Proposed Protocol for Chemoembolisation

Protocol for Management of Patients with Neuroendocrine Tumours Undergoing Surgery or an Embolisation Procedure

Neuroendocrine tumours (NET) can release a variety of peptides and hormones that are vasoactive. Carcinoid syndrome (diarrhoea, flushing and bronchospasm) is a consequence of serotonin release into the systemic circulation. Other products that can be potentially released by these tumours include histamine, kallikreins and catecholamines. Carcinoid syndrome occurs in 20-30% of patients with small bowel NETs that have metastasised to the liver. It may also occur in patients with small bowel NETs that have peritoneal metastases or in patients with large bowel, bronchial, ovarian and retroperitoneal NETs. Carcinoid syndrome is effectively managed in most patients with depot preparations of somatostatin analogues (octreotide or lanreotide).

Carcinoid crisis occurs when there is massive release of serotonin and other vasoactive hormones into the systemic circulation. It is characterised by severe flushing, diarrhoea, hypotension, hyperthermia and tachycardia. Occasionally severe hypertension can occur. Precipitants of carcinoid crisis include arterial embolisation, radiofrequency ablation, induction of anaesthesia, spinal anaesthesia, washing of the abdomen and manipulation of the tumour during surgery. Catecholamines released from the adrenals and sympathetic neurons may potentiate hormone release from the tumour.

Carcinoid heart disease occurs in more than 50% of patients with carcinoid syndrome. Tricuspid regurgitation is the most common abnormality, but pulmonary stenosis can also occur.

The following protocol describes best practice for patients with carcinoid syndrome undergoing surgery and ablative procedures. All patients should be discussed with an endocrinologist well in advance of any planned surgery.

Surgery

Risk stratification All patients with a known small bowel NET should have Chromogranin A and 24 hour urine 5HIAA measured within one month of surgery. Patients with any of the following are at high risk of carcinoid crisis:

 Large tumour bulk  Elevated Chromogranin A (>120 pmol/l) twice upper limit normal  Significantly elevated urine 5HIAA (>80 µmol/24hrs)  Known carcinoid syndrome  Symptoms suggestive of carcinoid syndrome

The Chromogranin A and urine 5HIAA cut-offs specified are entirely arbitrary and so this reinforces the need to discuss patients in advance with an endocrinologist. Correct Metabolic Derangement Prolonged diarrhoea can cause electrolyte disturbance and hypoproteinaemia. These should be corrected before major surgery.

Carcinoid heart disease All patients with known carcinoid heart disease should have an echocardiogram performed prior to major surgery. Patients with carcinoid heart disease should be discussed with a cardiologist. Some centres recommend valve replacement prior to resection of hepatic lesions because of the increased bleeding associated with right- sided valve lesions. Endocarditis prophylaxis is not routinely required as right-sided heart lesions would be considered only low to moderate endocarditis risk.

Somatostatin analogue therapy  Most patients with carcinoid syndrome should already be on a depot somatostatin analogue.  If the patient is not on somatostatin analogue therapy, and is at high risk of carcinoid crisis, or has been on long acting somatostatin analogue for less than 1 month (i.e. has only had one depot injection), commence octreotide 100µg tds by subcutaneous injection. Ideally this should be started at least 2 weeks prior to surgery, but is still of benefit if given over a shorter time.  All high risk patients should be given 100µg octreotide subcutaneously on the morning of surgery.  Consider night sedation prior to surgery, to reduce anxiety and the potential for endogenous catecholamines to stimulate hormone release.  Morphine, Pethidine and Tubocurare can precipitate serotonin release and should be avoided if possible. Good analgesia, e.g. with Fentanyl, will also reduce endogenous catecholamine release.

Urgent Surgery and Management of Carcinoid Crisis  If a high risk patient requires urgent surgery and has not had pre-treatment with somatostatin analogue (or it has only been started with 24 hours), before anaesthesia commence intravenous octreotide 500µg in 500ml saline at a rate of 50µg/h. Patients require cardiac monitoring because of a rare association between intravenous octreotide and cardiac conduction abnormalities.  For minor surgery, subcutaneous octreotide 100µg should suffice.  Flushing during anaesthesia should constitute a warning of cardiovascular instability.

If cardiovascular instability occurs:  Give a 100µg bolus of intravenous octreotide and increase the infusion rate to 100µg/hr.  Increase intravenous fluids as appropriate to help manage hypotension.  Catecholamines and other sympathomimetics should be avoided and alternative vasopressor therapy used if required.  Hypertension may be managed by increasing depth of anaesthesia. Vasodilators may be cautiously used – but should be discussed with an endocrinologist.  Parenteral ranitidine (50mg x 8hrly) and chlorpheniramine (10mg x 6 hrly) block H1 and H2 receptors and should be administered.  β-receptor agonists and Theophyllines may precipitate hormone release and paradoxically worsen bronchospasm. They should be used with extreme care. Octreotide and, over a longer time period, steroids should be used to control bronchospasm.

Post-operative care  Intravenous octreotide should be weaned off during the post-operative period slowly and the precise timing depends on intra-operative cardiovascular stability. Discuss with an endocrinologist.  Subcutaneous octreotide can continue post-operatively and the patient should be considered for depot therapy, if not already prescribed. Again discuss with an endocrinologist.  Maintain good analgesia and avoid dehydration.  Recheck Chromogranin A and 24 hour urine 5HIAA one month after surgery.

Transarterial Chemoembolisation (TACE)

This is a destructive therapy and so poses a significant risk of carcinoid crisis. The following protocol should be strictly observed:  All patients should have a 24hr urine collection for metanephrines done pre- operatively and this should be normal; this should be performed before discussion in the HPB MDT. If not discuss with an endocrinologist.  All patients with carcinoid syndrome should be established on a depot somatostatin analogue.

On the day of the procedure:  Intravenous octreotide 50µg/hour should be commenced at least one hour before the procedure and this should be continued for 24 hours after the procedure. Patients require cardiac monitoring because of a rare association between intravenous octreotide and cardiac conduction abnormalities.  Parenteral ranitidine (50mg x 8hrly) and chlorpheniramine (10mg x 6 hrly) block H1 and H2 receptors and should be administered one hour before the procedure and continued throughout the day.  A 24 hour urine collection for metanephrines and 5HIAA should be started on the morning of the procedure (need a urine container with acid).  Contact the endocrine registrar if any cardiovascular stability occurs, i.e. tachychardia, hypertensyion or hypotension. Blood samples should be taken for plasma adrenaline and normetadrenaline (discuss with the duty biochemist as a special lithium heparin tube containing metabisulphite is required).

1 st day post-procedure:  If there has been no cardiovascular instability, then wean off the intravenous octreotide by 25ug/hr every hour.  Prescribe oral Rantidine (150 mg b.d) and chlorpheniramine (4mg x 6 hourly) for the next two days. Portal Vein Embolisation

This is a less destructive procedure than TACE and is performed prior to hepatic resection. Carcinoid crisis can occur and patients need to be carefully assessed for the need for peri-procedural octreotide. In general, they should be managed as peri- operative patients rather than TACE, but if there is any doubt an octreotide infusion should be used as above. Discuss all cases with an endocrinologist beforehand.

Reference Akerstrom et al. ‘ENETS consensus guidelines for the standards of care in neuroendocrine tumors:pre- and periopertaive therapy in patients with neuroendocrine tumors.’ Neuroendocrinology 2009; 90:203-208.

Protocol prepared by Mark Strachan - March, 2011.