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3. The Management Of Hepatic Metastases In Gastrointestinal
3. The Management Of Hepatic Metastases In Gastrointestinal
3. The Management Of Hepatic Metastases In Gastrointestinal
3. The Management Of Hepatic Metastases In Gastrointestinal
3. The Management Of Hepatic Metastases In Gastrointestinal
3. The Management Of Hepatic Metastases In Gastrointestinal
3. The Management Of Hepatic Metastases In Gastrointestinal
3. The Management Of Hepatic Metastases In Gastrointestinal
3. The Management Of Hepatic Metastases In Gastrointestinal
3. The Management Of Hepatic Metastases In Gastrointestinal
3. The Management Of Hepatic Metastases In Gastrointestinal
3. The Management Of Hepatic Metastases In Gastrointestinal
3. The Management Of Hepatic Metastases In Gastrointestinal
3. The Management Of Hepatic Metastases In Gastrointestinal
3. The Management Of Hepatic Metastases In Gastrointestinal
3. The Management Of Hepatic Metastases In Gastrointestinal
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3. The Management Of Hepatic Metastases In Gastrointestinal

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  • 1. The management of hepatic metastases in gastrointestinal carcinoid All you need to know!! By Fiona Collingwood 5 th year medicine University of Adelaide
  • 2. Carcinoid tumours <ul><li>First described by Lubarsch in 1888 with the </li></ul><ul><li>discovery of multiple tumours in the ileum in two patients post-mortem </li></ul><ul><li>In 1907 Obendorfer termed the tumours as ‘Karzinoid tumoren’ as he recognised they were biologically distinct from adenocarcinoma </li></ul><ul><li>Neuroendocrine tumours, derived from enterochromaffin or Kulchitsky cells </li></ul><ul><li>Produce amines and acids </li></ul><ul><ul><li>Excessive production may lead to a clinical syndrome dependent upon bioactive product, i.e. Carcinoid syndrome, Zollinger-Ellison c an arise in nearly any tissue in the body, but over 65% arise in the GI tract </li></ul></ul><ul><li>Uncommon, incidence approx 1-2 per 100,000 </li></ul><ul><li>Double peak in age at 15-25yrs, and 60-75 yrs. </li></ul>
  • 3. Carcinoid metastases <ul><li>20% of patients present with distant metastases </li></ul><ul><li>5 year survival with no metastatic disease 75-99% </li></ul><ul><li>5 year survival with distant metastatic disease of midgut origin 0-40% (with no treatment) </li></ul><ul><li>Hepatic metastases can occur with very small tumours </li></ul><ul><ul><li>15-35% risk of metastasis with &lt;1cm </li></ul></ul><ul><ul><li>58- 100%! risk of metastasis with 1-2cm </li></ul></ul><ul><li>Carcinoid syndrome is a frequent presentation of those with distant metastases </li></ul><ul><ul><li>Symptoms include flushing, diarrhoea and wheezing </li></ul></ul><ul><li>Hepatic metastases are usually diffuse and not amenable to surgical resection </li></ul><ul><li>Metastases to other locations are uncommon, favouring local treatment of the liver lesions </li></ul>} Jejunal/Ileal primary
  • 4. Treatment Options <ul><li>As carcinoid tumours are relatively uncommon, and their clinical course varied, treatment should be considered on an individual basis in consultation with a multi-disciplinary team </li></ul><ul><li>Supportive care </li></ul><ul><li>Octreotide analogues </li></ul><ul><li>Interferon α </li></ul><ul><li>Systemic Chemotherapy </li></ul><ul><li>Curative liver resection </li></ul><ul><li>Surgical ligation of the hepatic artery </li></ul><ul><li>Hepatic Artery embolisation /chemoembolisation </li></ul><ul><li>Radiofrequency Ablation </li></ul><ul><li>Liver transplant </li></ul>
  • 5. Supportive Care <ul><li>The majority of symptoms that patients with hepatic metastases complain of are related to carcinoid syndrome </li></ul><ul><li>Thus treating and minimising the effects of carcinoid syndrome can greatly impact on a patients’ quality of life. </li></ul><ul><li>Measures include: </li></ul><ul><ul><li>Avoiding stress and foods that provoke flushes </li></ul></ul><ul><ul><li>Anti-diarrhoeals like Loperamide </li></ul></ul><ul><ul><li>Supplementation of vitamins and nicotinic acid to avoid pellagra </li></ul></ul>
  • 6. Octreotide Analogues <ul><li>Octreotide – a somatostatin analogue </li></ul><ul><li>Activates membrane receptors to interfere with hormone and neurotransmitter activation </li></ul><ul><li>Provides symptomatic relief in up to 80% of patients </li></ul><ul><li>Has been reported to inhibit tumour growth. </li></ul><ul><li>Needs to be given SC twice or three times daily </li></ul><ul><li>Newer slow release preparations can be given once fortnightly or monthly </li></ul><ul><li>Efficacy wanes over treatment period due to disease progression and tachyphylaxis </li></ul>
  • 7. Interferon α <ul><li>Introduced in 1982 as a treatment for carcinoid </li></ul><ul><li>Mechanism of action poorly understood </li></ul><ul><li>Theories include: </li></ul><ul><ul><li>Inhibition of cellular proliferation </li></ul></ul><ul><ul><li>Inhibition of angiogenesis </li></ul></ul><ul><ul><li>Immune cell mediated cytotoxicity </li></ul></ul><ul><ul><li>Inhibition of tumour growth by interruption of the cell cycle </li></ul></ul><ul><li>Data reports symptomatic improvement in 40-70% </li></ul><ul><li>Tumour shrinkage in 10-15% </li></ul><ul><li>Postulated synergistic effect with Octreotide </li></ul><ul><li>Recent prospective study by Faiss et al shows no difference in response rates with treatment with a single agent or combination therapy </li></ul>
  • 8. Chemotherapy <ul><li>Researched drugs include streptozocin, 5 FU and doxorubicin </li></ul><ul><li>Reserved for high grade malignancies only </li></ul><ul><li>Combination therapy has a poor response rate of only 15-30% </li></ul><ul><li>Chemotherapy is NOT considered first line therapy for carcinoid tumours </li></ul>
  • 9. Curative liver resection <ul><li>First line treatment where possible, however: </li></ul><ul><li>Possible in 10% of patients with liver mets, where the lesions are confined to only one lobe </li></ul><ul><li>Excellent response rates, with 5 year survival of 87% </li></ul><ul><li>Surgical mortality rates are 6%, low morbidity </li></ul><ul><li>Cholecystectomy usually performed at time of resection due to high incidence of gall bladder disease with adjuvant use of somatostatin analogues </li></ul><ul><li>If multilobular or bulky disease, a palliative debulking operation is useful for relief of symptoms, especially in patients with resistance to systemic therapies </li></ul>
  • 10. Surgical ligation of hepatic artery <ul><li>Hepatic dearterialisation first proposed by Bengmark in 1974 as the beneficial effects of hypoxia on tumour growth was theorised </li></ul><ul><ul><li>Procedure abandoned due to limited effects (about 4 months) due to reperfusion from collaterals, and the high peri operative morbidity and mortality (20%) </li></ul></ul><ul><li>Bengmark persevered, and developed the technique of isolated ligation of the hepatic artery </li></ul><ul><li>The modified technique involves a dilatable balloon catheter placed around the hepatic artery, which can be inflated for short intervals daily to create tissue hypoxia </li></ul><ul><li>Early studies showed a good response, with 60% symptom control at one year </li></ul><ul><li>Therefore, these techniques proved that tissue hypoxia has anti-tumoral effects, particularly in the highly vascular carcinoid mets, despite these techniques no longer being routinely used. </li></ul>
  • 11. Hepatic artery embolisation <ul><li>Localised therapy for hepatic metastases that are not amenable to surgical resection </li></ul><ul><li>Currently most widely accepted therapy for carcinoid liver mets </li></ul><ul><li>Technique involves hepatic artery catheterisation using the Seldinger technique, with angiography of the hepatic arterial tree and tumour vascularity </li></ul><ul><li>Branches of the hepatic artery supplying tumour regions are selectively embolised as proximally as possible (to minimise collateral development) to create tissue hypoxia </li></ul><ul><li>Agents for embolisation vary but include polyvinyl alcohol </li></ul>
  • 12. Hepatic artery chemoembolisation <ul><li>Chemoembolisation involves injecting a cytotoxic agent (i.e. Adriamycin or streptozotocin (STZ)) prior to the embolic agent </li></ul><ul><ul><li>The theory of localised combination therapy is that agents such as STZ are known to be more cytotoxic during anoxia </li></ul></ul><ul><li>Procedure is usually repeated every 3 months </li></ul><ul><li>Shown to have 60-99% improvement in patient symptoms </li></ul><ul><li>No comparative trials to determine effect on survival rates </li></ul><ul><li>Long term palliation up to 4 years can be achieved with repeated therapy </li></ul><ul><li>Most research has focussed on treatment of midgut primaries with hepatic mets </li></ul><ul><li>Side effects: RUQ pain, elevated LFT&apos;s and fever (postembolisation syndrome), renal toxicity, hepatic artery stenosis </li></ul>
  • 13. Radiofrequency ablation <ul><li>Can be performed percutaneously or laparoscopically </li></ul><ul><li>Percutaneous preferred as cheaper, less invasive and can utilise CT or MRI guidance </li></ul><ul><li>Relatively new therapy with few randomised controlled trials – little data reporting effectiveness or outcomes of procedure but promising early data </li></ul><ul><li>Considered in patients with multilobular disease who have failed hepatic artery embolisation </li></ul><ul><li>Theoretical advantage is that ablation of mets will reduce hormone secretion and tumour burden, thus improve symptoms </li></ul><ul><li>Proposed as a combination therapy with surgical resection </li></ul><ul><li>Technically very difficult procedure, as carcinoid mets are multiple (can be up to 20) and very small (mm’s to cm’s), with even the very small ones producing large amounts of hormones. </li></ul>
  • 14. Liver transplantation <ul><li>Reserved for patients with: </li></ul><ul><ul><li>End stage disease </li></ul></ul><ul><ul><li>Uncontrollable symptoms </li></ul></ul><ul><ul><li>Non-responsive to all other therapies </li></ul></ul><ul><ul><li>&lt;50y.o </li></ul></ul><ul><li>Recent analysis shows poor long term outcomes </li></ul><ul><li>Disease free survival at one year 62% </li></ul><ul><li>Disease free survival at five years 23% </li></ul><ul><li>Careful patient selection may show improved survival rates 60% 5year </li></ul><ul><li>Poor outcomes and the shortage of organs begs consideration of whether this procedure should be carried out at all </li></ul><ul><li>Transplantation perhaps should only be carried out in exceptional circumstances on a individual patient basis </li></ul>
  • 15. In summary…. <ul><li>Treatment for patients with hepatic metastases of gastrointestinal carcinoid should be considered on an individual patient basis by a multidisciplinary team due to its rarity and varied clinical course </li></ul><ul><li>Liver resection is the first line treatment, however only 10% of patients are candidates </li></ul><ul><li>Systemic treatment with somatostatin analogues is the first line for the remaining 90% however these therapies are aimed at symptom control rather than increasing long term survival </li></ul><ul><li>Local hepatic therapies such as chemoembolisation and ablative therapies should then be trialled where indicated </li></ul><ul><li>Patients with more than 50% involvement of liver with mets may not benefit from aggressive (localised hepatic) therapy </li></ul><ul><li>Liver transplantation is a potential option, but should be reserved for patients with isolated hepatic mets with severe symptoms refractory to other therapies </li></ul><ul><li>Aggressive management can increase 5 year survival to 50-70% </li></ul>
  • 16. References <ul><li>Zuetenhorst J, Taal B. Metastatic Carcinoid Tumours: a clinical review. Oncologist 2005; 10:123-131. </li></ul><ul><li>Ramage J et al. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours. Gut 2005; 54: 1-16. </li></ul><ul><li>O’Toole D, Maire F, Ruszniewski P. Ablative therapies for liver metastases of digestive endocrine tumours. Endocr Relat Cancer 2003; 10: 463- 468. </li></ul><ul><li>O’Toole D, Ruszniewski P. Chemoembolisation and other ablative therapies for liver metastases of gastrointestinal endocrine tumours. Best Pract Res Clin Gastroenterol . 2005; Aug: 19(4):585-94 </li></ul><ul><li>Blonski WC et al. Liver transplantation for metastatic neuroendocrine tumor: a case report and review of the literature. World J Gastroenterol. 2005; Dec 28:11(48):7676-83. </li></ul><ul><li>Touzios et al. Neuroendocrine hepatic metastases: does aggressive management improve survival? Ann Surg. 2005 May;241(5):776-83 </li></ul><ul><li>Kulke M, Mayer R. Carcinoid tumors. N Engl J Med. 1999; Mar 18: 340(11):858-68. </li></ul>

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