Neuroendocrine Tumours



Introduction

Neuroendocrine tumours (NETs) arise from neuroendocrine cells, which are found in almost all organs of the body, most commonly the gastrointestinal tract. These are relatively uncommon tumours with the estimated incidence of 3-5 people out of a 100 000 population being diagnosed with a NET per year. These tumours are generally slow growing and therefore, incidence of these tumours is much higher, 35 per 100 000 populations, second only to colorectal cancer in terms of gastrointestinal cancers but many people will not know they have it.

Carcinoid syndrome

Some of the tumours produce hormones that can cause symptoms, the most common collection of symptoms being known as carcinoid syndrome. Carcinoid syndrome encompasses the classic symptoms of facial flushing, diarrhoea and episodic abdominal pain. Carcinoid syndrome occurs in only 20-30% of patients with NETs arising from the small bowel and 5% of bronchial (lung) NETs. It develops less commonly in NETs from other primary sites.

The commonest three symptoms which indicate carcinoid syndrome are flushing, diarrhoea and cramping abdominal pain.

Flushing is the most common symptom described in 94% of patients in one study.  It is characteristically described as a sudden onset of pink to red discolouration involving the face and upper trunk. It lasts for a few minutes (5-10 minutes) and occurs intermittently and at any time throughout the day but especially during times of stress. Patients may not notice episodes of flushing; it is commonly noted by observers such as family members. Triggers that lead to flushing and diarrhoea include stress, tyramine-containing foods (chocolate, bananas and walnuts) and alcohol.

Symptoms of diarrhoea that occurs in 78-84% of patients are often sudden with urgency (needing to go suddenly to the toilet) associated with cramping abdominal pain, occurring both day and night (often irritable bowel syndrome settles at night time).

The cramping abdominal pain may be more common after large meals and is described by 50% of patients. Obstructive symptoms (abdominal distension, vomiting or no bowel motions for 1-2 days) may be “alarm” features. Wheezing occurs less commonly, in only 18% of patients, and is more commonly seen in patients with bronchial NETs.

Investigations

Carcinoid syndrome is due to the excess release of kinins and serotonin. Serotonin is metabolized to 5-hyroxyindolacetic acid (5-HIAA), which is excreted in the urine and can be measured with a spot urine test or a 24 hour urine collection. This test is >90% sensitive and specific for carcinoid syndrome, although false positives are common if a Tyramine-free diet is not adhered to during the test. Tyramine is found in bananas, chocolate, and caffeine. 48 hours prior to collection and 24 hours during collection, dietary restrictions required for accurate results. Urine should be collected in a bottle containing acid so that pH is less than 3.

Chromogranin A, is released from neuroendocrine cells and can be measured in the blood. This is a specialised test performed at reference laboratories which has a >90% sensitivity.

Treatment

Management of carcinoid syndrome

Nearly all patients with carcinoid syndrome have liver metastases (cancer which has spread) and many have unresectable disease. Consequently, symptomatic medical management is the initial mainstay of treatment. Surgery, embolization of metastases, radiofrequency ablation or radiolabeled octreotide is appropriate in some patients.

Surgical management

Curative surgical therapy should always be considered. However, most patients have advanced disease. Surgery is an option in patients with a resectable primary lesion (e.g., a bronchial carcinoid tumour without evidence of metastatic spread). Surgery should be considered when both the primary and secondary cancer can be resected. Prior to surgery patients should be commenced on octreotide infusion to prevent carcinoid crisis. It is commenced at least 2 hours prior to surgery and given until 48 hours after surgery.

Midgut tumours: occasionally midgut carcinoid tumours without or with limited liver involvement are suitable for curative removal. Midgut carcinoids involving the small bowel should be resected if that patient is fit enough to undergo surgery. Occasionally these patients present with small bowel obstruction and require emergency surgery. Resection of liver metastases can rectify hormonal markers and resolve symptoms. The type of surgery performed depends on the location, size and number of liver lesions. Other than resection, radiofrequency ablation may also be performed and may sometimes be used at the time of surgery.

Debulking surgery for liver disease should be considered as a palliative option in patients with symptoms related to carcinoid syndrome refractory to medical therapy or in whom there is evidence of clinical/radiologic progression of disease. In these cases, if resection of more than 90% of the tumor load is possible, then surgery may provide better symptom control and possibly longer survival.

Medical management

Symptoms (flushing, diarrhea, wheeze) are usually controlled with somatostatin analogues and interferon alfa. Second-line treatment for management of symptoms involves the use of radionuclide-targeted therapy or hepatic transarterial embolization and possibly chemotherapy. However, chemotherapy for midgut carcinoids lacks efficacy, with response rates of less than 25%. Newer experimental treatments such as tyrosine kinase inhibitors are being trialled, some with promising results.

Somatostatin analogues
Somatostatin analogues are suitable for all patients with carcinoid syndrome. Octreotide was the first developed somatostatin analogue. This can be administered as a subcutaneous or intravenous injection. However, due to the short half-life, a 3-times-daily regimen was previously required to maintain steady levels. As a result, long-acting preparations have been developed that last for 28 days. Both long-acting preparations have similar comparable binding profiles and bind with a high affinity to somatostatin receptor types 1 and 4. Somatostatin analogues also inhibit release of hormones from the pancreas. Steatorrhoea can occur with sustained use of these agents and is best treated with a pancreatic enzyme supplement.

Hepatic transarterial embolization
Liver metastases are often the cause of carcinoid syndrome and, therefore, if symptoms progress despite optimal medical management with biotherapy, there may be a role for hepatic embolization. The technique involves identifying the arterial blood supply to the hepatic metastases. If bilobar (in two areas of the liver) disease is present, then usually only 1 lobe is embolized at a time. Symptomatic improvement occurs in 40% to 80%. Embolization can be repeated, although its effectiveness diminishes with repeated episodes.

Radionuclide therapies

The high-intensity expression of somatostatin receptors in neuroendocrine tumours (NETs) is demonstrated by a positive Octreoscan or appropriate PET imaging. Somatostatin receptors are present in the majority of carcinoid tumours. This facilitates the use of radionuclide therapies composed of a radiolabelled Ligand attached to a somatostatin analogue, producing localized radionuclide activity. Radiolabeled somatostatin analogues can be given for inoperable or metastasized neuroendocrine tumours. Patients to be considered for this therapy need to have a positive Octreoscan or other appropriate tracer uptake. Patients need to be able to provide self-care, since for 24 hours they will be alone in a radioactive room.

Symptomatic improvement has been reported in 60% to 80% of cases. The use of radionucleotide therapies should be limited to specialist centres.

Other treatments

Generally chemotherapy has disappointing results in management of symptoms in patients with carcinoid syndrome. The commonly used regimens depend in part on the histology and site of the primary tumour. For bronchial tumours, etoposide and cisplatin can be used as first-line chemotherapy, while other centers recommend fluorouracil and streptozotocin.  For midgut carcinoid tumours, the best clinical response rate identified was in a study using doxorubicin and streptozotocin, where a 40% response rate was reported.

Other studies report response rates of usually less than 25% following a number of different chemotherapy regimens for well-differentiated midgut NETs. The response rate for poorly differentiated NETs with etoposide and cisplatin has been shown to be between 40% and 67%. This response rate does not necessarily correlate with improvement in carcinoid symptoms and often is related to tumour-related symptoms such as weight loss and tiredness. Protocols, dosing and combination of agents tend to vary, and chemotherapy should only be used in specialist centres.

Useful sites
Net Patient Foundation