training module 6 – version 1.1 for internal use only ® liver cancer treatment

Training Module 6 – Version 1.1

For Internal Use Only

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Liver Cancer Treatment



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Surgical Resection

Liver Transplantation

Radiation Therapy

Radiofrequenzy Ablation

Cryosurgery

Local Chemotherapy

Percutaneous Ethanol Injection

Systemic Chemotherapy




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Surgical resection may be a curative treatment for HCC

Surgical Resection

…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

But…



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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.



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In resected cancer patients with metastatic disease recurrence has occurred in 50% to 75% of the patients and remains the most important problem.

Surgical Resection

Absolute contraindications to resection of metastatic liver cancer are

Presence of extra hepatic metastasis

Inability to remove all hepatic disease



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Anatomic Liver Resections

I

II

III

IV

portal veinVI

V

VIII

VII

IX



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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 summary the limiting factors for a surgical resection of primary and secondary liver tumours are:



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Intraoperative complications are:

Postoperative complications are:

Liver failure

Ascites

Pleural effusions

Intraperitoneal infection

Major bile leak

Gastrointestinal bleeding

Blood loss

Surgical Resection - Complications



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Surgical Resection


Radiation Therapy


Cryosurgery

Local Chemotherapy






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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




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Limitations:

R.L. Jenkis et al., Cancer Chemother Pharmacol 1989: 23: 104-109

Not all patients are eligible for transplantation

Availability of donor organs

Patients require lifelong immunosupression

Contraindicated in patients with secondary liver cancer




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Survival data for patients with HCC undergoing liver transplantation:

R.L. Jenkis et al., Cancer Chemother Pharmacol 1989: 23: 104-109

49% at one year

37% at two years

30% at three years




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Surgical Resection


Radiation Therapy


Cryosurgery

Local Chemotherapy






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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.



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Surgical Resection


Radiation Therapy


Cryosurgery

Local Chemotherapy






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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



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Radiofrequency Ablation - Procedure

Thin needles are placed under imaging guidance into the tumour

Multiple electrode array

3 parallel electrodes



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The needles are connected to a radiofrequency generator and function as an electrode



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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

Coagulation necrosis



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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



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Surgical Resection


Radiation Therapy


Cryosurgery

Local Chemotherapy






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Cryosurgery

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



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Cryosurgery versus conventional surgery

Cryosurgery can treat

or

bilobar disease

as many as 8 or 10 lesions

tumours adjacent to major vessels



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Cryosurgery

In cryosurgery tumour cells are exposed to temperatures below -20°C for at least one minute

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



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Cryosurgery

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

Procedure:



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Cryosurgery

With this technique, patients with primary and secondary liver cancer can be treated if

the tumour size is less than 6cm

less than 50% cumulative liver volume is affected

Limitations:



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Cryosurgery

Outcome:

HCC with a tumour size less than 5cm

1 year survival 92.2%3 year survival 75.5%5 year survival 47.8%

Colorectal metastasis (mean diameter 4.4cm)

1 year survival 82.4%3 year survival 32.3%5 year survival 13.4%



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Surgical Resection


Radiation Therapy


Cryosurgery

Local Chemotherapy






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Local Chemotherapy

There are two different approaches to local chemotherapy treatment:

Transcatheter Arterial Chemoembolization (TACE)

Hepatic Artery Infusional Chemotherapy (HAC or HAI)



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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



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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



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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



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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



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Indications:

Unresectable HCCUnresectable metastasisReduction of progressionDownsize tumour before resection

Major Contraindications:

Extrahepatic diseasePoor liver functionLarge arteriovenous shuntingHepatic encephalopathy



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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.



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Complications:

Post embolization syndromeAcute progressive hepatic insuffiency (APHI)Pulmonary oil embolismLiver abscessCholecystitisNon-target embolization of the gutGastrointestinal bleedingOthers



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Outcome:

HCC

1 year survival 54-88%2 year survival 33-64%3 year survival 18-51%5 year survival <6%

Colorectal metastasis

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



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Local Chemotherapy

There are two different approaches to local chemotherapy treatment:


Hepatic Artery Infusional Chemotherapy (HAC or HAI)



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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)



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The chemotherapeutic drug is automatically delivered by an implanted pump which pumps it directly into the hepatic artery



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Complications:

Surgical complications (pump placement)Acute gastric or duodenal ulcersCatheter or hepatic artery thrombosis (10%)Septic complicationsBiliary sclerosis (20%)



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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%



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Surgical Resection


Radiation Therapy


Cryosurgery

Local Chemotherapy






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Percutaneous Ethanol Injection (PEI)

PEI is a local tumour ablative technique depending on the toxic effects of ethanol (alcohol)

Ethanol causes

Protein denaturationCellular dehydration



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Most common is the ‘Multi-Session’ approach in an outpatient setting

Procedure:

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



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There are only data for HCC available, these only retrieved from retrospective reviews without control.

Outcome:

HCC

1 year survival 93%2 year survival 80%3 year survival 68%



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Surgical Resection


Radiation Therapy


Cryosurgery

Local Chemotherapy






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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.



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Management of unresectable metastatic colorectal cancer (mCRC) - principles:

Palliation and control of symptoms

Control of tumour growth

Lengthen progression-free and overall survival



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Chemotherapeutic drugs in the management of unresectable metastatic colorectal cancer (mCRC):

Fluorouracil (5-FU)Uracil analogue, Patented in 1957Still core of most chemotherapy regimens

LeucovorinBiomodulation of 5-FUPotentates the cytotoxic activity of 5-FU

Irinotecan First new drug (mCRC) after more than 30 yearsPlant alkaloid, Topoisomerase I inhibitor

OxaliplatinForms DNA strand cross linksFirst platin analogue effective in CRC



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Chemotherapy regimen in the management of unresectable metastatic colorectal cancer (mCRC):

48 hours (2 days)48 hours (2 days)

Irinotecan 180mg/mIrinotecan 180mg/m22

Leucovorin 200mg/mLeucovorin 200mg/m22

5-FU infusion 600mg/m5-FU infusion 600mg/m2 2 22h22h2h2h 5-FU infusion 600mg/m5-FU infusion 600mg/m2 2 22h22h2h2h

5-FU bolus 400mg/m5-FU bolus 400mg/m22



cycle repeated every 14 dayscycle repeated every 14 days

FOLFIRI (Folinic acid, 5-FU, Irinotecan)



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Oxaliplatin 85mg/mOxaliplatin 85mg/m22






5-FU infusion 600mg/m5-FU infusion 600mg/m2 2 22h22h2h2h 5-FU infusion 600mg/m5-FU infusion 600mg/m2 2 22h22h2h2h




FOLFOX 4 (Folinic acid, 5-FU, Oxaliplatin)



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5-FU infusion 2400-3000mg/m5-FU infusion 2400-3000mg/m2 2 over 46-48hover 46-48h2h2h


FOLFOX 6 (Folinic acid, 5-FU, Oxaliplatin)



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5-FU infusion 2400-3000mg/m5-FU infusion 2400-3000mg/m2 2 over 46-48hover 46-48h2h2h


FOLFOX 6m (Folinic acid, 5-FU, Oxaliplatin)



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Oxaliplatin (FOLFOX) and irinotecan (FOLFIRI) based regimen seem to have similar safety and efficacy, with differing toxicity profiles.

Irinotecan 180mg/mIrinotecan 180mg/m22



Leucovorin 400mg/mLeucovorin 400mg/m22 or



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Duration of chemotherapy:

Traditional practice is to continue chemotherapy until:

Unacceptable toxicity

Clinical deterioration

Disease progression



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New chemotherapeutic drugs (mCRC):

Capecitabine (Xeloda®)Orally administered 5-FU precursorAs effective as intravenous 5-FU/Leucovorin

Bevacizumab (Avastin®)Monoclonal antibody Target: Vascular endothelial growth factorAntiangiogenesis In combination with FOLFOX

Cetuximab (Erbitux®)Monoclonal antibodyTarget: Epidermal growth factor receptorAffecting cellular growth, differentiation and

survivalIn combination with irinotecan or alone



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Surgical Resection


Radiation Therapy


Cryosurgery

Local Chemotherapy






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Other ablative modalities:

PAI – Percutaneous Acetic Acid Injection

MCT – Microwave Coagulation Therapy

LT – Laser Therapy



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What is most important to remember?

Different treatment techniques

Outcome and limitations

training module 6 – version 1.1 for internal use only ® liver cancer treatment

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