The recommendations contained in this guideline are a consensus of the Alberta Provincial Endocrine Tumour Team and are a synthesis of currently accepted approaches to management, derived from a review of relevant scientific literature. Clinicians applying these guidelines should, in consultation with the patient, use independent medical judgment in the context of individual clinical circumstances to direct care.# I n R e v i e w CLINICAL PRACTICE GUIDELINE ENDO-003
Neuroendocrine tumours (NETs) are a relatively rare family of tumours, occuring at a rate of about 5.25 cases per 100,000. 1 The most common primary site of NETs are the ileum and pancreas, but they can arise throughout the GI tract, lungs, thyroid, parathyroid, adrenal glands, and pituitary gland. 2 Patients with well-differentiated low and inter-mediate grade NETs often have a relatively good prognosis, while those with poorly-differentiated, high grade NETs fare less well. 3 These tumors are often classified as functioning or nonfunctioning, the latter of which do not present with hormone hypersecretion and are often found as a bulky tumour with metastatic disease. 4 Functioning NETs are often found earlier and may have a better prognosis. 4 Somatostatin analogues (Octreotide and Lanreotide), are commonly used in the treatment of functional NET's to manage symptoms associated with hormonal hypersecretion. Somatostatin regulates hormones and inhibits tumour secretions. Somatostatin analogues have been shown to control the production of hormones such as growth hormone (GH) and insulin-like growth factor 1 (IGF-1). 5 and also have an antitumor effect as suggested by the PROMID and CLARINET studies. 6,7 The purpose of this guideline is to provide evidence-based recommendations on the use of somatostatin analogues for NETs and to define which patients are candidates for treatment with these agents. The American Joint Committee on Cancer (AJCC; 7 th edition, 2010) staging for NETs can be found in Appendix A. 8 GUIDELINE QUESTIONS report response or survival outcomes, leaving a total of ten studies. The American Society of Clinical Oncology (ASCO) meeting abstracts database was searched (2009 through 2012 March) for relevant abstracts; five abstracts (phase III trials) were identified. In total, 15 studies were used as evidence to inform the recommendations on tumour control and symptom management.
Additional searches were conducted of the PubMED database for studies on the use of octreotide for carcinoid heart disease, malignant bowel obstruction, and increased calcitonin levels in medullary thyroid carcinoma. The searches included studies involving patients with any type malignancy (i.e., not limited to neuroendocrine tumours). The key words octreotide AND carcinoid heart disease or malignant bowel obstruction or calcitonin were used. Available data is presented in the discussion section.
For the 2014 update of the guideline the PubMED, MEDLINE and EMBASE databases were searched (2013 through 2014 October) for relevant publications using the following search terms: octreotide AND neuroendocrine tumour. In addition, the databases were searched (2009 through 2014 October) for relevant publications using the following search terms: lanreotide AND neuroendocrine tumour. A total of five additional studies were relevant and are summarized in the tables in Appendix B.

# TARGET POPULATION
The recommendations in this guideline apply to patients diagnosed with NETs of the gastrointestinal tract, pancreas, lungs, thyroid, parathyroid, adrenal glands, and pituitary gland, and NETs of unknown origin.
Described below are indications for the use of somatostatin analogues in neuroendocrine tumours (NETs). 2. Tumour control.
- Octreotide LAR has been shown in the PROMID study to slow tumour progression, as compared to placebo, in patients with locoregional unresectable or metastatic well-differentiated (low grade) NETs of mid-gut origin and those of unknown origin believed to be a mid-gut primary. Therefore, octreotide LAR should be considered for its anti tumour effect in patients with locoregional unresectable or metastatic well-differentiated (low grade) mid-gut NETs whose disease is progressing regardless of functional status of the tumour. o Octreotide LAR dosing for tumour control: 30 mg IM every 4 weeks. Note: therapeutic levels of octreotide would not be expected to be reached for 10-14 days after LAR injection.

# I n R e v i e w
CLINICAL PRACTICE GUIDELINE ENDO-003 Version 2
- Octreotide has not been compared to placebo in the phase III setting in patients with poorlydifferentiated mid-gut NETs or other NETs (i.e., non-mid-gut primaries) with locoregional unresectable disease or distant metastases. - Lanreotide has been shown in the CLARINET study to slow prolong progression free survival in comparison to placebo in patients with advanced well to moderately differentiated, nonfunctioning somatostatin receptor positive neuroendocrine tumors. o Lanreotide dosing for tumor control: 120 mg SC injection every 28 days

# Management of carcinoid heart disease.
- Octreotide is used to treat carcinoid crises. o Octreotide dosing for carcinoid heart disease: bolus of 100-500 mcg IV or by infusion; urgent situations may require high doses and up to 54,000 mcg has been reported. - There is a paucity of data on the use of octreotide for the prevention of carcinoid heart disease in patients with carcinoid tumours. However, given the life-threatening nature of carcinoid heart disease and the relative safety of octreotide, use of octreotide should be considered in this setting. o Patients with 5-HIAA levels greater than 50 mg/24 hours should be considered for octreotide therapy, with the goal of normalizing 5-HIAA 24-hour urine excretion, if possible. o Dosing for the prevention of carcinoid heart disease: octreotide LAR 20-30 mg IV every 4 weeks.

# Management of symptoms secondary to elevated calcitonin in medullary thyroid carcinoma.
- Octreotide has been shown to relieve symptoms associated with elevated calcitonin levels in patients with medullary thyroid carcinoma. Therefore, octreotide is recommended to manage symptoms (i.e., diarrhea) in patients with elevated calcitonin levels in medullary thyroid carcinoma. o Octreotide dosing for symptoms associated with metastatic medullary thyroid cancer: A trial of daily octreotide 100-250 TID mcg SC for 1-2 weeks with subsequent introduction of monthly octreotide LAR at a dose of 20-30 mg IM every 4 weeks. Octreotide can be given long-term without significant adverse effects.

# Management of Symptomatic Secretory Syndromes
Octreotide and lanreotide have been shown to improve symptoms associated with hypersecretory syndromes in patients with NETs. A small prospective study of 14 patients with functional metastatic gastroenteropancreatic neuroendocrine tumors (VIPoma, glucagonoma, gastrinoma, pancreatic and midgut carcinoids, and medullary thyroid carcinoma) examined the efficacy of octreotide therapy for 6 months. Efficacy was defined as a reduction in diarrhea and changes in 5-HIAA and CgA levels. Median urinary 5-HIAA and the number of stools decreased significantly (p=0.016 and p=0.009); decreases in CgA levels did not reach statistically significance (p=0.14). 11 In another small study, 9 patients with pancreatic NETs and 9 patients with metastatic carcinoid tumors were treated with octreotide, administered subcutaneously twice daily for 3 days, continuing for 2 to 12 months in patients with a response. Nearly all patients with a gastrinoma or glucagonoma responded with reduced hormone secretions, improved diarrhea, and improved skin lesions; however, in carcinoid syndrome, clinical efficacy was partial and inconstant. 12 Similar results have been reported elsewhere. 13 A double-blind randomized trial compared octreotide LAR at 10, 20, and in each of the four study arms were comparable (SC, 58.3%; 10 mg, 66.7%; 20 mg, 71.4%; 30 mg, 61.9%; P.72 for all pairwise comparisons). Stool frequency was also similar between groups, while flushing episodes were best controlled in the 20-mg LAR and SC groups. 14 A phase II trial combining 5-FU with LAR octreotide (20 mg monthly) in patients with advanced/metastatic well-differentiated NETs of the gastrointestinal tract (n=29) reported symptom relief in 60% of patients. A biochemical response (i.e., CgA levels) was observed in 48% of patients. 15 Based on the available data, octreotide is recommended for symptom control in patients with secretory syndromes, resulting from gastric NETs, carcinoid syndrome, and gastrinomas, insulinomas, somatostatinomas, glucagonomas, and VIPomas with locoregional disease or metastatic disease. The use of octreotide in this setting is supported elsewhere in Canada 4,16,17 and in the United States. 2 A trial of subcutaneous dose of 100-250 mcg three times per day for 1-2 weeks followed by intramuscular octreotide LAR 20-30 mg every 4 weeks is recommended. Similar dosing has been recommended elsewhere for use in this setting. 16,17 Dose and frequency may be increased for symptom control, as needed. Short-acting octreotide can be added to octreotide LAR for rapid relief of symptoms or for breakthrough symptoms. 2

# Tumour Control
Octreotide LAR has also been shown to slow tumour progression, as compared to placebo, in patients with locoregional unresectable or metastatic well-differentiated (low grade) NETs. The largest trial to date, the PROMID trial, is a phase III randomized controlled trial, comparing octreotide LAR (30 mg IM monthly) with placebo in patients with well-differentiated NETs of the midgut (n=85). The trial demonstrated both a greater rate of stable disease at 6 months (66.7% vs. 37.2%) and longer progression-free survival (14.3 vs. 6 months; p<.000072) in the octreotide-treated group, as compared to placebo. 7 Octreotide has not been compared to placebo in the phase III setting in patients with poorly-differentiated mid-gut NETs or other NETs (i.e., non-mid-gut primaries) with locoregional unresectable disease or distant metastases.
Based on the available data, octreotide LAR is recommended in patients with locoregional unresectable or metastatic well-differentiated (low grade) mid-gut NETs. Use of octreotide in this setting is supported elsewhere in Canada. 2 Recommended dosing for tumour control is LAR 30 mg IM every 4 weeks. Due to a lack of data, octreotide is not recommended for patients with poorly-differentiated mid-gut NETs or other NETs (i.e., non-mid-gut primaries) with locoregional unresectable disease or distant metastases for the purpose of tumor control.
More recently, the CLARINET trail investigated lanreotide in a randomized controlled trial of well to moderately differentiated enteropancreatic neuroendocrine tumours (grade 1 or 2). 6 Lanreotide was shown to significantly prolong progression-free survival compared to placebo (median not reached for lanreotide group vs. 18.0 months for placebo, p<0.001; hazard ratio for progression or death 0.47, 95% CI 0.30-0.73). At 24 months the estimated progression-free survival rate for the lanreotide group was 65.1% and 33.0% for the placebo group.

# Management of Carcinoid Heart Disease
Carcinoid heart disease results from exposure of the heart to high levels of tumour-derived vasoactive substances, such as serotonin, resulting in endocardial damage. Ventricular failure can occur. 17 5-HIAA levels; levels greater than 50 mg/24 hours are associated with an increased risk of developing carcinoid heart disease.  Octreotide is recommended for the treatment of carcinoid heart disease 17 based on its action on normalizing 5-HIAA levels.  The recommended dosing of octreotide in this setting is a bolus of 100-500 mcg IV or by infusion; however, urgent situations may require high doses.
The use of octreotide in the prophylactic setting is controversial because there is a paucity of data on its use in patients with carcinoid tumours in this setting. Based on consensus, the prophylactic use of octreotide should be considered in patients with carcinoid tumours. Canadian consensus guidelines recommend that early intervention with octreotide should be considered, given that toxicity is low and the morbidity and mortality rates associated with carcinoid heart disease are high. 17 Patients with 5-HIAA levels greater than 50 mg/24 hours should be considered for octreotide therapy, with the goal of normalizing 5-HIAA 24-hour urine excretion, if possible. 17 A dose of 20-30 mg IV every 4 weeks is recommended for the prevention of carcinoid heart disease 2.

# Management of Symptoms Secondary to Elevated Calcitonin in Medullary Thyroid Carcinoma
Octreotide has been shown to relieve symptoms associated with elevated calcitonin levels in patients with medullary thyroid carcinoma. A prospective study, among 22 patients with persistent or relapsed metastatic medullary thyroid carcinoma, evaluated the long-term use of somatostatin analogs. Following surgery, patients had an elevated serum calcitonin level (252-69482 pg/ml). Daily octreotide (0.4-1.0 mg SC) or monthly octreotide LAR (20-30 mg IM for 3-21 months) was given, along with systemic chemotherapy with or without external radiotherapy. Pre-existing diarrhea was improved in 8 patients (36.4% partial response), and remained stable in 10 patients. Calcitonin concentrations decreased more than 25% in 18% of patients (4 of 22). 24 Another somatostatin analog, lanreotide (slow-release), was shown to improve symptoms in seven patients with advanced and symptomatic medullary thyroid carcinoma. The number and intensity of bowel movements and flushing episodes decreased in nearly all patients (7 of 8) and plasma calcitonin levels decreased significantly in nearly all patients (6 of 7); the magnitude of decrease was 50% or more in half of these patients. 25 Similar results have been reported elsewhere. 26 Based on the available evidence, octreotide is recommended to manage symptoms (i.e., diarrhea) in patients with elevated calcitonin levels in medullary thyroid carcinoma. The recommended octreotide dosing in this setting is 100-250 TID mcg SC or monthly octreotide LAR at a dose of 20-30 mg IM every 4 weeks. Octreotide can be given long-term without significant adverse effects.
- Present the guideline at the local and provincial tumour team meetings and weekly rounds.
- Post the guideline on the Alberta Health Services website.
- Send an electronic notification of the new guideline to all members of CancerControl Alberta.
A formal review of the guideline will be conducted at the Annual Provincial Meeting in 2016. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.