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Liver Cancer Treatment ® Training Module 6 – Version 1.1 Liver Cancer Treatment ® Training Module 6 – Version 1.1 Surgical Resection Liver Transplantation Radiation Therapy Radiofrequenzy Ablation Cryosurgery Local Chemotherapy Percutaneous Ethanol Injection Systemic Chemotherapy Liver Cancer Treatment ® Training Module 6 – Version 1.1 Surgical Resection Liver Transplantation Radiation Therapy Radiofrequenzy Ablation Cryosurgery Local Chemotherapy Percutaneous Ethanol Injection Systemic Chemotherapy Liver Cancer Treatment ® Training Module 6 – Version 1.1 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 Liver Cancer Treatment ® Training Module 6 – Version 1.1 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. Liver Cancer Treatment ® Training Module 6 – Version 1.1 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. Liver Cancer Treatment ® Training Module 6 – Version 1.1 Anatomic Liver Resections IX VII I VIII II III V IV VI portal vein Liver Cancer Treatment ® Training Module 6 – Version 1.1 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) Liver Cancer Treatment ® Training Module 6 – Version 1.1 Surgical Resection - Complications Intraoperative complications are: Blood loss Postoperative complications are: Liver failure Ascites Pleural effusions Intraperitoneal infection Major bile leak Gastrointestinal bleeding Liver Cancer Treatment ® Training Module 6 – Version 1.1 Surgical Resection Liver Transplantation Radiation Therapy Radiofrequenzy Ablation Cryosurgery Local Chemotherapy Percutaneous Ethanol Injection Systemic Chemotherapy Liver Cancer Treatment ® Training Module 6 – Version 1.1 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 Liver Cancer Treatment ® Training Module 6 – Version 1.1 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 R.L. Jenkis et al., Cancer Chemother Pharmacol 1989: 23: 104-109 Liver Cancer Treatment ® Training Module 6 – Version 1.1 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: 104-109 Liver Cancer Treatment ® Training Module 6 – Version 1.1 Surgical Resection Liver Transplantation Radiation Therapy Radiofrequenzy Ablation Cryosurgery Local Chemotherapy Percutaneous Ethanol Injection Systemic Chemotherapy Liver Cancer Treatment ® Training Module 6 – Version 1.1 Radiation Therapy The use of radiotherapy is limited as the liver does not tolerate large doses (above 35Gy). Nevertheless radiotherapy has a useful palliation of pain, nausea and vomiting. role in Liver Cancer Treatment ® Training Module 6 – Version 1.1 Surgical Resection Liver Transplantation Radiation Therapy Radiofrequenzy Ablation Cryosurgery Local Chemotherapy Percutaneous Ethanol Injection Systemic Chemotherapy Liver Cancer Treatment ® Training Module 6 – Version 1.1 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 Liver Cancer Treatment ® Training Module 6 – Version 1.1 Radiofrequency Ablation - Procedure 3 parallel electrodes Multiple electrode array Thin needles are placed under imaging guidance into the tumour Liver Cancer Treatment ® Training Module 6 – Version 1.1 Radiofrequency Ablation - Procedure The needles are connected to a radiofrequency generator and function as an electrode Liver Cancer Treatment ® Training Module 6 – Version 1.1 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 Liver Cancer Treatment ® Training Module 6 – Version 1.1 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 Liver Cancer Treatment ® Training Module 6 – Version 1.1 Surgical Resection Liver Transplantation Radiation Therapy Radiofrequenzy Ablation Cryosurgery Local Chemotherapy Percutaneous Ethanol Injection Systemic Chemotherapy Liver Cancer Treatment ® Training Module 6 – Version 1.1 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 Liver Cancer Treatment ® Training Module 6 – Version 1.1 Cryosurgery versus conventional surgery or Cryosurgery can treat bilobar disease as many as 8 or 10 lesions tumours adjacent to major vessels Liver Cancer Treatment ® Training Module 6 – Version 1.1 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 Liver Cancer Treatment ® Training Module 6 – Version 1.1 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 Liver Cancer Treatment ® Training Module 6 – Version 1.1 Cryosurgery Limitations: With this technique, patients with secondary liver cancer can be treated if primary and the tumour size is less than 6cm less than 50% cumulative liver volume is affected Liver Cancer Treatment ® Training Module 6 – Version 1.1 Cryosurgery Outcome: HCC with a tumour size less than 5cm 1 year survival 3 year survival 5 year survival 92.2% 75.5% 47.8% Colorectal metastasis (mean diameter 4.4cm) 1 year survival 3 year survival 5 year survival 82.4% 32.3% 13.4% Liver Cancer Treatment ® Training Module 6 – Version 1.1 Surgical Resection Liver Transplantation Radiation Therapy Radiofrequenzy Ablation Cryosurgery Local Chemotherapy Percutaneous Ethanol Injection Systemic Chemotherapy Liver Cancer Treatment ® Training Module 6 – Version 1.1 Local Chemotherapy There are two different chemotherapy treatment: approaches to local Transcatheter Arterial Chemoembolization (TACE) Hepatic Artery Infusional Chemotherapy (HAC or HAI) Liver Cancer Treatment ® Training Module 6 – Version 1.1 Local Chemotherapy There are two different chemotherapy treatment: approaches to local Transcatheter Arterial Chemoembolization (TACE) Hepatic Artery Infusional Chemotherapy (HAC or HAI) Liver Cancer Treatment ® Training Module 6 – Version 1.1 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 Liver Cancer Treatment ® Training Module 6 – Version 1.1 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 Liver Cancer Treatment ® Training Module 6 – Version 1.1 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 Liver Cancer Treatment ® Training Module 6 – Version 1.1 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 Liver Cancer Treatment ® Training Module 6 – Version 1.1 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 Liver Cancer Treatment ® Training Module 6 – Version 1.1 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. Liver Cancer Treatment ® Training Module 6 – Version 1.1 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 Liver Cancer Treatment ® Training Module 6 – Version 1.1 Transcatheter Arterial Chemoembolization (TACE) Outcome: HCC 1 2 3 5 year year year year Colorectal metastasis survival survival survival survival 54-88% 33-64% 18-51% <6% 1 year survival 2 year survival 3 year survival 78% 35% 15% In general the outcome is hard to quantify in a metaanalysis as many different protocols are used by different groups Liver Cancer Treatment ® Training Module 6 – Version 1.1 Local Chemotherapy There are two different chemotherapy treatment: approaches to local Transcatheter Arterial Chemoembolization (TACE) Hepatic Artery Infusional Chemotherapy (HAC or HAI) Liver Cancer Treatment ® Training Module 6 – Version 1.1 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) Liver Cancer Treatment ® Training Module 6 – Version 1.1 Hepatic Artery Infusional Chemotherapy (HAC/HAI) The chemotherapeutic drug is automatically delivered by an implanted pump which pumps it directly into the hepatic artery Liver Cancer Treatment ® Training Module 6 – Version 1.1 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%) Liver Cancer Treatment ® Training Module 6 – Version 1.1 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% Liver Cancer Treatment ® Training Module 6 – Version 1.1 Surgical Resection Liver Transplantation Radiation Therapy Radiofrequenzy Ablation Cryosurgery Local Chemotherapy Percutaneous Ethanol Injection Systemic Chemotherapy Liver Cancer Treatment ® Training Module 6 – Version 1.1 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 Liver Cancer Treatment ® Training Module 6 – Version 1.1 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 transient pain and fever alcohol intoxication, Liver Cancer Treatment ® Training Module 6 – Version 1.1 Percutaneous Ethanol Injection (PEI) Outcome: There are only data for HCC available, these only retrieved from retrospective reviews without control. HCC 1 year survival 2 year survival 3 year survival 93% 80% 68% Liver Cancer Treatment ® Training Module 6 – Version 1.1 Surgical Resection Liver Transplantation Radiation Therapy Radiofrequenzy Ablation Cryosurgery Local Chemotherapy Percutaneous Ethanol Injection Systemic Chemotherapy Liver Cancer Treatment ® Training Module 6 – Version 1.1 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. Liver Cancer Treatment ® Training Module 6 – Version 1.1 Management of unresectable metastatic colorectal cancer (mCRC) - principles: Palliation and control of symptoms Control of tumour growth Lengthen progression-free and overall survival Liver Cancer Treatment ® Training Module 6 – Version 1.1 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 Liver Cancer Treatment ® Training Module 6 – Version 1.1 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 2 22h 2h 5-FU infusion 600mg/m infusion 600mg/m2 22h 2h 48 hours (2 5-FU days) 5-FU bolus 400mg/m2 5-FU bolus 400mg/m2 cycle repeated every 14 days Liver Cancer Treatment ® Training Module 6 – Version 1.1 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 2 22h 2h 5-FU infusion 600mg/m infusion 600mg/m2 22h 2h 48 hours (2 5-FU days) 5-FU bolus 400mg/m2 5-FU bolus 400mg/m2 cycle repeated every 14 days Liver Cancer Treatment ® Training Module 6 – Version 1.1 Chemotherapy regimen in the management of unresectable metastatic colorectal cancer (mCRC): FOLFOX 6 (Folinic acid, 5-FU, Oxaliplatin) Oxaliplatin 100mg/m2 Leucovorin 400mg/m2 over 46-48h 2h 5-FU infusion 2400-3000mg/m 48 hours 2(2 days) 5-FU bolus 400mg/m2 cycle repeated every 14 days Liver Cancer Treatment ® Training Module 6 – Version 1.1 Chemotherapy regimen in the management of unresectable metastatic colorectal cancer (mCRC): FOLFOX 6m (Folinic acid, 5-FU, Oxaliplatin) Oxaliplatin 85mg/m2 Leucovorin 400mg/m2 over 46-48h 2h 5-FU infusion 2400-3000mg/m 48 hours 2(2 days) 5-FU bolus 400mg/m2 cycle repeated every 14 days Liver Cancer Treatment ® Training Module 6 – Version 1.1 Chemotherapy regimen in the management of unresectable metastatic colorectal cancer (mCRC): Oxaliplatin 100mg/m2 Leucovorin 400mg/m2 or Irinotecan 180mg/m2 Leucovorin 200mg/m2 Oxaliplatin (FOLFOX) and irinotecan (FOLFIRI) based regimen seem to have similar safety and efficacy, with differing toxicity profiles. Liver Cancer Treatment ® Training Module 6 – Version 1.1 Duration of chemotherapy: Traditional practice is to continue chemotherapy until: Unacceptable toxicity Clinical deterioration Disease progression Liver Cancer Treatment ® Training Module 6 – Version 1.1 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®) Monoclonal antibody Target: Epidermal growth factor receptor Affecting cellular growth, differentiation and survival In combination with irinotecan or alone Liver Cancer Treatment ® Training Module 6 – Version 1.1 Surgical Resection Liver Transplantation Radiation Therapy Radiofrequenzy Ablation Cryosurgery Local Chemotherapy Percutaneous Ethanol Injection Systemic Chemotherapy Liver Cancer Treatment ® Training Module 6 – Version 1.1 Other ablative modalities: PAI – Percutaneous Acetic Acid Injection MCT – Microwave Coagulation Therapy LT – Laser Therapy Liver Cancer Treatment ® Training Module 6 – Version 1.1 What is most important to remember? Different treatment techniques Outcome and limitations
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