COSA:NETs guidelines/Surgery

Information on authorship and revision
Last reviewed:	November 2010
Author(s):	Ben Thomson (Chair), Jaswinder Samra, Jonathan Koea, Rob Padbury, Michael Crawford

Surgery

Surgery for localised tumours

Following recommended staging and multidisciplinary discussion, patients with localised neuroendocrine tumours should be considered for surgical resection.

Surgery should be undertaken in a surgical unit with adequate expertise and experience. All patients with non-pancreatic NET with carcinoid syndrome or a raised chromogranin A should have:

• consideration of pre-operative blockade with somatostatin analogues (see anaesthetic assessment)
• assessment for carcinoid heart disease with echocardiography.

Clinicians considering surgical treatment for hypergastrinaemic patients should be aware that most patients are not given somatostatin analogues, but are given proton pump inhibitors for treatment.

Neuroendocrine tumour	Treatment
Gastric	Normal gastrin levels (Type 3) - Radical gastric resection and lymphadenectomy Hypergastrinaemia (Type 1) - Tumour or tumours ≤ 1 cm – endoscopic resection where feasible, or observation, or: - Tumour or tumours > 1 cm – surgical resection. Zollinger-Ellison syndrome (Type 2) - Tumours ≤ 2 cm consider proton pump inhibitors +/- somatostatin analogues - Tumours > 2 cm consider gastric resection
Duodenal (excluding gastrinoma)	≤ 1 cm endoscopic or local resection > 1 cm – resection of applicable duodenum plus draining lymph nodes (Possible options would include local resection, partial duodenectomy or pancreaticoduodenectomy)
Pancreatic (Functioning & non functioning)	Resection of tumour and peripancreatic nodes including pancreaticoduodencectomy where appropriate
Pancreatic (Insulinoma)	Enucleation where possible - distal or central pancreatectomy if anatomically unsuitable Blind resections not recommended
Gastrinoma	Duodenal / Occult - Observation or - Duodenotomy with enucleation and periduodenal lymphadenectomy Pancreatic head - ≤ 5 cm and non invasive; enucleation where possible with periduodenal nodal dissection - > 5 cm or invasive; pancreaticoduodenectomy with peripancreatic nodal dissection Pancreatic body / tail - enucleation / resection
Jejunal / ileal	Segmental resection with wide lymphadenectomy where possible.
Appendiceal	Simple appendicectomy - ≤ 2cm Right hemicolectomy - > 2cm, positive margins, positive nodes or deep meso-appendiceal invasion, goblet cell carcinoid (+ bilateral salpingo-oophorectomy for goblet cell carcinoid)
Colon	Local resection using standard oncological criteria
Rectal	≤ 2cm endoscopic or trans-anal excision > 2 cm Anterior resection or abdominoperineal resection (APR)
Hepatic metastatic disease	Resection should be considered in the presence of resectable primary and hepatic metastatic disease

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Prophylactic cholecystectomy

Prophylactic cholecystectomy should be considered at laparotomy to prevent complications from gallstone disease as a result of long term somatostatin analogue use. Furthermore it may prevent local complications from liver directed therapy.

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Resectable metastatic disease

Resection of primary and metastatic disease should be considered if pre-operative assessment suggests that all the disease is completely resectable.

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Debulking resections for unresectable primary or metastatic disease

Only retrospective highly selected data is available to assess survival differences for palliative and debulking surgery.

There are several scenarios where surgery should be considered in the presence of unresectable metastatic disease. For patients with midgut carcinoids, palliative surgery to prevent intestinal obstruction or ischaemic complications secondary to desmoplastic mesenteric reaction offers the best chance of symptom control and has increased survival in highly selected case comparisons.

Palliative surgery should also be considered for large bowel obstruction.

Resection of primary disease leaving hepatic metastatic disease only may be indicated if it can be safely performed. This allows therapy to be directed at the hepatic metastases alone.

For locally advanced non-functioning pancreatic tumours there is no evidence to support debulking.

Before debulking is undertaken, appropriate staging should be done to exclude significant volume of extra-hepatic disease.

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Aims of debulking surgery

The aims of debulking resection include:

• acceptable operative morbidity and mortality
• palliation of symptoms
• prevention of obstruction.

Each patient should be treated on their own merits and should be assessed by a multidisciplinary team. Assessment of resectability should be by a gastrointestinal/hepatobiliary surgeon experienced in the treatment of neuroendocrine disease. The natural history for each patient is very different and therefore consideration of the tumour grade, Ki67 proliferation index, molecular imaging characteristics, co-morbidites and symptoms should be used in the decision making process.

Resection of the primary disease along with peritoneal or hepatic metastastic disease should be considered in patients in whom 90% of the disease can be safely removed.

Resection of primary tumour in the presence of metastatic disease.

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Debulking of non-hepatic disease

Debulking surgery can be considered for control of symptoms that are resistant to medical management. Surgery should be considered to prevent intestinal obstruction or ischaemic complications.

Before debulking is undertaken, appropriate staging should be done to exclude significant volume of extra-hepatic disease.

There are several scenarios where surgery should be considered in the presence of unresectable metastatic disease:

• For patients with midgut carcinoids, palliative surgery to prevent intestinal obstruction or ischaemic complications secondary to desmoplastic mesenteric reaction offers the best chance of symptom control and has increased survival in highly selected case comparisons.

• Palliative surgery should also be considered for large bowel obstruction.

• Resection of primary disease leaving hepatic metastatic disease only may be indicated if it can be safely performed. This allows therapy to be directed at the hepatic metastases alone.

Resection of pancreatic disease may be indicated for local complications of obstruction or bleeding. Each patient needs to be treated on their own merits. Otherwise there is no evidence to support debulking of locally advanced non-functioning pancreatic tumours.

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Debulking of hepatic metastases

Assessment of resectability by a hepatic surgeon is mandatory following appropriate available staging. Patients with resectable disease need to be considered for resection.

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In symptomatic patients

Resection +/- ablation of hepatic metastases should be considered in the treatment of patients with symptoms resistant to non-surgical management if at least 90% of the disease can be safely removed.

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In asymptomatic patients

Surgery is rarely indicated for asymptomatic patients. Non-operative treatment should be considered.

Considerations:

• hepatic resection for a large dominant metastases to improve liver directed therapy
• hepatic resection for dominant metastases resistant to non-operative therapy.

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Hepatic surgery post radiopeptide therapy

Following treatment with radiopeptide therapy there is currently no evidence:

• for downstaging of hepatic metastatic disease allowing surgical resection
• of impaired hepatic function or increased complications post surgery.

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Liver transplantation

Liver transplantation for metastatic disease isolated to the liver has previously been described. It has been utilised for patients with disease that is unresponsive to medical therapy and not otherwise treatable. The results for transplantation of such patients in Australia have been poor.

Liver transplantation is not recommended.

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Further points

Percutaneous biopsy

Percutaneous biopsy prior to consideration of surgery is not indicated. Occasional indications for biopsy should only be considered after multidisciplinary discussion. Diagnosis may be possible with a combination of radiological and radiopeptide imaging, biochemical markers and endoscopic biopsy.

NET patients considered for surgical management of metastatic disease should be considered for Laparoscopy if pre-operative workup fails to detect the primary site of disease. This may allow detection and management at the time of definitive surgery.

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Peri-operative management

The following guidelines have been developed and supplied by Dr Hilmy Ismail FANZCA and Dr David Skewes FANZCA, Peter MacCallum Cancer Centre.

Guidelines
Pre-operative Elicit history and examine for signs and symptoms: I a) Carcinoid Syndrome b) Carcinoid crises c) Cardiac disease Investigations Tumour activity: a) Urine 24 hour 5-HIAA levels IIa b) Plasma CgA IIb c) Liver Function including Coagulation d) Electrolytes and S. Protein IIc Imaging for assessment of systemic disease: a) Octreotide scan b) Gallium PET/CT Assessment of carcinoid heart disease: a) Cardiac Echo IIIa
FBC, ECG, CXR Correct electrolytes and optimise glycaemic control. Optimise right heart failure if present IIIb Consider valve replacement if transpulmonary gradient is 10mmHg or greater
Pre-Medications Consult with endocrinologist whenever possible. Octreotide therapy Subcutaneous short acting Octreotide 100-500 mcg daily in divided doses OR long acting (LAR) Octreotide 30-60 mg intramuscular injections every 4 weeks. Optimum timing of surgery is once stable symptom control has been achieved and 2 weeks after last injection of LAR Octreotide. IV Administer usual dose of subcutaneous Octreotide or 500 mcg subcutaneous (if previously untreated or for emergency) 2 hours prior to surgery. Ranitidine: 50 mg i/v or 150 mg orally 2 hours prior to surgery. Promethazine: 12.5 mg i/v or 10-20 mg orally 2 hours prior to surgery. Ondansetron: 4-8 mg i/v 2 hours prior to surgery. Dexamethasone: 2-4 mg i/v for gastric NETs. Antibiotic prophylaxis if cardiac valve pathology is present.
Intra operative management Start Octreotide infusion in holding bay, prior to insertion of invasive monitoring lines and regional blockade. Octreotide (500 mcg in 500mls N/saline) started at 1 mcg/kg/hr. Monitoring: Arterial line prior to regional anaesthesia and induction of general anaesthesia. Consider PiCCO or transoesophageal Doppler in the presence of cardiac involvement. Central venous pressure and access. V Neuraxial anaesthesia: Thoracic epidural either T6-7 for liver resection or T8-9 for lower abdominal procedures. Avoid loading epidural until end of resection to avoid hypotension. VI Induction and maintenance: A wide range of agents have safely been used including volatile agents. Avoid Ketamine. Succinylcholine is considered safe. Remifentanyl, Propofol TIVA acceptable. Peri-operative hypotension: Inform surgeon, stop handling tumour. Octreotide 10-100 mcg bolus, repeat. Phenylephrine 50-200 mcg bolus and infusion 0.1-2 mcg/kg/min. Increase depth of anaesthesia avoid adrenergic drugs. VI Cautious use of catecholamines may be acceptable to treat low cardiac output if already on Octreotide. Consider arginine-vasopresin, antihistamines, steroids, calcium chloride if hypotension is unresponsive. Peri-operative hypertension: Attenuate stress responses (intubation), treat pain, increase depth of anaesthesia. Octreotide 10-200 mcg i/v boluses. Labetolol, esmolol, GTN if unresponsive. Peri-operative bronchospasm: Octreotide 10-200 mcg i/v boluses. Antihistamine, nebulised ipratropium, steroids.
Post-operative care High Dependency Unit. Continue Octreotide infusion. Close liaison with endocrinology and referral for long term care. Avoid crisis precipitating events (extubation response, pain, hypothermia, hypercarbia).

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Notes peri-operative management

I. Classic features: Flushing (84%), diarrhoea (70%), heart disease (37%), bronchospasm (17%), myopathy (7%), abnormal skin pigmentation (7%). Typical cardiac involvement involves right side of heart (tricuspid regurgitation, pulmonary stenosis, pulmonary hypertension). Cardiac involvement is almost never seen if 5-HIAA levels are below 50mg/24 hrs.
IIa. 5-HIAA - Sensitivity 73%, Specificity 100%; May not be increased in foregut tumours; It is a marker of tumour activity, peri-operative complications and response to treatment.
IIb. CgA - Correlates with tumour bulk, not symptoms. Also not valid in patients on PPI’s and in renal impairment.
IIc. Tryptophan deficiency and diarrhoea can lead to hypo proteinaemia and hyponatraemia respectively.
IIIa. Cardiac Echo to determine a) Valvular heart disease b) Left and Right ventricular function c) Pulmonary hypertension.
IIIb. Right heart failure increases central venous pressure and can lead to high blood loss during liver surgery.
IV. 5-HIAA levels can be used to monitor effectiveness of treatment. LAR octreotide activity peaks at 2 weeks after injection.
V. Consider ultrasound guidance for central line placement in presence of tricuspid valve involvement. Also, pulmonary flow catheters may not be safe in presence of tricuspid plaque.
VI. Endogenous and exogenous catecholamines can trigger release of serotonin, causing further hypotension.

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References

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