Somatostatin Analogs

Number: 0693

Policy

1. Aetna considers octreotide (Sandostatin) medically necessary for members with any of the following indications:

   1. Acromegaly - treatment for any of the following conditions:

      1. For adjunctive therapy with irradiation to help relieve symptoms of acromegaly and possibly slow the rate of tumor growth; or
      2. For inability to tolerate bromocriptine; or
      3. For inadequate response to surgery or when surgical resection is not an option; or
      4. For inadequate therapeutic response to radiation.

      Note: The goal is to reduce growth hormone and insulin-like growth factor-1 (IGF-1, somatomedin C) levels to normal.

   2. Acquired immune deficiency syndrome (AIDS) - treatment of severe secretory diarrhea associated with AIDS when anti-microbial (eg. ciprofloxacin or metronidazole) or anti-motility agents (eg. loperamide or diphenoxylate and atropine) have become ineffective.
   3. Adrenal gland neuroendocrine tumors - for symptom control if somatostatin scintigraphy positive in patients with non-adrenocorticotropic hormone-dependent Cushing's syndrome with tumors less than 4 cm, benign imaging characteristics, and abnormal contralateral gland and symmetric cortisol production.
   4. Bowel obstruction - management of gastro-intestinal (GI) symptoms (e.g., nausea, pain, vomiting) of inoperable bowel obstruction in persons with terminal cancer.
   5. Carcinoid tumor - prophylactic treatment to prevent carcinoid crises prior to surgery of carcinoid tumor, and reversal of life‐threatening hypotension due to carcinoid crisis during induction of anesthesia
   6. Chemotherapy and/or radiation therapy-induced diarrhea - treatment when either: a) the member has ≥ Grade 3 diarrhea according to NCI common toxicityFootnotes for The NCI definitions for diarrhea^*; or b) the member has NCI Grade 1 or 2 diarrhea and have had a trial of loperamide or diphenoxylate and atropine.
   7. Congenital hyperinsulinism, to reduce insulin secretion where diazoxide has been unsuccessful.
   8. Enterocutaneous fistulae - amelioration of volume depletion from enterocutaneous fistulae.
   9. Gastrinoma - prophylactic treatment prior to surgery for gastrinoma.
   10. Gastroesophageal varices - treatment of acute bleeding of gastroesophageal varices associated with cirrhosis when used in conjunction with endoscopic band ligation or sclerotherapy, or alone if ligation/sclerotherapy is not immediately available.
   11. Islet cell tumors - stabilization of blood glucose levels in persons with functioning islet cell tumors (insulinomas or glucagonomas).
   12. Lung neuroendocrine tumors - for stage IIIb (T4 due to multiple lung nodules)-IV if octreotide scan positive or for symptoms of carcinoid syndrome.
   13. Malignancy - prophylactic treatment prior to pancreatic resection for malignancy.
   14. Meningiomas - treatment for surgically inaccessible recurrent or progressive meningiomas when further radiation is not possible.
   15. Neuroendocrine tumors - prophylactic treatment prior to hepatic artery embolization for non-resectable multiple and hormone-secreting neuroendocrine tumors.
   16. Neuroendocrine tumors of the GI tract, lung and thymus - for management of unresectable locoregional disease and/or distant metastases for tumor control, or for symptom control in persons with carcinoid syndrome, or supplemental treatment with short-acting octreotide for breakthrough symptoms in patients taking long-acting octreotide.
   17. Pancreatic fistulas - prevention and treatment of pancreatic fistulas following pancreatic surgery
   18. Pancreas neuroendocrine tumors - for treatment of symptoms related to hormone hypersecretion, or for tumor control in persons with unresectable locoregional disease and/or metastatic disease and clinically significant tumor burden or clinically significant progression.
   19. Pituitary adenomas - treatment of pituitary adenomas (including growth hormone-secreting and thyroid stimulating hormone-secreting adenomas).
   20. Short-bowel syndrome - management of persons with short bowel syndrome if daily intravenous fluid requirements are greater than 3 liters.
   21. Small or large cell neuroendocrine tumors - poorly differentiated (high-grade)/large or small cell neuroendocrine tumors, for symptom control of somatostatin scintitraphy positive. 
   22. Thymomas and thymic carcinomas - second-line therapy with or without prednisone following radiation therapy for locally advanced unresectable disease.
   23. Vasoactive intestinal polypeptide (VIP) secreting tumors - treatment of profuse watery diarrhea associated with VIP-secreting tumors.
   24. Zollinger Ellison syndrome - treatment of functioning gastrinomas (Zollinger Ellison syndrome).
        

2. Aetna considers octreotide experimental and investigational for all other indications, including any of the following, because its effectiveness for these indications has not been established:

   1. Acute pancreatitis, treatment; or
   2. Breast cancer, treatment of advanced breast carcinoma; or
   3. Chylothorax, treatment of chylothorax in neonates; or
   4. Congenital lymphedema, treatment; or
   5. Crohn's disease-associated refractory diarrhea, or
   6. Cirrhosis-associated hyponatremia; or
   7. Diabetes mellitus management (e.g., control of an excess of pro-angiogenic factors in diabetes-associated retinal complications); or
   8. Dumping syndrome; or
   9. Gastric paresis, treatment; or
   10. Hepatocellular carcinoma (HCC), treatment; or
   11. Lymphorrhea reduction in gynecological malignancies; or
   12. Non-variceal upper GI bleeding, treatment of acute bleeding; or
   13. Obestity, management (e.g., control of hyperinsulinemia); or
   14. Pancreaticoduodenectomy, management of individuals undergoing pancreaticoduodenectomy (Whipple's procedure); or
   15. Polycystic kidney disease, treatment; or
   16. Prostate cancer, management of hormone refractory prostate cancer; or
   17. Protein-losing enteropathy following the Fontan operation, treatment; or
   18. Small cell lung cancer, salvage therapy; or
   19. Thyroid cancer, treatment; or
   20. Thyroid eye disease, treatment; or
   21. Tumor-induced osteomalacia; or
   22. Vascular (arterio-venous) malformations of the gastro-intestinal tract (e.g., cecal AV malformation), treatment.

3.  Aetna considers lanreotide depot injection (Somatuline Depot) medically necessary for the treatment of any of the following indications:

   1. Acromegaly - treatment of acromegaly in persons who have had an inadequate response to or can not be treated with surgery and/or radiotherapy.

   2. Malignancy - Use in persons undergoing pancreatic resection for malignancy.

   3. Carcinoid syndrome – treatment for adults to reduce the frequency of short-acting somatostatin analogue rescue therapy.
      
      
   4. Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) – for the treatment of adults with unresectable, well- or moderately- differentiated, locally advanced or metastatic GEP-NETs to improve progression-free survival.
      
      
      1. Neuroendocrine tumors of the adrenal gland - for symptom control if somatostatin scintigraphy positive in patients with non-adrenocorticotropic hormone-dependent Cushing's syndrome with tumors less than 4 cm, benign imaging characteristics, and abnormal contralateral gland and symmetric cortisol production.
      2. Neuroendocrine tumors of the GI tract, lung and thymus - for management of unresectable locoregional disease and/or distant metastases for tumor control, or for symptom control in persons with carcinoid syndrome.
      3. Neuroendocrine tumors of the pancreas - for treatment of symptoms related to hormone hypersecretion, or for tumor control in persons with unresectable locoregional disease and/or metastatic disease and clinically significant tumor burden or clinically significant progression.
      4. Poorly differentiated (high-grade)/large or small cell neuroendocrine tumors -, for symptom control of somatostatin scintitraphy positive.
         
         
   5. Zollinger-Ellison syndrome treatment.

4. Aetna considers lanreotide depot injection experimental and investigational for all other indications because its effectiveness for these indications has not been established, including: 

   1. GI bleeding treatmennt,

   2. Hepatocellular carcinoma (HCC) treatment

   3. Polycystic kidney disease treatment. 

   4. Prostate cancer - treatment of castration-resistant prostate cancer.
      
      
5. Aetna considers pasireotide diaspartate solution for subcutaneous injection (Signifor) and pasireotide pamoate suspension for intramuscular injection (Signifor LAR) medically necessary for Cushing's disease, where pituitary surgery is not an option or has not been curative, and the member has no severe hepatic impairment (Child‐Pugh C). Continued use of pasireotide for Cushing's disease is considered medically necessary for persons with no severe hepatic impairment and with urinary free cortisol (UFC) level has decreased from baseline at start of pasireotide treatment.
   
   
6. Aetna considers pasireotide diaspartate (Signifor) experimental and investigational for all other indications (e.g. uveal melanoma).

7. Aetna considers pasireotide pamoate (Signifor LAR) medically necessary for the treatment of persons with acromegaly who have had an inadequate response to surgery and/or for whom surgery is not an option, and who have no severe hepatic impairment (Child‐Pugh C).

8. Aetna considers pasireotide pamoate (Signifor LAR) experimental and investigational for all other indications (e.g. uveal melanoma)..

Note: Octreotide, pasireotide and lanreotide are not covered for constitutional (idiopathic) tall stature because such use is not considered treatment of disease.

Footnotes for The NCI definitions for diarrhea^* The NCI definitions for diarrhea are, using a grading system: Grade 1: mild diarrhea, 2-3 stools above normal per day; Grade 2: mild to moderate: 4 to 6 stools above normal per day; Grade 3: moderate severe to severe: 7 or more stools above normal; and Grade 4 is severe: life-threatening consequences; urgent intervention indicated.

For Aetna's CPB on OctreoScan, please see CPB 0168 - Tumor Scintigraphy.

See also CPB 0170 - Growth Hormone (GH) and Growth Hormone Antagonists.

Background

Somatostatin, a hypothalamic peptide, regulates the functions of several endocrine and exocrine glands.  It acts on the anterior pituitary to inhibit the release of growth hormone and thyroid-stimulating hormone.  It is also secreted by cells in the pancreas and in the intestine where it inhibits the secretion of a variety of other hormones.  Its regulatory actions are mediated via 5 different receptors, which are expressed in a tissue-specific manner.  Somatostatin receptors are also present in neuroendocrine gastro-entero-pancreatic tumors.  Two long-acting somatostatin analogs, octreotide (Sandostatin) and lanreotide, are recognized by the receptor subtypes 2 and 5.  Gastrointestinal endocrine tumors include carcinoid tumors as well as vasoactive intestinal polypeptide (VIP)-secreting tumors.

Gastroenteropancreatic tumors are also classified as carcinoid tumors. The term carcinoid should be used for well‐differentiated neuroendocrine tumors (NETs) or carcinomas of the GI tract only. Carcinoid tumors are rare, slow‐growing tumors that originate in cells of the diffuse neuroendocrine system. They occur most frequently in tissues derived from the embryonic gut. Foregut tumors, which account for up to 25% of cases, arise in the lung, thymus, stomach, or proximal duodenum. Midgut tumors, which account for up to 50% of cases, arise in the small intestine, appendix, or proximal colon, with the appendix being the most common site of origin. Hindgut tumors, which account for approximately 15% of cases, arise in the distal colon or rectum. Other sites of origin include the gallbladder, kidney, liver, pancreas, ovary, and testis.

Carcinoid Tumors are neuroendocrine tumors derived from enterochromaffin or Kulchitsky cells which are widely distributed in the body. They may be found at any location in the body but usually originate in the foregut, midgut, or hindgut. The annual incidence of carcinoid tumors is around two cases per 100,000 and it varies with age, gender and race. Under the age of 50, incidence is twice as high in females, and at older ages a male dominance is observed.

Carcinoid tumor histology is ambiguous and malignancy is determined by metastases.  Many carcinoid tumors are found incidentally or from symptoms related to the hormones that the tumor secretes.  Carcinoid syndrome occurs when an abundance of hormones are produced from GI carcinoid metastases or a non-GI primary tumor.  The hallmark carcinoid symptoms include flushing, diarrhea, and cardiac involvement.  Treatment consists of a wide resection for local primaries and usually palliative, medical support for patients with metastases.  The tumors are very slow-growing and patients have lived for up to 30 years after metastasis is diagnosed.  Administration of somatostatin analogs (e.g., octreotide) controls many of the carcinoid symptoms.  Life‐threatening hypotension may occur due to a carcinoid crisis. Rapid bolus IV may be given in emergency situations.

Conventional therapy to inhibit the severe diarrhea and flushing episodes that result from carcinoid tumors is reduction in consumption of foods and stress that cause flushing; and loperamide, diphenoxylate‐atropine, serotonin antagonists, or codeine for diarrhea. Octreotide is a proper choice for patients who have not achieved adequate response from use of these prior agents. In a prospective, open, comparative study with a crossover design, octreotide 200 micrograms given subcutaneously 2 to 3 times daily for one month was well tolerated and effective in controlling symptoms in patients with carcinoid syndrome. Disappearance or improvement in flushes occurred in 68% of patients (17 of 25). In addition, 50% of patients (11 of 22) reported a disappearance or improvement of diarrhea. The mean decrease in the 24‐hour urinary biochemical tumor marker level was 25%. A decrease of greater than or equal to 25% in the 24‐hour level was observed in 50% of patients receiving octreotide (O'Toole et al, 2000a). In a six month clinical trial of 93 patients with metastatic carcinoid syndrome, overall mean daily flushing episodes and daily stool frequencies were as well controlled or similar in octreotide LAR depot as octreotide injection s.c.

Guidelines from the UKNetwork on Neuroendocrine Tumours stated that, when a carcinoid tumor is found before surgery, a potential carcinoid crisis should be prevented by prophylactic administration of octreotide, given by constant intravenous infusion for 12 hours prior to and at least 48 hours after surgery (Ramage et al, 2004).  The guidelines state that similar prophylactic measures may be required for gastrinoma surgery and for hepatic artery embolization of non-resectable multiple and hormone secreting neuroendocrine tumors.

Vasoactive Intestinal Peptide Tumors are rare cancers in which tumor cells arise from certain hormone‐producing cells called islet cells. These cells are most commonly located in the pancreas but may also be located in or around the adrenal glands. These VIPomas produce excessive amounts of vasoactive intestinal peptide which causes the symptoms of watery diarrhea. VIPomas are very rare cancers and very few new cases are reported each year (0.05 to 0.2 cases per million adults). Even fewer cases in children are reported. When they do develop in adults they appear most commonly between the ages of 40‐50 and usually develop in the pancreas. In children they most commonly appear around the adrenal glands. Treatment goals are to reduce the symptoms of profuse watery diarrhea associated with these secreting tumors. The severe watery diarrhea responds to octreotide and improves electrolyte imbalances and overall condition of the patient.

Guidelines stated that persons with VIPomas (watery diarrhea hypokalemia achlorhydria (WDHA) syndrome or Werner-Morrison syndrome) frequently respond dramatically to small doses of somatostatin analogs with cessation of diarrhea (Ramage et al, 2004).  The guidelines stated that improvements with somatostatin analogs have been reported in patients with glucagonomas, although there is no indication for somatostatin analogs if the patient has no syndrome.

UKNetwork on Neuroendocrine Tumour guidelines stated that gastrinomas are adequately controlled with high-dose proton pump inhibitors, and there is no definite added benefit in the control of symptoms by addition of somatostatin analogues.  The guidelines noted, however, that some groups advise the addition of somatostatin analogues in this situation (see, e.g., NCCN, 2005).  The guidelines stated that administration of somatostatin analogues has variable effects on blood glucose levels in insulinomas.  The guidelines explained that about 50 % of insulinomas have somatostatin receptors, and that somatostatin analogues may also possibly act by suppressing counter-regulatory hormones such as glucagons.

Acromegaly is an uncommon chronic progressive disorder in adults resulting from the hypersecretion of growth hormone (GH) and resultant elevated circulating insulin like growth factor‐1 (IGF‐1). This hypersecrection of growth hormone is most commonly caused by a benign tumor of the pituitary gland. It results in gradual enlargement of body tissues including the bones of the face, jaw, hands, feet and skull. Acromegaly can result in substantial morbidity and mortality rates due to cardiovascular, pulmonary, and malignant diseases two‐to‐four times higher than the general population if not treated.

Acromegaly occurs in about six out of 100,000 people. It occurs in frequency equally among men and women. The mean age of onset for women is 34.9 years and 32.7 years in men. The mean age for diagnosis in men is 42.3 years and 43.8 for women.

Conventional therapy is aimed at reducing GH and IGF‐1 levels to normal, eliminating or reducing tumor growth, and alleviating clinical signs and symptoms to reduce comorbidities. Standard therapy is transphenoidal surgery, dopamine agonists, somatostatin analogues, GH receptor antagonists, and radiotherapy. Patients who are not eligible for surgery or who have had an inadequate response to dopamine agonist or radiation would instigate a trial of somatostatin analogues. A randomized, double‐blind, placebo controlled, multicenter trial of 115 acromegalic patients demonstrated the effectiveness of 100 micrograms subcutaneously every 8 hours for a six month period.(Ezzat et al, 1992). About half of the patients experienced a reduction in GH and about two thirds in IGF‐1. Three principal studies were performed providing up to 30 months of exposure to octreotide LAR depot who had previously responded to octreotide injection s.c. Growth hormone and IGF‐1 levels were at least as well controlled on octreotide LAR depot as they were on octreotide injection s.c.

Chemotherapy or radiation induced diarrhea is a debilitating and potentially lifethreatening side effect of cancer treatments. Severe diarrhea often results in delay of treatment or dose reductions. In a multicenter, randomized trial of long‐acting octreotide for prevention of CID, 147 patients were randomized to receive 30 mg or 40 mg octreotide LAR with chemotherapy. The first dose was given seven‐to‐14 days before Day 1 of the next chemotherapy cycle and the second dose coincided with the initiation of the chemotherapy cycle. Subsequent treatment was give q28 days. 124 patients were efficacy evaluable. Among respondents at study end (n=74) 56% treated with either dose of LAR reported satisfaction to extreme satisfaction with therapy. Fewer patients experienced severe diarrhea, required less IV fluid supplementation, and had fewer diarrhea‐related healthcare visits. (Rosenoff S. et al.)

Treatment of AIDS related diarrhea is often difficult because the cause of the diarrhea may be multifactorial and resistant to current therapy. In a review article evaluating the use of octreotide in the treatment of refractory diarrhea, Fried (1999) evaluated seven uncontrolled and three controlled studies of treatment of AIDS‐related diarrhea. In the study with the highest number of patients, stool frequency and volume decreased significantly with the use of octreotide in all patients. This was typical in all the studies.

Octreotide

Octreotide is the acetate salt of a cyclic octapeptide. It is a long‐acting octapeptide with pharmacologic properties mimicking those of the natural hormone somatostatin. Octreotide is a more potent inhibitor of growth hormone, glucagons, and insulin than somatostatin. It suppresses LH response to GnRH, decreases splanchnic blood flow, and inhibits release of serotonin, gastrin, vasoactive intestinal peptide, secretin, motilin, and pancreatic polypeptide.

Octreotide is indicated for long‐term maintenance therapy in acromegalic patients, for long‐term treatment of the severe diarrhea and flushing episodes associated with metastatic carcinoid tumors, and for long‐term treatment of the profuse waterydiarrhea associated with VIP‐secreting tumors. Other medical alternatives exist including, but not limited to: transphenoidal surgical resection; radiation therapy; dopamine agonists; serotonin antagonists; somatostatin analogues; GH receptor antagonists; and anti‐diarrhea agents (e.g. loperamide, diphenoxylate‐atropine).

Currently, somatostatin analogs are the most effective medical therapy available for the treatment of acromegaly.  Octreotide is the first somatostatin analog used for this indication.  Initially, it was administered subcutaneously at doses of 100 to 500 ug thrice-daily.  The advent of depot formulations, such as LAR octreotide, slow-release lanreotide and lanreotide autogel (Somatuline Autogel), improved patients' compliance with long-term therapy, overcoming the inconvenience of multiple daily doses.  It has been reported that somatostatin analogs induce biochemical control and tumor shrinkage in about 50 to 70 % and 30 to 60 % of patients with acromegaly, respectively.

Recommended Treatment for Acromegaly

• Initial therapy

  • Should begin therapy with octreotide injection S.C. in an initial dose of 50 mcg t.i.d.
  • Should be maintained on octreotide injection S.C. for two weeks to determine tolerability. (Doses may range from 100 mcg up to 500 mcg t.i.d. for maximum effect).
  • Members who tolerate drug and are considered “responders” based on GH and IGF‐1 levels can be switched to octreotide LAR depot.

• Continuum Therapy

  • Can be switched to octreotide LAR depot in a dose of 20 mg given IM intragluteally at four week intervals for three months.
  • At the end of three months octreotide LAR depot may be continued at the same level or increased or decreased based on the following regimen:
    • GH ≤2.5 ng/mL, IGF‐1 normal and clinical symptoms controlled: maintain octreotide LAR depot dosage at 20 mg every four weeks
    • GH>2.5 ng/mL IGF‐1 elevated, and/or clinical symptoms uncontrolled, increase octreotide LAR depot dosage to 30 mg every four weeks
    • GH≤ 1ng/mL IGF‐1 normal and clinical symptoms controlled, reduce octreotide LAR depot dosage to 10 mg every four weeks.

• Members whose GH, IGF‐1, and symptoms are not adequately controlled at a dose of 30 mg may have the dose increased to 40 mg every four weeks. Doses higher than 40 mg are not recommended.

Administration of octreotide LAR depot at intervals greater than four weeks is not recommended because there is no adequate information on whether such members could be satisfactorily controlled.

Recommended Treatment for Carcinoid Tumors and VIPomas:

• Initial Therapy - Should begin therapy with octreotide injection S.C.
  • Carcinoid Tumor‐ suggested daily dose during the first two weeks of therapy ranges from 100‐600 mcg/day in two‐to‐four divided doses. (Some members may require up to 1500 mcg/day)
  • VIPomas‐ suggested daily dose is 200‐300 mcg in two‐to‐four divided doses. (Doses in excesses of 450 mcg/day are usually not required).
  • Members should be maintained for two weeks to determine tolerability and then can be switched to octreotide LAR depot.
• Continuum Therapy
  • Can be switched to octreotide LAR depot in a dose of 20 mg given IM intragluteally at four week intervals for two months.
  • Members should continue to receive octreotide injection s.c. for at least two weeks in the same dosage they were taking before the switch in order to reach therapeutically effective levels following initial injection of octreotide LAR depot.
  • After two months of a 20 mg dosage of octreotide LAR depot, dosage may be increased to 30 mg every four weeks if symptoms are not adequately controlled.
  • Members who receive good control on a 20 mg dose may have their dose lowered to 10 mg for a trial period.If symptoms recur, dosage should then be increased to 20 mg every four weeks.
  • Dosages higher than 30 mg are not recommended because there is no information on their usefulness.

Administration of octreotide LAR depot at intervals greater than four weeks is not recommended because there is no adequate information on whether such members could be adequately controlled.

Treatment of Chemotherapy or Radiation Induced Diarrhea

• Recommended Treatment - The optimal dose of Sandostatin Injection has not been established but subcutaneous doses ranging from 100 mcg b.i.d. to 2000 mcg t.i.d. (200 mcg‐6000 mcg/day) and from 50 to 150 mcg per hour by continuous subcutaneous infusion (1200 mcg‐3600 mcg per day) have been reported to be effective. Doses should be titrated to achieve required response. 

A consensus development panel on diarrhea management (Harris et al, 1995) established guidelines for octreotide dose titration in patients with secretory diarrhea.  In general, the panel recommended an aggressive approach in selecting the initial octreotide dose and in making subsequent dose escalations in patients with secretory diarrhea associated with various conditions including carcinoids, VIPomas, AIDS, short bowel syndrome (SBS), radiation therapy, and chemotherapy.  The American Gastroenterological Association (2003) stated that octreotide is rarely needed for SBS.  It should only be used if daily intravenous fluid requirements are greater than 3 liters.

Several meta-analyses indicated that octreotide is useful in the management of patients with acute bleeding of gastroesophageal varices.  Imperiale and co-workers (1995) reported that somatostatin is more effective in controlling acute hemorrhage from esophageal varices and has a lower risk of adverse effects than vasopressin.  Corley and colleagues (2001) stated that their findings favor octreotide over vasopressin/terlipressin in the control of esophageal variceal bleeding and suggest it is a safe and effective adjunctive therapy after variceal obliteration techniques.  Moreover, trials are needed to determine the optimal dose, route, and duration of octreotide treatment.  Gross et al (2001) concluded that ligation is the most effective treatment option for ongoing variceal bleeding.  Additionally, no significant difference was found between the effectiveness of sclerotherapy and treatment with somatostatin or octreotide.  The authors recommended that administration of somatostatin or octreotide may be recommended as 1st-line therapy if ligation is not immediately available.

Erstad (2001) noted that “while additional investigations are needed … there is substantial evidence that octreotide is an effective therapy with relatively few adverse effects when used in the management of acute variceal bleeding”.  Rossle (2003) stated that the recommended standard treatment for acute variceal bleeding consists of immediate drug treatment with terlipressin or octreotide together with early endoscopic band ligation or sclerotherapy.  Furthermore, the United Kingdom guidelines on the management of variceal hemorrhage in cirrhotic patients (Jalan and Hayes, 2000) stated that variceal band ligation is the method of choice to control bleeding.  If banding is difficult because of continued bleeding or this technique is unavailable, endoscopic variceal sclerotherapy should be performed.  If endoscopy is unavailable, vasoconstrictors such as octreotide or glypressin may be used while more definitive therapy is arranged.

While there is adequate evidence that octreotide is beneficial in the management of patients with acute bleeding of gastroesophageal varices, there is insufficient evidence that it is effective in the treatment of acute non-variceal gastrointestinal bleeding.  In this regard, a multidisciplinary consensus group representing 11 national societies does not recommend the use of somatostatin and octreotide in the management of patients with acute non-variceal upper gastrointestinal bleeding (Barkun et al, 2003).

Results from several randomized controlled studies also indicated that octreotide is useful in the management of patients with in-operable malignant bowel obstruction.  Ripamonti et al (2000) stated that such patients should undergo treatment with anti-secretory drugs so as to evaluate the possibility of removing the nasogastric tube.  When a more rapid reduction in gastrointestinal secretions is desired, octreotide should be considered as the drug of choice.  Mercadante and colleagues (2000) reported that octreotide induced a significantly rapid reduction in the number of daily episodes of vomiting and intensity of nausea compared with hyoscine butylbromide at the different time intervals examined.  Octreotide was more effective than hyoscine butylbromide (at the doses used in this study) in controlling gastrointestinal symptoms of bowel obstruction (e.g., nausea, vomiting, and pain).  Furthermore, Mystakidou and associates (2002) concluded that the administration of octreotide, in combination with traditional pharmacological treatment, can be very effective in managing symptoms of in-operable bowel obstruction in terminal cancer patients.

There is ongoing research to expand the therapeutic role of octreotide -- for use in the management of patients with acute pancreatitis, advanced breast cancer, diabetes mellitus, gastric paresis, hepatocellular carcinoma, hormone refractory prostate cancer, obesity, protein-losing enteropathy following the Fontan operation, thyroid cancer, and thyroid eye disease.  However, the effectiveness of octreotide for these indications has not been established.

Hejna et al (2002) stated that there appears to be evidence that somatostatin analogs are able to enhance the therapeutic effects of hormonal intervention in patients with breast cancer, prostate cancer and probably pancreatic cancer.  However, interpretation of these findings is confounded by the fact that patients were heavily pre-treated in some studies and response criteria have not been uniformly applied.  Furthermore, most studies have not been designed to distinguish between receptor-mediated (direct) and indirect effects of somatostatin analogs in tumor patients.  The authors concluded that there can be no doubt about the wide therapeutic index and the high efficacy of somatostatin analogs in the symptomatic management of neuroendocrine tumors.  Apart from these indications, the data do not justify recommendation of these agents as anti-neoplastic drugs outside of clinical trials, as the optimal dose and schedule of application for anti-neoplastic activity has not been defined for currently used agents.  Well-designed clinical studies including investigation of the status of somatostatin receptors before treatment, evaluation of an indirect mechanism of somatostatin analogs, as well as assessment of optimal combination of hormone therapy and chemotherapy with somatostatin analogs are needed.

In a randomized, multi-center prospective trial assessing LAR octreotide plus tamoxifen as a first line therapy for advanced breast carcinoma (n = 203), Bajetta et al (2002) concluded that there is no indication for adding somatostatin analogs to tamoxifen in the treatment of patients with advanced breast carcinoma.

Octreotide has also been used to treat advanced malignant thymoma that is refractory to conventional chemotherapeutic agents.  In a review, Kurup and Loehrer (2004) stated that thymomas and thymic carcinomas, which are rare epithelial tumors arising from the thymus gland, are the most common tumors of the anterior mediastinum.  Thymomas are generally encapsulated, slow-growing tumors that have a “bland” histologic appearance.  Thymic carcinomas possess more overtly malignant histologic features than thymomas and are more likely to present as invasive or disseminated disease.  Surgery is the treatment of choice for localized thymic tumors, with complete resection being the most important prognostic factor.  Complete resection also improves survival in locally invasive thymic tumors.  Adjuvant post-operative radiation therapy may improve the outcome in patients with invasive disease, although the data are conflicting.  Multi-modal regimens, including neoadjuvant combination chemotherapy, surgery, and/or post-operative radiation therapy, are recommended for patients with advanced thymomas and thymic carcinomas.  The authors stated that use of octreotide plus prednisone has produced responses in thymomas, but the dosing and schedule have not been clearly defined.  The authors concluded that prospective studies have been limited, and, as such, enrollment in clinical trials is encouraged.

In a phase II study (Palmieri et al, 2002), 16 patients with advanced thymic tumors, unresponsive to conventional chemotherapeutic regimens, were enrolled in the study.  The schedule included administration of somatostatin analog octreotide (1.5 mg/day subcutaneously) associated with prednisone (0.6 mg/kg/day orally for 3 months, 0.2 mg/kg/day orally during follow-up).  In 8 cases, octreotide was replaced by the long-acting analog lanreotide (30 mg/every 14 days intramuscularly).  Treatment was prolonged until progression of disease was documented.  The overall response rate among 16 evaluable patients was 37 %.  One patient (6 %) had a complete response, 5 (31 %) had a partial response, 6 obtained a stabilization of disease, and 4 progressed during the treatment.  After a median follow-up of 43 months, the median survival was 15 months, and median time to progression was 14 months.  The investigators reported that treatment was generally well-tolerated with acceptable toxicity: cholelithiasis (1 patient), grade 2 cushingoid appearance (3 patients), grade 1 diarrhea (5 patients), grade 2 hyperglycemia (3 patients).  The authors concluded that treatment with somatostatin analogs and prednisone has shown efficacy in patients with recurrent and metastatic malignant thymic tumors refractory to standard therapeutic options.  The results obtained are very satisfactory given the lack of effective alternative treatments.  Such therapy is not burdened by the same toxicity of chemotherapy; thus, it can be administered to heavily pretreated patients.  Somatostatin analogs and prednisone are well-tolerated, and the long-acting analog lanreotide, which requires fewer injections, improves patients' compliance.

In a phase II clinical trial, Loehrer et al (2004) determined the objective response rate, duration of remission and toxicity of octreotide alone or with the later addition of prednisone in patients with unresectable, advanced thymic malignancies in whom the pre-treatment octreotide scan was positive.  A total of 42 patients with advanced thymoma or thymic carcinoma were entered into the trial, of whom 38 were fully assessable (1 patient had inconclusive histology; 3 patients had negative octreotide scan).  Patients received octreotide 0.5 mg subcutaneously three times a day.  At 2 months, patients were evaluated.  Responding patients continued to receive octreotide alone; patients with progressive disease were removed from the study.  All others received prednisone 0.6 mg/kg orally qid for a maximum of 1 year.  Two complete (5.3 %) and 10 partial responses (25 %) were observed (4 partial responses with octreotide alone; the remainder with octreotide plus prednisone).  None of the 6 patients without pure thymoma responded.  The 1- and 2-year survival rates were 86.6 % and 75.7 %, respectively.  Patients with an Eastern Cooperative Oncology Group performance status of 0 lived significantly longer than did those with a performance status of 1 (p = 0.031).  The authors found that octreotide alone has modest activity in patients with octreotide scan-positive thymoma.  The authors noted that prednisone improves the overall response rate but is associated with increased toxicity.  The authors concluded that additional studies with the agent are warranted.

Octreotide has also been evaluated as a treatment for constitutional tall stature.  Noordam et al (2006) stated that an optimal treatment for tall stature in boys in terms of safety and effectiveness is not available.  Treatment with somatostatin analogue 201-995 (SMS) has been tried with positive short-term results.  These investigators assessed the effect of SMS treatment on reducing adult height.  Over 2 years, 16 boys presenting to the authors' university hospital with tall stature (constitutional tall stature (n = 13), Marfan syndrome (n = 2) and tethered spinal cord (n = 1)) with a predicted final height above 197 cm were included in the study and prospectively followed until final height was reached.  As 1 boy was lost to follow-up, these researchers reported on 15 boys.  Treatment with SMS as a single subcutaneous dose was started and continued until final height was reached.  In 8 boys androgens were given to induce puberty after the start of SMS and 5 boys were on treatment with androgens prior to SMS treatment.  Effect on reduction of final height prediction, calculated with the index of potential height based on the bone age of Greulich and Pyle, was the main outcome measure.  Standard anthropometric assessments were performed a year before and every 3 months during treatment.  Bone age was assessed by the method of Greulich and Pyle at the start and after 6 and 12 months.  Mean reduction in final height prediction (predicted adult height minus achieved adult height) was -0.1 cm (range of -6.4 to +5.7).  In 3 boys, asymptomatic microlithiasis of the gall bladder was diagnosed.  The authors concluded that, in spite of encouraging short-term results, long-term treatment with SMS does not reduce final height in a manner sufficient to justify SMS treatment in tall stature.

The efficacy of octreotide in the treatment of angiodysplasias has been limited to case reports and small series, in which a response has been observed in some patients.  Szilagyi and Ghali (2006) stated that vascular malformation (AVM) in the gastrointestinal tract is an uncommon, but not rare, cause of bleeding and iron deficiency anemia, especially in an aging population.  While endoscopic coagulative therapy is the method of choice for controlling bleeding, a substantial number of cases require additional therapy.  Adjunctive or even primary pharmacotherapy may be indicated in recurrent bleeding.  However, there is little evidence-based proof of effectiveness for any agent.  The bulk of support is derived from anecdotal reports or case series.  These researchers compared the outcome of AVM after no intervention, coagulative therapy or focus on pharmacological agents.  Most of the literature encompassed 2 common AVMs, angiodysplasia and hereditary hemorrhagic telangiectasia.  Similarly, the bulk of information evaluated 2 therapies, hormones (estrogen and progesterone) and the somatostatin analogue octreotide.  Of these, the former is the only therapy evaluated in randomized trials, and the results are conflicting without clear guidelines.  The latter therapy has been reported only as case reports and case series without prospective trials.

Octreotide has been investigated as a treatment for small cell lung cancer.  Charpidou and colleagues (2006) evaluated the effectiveness of pegylated liposomal doxorubicin (Caelyx) combined with Sandostatin LAR as salvage treatment of small cell lung cancer (SCLC) in platinum-pretreated patients.  A total of 9 pretreated patients (median age of 53.5 years, performance status [PS]: 0 to 1) with histologically confirmed SCLC were treated intravenously with Caelyx 40 mg/m2 on day 1 and Sandostatin LAR 30 mg (intramuscular) on day 1 every 28 days.  Four (44 %) out of the 9 patients had received 2 prior regimens and 5 (55 %) were refractory to front-line chemotherapy.  No complete or partial responses were observed.  Disease stabilization was obtained in 2 (22 %) patients.  The median overall survival was 18.7 months and the median time to progression was 9.1 months.  The authors concluded that the combination of Caelyx and Sandostatin LAR was inactive as salvage treatment in this poor prognosis group of patients with relapsed SCLC.  However, the combination would merit further investigation in patients pretreated with one prior regimen.

There is evidence to support the use of octreotide for ameliorating volume depletion in enterocutaneous fistulae.  According to Sabiston Textbook of Surgery (Townsend et al, 2007): "The volume depletion that occurs from a proximal small bowel fistula may present a formidable problem.  Agents that inhibit gut motility, such as codeine or diphenoxylate, are generally not helpful.  The long-acting somatostatin analogue octreotide has been used in patients with enterocutaneous fistulas, with a successful decrease in the volume of output.  Some series have reported that octreotide significantly improved the rate of fistula closure, whereas other studies have failed to document this increased closure rate.  However, there is no doubt that octreotide greatly ameliorates the problems associated with a massive volume loss and allows better control of the fistula tract."

A randomized controlled trial of the use of somatostatin in enterocutaneous fistulae by Jamil et al (2004) concluded that "[s]omatostatin and its analogues have shown some beneficial effects with regard to fistula closure rate and hospital stay, but the effects are statistically insignificant....Thus the role of somatostatin is not established in the closure of enterocutaneous fistula".

In a Cochrane review, Jia and colleagues (2010) evaluated the effect of octreotide therapy on the survival of patients with advanced hepatocellular carcinoma (HCC).  The secondary endpoints were to assess tumor response, quality of life and adverse effects.  PUBMED, MEDLINE, OVID and SPRINGER databases were searched through January 2009.  Randomized controlled trials that compared octreotide treatment with placebo or no treatment were selected.  Finally, 4 randomized controlled trials (3 of which were high quality trials) published in 1998 or later with a total of 373 patients were included in this review.  Because a significant clinical heterogeneity existed between the included trials, making meta-analysis inappropriate; only a narrative systematic review was performed.  Of the 3 high-quality trials, only 1 (n = 126) reported octreotide could improve survival and quality of life of HCC patients, whereas the other 2 (n = 189) suggested octreotide did not have survival benefit in HCC; moreover, none of the 3 trials indicated that octreotide has significant beneficial effect on tumor regression or decrease of tumor mass.  Nonetheless, serious adverse effects were not reported in these included trials.  In this review, results from included randomized controlled trials demonstrated no clear benefit of octreotide therapy in advanced HCC patients.  In order to detect a realistic treatment advantage, further larger well-designed multi-center randomized trials will have to be conducted.

In a Cochrane review, Das and Shah (2010) evaluated the safety and effectiveness of octreotide in the treatment of chylothorax in neonates.  These investigators searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE and EMBASE (to March 7, 2010).  They assessed the reference lists of identified trials and abstracts from the annual meetings of the Pediatric Academic Societies published in Pediatric Research (2002 to 2009) without language restrictions.  They planned to include randomized or quasi-randomized controlled trials of octreotide in the treatment of congenital or acquired chylothorax in term or preterm neonates, with any dose, duration or route of administration.  Data on primary (amount of fluid drainage, respiratory support, mortality) and secondary outcomes (side effects) were planned to be collected and analysed using mean difference, relative risk and risk difference with 95 % confidence intervals.  No randomized controlled trials were identified.  A total of 19 case reports of 20 neonates with chylothorax in whom octreotide was used either subcutaneously or intravenously were identified.  Fourteen case reports described successful use (resolution of chylothorax), 4 reported failure (no resolution) and 1 reported equivocal results following use of octreotide.  The timing of initiation, dose, duration and frequency of doses varied markedly.  Gastrointestinal intolerance and clinical presentations suggestive of necrotizing enterocolitis and transient hypothyroidism were reported as side effects.  The authors concluded that no practice recommendation can be made based on the evidence identified in this review.  A prospective registry of chylothorax patients and a subsequent multi-center randomized controlled trial are needed to assess the safety and effectiveness of octreotide in the treatment of chylothorax in neonates.

Congenital Hyperinsulinism

Vieira et al (2010) noted that congenital hyper-insulinism (CHI) of infancy is the most common cause of hypoglycemia in newborns and infants.  Several molecular mechanisms are involved in the development of CHI, but the most common genetic defects are inactivating mutations of the ABCC8 or KCNJ11 genes.  The classical treatment for CHI has been pancreatectomy that eventually leads to diabetes.  More recently, conservative treatment has been attempted in some cases, with encouraging results.  Whether or not the patients with heterozygous ABCC8 mutations submitted to conservative treatment may spontaneously develop type 2 diabetes in the long run, is a controversial issue.  These investigators reported a family carrying the dominant heterozygous germ line E1506K mutation in ABCC8 associated with persistent hypoglycemia in the newborn period and diabetes in adulthood.  The mutation occurred as a de-novo germ line mutation in the mother of the index patient.  Her hypoglycemic symptoms as a child occurred after the 4th year of life and were very mild, but she developed glucose metabolism impairment in adulthood.  On the other hand, in her daughter, the clinical manifestations of the disease occurred in the neonatal period and were more severe, leading to episodes of tonic-clonic seizures that were well controlled with octreotide or diazoxide.  The authors concluded that these findings corroborated the hypothesis that the dominant E1506K ABCC8 mutation, responsible for CHI, predisposed to the development of glucose intolerance and diabetes later in life.

Bas et al (2012) stated that the most common reason for refractory hypoglycemia in newborns is CHI.  These researchers reported a girl with CHI due to novel homozygous mutation (c.2041-25 G>A; aberrant splicing mutation) in the ABCC8 gene encoding SUR1 and during somatostatin analog (octreotide) discontinuation developed by non-hypoglycemic seizures.  The newborn (birth weight of 3,750 g) was referred to the authors’ clinic because of hypoglycemic seizures at 4 hours post-natal.  On admission, blood glucose was 24 mg/dL and intravenous glucose infusion was started.  The patient's insulin level was 27 mIU/ml during the hypoglycemic period.  Phenobarbital (5 mg/ kg/day) was added because of short-acting generalized clonic seizures.  Although the patient received high doses of diazoxide, esidrex, and octreotide approximately for 2 months, hypoglycemic episodes continued.  Then the patient had near-total pancreatectomy, and pathology confirmed a diffuse form of CHI.  There was homozygous mutation in the ABCC8 gene encoding SUR1, which confirmed the diagnosis of autosomal recessive CHI.  During octreotide discontinuation, the patient developed non-hypoglycemic seizures, which were controlled by re-starting the previous doses.  In the light of in-vitro and in-vivo studies on anti-epileptic effects of somatostatin, the authors believed that seizures in this case have developed secondary octreotide discontinuity.

Celik et al (2013) stated that CHI denotes an inappropriate secretion of insulin from pancreatic β-cells in the presence of a low blood glucose level due to various genetic causes.  Diazoxide is the first-line medical treatment for CHI.  In case of failure, a somatostatin analogue called octreotide is used.  A prolonged QT interval is an unusual side effect of octreotide which can be lethal if unrecognized.  These investigators reported on a 35-day old infant who was diagnosed with CHI on the 3rd day of his life and underwent pancreatectomy due to failure of medical treatment at 8 months.  His genetic analysis revealed a compound heterozygosity for a novel missense mutation (p.Met115Val) and a nonsense mutation (p.Trp1339X) in the ABCC8 gene.  Furthermore, at the 6th month of follow-up, a long QT (0.49 s) was determined by ECG examination, which was normalized following discontinuation of octreotide treatment after pancreatectomy.  Thus, the long QT was considered to be secondary to octreotide medication.  The authors recommended ECG monitoring before and during octreotide treatment in order to recognize a prolonged QT interval and to prevent related complications in cases with CHI.

Durmaz et al (2014) noted that hyperinsulinemic hypoglycemia (HH) is the commonest cause of persistent hypoglycemia in the neonatal and infancy periods.  Mutations in the ABCC8 and KCNJ11 genes, which encode subunits of the ATP-sensitive potassium channel in the pancreatic beta cell, are identified in approximately 50 % of these patients.  The first-line drug in the treatment of HH is diazoxide.  Octreotide and glucagon can be used in patients who show no response to diazoxide.  Nifedipine has been shown to be an effective treatment in a small number of patients with diazoxide-unresponsive HH.  These researchers reported a HH patient with a homozygous ABCC8 mutation (p.W1339X) who underwent a near-total pancreatectomy at 2 months of age due to a lack of response to diazoxide and octreotide treatment.  Severe hypoglycemic attacks continued following surgery, while the patient was being treated with octreotide.  These attacks resolved when nifedipine was introduced.  While this patient responded well to nifedipine, the dosage could not be increased to 0.75 mg/kg/day due to development of hypotension, a reported side effect of this drug.  This patient, now aged 4 years, is receiving a combination of nifedipine and octreotide treatment.  He is under good control and shows no side effects.  The authors concluded that nifedipine treatment can be started in patients with HH who showed a poor response to diazoxide and octreotide treatment.

Minute et al (2015) stated that CHI due to diffuse involvement of the pancreas is a challenging and severe illness in children.  Its treatment is based on chronic therapy with diazoxide and/or octreotide, followed by partial pancreatectomy, which is often not resolutive.  Sirolimus, a mammalian target of rapamycin inhibitor, was reported to be effective in treating CHI in infants.  These investigators reported the case of an 8-year old boy affected by a severe form of CHI due to a bi-allelic heterozygous ABCC8 mutation who responded to sirolimus with a dramatic improvement in his glucose blood level regulation and quality of life, with no serious adverse events after 6 months of follow-up.  The authors concluded that this was the first report of a successful intervention in an older child.  It provided a promising basis for further studies comparing sirolimus with other treatments, particularly in older children.

Furthermore, an UpToDate review on “Treatment and complications of persistent hyperinsulinemic hypoglycemia of infancy” (Sunehag and Haymond, 2017) states that “Pharmacologic therapy for hyperinsulinism may involve treatment with diazoxide (a specific ATP-dependent potassium [KATP] channel agonist in normal beta cells), somatostatin analogues (e.g., octreotide), or calcium channel blockers (e.g., nifedipine) …. Somatostatin analogues (e.g., octreotide) can be tried as a second-line therapy to reduce insulin secretion if treatment with diazoxide is unsuccessful”.

Crohn's Disease-Associated Refractory Diarrhea

Martelli and associates (2017) stated that diarrhea is one of the main symptoms of Crohn's disease (CD).  It is usually significantly improved with specific CD treatments, loperamide or cholestyramine.  However, in some cases, diarrhea becomes refractory.  In an uncontrolled, open-label study, these researchers evaluated the safety and effectiveness of octreotide in this situation.  A total of 15 patients with CD refractory diarrhea defined by at least an average of 5 smooth or liquid stools per day despite an optimized CD treatment were included from 3 Belgian centers; 2 patients were lost to follow-up.  A subcutaneous injection of 100 μg octreotide was administered 3 times a day for 3 days.  When the drug had been well-tolerated, an intramuscular injection of 30 mg octreotide (Sandostatin^® LAR 30) was realized; evaluation was carried out at day 31.  The primary end-point was to assess the effect on the mean number of smooth or liquid stools per day.  A significant reduction (p = 0.0001) of the average number of smooth or liquid stools over the last 7 days was observed between baseline and day 31.  The maximum number of smooth or liquid stools also significantly decreased (p = 0.0009); 4 patients (26.7 %) presented mild non-specific adverse events (AEs) but no serious AE.  These investigators also observed a significant decrease (p = 0.0006) of the Harvey-Bradshaw Index (HBI) and a significant improvement (p = 0.0012) of the inflammatory bowel disease questionnaire (IBDQ).  The authors concluded that octreotide appeared safe and effective in CD refractory diarrhea, in addition to CD treatments.  It significantly improved the number of liquid or smooth stools, the HBI and the IBDQ.  These preliminary findings need to be validated by well-designed studies.

Cirrhosis-Associated Hyponatremia

Gastrointestinal Bleeding from Vascular Malformations

Iannone and colleagues (2016) stated that GI vascular malformations are responsible for 2 to 8 % of all cases of bleeding and 30 to 40 % of all obscure hemorrhages, being the most frequent cause of occult bleeding in older people.  These investigators provided an up-to-date review on the use of octreotide in bleeding from both hereditary and acquired vascular malformations of the GI tract.  They performed a systematic literature search using the keywords "gastrointestinal vascular malformation", "octreotide", "angiodysplasia", "portal hypertensive gastropathy", "gastric antral vascular ectasia", and "hereditary vascular malformations".  The 1st line therapy of acute/chronic bleeding from digestive vascular malformations is endoscopy, followed by angiographic embolization and surgical resection when this is unsuccessful.  In the setting of difficult-to-treat patients, octreotide has been proposed as an alternative therapeutic strategy.  Studies reported in the literature showed octreotide to be safe and effective, but described only a small number of enrolled patients, heterogeneous therapeutic schedules and short-term follow-up, with the exception of acute bleeding from esophageal varices.  As a consequence, the use of octreotide is not approved in this setting and it is currently still prescribed as an off-label drug.  The authors concluded that studies in larger populations are needed to confirm the promising results observed in the small case series reports, so as to provide physicians with a therapeutic option for patients without available alternatives.

Lymphorrhea Reduction in Gynecological Malignancies

Weinberger and co-workers (2017) stated that the effect of octreotide on lymphorrhea reduction in gynecological malignancies has only been examined in case studies.  In 2014 there was a prospective, randomized, single-institution study.  Patients underwent surgery including pelvic or pelvic and para-aortic lymphadenectomy for cervical, uterine and ovarian cancers.  Octreotide was evaluated in relation to diagnosis, surgery (laparoscopy versus laparotomy), pelvic and/or para-aortic lymphadenectomy, number of removed lymph nodes and their positivity, neoadjuvant chemotherapy, adjuvant chemotherapy, adjuvant radiotherapy, albumin, body mass index (BMI), number of days with drains post-operatively, number of days in hospital, blood loss during surgery, time of surgery, total number of drains placed into abdominal cavity.  In follow up period, within 1 year after surgery, these investigators searched for lymphocele, lymph-edema of lower extremities and lymphatic ascites in relation to lymphorrhea.  A total of 44 patients (9 cervical, 19 endometrial and 16 ovarian cancers) were enrolled in 2 statistically comparable randomized groups.  "Octreotide group", which paradoxically showed lymphorrhea of 4,082 ml on average, (without 1,992 ml, p = 0.001), needed drainage for more days (p = 0.001).  The diagnosis had no influence on lymphorrhea in both groups (p = 0.966).  Neoadjuvant chemotherapy was administered (p = 0.026), the more lymph nodes were removed (p = 0.018), the more days the drainage was in place (p < 0.001), the bigger the lymphorrhea; no relationship between lymphorrhea and age (p = 0.631), albumin level (p = 0.584), BMI (p= 0.966) or number of positive nodes (p = 0.259), length of surgery (p = 0.206), blood loss (p = 0.494); nor lymphedema (p = 0.404), nor lymphocele (p = 0.086), correlated with post-operative lymphorrhea.  Lymphatic ascites was associated with lymphorrhea (p = 0.048).  The authors concluded that octreotide did not reduce lymphorrhea and the incidence of lymphocele, lymphedema of lower extremities and lymphatic ascites within 1 year of follow-up period after surgery.  Based on these findings, the authors do not recommend the use of octreotide in oncogynecological patients following pelvic and/or para-aortic lymphadenectomy.

Tumor-Induced Osteomalacia

Ovejero and colleagues (2017) noted that tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome in which unregulated hyper-secretion of fibroblast growth factor 23 (FGF23) by phosphaturic mesenchymal tumors (PMT) causes renal phosphate wasting, hypophosphatemia, and osteomalacia.  The resulting mineral homeostasis abnormalities and skeletal manifestations can be reversed with surgical resection of the tumor.  Unfortunately, PMTs are often difficult to locate, and medical treatment with oral phosphate and vitamin D analogs is either insufficient to manage the disease or not tolerated.  Octreotide has been proposed as a potential treatment for TIO due to the presence of SSTR on PMTs; however, the role of somatostatin signaling in PMTs and the effectiveness of treatment of TIOs with somatostatin analogs is unclear.  These researchers  evaluated the effectiveness of octreotide therapy in TIO – 5 subjects with TIO were treated with octreotide for 3 days.  Blood intact FGF23, phosphate, and 1,25(OH)2 D3 , and tubular reabsorption of phosphate (TRP) were measured at frequent time-points during treatment.  Octreotide's effects were examined by comparing group means of the biochemical parameters at each time-point to mean baseline values.  The authors reported that there were no significant changes in blood phosphate, FGF23, 1,25(OH)2 D3 , or TRP during octreotide treatment, consistent with a lack of effectiveness of octreotide in treating TIO.

Cecal Arterio-Venous malformation

Sami and colleagues (2014) stated that angio-dysplasia (AD) of the GI tract is an important condition that can cause significant morbidity and rarely mortality.  These investigators provided an up-to-date comprehensive summary of the literature evaluating this disease entity with a particular focus on pathogenesis as well as current and emerging diagnostic and therapeutic modalities.  Recommendations for treatment will be made on the basis of the current available evidence and consensus opinion of the authors.  These researchers performed a systematic literature search, which used the keywords “angiodysplasia” or “arteriovenous malformation” or “angioectasia” or “vascular ectasia” or “vascular lesions” or “vascular abnormalities” or “vascular malformations” in the title or abstract.  Most AD lesions (54 to 81.9 %) were detected in the caecum and ascending colon.  They may develop secondary to chronic low-grade intermittent obstruction of submucosal veins coupled with increased vascular endothelial growth factor (VEGF)-dependent proliferation.  Endo-therapy with argon plasma coagulation resolved bleeding in 85 % of patients with colonic AD.  In patients who failed (or were not suitable for) other interventions, treatment with thalidomide or octreotide could lead to a clinically meaningful response in 71.4 % and 77 % of patients, respectively.  The authors concluded that AD is a rare cause of both overt and occult GI bleeding especially in the older patients.  Advances in endoscopic imaging and therapeutic techniques have led to improved outcomes in these patients.  The choice of treatment should be decided on a patient-by-patient basis.  They stated that further research is needed to better understand the pathogenesis and identify potential therapeutic targets.

Dumping Syndrome

Didden and colleagues (2006) stated octreotide therapy is effective in controlling severe dumping symptoms during short-term follow-up but little is known about long-term results.  These investigators reported on the long-term results of patients with severe dumping syndrome treated with subcutaneous or depot IM (long-acting release) octreotide.  They followed-up 34 patients with severe dumping syndrome refractory to other therapeutic measures treated between 1987 and 2005 with octreotide subcutaneous/long-acting release.  At regular intervals symptoms, quality of life (QOL), weight, fecal fat excretion and gallstone formation were evaluated.  All patients had excellent initial relief of symptoms during octreotide subcutaneous therapy.  However, during follow-up 16 patients stopped therapy because of side effects (n = 9) or loss of efficacy (n = 7); 4 patients died.  A total of 14 patients (41 %) remained using octreotide (follow-up 93 +/- 15 months), 7 were on octreotide subcutaneous and 7 on octreotide long-acting release.  Patients with severe dumping (both early and late) fared better on subcutaneous than long-acting release despite the inconvenience of frequent injections.  Dumping symptoms were reduced by 50 % even in long-term users.  Body weight continued to increase during therapy despite more pronounced steatorrhea.  The authors concluded that the long-term the efficacy of octreotide was much less favorable compared with short-term treatment.

Peeters and associates (2010) evaluated the research that has been conducted into the use of Sandostatin to control the debilitating symptoms of diarrhea in a number of different etiologies.  These were cancer-related diarrheas, including diarrhea related to chemotherapy, radiotherapy, neuroendocrine tumor carcinoid syndrome, VIP-secreting tumors and also non-cancer related diarrhea, including SBS, ileostomy and jejunostomy, dumping syndrome, graft versus host disease (GVHD) and AIDS-related diarrhea.  There is an increasing recognition of the need to balance the cost of care with patient outcome.  It is becoming clear that although the cost of a therapeutic regimen with Sandostatin is substantially greater than the current non-specific therapy, the overall cost is potentially greater without the use of Sandostatin for patients with refractory diarrhea due to the inevitable need for further treatment and/or hospitalization with intravenous fluid supplementation.  Initial trials and reports from pre-clinical testing and clinical practice have shown promising results and, although in the majority of cases they strengthened the view taken in the published consensus guidelines for the use of Sandostatin for refractory diarrhea.  The authors stated that further, larger scale, comparative clinical trials are needed for any evidence-based definition of dosage and efficacy as a treatment or prophylactic agent to combat and control diarrhea.

Sato and colleagues (2013) noted that dumping syndrome, or rapid gastric emptying, is a frequent complication after gastric surgery.  In this case, the patient was a 47-year old woman who 10 years previously had undergone distal gastrectomy with Billroth I reconstruction for early-stage gastric cancer.  She presented with symptoms of weakness, headache, palpitation, sweating, dizziness and significant fatigue between 1 and 2 hours after a meal.  Because a 75 g oral glucose tolerance test (75 g-OGTT) induced both acute post-prandial tachycardia (within 1 hour) and post-prandial hypoglycemia, these investigators diagnosed this patient with early and late dumping syndrome.  Dietary measures and acarbose improved symptoms of late dumping syndrome but did not prevent the symptoms of early dumping syndrome such as post-prandial tachycardia, weakness, headache, palpitation, and dizziness.  Thus, they used octreotide, which has been reported as an effective therapy for early dumping syndrome.  Octreotide prevented the symptoms of early dumping syndrome, especially post-prandial tachycardia, but caused post-prandial hyperglycemia.  Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) were completely suppressed during the 75 g-OGTT following subcutaneous injection of octreotide.  No change was observed in VIP, which is the GI peptide hormone generally responsible for early dumping syndrome, suggesting possible contribution of incretins in early dumping syndrome of this patient.

The authors stated that this study had several drawbacks.  Although octreotide improved symptoms of dumping syndrome, octreotide inhibited both insulin secretion per se, and incretins, during a 75g-OGTT.  It was difficult to conclude whether the inhibitory effects of octreotide on incretins were a direct effect of GLP-1 on vasodilatation or an indirect effect via insulin secretion from pancreatic β-cells.  These researchers were also unable to measure enteroglucagon, peptide YY, pancreatic polypeptide and neurotensin.  It was possible that octreotide improved symptoms through one of these hormones.  Further study is needed to explore this.  These investigators treated this patient with octreotide for several times, but did not continue this therapy because of the past history of cholelithiasis and post-prandial hyperglycemia.  The authors stated that these data suggested that increased secretion of GLP-1 and GIP might be an alternative mechanism leading to the occurrence of early dumping syndrome.

Mohammadi and co-workers (2017) noted that hypoglycemia due to late dumping is a significant problem post-esophagectomy but may not always be diagnosed sufficiently early.  It can be difficult to treat and may severely compromise QOL.  These investigators reported on the case of a patient who developed severe hypoglycemic episodes post‐esophagectomy who failed to respond to conventional measures, but was treated with pasireotide with moderately effective hypoglycemic control.  The authors concluded that the combination of diazoxide and octreotide and particularly pasireotide my transform the patient's life and should be considered in all problematic cases.

Furthermore, an UpToDate review on “Postgastrectomy complications” (Ashley, 2018) states that “Most patients with dumping can be treated conservatively with dietary changes (frequent small meals that are high in fiber and protein and low in carbohydrates, separation of liquid from solid during meals).  Symptoms tend to resolve in most patients as they learn to avoid foods that aggravate the problem (e.g., simple sugar).  Octreotide may also help in severe cases of dumping but is rarely required.  A study of 30 patients with dumping treated with either subcutaneous octreotide, administered 3 times a day, or its long-acting formulation (Octreotide LAR), which is given monthly, reported that both significantly reduced dumping symptoms and improved quality of life”.

Spinal Paraganglioma

Yin et al (2017) stated that paraganglioma rarely develops in the spine.  With few cases reported, little knowledge about this disease was known.  These investigators illustrated the clinical features, imaging manifestations, pathological appearances and long-term outcomes of the consecutive surgeries by literature review.  The clinical and follow-up data of 18 patients who were diagnosed of spinal paraganglioma and treated with surgeries in the authors’ hospitals from 2003 to 2014 were retrospectively analyzed.  A total of 14 patients radiographed of intra-spinal tumor underwent extra-capsular tumor resection.  Of 5 patients with obvious vertebral bone damage, 4 cases underwent piecemeal resection, and the left one with sacral tumor underwent en bloc tumor excision.  Spinal reconstruction was performed in all cases.  Follow-up lasted for 16 to 96 months (average of 44.1 months).  There was no local recurrence or distant metastasis in cases without obvious bone invasion.  Of those 5 cases with vertebral bone damage, 1 case suffered and survived from the repeat relapse of T1 vertebral body tumor.  Local recurrence was not observed in 1 case with T10 vertebral tumor after tumor resection, but the tumor metastasized to T2 attachment during the follow-up and was finally eradicated by re-operation.  No tumor recurrence was observed in the remaining 3 cases.  The authors concluded that paraganglioma, usually benign, rarely occurs.  Surgical resection, especially complete surgical resection, is preferred to treat spinal paraganglioma.  Chemotherapy, radiotherapy, use of octreotide and other somatostatin are selected as adjuvant therapies, but their effects remain unknown.

Furthermore, National Comprehensive Cancer Network’s Drugs & Biologics Compendium (2018) does not list paraganglioma as a recommended indication of octreotide acetate (LAR).

Lanreotide (Somatuline Depot)

Lanreotide is an octapeptide analog of natural somatostatin. The mechanism of action is believed to be similar to that of natural somatostatin.

Somatuline Depot (lanreotide) is indicated for: the long‐term treatment of acromegalic patients who have had an inadequate response to or cannot be treated with surgery and/or radiotherapy the treatment of adult patients with unresectable, well‐ or moderately‐differentiated, locally advanced or metastatic gastroenteropancreatic tumors (GEP‐NETs) to improve progression‐free survival

In August 2007, the FDA approved lanreotide injection (Somatuline Depot) for the long-term treatment of patients with acromegaly who have had an inadequate response to or can not be treated with surgery and/or radiotherapy.  The most common side effects (incidence greater than 5 %) associated with lanreotide injection are diarrhea, cholelithiasis, abdominal pain, nausea, injection site reaction, flatulence, arthralgia, and loose stools.

The recommended dose of lanreotide for acromegaly is 90 mg given via deep subcutaneous route, at four week intervals for three months.

After three months, dosage may be adjusted as follows:

• GH > 1 to ≤ 2.5 ng/mL, IGF‐1 normal and clinical symptoms controlled: maintain Somatuline Depot dose at 90 mg every four weeks.
• GH > 2.5 ng.mL, IGF‐1 elevated and/or clinical symptoms uncontrolled, increase Somatuline Depot dose to 120 mg every four weeks.
• GH ≤1 ng/mL, IGF‐1 normal and clinical symptoms controlled: reduce Somatuline Depot dose to 60 mg every four weeks.

The recommended dose of lanreotide for gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is 120 mg administered every 4 weeks by deep subcutaneous injection.

Lanreotide may reduce gallbladder motility and lead to a gallstone formation therefore, patients may need to be monitored periodically.

Patients treated with lanreotide may experience hypoglycemia or hyperglycemia. Blood glucose levels should be monitored when lanreotide treatment is initiated or when the dose is altered, and antidiabetic treatment should be adjusted accordingly.

Decrease in heart rate may occur. Use with caution in at‐risk patients.

Samonakis et al (2008) noted that somatostatin (SST) acts as an inhibitory peptide of various secretory and proliferative processes.  Apart from neuroendocrine tumors, where SST analogs have an established role, they have been tested in other tumors such as hepatocellular carcinoma (HCC).  Several positive reports have been published.  Approximately 40 % of patients respond with improved survival and an impressive quality of life.  A usual misunderstanding in trial designs is that, although SST is not a rescue drug, selection of patients is inappropriate, with mostly moribund patients being recruited.  Somatostatin analogs do not seem to work in 60 % of HCCs and this has been linked to the presence of SST receptors (SSTR) in the tumor, while several resistance mechanisms might be involved.  Future management should engage more specific SST analogs targeted to a tumor with a known SSTR map.  The use of SST analogs as an adjunct therapy in combination with other treatment modalities should also be investigated.

Mitsogiannis and colleagues (2009) stated that despite initial sensitivity to hormone treatment, prostate cancer eventually progresses to a castration-resistant stage (CRPC), which carries an ominous prognosis.  Lanreotide has been shown to be highly effective in treating various hyper-secretory disorders and tumors.  It has been given to patients with CRPC within a novel treatment concept, with the aim of targeting not only cancer cells but also various factors secreted in the tumor cell milieu that confer protection from apoptosis.  Within this concept, lanreotide has been administered as part of the "anti-survival factor therapy" in combination with dexamethasone and a gonadotropin releasing hormone (GnRH) analog.  It has also been given combined with estrogens in patients with CRPC.  The so far published series have documented a clinical response in many patients treated along with significant improvement in parameters related to quality of life.  The authors concluded that in view of these promising results, large-scale, randomized, controlled trials are needed to clearly define the exact role of lanreotide and other SST analogs in the treatment of patients with CRPC.

In a randomized, cross-over, placebo-controlled trial, Ruggenenti and colleagues (2005) compared the risk/benefit profile of 6-month treatment with octreotide LAR depot (40 mg intramuscularly every 28 days) or placebo in autosomal-dominant polycystic kidney disease (ADPKD) patients with mild-to-moderate renal insufficiency and no evidence of other kidney disease.  Volumes of kidney structures were evaluated by a 2-slice computed tomography (CT) scanner; while glomerular filtration rate (GFR) was estimated by iohexol plasma clearance.  One patient on octreotide and 1 on placebo were prematurely withdrawn because of non-symptomatic, reversible colelithiasis and asthenia, respectively.  In the remaining 12 patients octreotide was well-tolerated.  Kidney volume increased by 71 +/- 107 ml (p < 0.05) on octroetide and by 162 +/- 114 ml (p < 0.01) on placebo.  The percent increase was significantly lower on octroetide (2.2 +/- 3.7 % versus 5.9 +/- 5.4 %) (p < 0.05).  Cystic volume tended to increase less on octreotide than on placebo (3.0 +/- 6.5 % versus 5.6 +/- 5.8 %).  The "parenchymal" volume non-significantly increased by 2.5 +/- 8.4 % on placebo and slightly decreased by 4.4 +/- 8.9 % on octreotide.  The GFR did not change significantly during both treatment periods.  The authors concluded that in ADPKD patients, 6-month octreotide therapy is safe and may slow renal volume expansion.  This may reflect an inhibited growth in particular of smallest cysts beyond the detection threshold of CT scan evaluation.  Whether this effect may prove reno-protective in the long-term should be tested in additional trials of longer duration.

Edelstein (2008) noted that ADPKD is the most common life-threatening hereditary disease in the United States and causes end-stage renal failure requiring dialysis and renal transplantation.  There is no effective treatment for ADPKD in humans.  However, there are now multiple clinical trials testing a host of therapeutic interventions in children and adults with ADPKD.  The major therapeutic interventions being tested in patients with ADPKD include everolimus, octreotide, sirolimus, statins, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers.

Hogan et al (2010) enrolled 42 patients with severe polycystic liver disease (PLD) resulting from ADPKD or autosomal dominant PLD (ADPLD) in a randomized, double-blind, placebo-controlled trial of octreotide.  These researchers randomly assigned 42 patients in a 2:1 ratio to octreotide LAR depot (up to 40 mg every 28 +/ -5 days) or placebo for 1 year.  The primary end point was percent change in liver volume from baseline to 1 year, measured by MRI.  Secondary end points were changes in total kidney volume, GFR, quality of life, safety, vital signs, and clinical laboratory tests.  Thirty-four patients had ADPKD, and 8 had ADPLD.  Liver volume decreased by 4.95 % +/- 6.77 % in the octreotide group but remained practically unchanged (+0.92 % +/- 8.33 %) in the placebo group (p = 0.048).  Among patients with ADPKD, total kidney volume remained practically unchanged (+0.25 % +/- 7.53 %) in the octreotide group but increased by 8.61 % +/- 10.07 % in the placebo group (p = 0.045).  Changes in GFR were similar in both groups.  Octreotide was well-tolerated; treated individuals reported an improved perception of bodily pain and physical activity.  The authors concluded that octreotide slowed the progressive increase in liver volume and total kidney volume, improved health perception among patients with PLD, and had an acceptable side effect profile.

Hutchinson et al (2010) described a case of obscure gastrointestinal bleeding in a male with non-cirrhotic portal hypertension who required multiple admissions and repeated blood transfusions over a 5-month period.  Upper and lower gastrointestinal endoscopy failed to establish a cause for bleeding, which was eventually ascribed to universal portal hypertensive stigmata in stomach, small bowel and colon, which were not amenable to endoscopic therapy.  On account of extensive venous thrombosis, neither surgical shunting nor interventional radiology was an option.  Initial management with prothrombotic agents failed.  This patient was successfully stabilized on long-acting somatostatin (SMS) analog therapy using lanreotide, resulting in avoidance of further admissions and blood transfusion and restoration of his independence and quality of life.  The use of short-acting SMS analogs is recognized in acute variceal hemorrhage secondary to portal hypertension in cirrhosis, and long-acting SMS analog therapy has been described in obscure gastrointestinal bleeding though secondary to angiodysplasia.  However, the potential role of long-term SMS analogs in non-cirrhotic portal hypertensive bleeding of this type has not been reported earlier.  This case supports its use in this scenario in the absence of surgical options and when only palliative approaches are available.

Brown et al (2010) reviewed pooled clinical response rates from prospective studies using somatostatin analogs for prevention of recurrent bleeding from gastrointestinal angiodysplasia and quantified the effects that therapy has on the use of blood transfusions.  These investigators searched several electronic databases including PubMed for full journal articles published after 1966 reporting on the use of somatostatin analogs in the treatment of gastrointestinal angiodyplasia.  They hand searched the reference lists of all retrieved articles.  Prospective studies involving 10 or more patients were included in the analysis.  They calculated the pooled proportion of patients who had a clinical response to therapy in the selected studies and the weighted mean difference (MD) in transfusion requirements before and after therapy.  Heterogeneity between the studies was assessed using the I2 statistic.  A total of 3 studies involving 62 patients met the inclusion criteria.  The proportional meta-analysis showed a clinical response to treatment of 0.76 (95 % confidence intervals [CI]: 0.64 to 0.85).  The weighted MD in transfusion requirements before starting therapy (control group) and after treatment initiation (treatment group) was -2.2 (95 % CI: -3.9 to -0.5).  No significant heterogeneity was seen between the studies.  The authors concluded that a significant number of patients with bleeding gastrointestinal angiodysplasia respond to treatment with octreotide by reducing the need for blood products.  They stated that, however, as all the included studies had small sample sizes, multi-center randomized trials are needed to confirm these findings.

In a Cochrane review, Gurusamy et al (2010) examined if prophylactic somatostatin analogs should be used routinely in pancreatic surgery.  These investigators searched the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, issue 4), MEDLINE, EMBASE and Science Citation Index Expanded to November 2009.  They included randomized controlled trials comparing prophylactic somatostatin or one of its analogs versus no drug or placebo during pancreatic surgery (irrespective of language or publication status).  Two authors independently assessed trials for inclusion and independently extracted data.  They analyzed data with both the fixed-effect and the random-effects models using Review Manager (RevMan).  They calculated the risk ratio (RR), MD or standardized mean difference (SMD) with 95 % CI based on an intention-to-treat or available case analysis.  When it was not possible to perform either of the above, these researchers performed per protocol analysis.  A total of 17 trials (of high risk of bias) involving 2,143 patients were identified.  The overall number of patients with post-operative complications was lower in the somatostatin analog group (RR 0.71; 95 % CI: 0.62 to 0.82) but there was no difference in the peri-operative mortality, re-operation rate or hospital stay between the groups.  The incidence of pancreatic fistula was lower in the somatostatin analog group (RR 0.64; 95 % CI: 0.53 to 0.78).  The proportion of these fistulas that were clinically significant was not mentioned in most trials.  On inclusion of trials that clearly distinguished clinically significant fistulas, there was no difference between the two groups (RR 0.69; 95 % CI: 0.34 to 1.41).  Subgroup analysis revealed a shorter hospital stay in the somatostatin analog group than the controls for patients with malignant etiology (MD -7.57; 95 % CI: -11.29 to -3.84).  The authors concluded that somatostatin analogs reduce peri-operative complications but do not reduce peri-operative mortality.  In those undergoing pancreatic surgery for malignancy, they shorten hospital stay.  Further adequately powered trials with low risk of bias are necessary.  Based on the current available evidence, the authors recommended somatostatin and its analogs for routine use in patients undergoing pancreatic resection for malignancy.  There is currently no evidence to support their routine use in pancreatic surgeries performed for other indications.

O'Toole and colleagues (2000) stated that the somatostatin analogs lanreotide and octreotide have previously been shown to be effective in controlling flushing and diarrhea in patients with carcinoid syndrome.  As lanreotide requires injection only every 10 days, compared with twice-daily injections of octreotide, a direct comparison between these 2 treatments in terms of patient acceptability, patient preference, and efficacy in controlling symptoms was performed in patients with carcinoid syndrome.  A total of 33 patients with carcinoid syndrome were included in an open, multi-center, cross-over study.  Half of the patients received octreotide 200 microg subcutaneously twice- or thrice-daily for 1 month followed by lanreotide 30 mg intramuscularly every 10 days for 1 month, while the other 50 % commenced with lanreotide followed by octreotide in a similar fashion.  Quality-of-life assessments were performed at each visit and patient preference for one of the two treatments evaluated.  The number and intensity of flushing episodes and bowel movements, urinary 5- hydroxy indole acetic acid (5-HIAA) levels, and plasma serotonin levels were recorded.  No significant differences were found between lanreotide and octreotide in terms of quality-of- life.  The majority of patients (68 %) preferred lanreotide (p = 0.03), largely due to its simplified mode of administration.  Disappearance or improvement in flushes occurred in 53.8 % of patients (14 of 26) while on lanreotide and in 68 % (17 of 25) on octreotide.  A disappearance or improvement of diarrhea in 45.4 % (10 of 22) on lanreotide, compared with 50 % (11 of 22) on octreotide, was also observed.  Lanreotide and octreotide were equally effective in reducing urinary 5-HIAA levels and plasma serotonin levels.  Both treatments were well-tolerated, with mild symptoms of abdominal pain and nausea observed in 29 % and 14 % receiving octreotide and lanreotide, respectively.  The authors concluded that lanreotide and octreotide are equally efficacious in terms of symptom control and reduction in tumor cell markers for patients with carcinoid syndrome.  Due to its simplified mode of administration, most patients prefer treatment with lanreotide.

In a 6-month, open, non-controlled, multi-center, dose-titration study, Ruszniewski et al (2004) evaluated the efficacy and safety of 28-day prolonged-release (PR) lanreotide in the treatment of carcinoid syndrome.  Eligible patients had a carcinoid tumor with greater than or equal to 3 stools/day and/or greater than or equal to 1 moderate/severe flushing episodes/day.  Six treatments of 28-day PR lanreotide were administered by deep subcutaneous injection.  The dose for the first 2 injections was 90 mg.  Subsequent doses could be titrated (60, 90, 120 mg) according to symptom response.  A total of 71 patients were treated.  Flushing decreased from a mean of 3.0 at baseline to 2.3 on day 1, and 2.0 on day 2, with a daily mean of 2.1 for the first week post-treatment (p < 0.05).  Diarrhea decreased from a mean of 5.0 at baseline to 4.3 on day 1 (p < 0.05), and 4.5 on day 2, with a daily mean of 4.4 for the first week post-treatment (p < 0.001).  Symptom frequency decreased further after the second and third injections, and reached a plateau after the 4rth injection.  By month 6, flushing and diarrhea had significantly decreased from baseline by a mean of 1.3 and 1.1 episodes/day, respectively (both p < or = 0.001); 65 % of patients with flushing as the target symptom and 18 % of diarrhea-target patients achieved greater than or equal to 50 % reduction from baseline.  Median urinary 5-HIAA and chromogranin A levels decreased by 24 and 38 %, respectively.  Treatment was well-tolerated; 28-day PR lanreotide was effective in reducing the symptoms and biochemical markers associated with carcinoid syndrome.

Khan et al (2011) presented long-term results of prolonged release lanreotide in a large cohort of patients with malignant carcinoid syndrome, assessing clinical and objective response and tolerance.  A total of 76 patients with metastatic midgut neuroendocrine tumors and carcinoid syndrome were included in this 9-year retrospective study.  Clinical response was based on symptom score with radiological assessment based on RECIST (Response Evaluation Criteria In Solid Tumours).  Data were available in 69 patients; 94 % achieved symptomatic response at first follow-up visit; 46 % had loss of symptomatic response, but 44 % of these achieved control with an increase in dose of prolonged release lanreotide.  Overall, symptoms were well-controlled throughout the study period with prolonged release lanreotide alone in 74 % of patients; 26 % required additional treatment despite good initial response.  Only 30 % demonstrated radiological progression.  Eleven patients who were switched from octreotide LAR had return of symptomatic control.  No significant adverse effects were experienced.  The authors concluded that prolonged release lanreotide provides good symptomatic control of diarrhea and flushing as well as tumor stability in patients with malignant carcinoid syndrome.

Also, an UpToDate review on "Treatment of the carcinoid syndrome" (Goldfinger and Strosberg, 2012) states that "[w]e usually begin therapy with octreotide LAR 20 to 30 mg every four weeks.  Depot lanreotide is another alternative to octreotide LAR".

Guidelines from the National Comprehensive Cancer Network (NCCN, 2014) recommend octreotide acetate and long-acting octreotide acetate (LAR) for the following indications:

• Meningiomas - Treatment for surgically inaccessible recurrent or progressive meningiomas when further radiation is not possible.
• Lung neuroendocrine tumors - Consider for stage IIIb (T4 due to multiple lung nodules)-IV if octreotide scan positive or for symptoms of carcinoid syndrome.
• Neuroendocrine tumors of the adrenal gland - Consider for symptom control if somatostatin scintigraphy positive in patients with non-adrenocorticotropic hormone-dependent Cushing's syndrome with tumors less than 4 cm, benign imaging characteristics, and abnormal contralateral gland and symmetric cortisol production.
• Neuroendocrine tumors of the gastrointestinal tract, lung, and thymus
   
  
  • Treatment of underlying Zollinger-Ellison syndrome.
  • Management of unresectable locoregional disease and/or distant metastases as
    
    
    • tumor control
    • symptom control in patients with carcinoid syndrome
    • supplemental treatment for breakthrough symptoms in patients taking long-acting octreotide (short-acting octreotide only).
       
• Neuroendocrine tumors of the pancreas
  
  
  • Treatment of symptoms related to hormone hypersecretion.
  • Consider for tumor control in patients with unresectable locoregional disease and/or metastatic disease and clinically significant tumor burden or clinically significant progression if not already given (long-acting octreotide only).
     
• Poorly differentiated (high-grade)/large or small cell neuroendocrine tumors - Consider for symptom control if somatostatin scintigraphy positive.
• Thymomas and thymic carcinomas - Second-line therapy with or without prednisone following radiation therapy for locally advanced unresectable disease (short-acting octreotide only).

Guidelines from the National Comprehensive Cancer Network on neuroendocrine tumors (2013) recommend lanreotide as an alternative to octreotide for symptomatic relief from neuroendocrine tumors (carcinoid tumors, neuroendocrine tumors of the pancreas (islet cell tumors), pheochromocytoma/paraganglioma, and poorly differentiated neuroendocrine tumors). The NCCN guidelines state that lanreotide is approved for symptom control in Europe. Lanreotide has a similar mechanism of action as octreotide and may be preferable in patients who have difficulty tolerating an intramuscular (IM) versus subcutaneous (SC) injection.

In December 2014, Somatuline Depot was FDA-approved to improve progression-free survival (PFS) in patients with unresectable, well- or moderately- differentiated locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs). FDA approval for the treatment of GEP-NETs indication was based on a multicenter, randomized, double-blind, placebo-controlled trial of 204 patients (median age 63 yrs) with unresectable, well or moderately differentiated, metastatic or locally advanced, gastroenteropancreatic neuroendocrine tumors. “Patients were randomized to receive Somatuline Depot 120 mg (n=101) or placebo (n=103) every 4 weeks until disease progression, unacceptable toxicity, or a maximum of 96 weeks of treatment. Randomization was stratified by the presence or absence of prior therapy and by the presence or absence of disease progression within 6 months of enrollment. The major efficacy outcome measure was progression-free survival, defined as time to disease progression as assessed by central independent radiological review using the Response Evaluation Criteria in Solid Tumors (RECIST 1.0) or death. Disease progression was present in 9 of 204 patients (4.4%) in the 6 months prior to enrollment and 29 patients (14%) received prior chemotherapy. Ninety-one patients (45%) had primary sites of disease in the pancreas, with the remainder originating in the midgut (35%), hindgut (7%), or unknown primary location (13%). The majority (69%) of the study population had grade 1 tumors. Baseline prognostic characteristics were similar between arms with one exception; there were 39% of patients in the Somatuline Depot arm and 27% of patients in the placebo arm who had hepatic involvement by tumor of greater than 25%. Patients on the Somatuline Depot arm had a statistically significant improvement in progression-free survival compared to patients receiving placebo” (FDA, 2017).

NCCN guidelines (2014) recommend lanreotide for the following indications:

• Neuroendocrine tumors of the adrenal gland - Consider for symptom control if somatostatin scintigraphy positive in patients with non-adrenocorticotropic hormone-dependent Cushing's syndrome with tumors less than 4 cm, benign imaging characteristics, and abnormal contralateral gland and symmetric cortisol production.
• Neuroendocrine tumors of the gastrointestinal tract, lung, and thymus 
   
  
  • Treatment of underlying Zollinger-Ellison syndrome.
  • Management of unresectable locoregional disease and/or distant metastases as
    
    
    • tumor control
    • symptom control in patients with carcinoid syndrome
       
• Neuroendocrine tumors of the pancreas
   
  
  • Treatment of symptoms related to hormone hypersecretion.
  • Consider for tumor control in patients with unresectable locoregional disease and/or metastatic disease and clinically significant tumor burden or clinically significant progression if not already given.
     
• Poorly differentiated (high-grade)/large or small cell neuroendocrine tumors - Consider for symptom control if somatostatin scintigraphy positive.

The Alberta Provincial CNS Tumour Team’s clinical practice guideline on “Pituitary adenomas” (2012) stated that standard treatment options [for growth hormone- and thyroid stimulating hormone-secreting adenomas] include surgery (usually a trans-sphenoidal approach), bromocriptine, somatostatin analog (e.g., octreotide), growth-hormone antagonist, or surgery plus post-operative radiotherapy.  Maximal reductions in growth-hormone levels may not be seen for years after institution of radiotherapy, during which time medical therapy may continue to be required.

Also, an UpToDate review on “Thyrotropin (TSH)-secreting pituitary adenomas” (Weiss and Refetoff, 2013) states that “The somatostatin analogue octreotide is effective in nearly all patients.  One series evaluated 73 patients treated with octreotide (50 to 750 micrograms given subcutaneously two or three times daily), most of whom had already undergone surgery …. The most appropriate therapy for patients with TSH-secreting pituitary adenomas is transsphenoidal resection of the tumor.  Transsphenoidal resection results in cure in about one-third of patients, improvement in one-third, and no change in one-third.  Because of the relatively poor results of surgery, many patients need additional therapy (e.g., dopamine agonists, octreotide)”.

Drymousis et al (2013) examined if the prophylactic administration of somatostatin or somatostatin analogs in patients undergoing pancreaticoduodenectomy (Whipple's procedure) is beneficial in terms of improved surgical outcomes, reduced morbidity or reduced mortality.  A total of 118 papers were found using the reported searches of which 5 represented the best evidence (1 meta-analysis, 1 systematic review and 3 randomized control trials).  The authors, date, journal, study type, population, main outcome measures and results were tabulated.  There is evidence that the peri-operative administration of somatostatin or somatostatin analogs reduces biochemical incidence of pancreatic fistula but, it is still unclear if there is a beneficial effect in the incidence of clinically significant pancreatic fistula.  The authors concluded that further adequately powered trials with low-risk of bias are necessary.  From the available data, somatostatin or somatostatin analogs have no effect on mortality post-pancreaticoduodenectomy.

Furthermore, an UpToDate review on “Pancreaticoduodenectomy (Whipple procedure): Techniques” (Reber, 2013) does not mention the prophylactic use of octreotide or somatostatin analogs.

In a meta-analysis, Xu and colleagues (2013) evaluated the safety and effectiveness of octreotide on primary moderate-to-severe acute pancreatitis.  The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, PubMed, EMBASE, Science Citation Index Expanded (SCI-E), and Chinese Biomedicine Database (CBM) were searched in September 2011.  Major outcomes contained mortality, incidence rate of complications, rate of surgical intervention, and length of hospital stay.  A total of 11 randomized clinical trials (RCTs) with 720 participants were included and evaluated, only 2 of which had a high study quality and were combined in meta-analysis.  The pool estimate of RR of mortality was 0.88 (95 % CI: 0.53 to 1.45) and that of incidence rate of complication was 1.08 (95 % CI: 0.94 to 1.26); both of which had no significant difference.  The other 2 outcomes could not be combined for lack of enough data.  The authors concluded that present evidence does not approve octreotide's benefit in the major health outcomes of moderate-to-severe acute pancreatitis and further RCTs with high quality and large sample size are needed.

In a multi-center, randomized, single-blind, placebo-controlled, parallel-group trial, Caroli et al (2013) examined the effect of 3 years of octreotide-LAR treatment on kidney and cyst growth and renal function decline in participants with polycystic kidney disease.  Adult (greater than 18 years) patients with estimated GFR of 40 ml/min per 1.73 m(2) or higher were randomly assigned (central allocation by phone with a computerized list, 1:1 ratio, stratified by center, block size 4 and 8) to 3 year treatment with two 20-mg IM injections of octreotide-LAR (n = 40) or 0.9 % sodium chloride solution (n = 39) every 28 days.  Study physicians and nurses were aware of the allocated group; participants and outcome assessors were masked to allocation.  The primary end-point was change in total kidney volume (TKV), measured by MRI, at 1 year and 3 year follow-up.  Analyses were by modified intention-to-treat.  Recruitment was between April 27, 2006, and May 12, 2008.  A total of 38 patients in the octreotide-LAR group and 37 patients in the placebo group had evaluable MRI scans at 1 year follow-up, at this time-point, mean TKV increased significantly less in the octreotide-LAR group (46.2 ml, SE 18.2) compared with the placebo group (143.7 ml, 26.0; p = 0.032).  A total of 35 patients in each group had evaluable MRI scans at 3 year follow-up, at this time-point, mean TKV increase in the octreotide-LAR group (220.1 ml, 49.1) was numerically smaller than in the placebo group (454.3 ml, 80.8), but the difference was not significant (p = 0.25); 37 (92.5 %) participants in the octreotide-LAR group and 32 (82.1 %) in the placebo group had at least 1 adverse event (p = 0·16).  Participants with serious adverse events were similarly distributed in the 2 treatment groups.  However, 4 cases of cholelithiasis or acute cholecystitis occurred in the octreotide-LAR group and were probably treatment-related.  The authors concluded that these findings provided the background for large RCTs to test the protective effect of somatostatin analogs against renal function loss and progression to end-stage kidney disease.

Sideris et al (2012) noted that for decades, somatostatin analogs ([SAs]; including octreotide and lanreotide) have been indicated for relief of the symptoms of flushing, diarrhea, and wheezing associated with secretory neuroendocrine tumors (NETs).  Recently, it has been suggested that SAs may provide direct and indirect anti-tumor effects in secretory and non-secretory NETs in addition to symptom control in secretory NETs.  These investigators performed a systematic review of Medline to identify studies that examined the anti-tumor effects of octreotide or lanreotide for patients with NETs.  Additional studies not published in the peer-reviewed literature were identified by searching online abstracts.  In all, 17 octreotide trials and 11 lanreotide trials that included anti-tumor effects were identified.  Partial response rates were between 0 % and 31 %, and stable disease rates were between 15 % and 89 %.  Octreotide was the only SA for which results of a phase III, randomized, placebo-controlled clinical trial (PROMID) that investigated anti-tumor effects were published.  After 6 months of treatment in this randomized phase III trial, stable disease was observed in 67 % of patients (hazard ratio [HR] for time to disease progression: 0.34; 95 % CI: 0.20 to 0.59; p = 0.000072).  The authors concluded that in addition to symptom control for NETs, the data supported an anti-tumor effect of SAs and suggested that they may slow tumor growth.  Long-acting repeatable octreotide has been shown to have an anti-tumor effect in a randomized phase III trial in mid-gut NETs, whereas results are pending in a corresponding controlled trial (CLARINET) with lanreotide for patients with intestinal and pancreatic primary NETs.

Toumpanakis and Caplin (2013) stated that SAs are the standard of care for controlling symptoms of patients with functional gastroenteropancreatic neuroendocrine tumors (GEP-NETs).  Somatostatin analogs control symptoms in more than 70 % of patients with carcinoid syndrome.  Similar results are obtained in patients with functional, hormone-secreting, pancreatic NETs.  The use of SAs as anti-proliferative agents has been established only recently.  Retrospective studies have shown stabilization of tumor growth in greater than 50 % of patients with progressive disease.  The results of a recent randomized phase III trial (PROMID [Placebo-Controlled, Double-Blind, Prospective, Randomized Study on the Effect of Octreotide LAR in the Control of Tumor Growth in Patients with Metastatic Neuroendocrine Midgut Tumors]) demonstrated that the median time to progression in patients with mid-gut carcinoid tumors treated with octreotide LAR was more than twice as long compared to that of patients treated with placebo.  The results of a phase III study (CLARINET) of lanreotide versus placebo in non-functional NETs are not yet available.  More studies are needed to determine whether combining SAs with novel targeted treatments will result in enhanced anti-proliferative activity compared to treatment with a SA alone.  Studies are ongoing using pan-receptor agonists (e.g., pasireotide) and chimeric dimers, which possess features of somatostatin and dopamine agonists (dopastatins) and are thought to enhance symptom control by binding multiple receptors (somatostatin and dopamine receptors).  Somatostatin receptor antagonists are also currently being developed for clinical use.  Peptide receptor radionuclide therapy, consisting of yttrium-90 and lutetium-177 isotopes conjugated with SAs, appeared to be effective in advanced NETs.  The authors concluded that randomized studies are needed to definitively establish the safety and effectiveness of this strategy compared to other available treatments, and to determine which radiolabeled isotopes or combinations are most effective.

Caplin and colleagues (2014) noted that SAs are commonly used to treat symptoms associated with hormone hyper-secretion in neuroendocrine tumors; however, data on their anti-tumor effects are limited.  In a randomized, double-blind, placebo-controlled, multi-national study, these investigators examined the effects of lanreotide in patients with advanced, well-differentiated or moderately differentiated, non-functioning, somatostatin receptor-positive neuroendocrine tumors of grade 1 or 2 (a tumor proliferation index [on staining for the Ki-67 antigen] of less than 10 %) and documented disease-progression status.  The tumors originated in the pancreas, mid-gut, or hind-gut or were of unknown origin.  Patients were randomly assigned to receive an extended-release aqueous-gel formulation of lanreotide (Autogel [known in the United States as Depot], Ipsen) at a dose of 120 mg (101 patients) or placebo (103 patients) once every 28 days for 96 weeks.  The primary end-point was progression-free survival (PFS), defined as the time to disease progression (according to the RECIST, version 1.0) or death.  Secondary end-points included overall survival (OS), quality of life (assessed with the European Organization for Research and Treatment of Cancer questionnaires QLQ-C30 and QLQ-GI.NET21), and safety.  Most patients (96 %) had no tumor progression in the 3 to 6 months before randomization, and 33 % had hepatic tumor volumes greater than 25 %.  Lanreotide, as compared with placebo, was associated with significantly prolonged PFS (median not reached versus median of 18.0 months, p < 0.001 by the stratified log-rank test; HR for progression or death, 0.47; 95 % CI: 0.30 to 0.73).  The estimated rates of PFS at 24 months were 65.1 % (95 % CI: 54.0 to 74.1) in the lanreotide group and 33.0 % (95 % CI: 23.0 to 43.3) in the placebo group.  The therapeutic effect in pre-defined subgroups was generally consistent with that in the overall population, with the exception of small subgroups in which confidence intervals were wide.  There were no significant between-group differences in quality of life or OS.  The most common treatment-related adverse event was diarrhea (in 26 % of the patients in the lanreotide group and 9 % of those in the placebo group).  The authors concluded that lanreotide was associated with significantly prolonged PFS among patients with metastatic enteropancreatic neuroendocrine tumors of grade 1 or 2 (Ki-67 less than 10 %).

An UpToDate review on “Metastatic pancreatic neuroendocrine tumors and poorly differentiated gastroenteropancreatic neuroendocrine carcinomas: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion” (Chan et al, 2014) states that “Lanreotide, another long-acting somatostatin analog, can be self-administered once monthly using a deep subcutaneous injection and appears to have similar efficacy to octreotide.  While available internationally, it is currently approved only for the treatment of acromegaly in the United States”.

On September 18, 2017, Ipsen Biopharmaceuticals, Inc. announced the U.S. FDA approval of Somatuline Depot (lanreotide) injection 120 mg for the treatment of carcinoid syndrome, which when used, reduces the frequency of short-acting somatostatin analogue rescue therapy (Ipsen, 2017).

FDA approval for the carcinoid syndrome treatment indication was based on a multicenter, randomized, 16-week, double-blind, placebo-controlled trial (Study 4). The trial included 115 patients with histopathologically-confirmed neuroendocrine tumors and a history of carcinoid syndrome (flushing and/or diarrhea) who were treatment naïve or stable on another somatostatin analog and who were randomized 1:1 to receive Somatuline Depot 120 mg (n=59) or placebo (n=56) by deep subcutaneous injection every 4 weeks. The mean patient age was 59 years old (range 27 to 85 years). “Patients were instructed to self-administer a short-acting somatostatin analog (octreotide) as rescue medication as needed for symptom control. The use of rescue therapy and the severity and frequency of diarrhea and flushing symptoms were reported daily in electronic patient diaries. During the 16 week double-blind phase, the primary efficacy outcome measure was the percentage of days in which patients administered at least one injection of rescue medication for symptom control. Average daily frequencies of diarrhea and flushing events were assessed secondarily.” “Patients in the Somatuline Depot arm experienced 15% fewer days on rescue medication compared to patients in the placebo arm (34% vs. 49% of days, respectively; p=0.02). The average daily frequencies of diarrhea and flushing events in patients treated with Somatuline Depot (and rescue medication) were numerically lower relative to patients treated with placebo (and rescue medication), but were not statistically significantly different via hierarchical testing” (FDA, 2017).

The most common adverse reactions occurring in “greater than 10% of patient who received Somatuline Depot in the GEP-NET trial were abdominal pain (34%), musculoskeletal pain (19%), vomiting (19%), headache (16%), injection site reaction (15%), hyperglycemia (14%), hypertension (14%), and cholelithiasis (14%). Adverse reactions occurring in the carcinoid syndrome trial were generally similar to those in the GEP-NET trial. Adverse reactions occurring in greater than 5% of patients who received Somatuline Depot in the carcinoid syndrome trial and occurring at least 5% greater than placebo were headache (12%), dizziness (7%) and muscle spasm (5%)” (Ipsen, 2017).

Pasireotide Diaspartate (Signifor)

Pasireotide is a somatostatin analogue that binds to multiple somatostatin receptor subtypes found in various human tissues. Binding of pasireotide to these receptors causes inhibition of adrenocorticotropic hormone (ACTH) secretion which, in turn, leads to decreased cortisol secretion. The debilitating manifestations of Cushing’s disease are associated with excess cortisol.

Signifor (pasireotide) is indicated for the treatment of adult patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative.

Cushing’s disease is a rare and life‐threatening endocrine disorder that results from long‐term exposure to excess levels of the hormone, cortisol. This excess is caused by a pituitary tumor that prompts the over‐production of cortisol. The first‐line approach is surgery to remove the tumor.

Titrate dosage based on treatment response (ie. clinically meaningful reduction in 24‐hour urinary free cortisol (UFC) and/or improvements in signs and symptoms of disease) and tolerability

Testing Prior to Dosing: fasting plasma glucose, hemoglobin A1c, liver tests, electrocardiogram (ECG), and gallbladder ultrasound

Dosing Adjustments in Patients with Hepatic Impairment:

• Child Pugh B: Recommended initial dosage is 0.3 mg twice a day and maximum dosage is 0.6 mg twice a day
• Child Pugh C: Avoid use in these patients

Urinary Free Cortisol (UFC) is a biochemical marker of hypercortisolism.

Pasireotide is mainly eliminated by biliary excretion. Cholelithiasis has been frequently reported with pasireotide. Performing gallbladder ultrasounds before starting treatment and at 6‐month intervals is recommended.

The recommended initial dosage of Signifor (pasireotide) for Cushing's disease is 0.6mg or 0.9mg given by subcutaneous injection twice daily. The dosage range is 0.3mg to 0.9mg twice daily based on treatment response, tolerability, and hepatic impairment.

Pasireotide Pamoate (Signifor LAR)

Pasireotide pamoate is a long‐acting cyclohexapeptide analog of natural somatostatin. The mechanism of action is believed to be similar to that of natural somatostatin which binds to somatostatin receptors on neuroendocrine tissue such as those found in growth hormone (GH) secreting pituitary adenomas. These tumors produce high levels of GH and insulin‐like growth factor‐1 (IGF‐1) which are associated with acromegaly. As with pasireotide diaspartate, pasireotide pamoate also binds and activates the SSTRs resulting in inhibition of ACTH secretion, which leads to decreased cortisol secretion.

On December 15, 2014, the FDA approved Signifor LAR injectable suspension, for intramuscular use, as an orphan drug for the treatment of patients with acromegaly who have had an inadequate response to surgery and/or for whom surgery is not an option (Novartis, 2014).

The FDA approval was based on two multicenter phase III studies, C2305 and C2402, which respectively examined medically naïve patients who have had prior surgery or for whom surgery was not an option and patients with acromegaly inadequately controlled on first generation somatostatin analogues. In both studies, higher rates of full biochemical control (defined as mean GH level < 2.5mcg/L and normal IGF-1 levels) were achieved with pasireotide compared to a first generation somatostatin analog. 

The C2305 study was a multicenter, randomized, double-blind study in patients with active acromegaly who were not previously treated with medication (medically naïve), and had persistent disease despite prior surgery or were ineligible for surgery. Patients were randomized to receive either pasireotide (starting dose of 40 mg with possibility to up-titrate to 60 mg) or the active comparator. 

The efficacy endpoint of proportion of patients achieving full GH and IGF-1 biochemical control at month 12 was met. Specifically, the percentage of patients achieving biochemical control was 31.3% for pasireotide and 19.2% for the active comparator (p < .01 for treatment difference). Biochemical control was achieved early in the study (i.e., month 3) by 30.1% of patients in the pasireotide arm.  Ninety-eight percent of patients treated with pasireotide had either a reduction or no change in tumor volume from baseline as assessed by MRI at month 12. Additionally, ring size and acromegaly symptoms score (i.e., headache, fatigue, perspiration, paresthesia or tingling sensation in limbs, and osteoarthralgia or joint pain) were followed. At month 12, reductions in ring size and in symptom severity scores in both treatment groups compared to baseline were noted.

The most common adverse events with pasireotide versus the active comparator in this study were diarrhea (39% vs. 45%), cholelithiasis (26% vs. 36%), hyperglycemia (29% vs. 8%) and diabetes mellitus (26% vs. 4%). 

The C2402 study was a randomized study evaluating the efficacy and safety of double-blind pasireotide (40 mg and 60 mg) versus continued open-label pre-trial somatostatin analog therapies at maximal or near maximal doses in 198 patients with inadequately controlled acromegaly. Inadequate control was defined as mean GH level > 2.5 mcg/L and IGF-1 > 1.3 times the sex- and age-adjusted upper normal limit. 

The efficacy endpoint of the proportion of patients achieving biochemical control, as defined by GH and IGF-1 levels, at 6 months with pasireotide 40 mg or 60 mg versus continued pre-trial somatostatin analog therapy, was met for both pasireotide doses. Specifically, 15.4% and 20.0% of patients treated with pasireotide 40 mg and 60 mg, respectively, achieved full GH and IGF-1 biochemical control at 6 months compared with 0% in the pre-trial therapy somatostatin analog control arm. Biochemical control was achieved by month 3 in 15.4% and 18.5% of patients in the pasireotide 40 mg and 60 mg arms, respectively. Eighty-one percent and 70% of patients treated with pasireotide 40 mg and 60 mg, respectively, had either a reduction or no change in tumor volume from baseline as assessed by MRI at month 6. 

The most common adverse events associated with pasireotide 40 mg, 60 mg and pre-trial somatostatin analog therapies in this study were hyperglycemia (33%, 30%, 14%) and diabetes mellitus (21%, 31%, 9%).

On June 29, 2018, the FDA also approed Signifor LAR for the treatment of patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative. The FDA approved Signifor LAR for Cushing's disease based on results from a Phase 3, randomized, double-blind, multicenter study that evaluated the safety and efficacy of two dose regimens of Signifor LAR over a 12-month treatment period in patients with persistent or recurrent Cushing’s disease, or de novo patients who were not considered candidates for pituitary surgery (G2304 Study group; Lacroix et al 2018) .

Lacroix et al (2018) stated Cushing's disease is a rare debilitating endocrine disorder for which few prospective interventional studies have been done. The authors report results of the first phase 3 trial assessing long-acting intramuscular pasireotide in patients with Cushing's disease. This trial recruited patients aged 18 years or older with persistent, recurrent, or de-novo (non-surgical candidates) Cushing's disease who had a mean urinary free cortisol (mUFC) concentration (from three 24 h samples) of 1·5-5·0 times the upper limit of normal (ULN), a normal or greater than normal morning plasma adrenocorticotropic hormone concentration, and a pituitary source of Cushing's syndrome, from 57 sites across 19 countries. Patients were excluded if they had received previous pasireotide treatment, mitotane therapy within 6 months, and pituitary irradiation within 10 years. The patients were randomly allocated 1:1 (block size of four) using an interactive-response-technology system to intramuscular pasireotide 10 mg or 30 mg every 4 weeks for 12 months (in the core phase). The authors stratified randomisation by screening mUFC concentration (1·5 to less than 2·0 × ULN and 2·0-5·0 × ULN). The dose could be uptitrated (from 10 mg to 30 mg or from 30 mg to 40 mg) at month 4 if the mUFC concentration was greater than 1·5 × ULN, and at month 7, month 9, or month 12 if the mUFC concentration was greater than 1·0 × ULN. Investigators, patients, site personnel, and those assessing outcomes were masked to dose group allocation. The primary endpoint was the proportion of patients in each group with an mUFC concentration of less than or equal to the ULN at month 7. Efficacy analyses were based on intention to treat. Between Dec 28, 2011, and Dec 9, 2014, 150 patients were randomly allocated to receive pasireotide 10 mg (74 [49%] patients) or 30 mg (76 [51%] patients). The primary efficacy endpoint was met by 31 (41·9% [95% CI 30·5-53·9]) of 74 patients in the 10 mg group and 31 (40·8% [29·7-52·7]) of 76 in the 30 mg group.

The most common adverse events were hyperglycaemia (36 [49%] in the 10 mg group and 36 [47%] in the 30 mg group), diarrhoea (26 [35%] and 33 [43%]), cholelithiasis (15 [20%] and 34 [45%]), diabetes mellitus (14 [19%] and 18 [24%]), and nausea (15 [20%] and 16 [21%]). Serious adverse events suspected to be study drug related were reported in eight (11%) patients in the 10 mg group and four (5%) in the 30 mg group. Two (3%) patients in the 30 mg group died during the study (pulmonary artery thrombosis and cardiorespiratory failure); neither death was judged to be related to the study drug. The authors concluded that long-acting pasireotide normalised mUFC concentration in about 40% of patients with Cushing's disease at month 7 and had a similar safety profile to that of twice-daily subcutaneous pasireotide. Long-acting pasireotide is an efficacious treatment option for some patients with Cushing's disease who have persistent or recurrent disease after initial surgery or are not surgical candidates, and provides a convenient monthly administration schedule.

The initial dose of pasireotide (Signifor LAR) for acromegaly is 40 mg by intramuscular injection once every 4 weeks (every 28 days). The initial dose of pasireotide (Signifor LAR) for Cushing’s Disease is 10 mg by intramuscular injection once every 4 weeks (every 28 days). The product labeling recommends that dosing be adjusted based upon biochemical response and tolerability and for patients with moderately impaired hepatic function (Child-Pugh B).

Signifor LAR must be reconstituted immediately before use and administered by a trained healthcare professional.

Recommended tests prior to dosing: fasting plasma glucose, hemoglobin A1c, liver tests, electrocardiogram (ECG), and gallbladder ultrasound.

After 3 months of initial treatment with 40 mg every 28 days, the dose may be increased to a maximum of 60 mg for patients who have not normalized growth hormone (GH) and/or age and sex adjusted insulin‐like growth factor‐1 (IGF‐1) levels and who tolerate this dose. In patients with moderate hepatic impairment (Child‐Pugh B), the recommended initial dose is 20mg every 28 days up to a maximum dose of 40mg. Avoid use in patients with severe hepatic impairment (Child‐Pugh C).

Management of adverse reactions or over‐response to treatment (age and sex adjusted IGF‐1 less than the lower limit of normal) may require dose reduction. The dose may be decreased, either temporarily or permanently, by 20 mg decrements.

Adverse drug reactions associated with pasireotide and occurring in ≥ 20% of patients were diarrhea, cholelithiasis, hyperglycemia and diabetes mellitus. Warnings include hyperglycemia and diabetes, sometimes severe. The labeling recommends monitoring of glucose levels periodically during therapy. Other warnings include bradycardia and QT Prolongation. The labeling recommends use with caution in at-risk patients. ECG and electrolytes should be evaluated prior to dosing and periodically while on treatment. The labeling states that patients should also be monitored for elevated liver enzymes, cholelithiasis and pituitary hormone deficiencies.

Pasireotide is mainly eliminated by biliary excretion. Cholelithiasis has been frequently reported with pasireotide. Performing gallbladder ultrasounds before starting treatment and at 6‐month intervals is recommended.

Prevention and Treatment of Pancreatic Fistulas Following Pancreatic Surgery

Machado (2012) stated that resection of pancreas, especially pancreaticoduodenectomy, is a complex procedure, usually performed in selected patients with benign and malignant disease of the pancreas and peri-ampullary region.  Despite significant improvements in the safety and effectiveness of pancreatic surgery, pancreatico-enteric anastomosis continues to be the “Achilles heel” of pancreaticoduodenectomy, due to its association with a measurable risk of leakage or failure of healing, leading to pancreatic fistula.  The morbidity rate after pancreaticoduodenectomy remains high in the range of 30 % to 65 %, although the mortality has significantly dropped to below 5 %.  Most of these complications are related to pancreatic fistula, with serious complications of intra-abdominal abscess, post-operative bleeding, and multi-organ failure.  Several pharmacological and technical interventions have been suggested to decrease the pancreatic fistula rate, but the results have been controversial.

In a Cochrane review, Gurusamy and associates (2013) examined if prophylactic somatostatin analogs should be used routinely in pancreatic surgery.  These investigators searched the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 1), MEDLINE, EMBASE and Science Citation Index Expanded to February 2013.  They included RCTs comparing prophylactic somatostatin or one of its analogs versus no drug or placebo during pancreatic surgery (irrespective of language or publication status).  Two review authors independently assessed trials for inclusion and independently extracted data.  They analyzed data with both the fixed-effect and random-effects models using Review Manager (RevMan).  They calculated the RR, MD or SMD with 95 % CI based on an intention-to-treat or available case analysis.  When it was not possible to perform either of the above, these researchers performed a per protocol analysis.  They identified 21 trials (19 trials of high risk of bias) involving 2,348 people.  There was no significant difference in the peri-operative mortality (RR 0.80; 95 % CI: 0.56 to 1.16; n = 2,210) or the number of people with drug-related adverse effects between the 2 groups (RR 2.09; 95 % CI: 0.83 to 5.24; n = 1,199).  Quality of life was not reported in any of the trials.  The overall number of participants with post-operative complications was significantly lower in the somatostatin analog group (RR 0.70; 95 % CI: 0.61 to 0.80; n = 1,903); but there was no significant difference in the re-operation rate (RR 1.26; 95 % CI: 0.58 to 2.70; n = 687) or hospital stay (MD -1.29 days; 95 % CI: -2.60 to 0.03; n = 1,314) between the groups.  The incidence of pancreatic fistula was lower in the somatostatin analog group (RR 0.66; 95 % CI: 0.55 to 0.79; n = 2,206).  The proportion of these fistulas that were clinically significant was not mentioned in most trials.  On inclusion of trials that clearly distinguished clinically significant fistulas, there was no significant difference between the 2 groups (RR 0.69; 95 % CI: 0.38 to 1.28; n = 292).  The authors concluded that somatostatin analogs may reduce peri-operative complications but do not reduce peri-operative mortality.  Further adequately powered trials with low risk of bias are necessary.  Moreover, they stated that based on the current available evidence, somatostatin and its analogs are recommended for routine use in people undergoing pancreatic resection.

Allen and colleagues (2014) conducted a single-center, randomized, double-blind trial of peri-operative subcutaneous pasireotide (a somatostatin analog that has a longer half-life than octreotide and a broader binding profile) in patients undergoing either pancreaticoduodenectomy or distal pancreatectomy.  These researchers randomly assigned 300 patients to receive 900 μg of subcutaneous pasireotide (152 patients) or placebo (148 patients) twice-daily beginning pre-operatively on the morning of the operation and continuing for 7 days (14 doses).  Randomization was stratified according to the type of resection and whether the pancreatic duct was dilated at the site of transection.  The primary end-point was the development of pancreatic fistula, leak, or abscess of grade 3 or higher (i.e., requiring drainage).  The primary end-point occurred in 45 of the 300 patients (15 %).  The rate of grade 3 or higher post-operative pancreatic fistula, leak, or abscess was significantly lower among patients who received pasireotide than among patients who received placebo (9 % versus 21 %; RR, 0.44; 95 % CI: 0.24 to 0.78; p = 0.006).  This finding was consistent among 220 patients who underwent pancreaticoduodenectomy (10 % versus 21 %; RR, 0.49; 95 % CI: 0.25 to 0.95) and 80 patients who underwent distal pancreatectomy (7 % versus 23 %; RR, 0.32; 95 % CI: 0.10 to 0.99), as well as among 136 patients with a dilated pancreatic duct (2 % versus 15 %; RR, 0.11; 95 % CI: 0.02 to 0.60) and 164 patients with a non-dilated pancreatic duct (15 % versus 27 %; RR, 0.55; 95 % CI: 0.29 to 1.01).  The authors concluded that peri-operative treatment with pasireotide decreased the rate of clinically significant post-operative pancreatic fistula, leak, or abscess.

An UpToDate review on “Pancreatic fistulas: Management” (Vege and Kendrick, 2015) states that “Supportive care for PFs includes somatostatin analogue, octreotide (100 micrograms subcutaneously three times a day) in patients with high-output PFs or those that result in electrolyte abnormalities or skin breakdown.  Somatostatin preparations may be effective in the reduction of fistula output but not the rate of fistula closure.  In a 2012 meta-analysis of seven randomized trials that included 297 patients of which 102 had pancreatic fistulas, closure rates were not significantly higher in patients treated with somatostatin analogues as compared with controls”.

Congenital Lymphedema

An UpToDate review on “Prevention and treatment of lymphedema” (Mohler and Mondry, 2015) does not mention octreotide as a therapeutic option.

Uveal Melanoma

In a phase-II clinical trial, Shoushtari and colleagues (2016) tested the hypothesis that inhibiting mammalian target of rapamycin and insulin-like growth factor-1 receptor would be effective in metastatic uveal melanoma.  This was a study of everolimus 10-mg daily plus pasireotide long-acting release (LAR) 60-mg every 28 days enrolling patients with progressive, metastatic uveal melanoma to treatment until progression by RECIST 1.1 or unacceptable toxicity.  The primary end-point was clinical benefit rate, defined as any objective response or RECIST 1.1 stable disease at 16 weeks.  A subset of patients underwent baseline indium-111-octreotide scans.  A total of 14 patients were enrolled, of which 13 were evaluable for the primary end-point, before the study was terminated due to poor accrual; 3 of 13 (26 %) patients obtained clinical benefit; 7 of 13 (54 %) had stable disease lasting for a median of 8 weeks (range of 8 to 16 weeks).  Grade-3 AEs deemed at least possibly related to study drugs were hyperglycemia (n = 7), oral mucositis (n = 2), diarrhea (n = 1), hypophosphatemia (n = 1), and anemia (n = 1); 7 of 14 (50 %) patients required at least 1 dose reduction due to toxicity; 7 of 8 (88 %) patients with baseline indium-111-octreotide scans had at least 1 avid lesion, with significant intra-patient heterogeneity.  There was a trend toward an association between octreotide avidity and cytostatic response to therapy (p = 0.078).  The authors concluded that the combination of everolimus and pasireotide had limited clinical benefit in this small metastatic uveal melanoma cohort.  They stated that further investigation into the relationship between somatostatin receptor expression and cytostatic activity of somatostatin analogs is needed.

Appendix

Sandostatin Dosing

Octreotide acetate injection is available in ampules and vials containing:

• 50 mcg/mL ampule
• 100 mcg/mL ampule
• 500 mcg/mL ampule

Octreotide acetate injection is available in multi dose vials containing:

• 200 mcg/mL vial
• 1000 mcg/mL vial

Octreotide acetate injection is available in a single dose syringe as follows:

• 50 mcg/mL
• 100 mcg/mL
• 500 mcg/mL

Octreotide acetate is available as Sandostatin LAR Depot in single dose vials:

• 10 mcg
• 20 mcg
• 30 mcg

The FDA-approved labeling of Sandostatin (octreotide acetate) injection has the following recommendations regarding dosage and administration:

• Patients not currently receiving Sandostatin Injection subcutaneously:
  • Acromegaly: 50 mcg three times daily Sandostatin Injection subcutaneously for 2 weeks followed by Sandostatin LAR 20 mg intragluteally every 4 weeks for 3 months.
  • Carcinoid Tumors and VIPomas: Sandostatin Injection subcutaneously 100-600 mcg/day in 2-4 divided doses for 2 weeks followed by Sandostatin LAR 20 mg every 4 weeks for 2 months.
• Patients currently receiving Sandostatin Injection subcutaneously:
  • Acromegaly: 20 mg every 4 weeks for 3 months
  • Carcinoid Tumors and VIPomas: 20 mg every 4 weeks for 2 months
• Renal Impairment, patients on dialysis: 10 mg every 4 weeks
• Hepatic Impairment, patients with cirrhosis: 10 mg every 4 weeks

Somatuline Depot Dosing

Lanreotide is available as Somatuline Depot Injection as 60 mg, 90 mg, and 120 mg in a pre‐filled syringe.

The FDA-approved labeling of Somatuline Depot (lanreotide) injection has the following recommendations regarding dosage and administration:

• Deep subcutaneous injection into the superior external quadrant of the buttock. Injection site should be alternated between the right and left sides from one injection to the next.
• Acromegaly: recommended starting dose is 90 mg every 4 weeks for 3 months. After 3 months, dosage may be adjusted based on GH and/or IGF-1 levels. Dose range is 60 mg to 120 mg.
  
  • Patients who are controlled on Somatuline Depot 60 or 90 mg may be considered for an extended dosing interval of 120 mg every 6 or 8 weeks.
  • GH and IGF-1 levels should be obtained 6 weeks after this change in dosing regimen to evaluate persistence of patient response.
  • Moderate and Severe Renal and Hepatic Impairment: Initial dose is 60 mg every 4 weeks for 3 months. Adjust thereafter based on GH and/or IGF-1 levels.
• GEP-NETs: 120 mg every 4 weeks. Somatuline Depot has not been studied in patients with hepatic impairment for this indication.
• Carcinoid Syndrome: 120 mg every 4 weeks. If patient is already being treated with Somatuline Depot for GEP-NET, do not administer an additional dose for treatment of carcinoid syndrome.
  

Signifor Dosing

Pasireotide is available as Signifor for injection in 0.3 mg/mL, 0.6 mg/mL, and 0.9 mg/mL single‐dose ampules.

The recommended initial dosage of Signifor (pasireotide) is 0.6 mg or 0.9 mg given by subcutaneous injection twice-daily. The dosage range is 0.3 mg to 0. 9 mg twice-daily based on treatment response, tolerability, and hepatic impairment.

Signifor LAR Dosing

Pasireotide pamoate for injectable suspension is available as Signifor LAR in 10 mg, 20 mg, 30 mg, 40 mg, and 60 mg, powder in a vial to be reconstituted with the provided 2 mL diluent. 

The FDA-approved labeling of Signifor LAR injection has the following recommendations for dosing and administration: 

• The initial dose is 40 mg by intramuscular injection once every 4 weeks (every 28 days) for acromegaly.
• The initial dose is 10 mg by intramuscular injection once every 4 weeks (every 28 days) for Cushing's disease.
• Adjust dose based on biochemical response and tolerability. 
• Evaluate fasting plasma glucose, hemoglobin A1c, liver enzyme tests, electrocardiogram (ECG), serum magnesium and serum potassium prior to starting. 
• Optimize glucose control in patients with poorly controlled diabetes mellitus prior to starting.
• Patients with Hepatic Impairment:
  • Child Pugh B: For acromegaly, the recommended initial dose is 20 mg every 4 weeks and maximum dose is 40 mg every 4 weeks; For Cushing's disease, the recommended initial dose is 10 mg once every 4 weeks and maximum dose is 20 mg once every 4 weeks.
  • Child Pugh C: Avoid use in these patients.
• Follow reconstitution and administration instructions.
  
  

The above policy is based on the following references: