic drugs in the management of unresectable metastatic colorectal cancer (mCRC):
Fluorouracil (5-FU)
Uracil analogue, Patented in 1957
Still core of most chemotherapy regimens
Leucovorin
Biomodulation of 5-FU
Potentates the cytotoxic activity of 5-FU
Irinotecan
First new drug (mCRC) after more than 30 years
Plant alkaloid, Topoisomerase I inhibitor
Oxaliplatin
Forms DNA strand cross links
First platin analogue effective in CRC 

53. cycle repeated every 14 days
Liver Cancer Treatment
Chemotherapy regimen in the management of unresectable metastatic colorectal cancer (mCRC):
FOLFIRI (Folinic acid, 5-FU, Irinotecan)
Irinotecan 180mg/m2
Leucovorin 200mg/m2
Leucovorin 200mg/m2 2h
48 hours (2 days)
5-FU infusion 600mg/m2 22h 2h
5-FU infusion 600mg/m2 22h
5-FU bolus 400mg/m2
5-FU bolus 400mg/m2
cycle repeated every 14 days 

54. cycle repeated every 14 days
Liver Cancer Treatment
Chemotherapy regimen in the management of unresectable metastatic colorectal cancer (mCRC):
FOLFOX 4 (Folinic acid, 5-FU, Oxaliplatin)
Oxaliplatin 85mg/m2
Leucovorin 200mg/m2
Leucovorin 200mg/m2 2h
48 hours (2 days) 2h
5-FU infusion 600mg/m2 22h
5-FU infusion 600mg/m2 22h
5-FU bolus 400mg/m2
5-FU bolus 400mg/m2
cycle repeated every 14 days 

55. cycle repeated every 14 days
Liver Cancer Treatment
Chemotherapy regimen in the management of unresectable metastatic colorectal cancer (mCRC):
FOLFOX 6 (Folinic acid, 5-FU, Oxaliplatin)
Oxaliplatin 100mg/m2
Leucovorin 400mg/m2 2h
48 hours (2 days)
5-FU infusion mg/m2 over 46-48h
5-FU bolus 400mg/m2
cycle repeated every 14 days 

56. cycle repeated every 14 days
Liver Cancer Treatment
Chemotherapy regimen in the management of unresectable metastatic colorectal cancer (mCRC):
FOLFOX 6m (Folinic acid, 5-FU, Oxaliplatin)
Oxaliplatin 85mg/m2
Leucovorin 400mg/m2 2h
48 hours (2 days)
5-FU infusion mg/m2 over 46-48h
5-FU bolus 400mg/m2
cycle repeated every 14 days 

57. Liver Cancer Treatment
Chemotherapy regimen in the management of unresectable metastatic colorectal cancer (mCRC):
Oxaliplatin 100mg/m2
Leucovorin 400mg/m2
Irinotecan 180mg/m2
Leucovorin 200mg/m2 or
Oxaliplatin (FOLFOX) and irinotecan (FOLFIRI) based regimen seem to have similar safety and efficacy, with differing toxicity profiles. 

58. Liver Cancer Treatment
Duration of chemotherapy:
Traditional practice is to continue chemotherapy until:
Unacceptable toxicity
Clinical deterioration
Disease progression

59. Liver Cancer Treatment
New chemotherapeutic drugs (mCRC):
Capecitabine (Xeloda®)
Orally administered 5-FU precursor
As effective as intravenous 5-FU/Leucovorin
Bevacizumab (Avastin®)
Monoclonal antibody
Target: Vascular endothelial growth factor
Antiangiogenesis
In combination with FOLFOX
Cetuximab (Erbitux®)
Target: Epidermal growth factor receptor
Affecting cellular growth, differentiation and survival
In combination with irinotecan or alone 

60. Liver Cancer Treatment
Surgical Resection
Liver Transplantation
Radiation Therapy
Radiofrequenzy Ablation
Cryosurgery
Local Chemotherapy
Percutaneous Ethanol Injection
Systemic Chemotherapy 

61. Liver Cancer Treatment
Other ablative modalities:
PAI – Percutaneous Acetic Acid Injection
MCT – Microwave Coagulation Therapy
LT – Laser Therapy 

62. Liver Cancer Treatment
What is most important to remember?
Different treatment techniques
Outcome and limitations 

63. Liver Cancer Treatment
Further Readings
DeVita et al.: Cancer – Principles & Practice of Oncology 2005, 7th edition, 2898 pages, ISBN
E.Kuntz & H.-D.Kuntz: Hepatology 2002, NY, Springer Verlag, 825 pages, ISBN
S.T.Rosen: Liver-Directed Therapy for Primary and Metastatic Liver Tumors 2001, Springer Verlag, 322 pages, ISBN
T.R.Harrison et al.: Principles of Internal Medicine 1994, 13th edition, Braunwald Isselbachr ISBN
R.Souhami & J.Tobias: Cancer and its Management 2005, Blackwell Publishing, 544 pages, ISNB