Clinical UM Guideline

 

Subject: Octreotide acetate (Sandostatin®; Sandostatin® LAR Depot)
Guideline #:  CG-DRUG-45 Publish Date:    12/27/2017
Status: Revised Last Review Date:    11/02/2017

Description

 

This document addresses the clinical uses of octreotide acetate (Sandostatin, and Sandostatin LAR Depot, Sandoz GmbH, Schaftenau, Austria [Novartis Pharmaceuticals Corporation, East Hanover, NY, USA]), approved by the U.S. Food and Drug Administration (FDA) to treat acromegaly, carcinoid tumors, vasoactive intestinal peptide tumors, and used as off-label treatment for other conditions. Both drugs are somatostatin analogues, an acetate salt of a long-acting cyclic octapeptide with pharmacologic properties mimicking those of the natural hormone somatostatin.

 

Clinical Indications

Medically Necessary:

I.  Acromegaly

Octreotide acetate (Sandostatin, Sandostatin LAR Depot) is considered medically necessary for the treatment of acromegaly in individuals who have had an inadequate response to or cannot be treated with one or more of the following:

  1. Surgical resection; or
  2. Pituitary irradiation; or
  3. Bromocriptine mesylate at maximally tolerated doses.

II.  Carcinoid Tumors (Well-differentiated Neuroendocrine Tumors)

  1. Octreotide acetate (Sandostatin, Sandostatin LAR Depot) is considered medically necessary for carcinoid tumors for any of the following indications:
    1. Metastatic carcinoid tumors; or
    2. Carcinoid syndrome to suppress or inhibit severe diarrhea and flushing episodes associated with the disease; or
    3. Prophylactic administration prior to biopsy in an individual with a suspected functioning carcinoid tumor; or
    4. Prophylactic administration prior to induction of anesthesia in an individual with a functional carcinoid tumor; or
    5. Prophylactic administration perioperatively to a surgical procedure in an individual with a functional carcinoid tumor.
  2. Supplemental treatment with short-acting octreotide acetate (Sandostatin) is considered medically necessary for rapid relief of symptoms or for breakthrough symptoms in individuals taking long-acting octreotide acetate (Sandostatin LAR Depot) when any of the criteria are met for carcinoid tumors.

III.  Other Neuroendocrine Tumors

  1. Octreotide acetate (Sandostatin, Sandostatin LAR Depot) is considered medically necessary for neuroendocrine tumors for any of the following indications:
    1. Management of unresectable locoregional disease or distant metastasis; or
    2. As treatment of the profuse watery diarrhea associated with VIPomas; or
    3. Treatment of underlying hypergastrinemic Zollinger-Ellison syndrome; or
    4. Prophylactic treatment prior to surgery for gastrinoma.
  2. Supplemental treatment with short-acting octreotide acetate (Sandostatin) is considered medically necessary for rapid relief of symptoms or for breakthrough symptoms in individuals taking long-acting octreotide acetate (Sandostatin LAR Depot) when any of the criteria are met for neuroendocrine tumors.

IV.  Other Indications

  1. Octreotide acetate (Sandostatin, Sandostatin LAR Depot) is considered medically necessary for an individual when criteria are met for any of the following indications:
    1. Bleeding gastroesophageal (GE) varices when both of the following are met:
      • GE varices are associated with liver disease; and
      • Octreotide acetate is used in combination with endoscopic therapy (that is, band ligation or sclerotherapy) or alone if endoscopic therapy is not immediately available; or
    2. Central nervous system (CNS) meningiomas that are surgically inaccessible, recurrent, or progressive and the individual is not a candidate for further radiation therapy; or
    3. Chemotherapy or radiation-induced diarrhea that is unresponsive to conventional antidiarrheal medications (for example, diphenoxylate and atropine or loperamide); or
    4. Malignant bowel obstruction - to manage gastrointestinal (GI) symptoms (such as nausea, pain, or vomiting).
  2. Supplemental treatment with short-acting octreotide acetate (Sandostatin) is considered medically necessary for rapid relief of symptoms or for breakthrough symptoms in individuals taking long-acting octreotide acetate (Sandostatin LAR Depot) when any of the criteria are met for other indications.

Not Medically Necessary:

Octreotide acetate (Sandostatin, Sandostatin LAR Depot) is considered not medically necessary when the criteria are not met and for all other indications, including but not limited to treatment of:

  1. Chylothorax; or
  2. Diarrhea associated with acquired immunodeficiency syndrome (AIDS); or
  3. Gastrointestinal (GI) tract conditions, such as:
    1. Bleeding from vascular malformations (such as, angiodysplasias, angioectasias, or arteriovenous malformations); or
    2. Gastroparesis; or
    3. Pancreatitis; or
    4. Prevention of postoperative complications (for example, fistulae) following pancreatic surgery; or
    5. Short bowel syndrome; or
    6. Upper GI bleeding (such as, non-variceal hemorrhage); or
  4. Graves' ophthalmopathy; or
  5. Hypothalamic obesity (control of hyperinsulinemia); or
  6. Other carcinomas (such as, adrenal gland tumors, advanced breast cancer, hepatocellular cancer, or prostate cancer); or
  7. Polycystic kidney disease.
Coding

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

HCPCS

 

J2353

Injection, octreotide, depot form for intramuscular injection, 1 mg 

J2354

Injection, octreotide, nondepot form for subcutaneous or intravenous injection, 25 mcg

 

 

ICD-10 Diagnosis

 

C18.0-C18.9

Malignant neoplasm of colon [associated bowel obstruction]

C25.0-C25.9

Malignant neoplasm of pancreas [related VIPoma syndrome]

C37

Malignant neoplasm of thymus

C48.1-C48.8

Malignant neoplasm of peritoneum [associated bowel obstruction]

C57.00-C57.4

Malignant neoplasm of other and unspecified female genital organs [associated bowel obstruction]

C70.0-C70.9

Malignant neoplasm of meninges

C75.1

Malignant neoplasm of pituitary gland

C7A.00-C7A.8

Malignant neuroendocrine tumors (carcinoid tumors)

C7B.00-C7B.8

Secondary neuroendocrine tumors

D01.7

Carcinoma in situ of other specified digestive organs [pancreas]

D13.7

Benign neoplasm of endocrine pancreas

D15.0

Benign neoplasm of thymus

D32.0-D32.9

Benign neoplasm of meninges

D35.2

Benign neoplasm of pituitary gland

D3A.010-D3A.8

Benign neuroendocrine tumors

E05.80-E05.81

Other thyrotoxicosis

E16.0-E16.9

Other disorders of pancreatic internal secretion

E22.0

Acromegaly and pituitary gigantism

E31.20-E31.23

Multiple endocrine neoplasia [MEN] syndrome

E34.0

Carcinoid syndrome

H47.49

Disorders of optic chiasm in (due to) other disorders

I85.11

Secondary esophageal varices with bleeding

K56.690-K56.699

Other intestinal obstruction

K59.1

Functional diarrhea

K70.0-K75.9

Disease of liver [related bleeding esophageal varices]

R19.7

Diarrhea, unspecified

T66.XXXA-T66.XXXS

Radiation sickness, unspecified, initial encounter

Z85.841

Personal history of malignant neoplasm of brain

Z85.845

Personal history of malignant neoplasm of other parts of nervous tissue

Discussion/General Information

Octreotide acetate (Sandostatin, Sandostatin LAR Depot)

Octreotide acetate (Sandostatin) for injectable suspension is a cyclic octapeptide consisting of microspheres of the biodegradable glucose polymer, D, L-lactic and glycolic acids copolymer, containing octreotide. The agent is a clear sterile solution of octreotide acetate salt prepared in a buffered lactic acid solution for administration by intravenous (IV) or deep subcutaneous (SC) injection. Octreotide mimics the action of somatostatin. The principal effects of octreotide include inhibition of growth hormone (GH), glucagon, and insulin; other effects include reduction of luteinizing hormone response to gonadotropin-releasing hormone, reduction of splanchnic blood flow (that is, visceral blood flow to the mesenteric, splenic and hepatic beds), and inhibition of release of several gastrointestinal hormones (such as, gastrin, motilin, pancreatic polypeptide, secretin, serotonin, and vasoactive intestinal peptide).

Octreotide acetate injection (Sandostatin Product Information [PI] label, 2012) is approved by the FDA for the following uses:

  1. Acromegaly: To reduce blood levels of growth hormone and IGF-I (somatomedin C) in acromegaly patients who have had an inadequate response to or cannot be treated with surgical resection, pituitary irradiation, and bromocriptine mesylate at maximally tolerated doses.
  2. Carcinoid tumors: For symptomatic treatment of individuals with metastatic carcinoid tumors where it suppresses or inhibits the severe diarrhea and flushing episodes associated with the disease.
  3. Vasoactive intestinal peptide (VIP) secreting tumors (VIPomas): In the treatment of the profuse watery diarrhea associated with VIP-secreting tumors.

Octreotide acetate for injectable suspension (Sandostatin LAR Depot PI label, 2016) is a long-acting somatostatin analogue for use in individuals in whom initial treatment with octreotide acetate (Sandostatin SC injection) has been shown to be effective and tolerated. Octreotide acetate for injectable suspension is FDA approved for the following uses:

  1. Acromegaly: Long-term maintenance therapy in acromegalic individuals who have had an inadequate response to surgery and/or radiotherapy, or for whom surgery and/or radiotherapy is not an option. The goal of treatment in acromegaly is to reduce GH and IGF-1 levels to normal.
  2. Carcinoid tumors: Long-term treatment of the severe diarrhea and flushing episodes associated with metastatic carcinoid tumors.
  3. VIPomas: Long-term treatment of the profuse watery diarrhea associated with VIP-secreting tumors.

The effect of Sandostatin LAR Depot maintains all of the clinical and pharmacological characteristics of the immediate-release dosage form with the added feature of slow release of octreotide acetate from the site of injection, reducing the need for frequent administration. It is designed to be injected intramuscularly (IM) once every 4 weeks and must be administered under the supervision of a physician.

Both formulas of octreotide acetate have off-label oncology and non-oncologic indications. The National Comprehensive Cancer Network® (NCCN) Drugs and Biologics Compendium® and NCCN Clinical Practice Guidelines (CPGs) in Oncology® include recommendations for use of octreotide acetate (Sandostatin, Sandostatin LAR Depot) based on category 2A evidence (low-level) and uniform consensus that the intervention is appropriate. The peer-reviewed published medical literature includes case series, other studies of varying methodological design, and a number of meta-analyses evaluating a large body of evidence for use of octreotide acetate for symptom control, disease staging and grading, and consideration of surgical and radiation options for CNS cancer (meningiomas), NETs (such as, adrenal, carcinoid, lung, pancreas), poorly differentiated (high-grade or anaplastic) small cell/atypical lung carcinoids, and thymic carcinoma and thymomas.

Other off-label uses of octreotide acetate have been studied extensively since the 1980’s. Although there is a lack of high quality, randomized controlled trials (RCTs), octreotide acetate has become standard therapy for the management of symptoms and treatment of other conditions including, but not limited to, bleeding GE varices, chemotherapy or radiation-induced diarrhea, and preoperative management of life-threatening hypotension due to carcinoid crisis during anesthesia induction (such as, prior to biopsy for a suspected functioning carcinoid tumor or surgical resection of a pancreatic NET).

Clinical Indications for Octreotide Acetate

Acromegaly

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 hypersecretion of GH is most commonly caused by a benign tumor of the pituitary gland. It results in gradual elongation and enlargement of bones of the extremities (hands and feet) and certain bones of the skull, particularly the frontal bones and jaws. 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. The prevalence of acromegaly is approximately 6 out of 100,000 people and occurs in equal frequency among men and women. Conventional therapy for acromegaly 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 transsphenoidal surgery, dopamine agonists, somatostatin analogues, GH receptor antagonists, and radiotherapy. Octreotide acetate, a somatostatin analogue, is selective in its hormonal inhibition and is initiated in an individual who is ineligible for surgery or has had an inadequate response to a dopamine agonist or radiation therapy (DrugPoints, 2017; Sandostatin PI label, 2012; Sandostatin LAR Depot PI label, 2016).

Sandostatin injection received FDA approval in 1988 for the treatment of adult acromegaly based on the results of a randomized, double-blind, placebo-controlled, multicenter trial of 115 individuals that demonstrated efficacy when 100 micrograms of Sandostatin was administered SC every 8 hours for a 6-month period (Ezzat, 1992). About one-half of the individuals experienced a reduction in GH and about two-thirds a reduction in IGF‐1.

Sandostatin LAR Depot received FDA approval in 1998 for long-term maintenance therapy of acromegalic individuals for whom medical treatment is appropriate and who are responsive to and can tolerate octreotide acetate injection (Sandostatin). The FDA approval was based on the results of two open-label clinical trials evaluating a 48-week treatment with Sandostatin LAR Depot in 143 treatment naïve (de novo) acromegalic individuals. The median reduction in tumor volume was 20.6% in Study 1 (49 participants) at 24 weeks and 24.5% in Study 2 (94 participants) at 24 weeks and 36.2% at 48 weeks. A few participants received doses of 10 mg and a few required doses of 40 mg. GH and IGF-1 levels were at least as well controlled with Sandostatin LAR Depot as they had been on Sandostatin injection and this level of control remained for the entire duration of the trials. A third trial was a 12-month study that enrolled 151 individuals who had a GH level < 10 ng/mL after treatment with Sandostatin injection (most had levels < 5 ng/mL). The starting dose of Sandostatin LAR Depot was 20 mg every 4 weeks for 3 doses. Thereafter, participants received 10 mg, 20 mg, or 30 mg every 4 weeks, depending upon the degree of GH suppression. GH and IGF-1 were at least as well controlled on Sandostatin LAR Depot as they had been on Sandostatin injection. Over the course of these trials, once-monthly injections of Sandostatin LAR Depot substantially reduced or normalized growth hormone and/or IGF-1 levels in the majority of participants. In addition, most participants showed an improvement in the symptoms associated with the disease (Sandostatin LAR Depot PI label, 2016).

The long-term efficacy of octreotide acetate in the treatment of acromegaly has been confirmed in other clinical trials and a meta-analysis (Ayuk, 2004; Cozzi, 2006; Giustina, 2012; Mercado, 2007; Newman, 1995).

An American Association of Clinical Endocrinologists (AACE) (Katznelson, 2011) clinical practice guideline for the diagnosis and treatment of acromegaly recommends octreotide acetate as effective in normalizing IGF-I and GH levels in approximately 55% of individuals. The clinical and biochemical response to octreotide acetate is inversely related to tumor size and degree of GH hypersecretion. A 2-week trial of octreotide acetate is recommended before institution of octreotide LAR therapy; although, this panel feels that a single test dose to rule out a severe reaction is sufficient. Guidelines also recommend counseling for potential side effects.

The Endocrine Society (Katznelson, 2014) has published an evidence-based clinical practice guideline addressing clinical issues regarding the evaluation and management of acromegaly, including the appropriate biochemical assessment, a therapeutic algorithm, use of medical monotherapy or combination therapy, and management during pregnancy. For example, the guideline recommends medical therapy in an individual with persistent disease following surgery and the use of a somatostatin receptor ligand (SRLs), including octreotide acetate, for those individuals with significant disease (that is, moderate-to-severe signs and symptoms of GH excess and without local mass effects). For individuals attempting to conceive, the guideline suggests discontinuing long-acting SRL formulations, including octreotide LAR, for approximately 2 months before attempts to conceive, with use of octreotide LAR as necessary until conception.

Carcinoid Tumors (Well-differentiated Neuroendocrine Tumors)

Carcinoid tumors, also called carcinoids, are rare, slow-growing tumors of the neuroendocrine cells (enterochromaffin or Kulchitsky cells) widely found in many organs of body, but usually originate in the digestive tract (foregut, midgut, or hindgut) or lung. Foregut tumors arise in the lung, thymus, stomach, or proximal duodenum and account for up to 25% of cases. Midgut tumors, which account for up to 50% of cases, arise in the small intestine, appendix, or proximal colon. Hindgut tumors arise in the distal colon or rectum and account for approximately 15% of cases. Other sites of origin include the gallbladder, kidney, liver, pancreas, ovary, and testis. The cells from these tumors release certain hormones into the bloodstream.

GI carcinoid tumors, especially tumors of the small intestine, are often associated with other cancers and found while staging or investigating symptoms from other tumors. According to the NCI (2015):

The term carcinoid should be used for well-differentiated neuroendocrine tumors (NETs) or carcinomas of the GI tract only; the term should not be used to describe pancreatic NETs or islet cell tumors. Data regarding carcinoids and other NETs, such as poorly differentiated neuroendocrine carcinomas, may be combined in some epidemiologic and clinical studies, rendering separate consideration difficult.

Carcinoid syndrome, which occurs in fewer than 20% of individuals with carcinoid tumors, occurs when there is an excess of hormones produced from GI carcinoid metastases or a non-GI primary tumor. Hormone levels may become sufficiently high to cause severe and debilitating facial flushing, bronchoconstriction (asthma-like wheezing attacks), abdominal pain and diarrhea, rapid heartbeat, and other symptoms. The severe diarrhea associated with the condition can consist of over 12 episodes per day, and cause marked debilitation with depletion of fluids, electrolytes, and proteins. Resection of the primary tumor and local lymph nodes, which may be possible in as many as 20% of individuals, is the only potential curative therapy for GI carcinoids. For some individuals, endoscopic surgery may be suitable for some tumors depending on the location, number, size, and degree of malignancy (NCI, 2015; Plockinger, 2004).

The development of both formulations of octreotide acetate has been important in the improvement of symptoms of carcinoid syndrome, resulting in a significant improvement in quality of life with relatively mild adverse effects. In 1988, the FDA approved octreotide acetate (Sandostatin) for the symptomatic treatment of individuals with metastatic carcinoid tumors to suppress or inhibit the severe diarrhea and flushing episodes associated with the disease. The studies of Sandostatin were not designed to show an effect on the size, rate of growth or development of metastases. In a prospective, open, comparative crossover study, Sandostatin 200 micrograms given 2 to 3 times daily SC for 1 month was well tolerated and effective in controlling symptoms in individuals with carcinoid syndrome. Disappearance or improvement in flushes occurred in 17 of 25 participants (68%). In addition, 11 of 22 participants (50%) reported a disappearance or improvement of diarrhea. The mean decrease in the 24‐hour urinary biochemical tumor marker level was 25%. A decrease of ≥ 25% in the 24‐hour level was observed in 50% of participants receiving Sandostatin (O'Toole, 2000).

The subsequent FDA approval of Sandostatin LAR Depot for the treatment of carcinoid syndrome was based on a 6-month trial that compared intragluteal injections of the long-acting agent to 93 previously-treated individuals who were responsive to 3 times a day SC Sandostatin injections. A total of 67 participants were randomized at baseline to receive double-blind doses of 10 mg, 20 mg, or 30 mg Sandostatin LAR Depot every 28 days. A total of 26 participants continued on their previous Sandostatin injection regimen (100-300 mcg, 3 times daily). In any given month after steady-state levels of octreotide acetate were reached, approximately 35%-40% of the participants who received Sandostatin LAR Depot required supplemental SC Sandostatin injection therapy, usually for a few days, to control exacerbation of carcinoid symptoms. Over the 6-month treatment period, approximately 50%-70% of participants who completed the trial on Sandostatin LAR Depot required supplemental therapy with Sandostatin SC injection to control exacerbation of carcinoid symptoms, although steady-state serum Sandostatin LAR Depot levels had been reached. Overall, mean daily stool frequency was as well controlled on Sandostatin LAR Depot as on Sandostatin injection (approximately 2-2.5 stools/day). Mean daily flushing episodes were similar at all doses of Sandostatin LAR Depot and on Sandostatin injection (approximately 0.5-1 episode/day). In a subset of participants with variable severity of disease, median 24 hour urinary 5-HIAA (5-hydroxyindole acetic acid) levels were reduced by 38%-50% in the groups randomized to Sandostatin LAR Depot. The reductions are within the range reported in the published literature for individuals treated with octreotide acetate (about 10%-50%) (Sandostatin LAR Depot PI label, 2016).

A total of 78 participants with malignant carcinoid syndrome who had participated in this 6-month trial, subsequently participated in a 12-month extension study in which they received 12 injections of Sandostatin LAR Depot at 4-week intervals. For those who remained in the extension trial, diarrhea and flushing were as well controlled as during the 6-month trial. Because malignant carcinoid disease is progressive, as expected, a number of deaths (8 participants, 10%) occurred due to disease progression or complications from the underlying disease. An additional 22% of participants prematurely discontinued Sandostatin LAR Depot due to disease progression or worsening of carcinoid symptoms (Sandostatin LAR Depot PI label, 2016).

In summary, there are numerous published clinical trials, retrospective case series, and a meta-analysis confirming the short- and long-term efficacy of both formulations of octreotide acetate in the management of carcinoid tumors and carcinoid syndrome (Garland, 2003; Kvols, 1986; Rubin, 1999; Toumpanakis, 2009).

Management and Prevention of Carcinoid Crisis

Carcinoid crisis is a life-threatening form of carcinoid syndrome which results from the release of hormones and other active compounds from a carcinoid tumor. The main symptom is wide blood pressure fluctuations with predominance of hypotension. Carcinoid crisis may be triggered by tumor manipulation (for example, biopsy, surgical interventions), or by anesthesia (NCI, 2015); therefore, octreotide acetate should be readily available prior to and during any surgical procedure, in particular, resection of hepatic metastases. In individuals with extensive tumor bulk, carcinoid crisis has been reported less frequently after chemotherapy, hepatic arterial embolization, or radionuclide interventions (Boudreaux, 2010; Kinney, 2001).

Ramage and colleagues (2004) published guidelines for the management of gastroenteropancreatic NET which included recommendations for the use of octreotide acetate prophylactically prior to anesthesia induction in individuals with functioning carcinoid tumors to prevent life-threatening hypotension due to carcinoid crisis. The guideline states:

When a functioning carcinoid tumour is found before surgery, a potential carcinoid crisis should be prevented by prophylactic administration of octreotide, given by constant intravenous infusion at a dose of 50 mg/h for 12 hours prior to and at least 48 hours after surgery.

The NCCN CPG for NETs (2017) includes a recommendation for use of parenteral octreotide acetate therapy “prior to induction of anesthesia in patients with functional neuroendocrine tumors to prevent carcinoid crisis and be discontinued the next day if there are no issues.” In addition, “octreotide premedication is required before biopsy in a suspected functioning carcinoid tumor” (NETs of unknown primary).

Vasoactive Intestinal Peptide Tumors (VIPomas)

A VIPoma, also referred to as Werner-Morrison syndrome or watery diarrhea hypokalemia achlorhydria (WDHA) syndrome, is a neuroendocrine tumor that arises 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. VIPomas produce excessive amounts of VIP (vasoactive intestinal peptide), which controls intestinal water and electrolyte flow. A debilitating symptom of VIPomas is sudden, intense secretory (watery) diarrhea. VIPomas are rare cancers and few new cases are reported each year (0.05 to 0.2 cases per million adults). Even fewer cases are reported in children. When VIPomas 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. A treatment goal for an individual with a VIPoma includes reducing the symptom of profuse watery diarrhea associated with the secreting tumor(s). Once an individual has stabilized, excision of the primary tumor and regional nodes is the first line of therapy for clinically localized disease. For locally advanced or metastatic disease, when curative resection is not possible, debulking and removal of gross disease, including metastases, should be considered to alleviate the characteristic manifestations of VIP overproduction. Palliative surgery is indicated in extensive disease, followed by octreotide acetate therapy. The severe watery diarrhea responds to octreotide acetate and improves electrolyte imbalances and the overall condition of the individual. Octreotide acetate or lanreotide may also improve hormone-mediated symptoms, reduce tumor bulk and prevent local and systemic effects (DrugPoints, 2017; NCCN, 2017; NCI, 2015).

The FDA approvals of both formulations of octreotide acetate (Sandostatin, Sandostatin LAR Depot) for the treatment of VIPomas is based on cumulative data from single case studies and small case series of individuals who responded to treatment as demonstrated by improvement in electrolyte imbalance and overall condition.

Off-FDA Label Indications for Octreotide Acetate

Octreotide acetate has been studied for numerous off-FDA label oncology and non-oncology related indications. In the absence of large, prospective, RCTs in the peer-reviewed published medical literature, the use of both formulations of octreotide acetate are accepted as standard therapy by practicing physicians specializing in the management of individuals with specific clinical circumstances and conditions. The NCCN CPGs in Oncology (2016-2017) and the NCCN Drugs and Biologics Compendium (2017) include category 2A off-label recommendations for use of octreotide acetate (Sandostatin, Sandostatin LAR Depot) for symptom control or treatment of numerous oncology-related conditions.

CNS - Meningiomas

A CNS meningioma is a type of slow-growing tumor that forms in the meninges (thin layers of tissue that cover and protect the brain and spinal cord). Meningiomas usually occur in adults and are typically diagnosed by computed tomography (CT) or magnetic resonance imaging (MRI); in addition, octreotide scan and biopsy may be considered for confirmation of the diagnosis. Surgical resection is the treatment of choice for individuals with symptomatic disease while radiation therapy is performed for non-surgical candidates. Chemotherapy is considered for surgically inaccessible recurrent or progressive meningiomas when further radiation is not possible, including the off-label use of octreotide acetate for somatostatin receptor-positive tumors (NCCN, 2017). The NCCN category 2A off-label recommendation is based on uniform consensus that the intervention is appropriate and data from a prospective pilot study and a small phase II study that demonstrated partial efficacy (mixed results) of octreotide acetate in individuals with treatment-refractory meningiomas. Chamberlain and colleagues (2007) reported on 16 individuals who received octreotide acetate LAR as salvage therapy for recurrent meningiomas. Participants received 2 to 15 cycles (median, 4.5 cycles) of octreotide acetate with minimal toxicity. The median survival was 7.5 months with 44% of participants (n=7) achieving overall progression-free survival (PFS) at 6 months. In the phase II study, Johnson and colleagues (2011) evaluated 12 individuals who received SC octreotide acetate 3 times per day as tolerated for recurrent or progressive meningioma and meningeal hemangiopericytoma. Imaging was performed every 3 months during therapy. No radiographic responses were observed. A total of 11 of the 12 participants experienced progression, with a median time to progression of 17 weeks. Only 2 participants experienced long progression-free intervals (30 months and ≥ 18 years). The median duration of survival was 2.7 years; however, despite being well-tolerated, octreotide acetate failed to produce objective tumor response in the majority of study participants.

Chemotherapy or Radiation-induced Diarrhea

Octreotide acetate has been effective in the management of chemotherapy or radiation-induced diarrhea that is unresponsive to conventional antidiarrheal medications. Yavuz and colleagues (2002) reported the efficacy of octreotide acetate in a RCT comparing octreotide acetate with diphenoxylate hydrochloride plus atropine sulfate for acute radiation-induced diarrhea (ARID). A total of 61 participants with Grade 2 (4 to 6 stools per day) or Grade 3 (≥ 7 stools per day, National Cancer Institute Common Toxicity Criteria) diarrhea associated with pelvic radiotherapy were assigned randomly to receive SC octreotide acetate administered 3 times per day (n=33) or diphenoxylate and atropine orally, 4 times per day (n=28). Radiotherapy was delivered to all participants with conventional high-energy photons in a total dose ≥ 45 Gy, which exceeds the tolerance of intestine. There was no significant difference in participant characteristics or radiotherapy applied between the 2 groups. A total of 20 of the 33 participants receiving octreotide acetate (61%) had complete resolution of diarrheal symptoms within the first 3 days, while only 4 of 28 participants receiving diphenoxylate (14%) had complete response by day 3 (p=0.002). Fifteen of 28 participants in the octreotide acetate group and 6 of 33 participants in the diphenoxylate group discontinued pelvic radiation because of severe diarrhea.  

Benson and colleagues (2004) updated practice guidelines from those previously published in the Journal of Clinical Oncology in 1998. A multidisciplinary panel of oncology experts reviewed the recent literature and recommends that if mild to moderate chemotherapy-induced diarrhea persists for more than 48 hours despite treatment with loperamide, it should be discontinued and the individual started on a second-line antidiarrheal agent such as octreotide acetate. The panel noted that in the majority of mild to moderate cases of radiation-induced diarrhea, octreotide acetate may not be sufficiently effective. For complicated cases of chemotherapy-induced diarrhea, aggressive management should involve antibiotics, IV fluids, and octreotide acetate. A complicated case of radiation-induced diarrhea may require hospitalization, and octreotide acetate therapy may or may not be appropriate.

An open-label, randomized, multicenter study by Rosenoff and colleagues (2006) assessed the effects of two dose levels of octreotide acetate long-acting release (LAR) in individuals with active or prior chemotherapy-induced diarrhea. Participants were randomized to receive up to six doses of either 30 mg or 40 mg of octreotide LAR. The primary endpoint was the proportion of participants experiencing severe diarrhea during the trial. Secondary endpoints included the proportion of participants requiring IV fluids due to diarrhea, unscheduled visits to healthcare professionals due to diarrhea, and changes in primary therapy, as well as treatment satisfaction and quality of life. A total of 124 of the 147 randomized participants who received at least one dose of octreotide acetate were efficacy-evaluable. Fewer participants in the 40 mg group compared with those in the 30 mg group experienced severe diarrhea (61.7% vs. 48.4%; p=0.14), required IV fluids (31.7% vs. 18.8%; p=0.10), and had diarrhea-related unscheduled healthcare visits (41.7% vs. 28.1 %; p=0.11); however, these differences were not statistically significant. Adverse events (AEs) were balanced between the 2 groups.

Hoff and colleagues (2014) explored the use of octreotide LAR in the prevention of chemotherapy-induced diarrhea in individuals with colorectal cancer starting adjuvant or first-line treatment with a chemotherapy combination containing fluorouracil, capecitabine, and/or irinotecan. Participants in the trial received octreotide LAR IM every 4 weeks (experimental arm) or the physician's treatment of choice in case of diarrhea (control arm). Most of the 139 participants received fluorouracil- and oxaliplatin-containing chemotherapy regimens. The rate of diarrhea was 76.1% in the experimental group (n=68) and 78.9% in the control group (n=71). Treatment with octreotide LAR did not prevent or reduce the severity of chemotherapy-induced diarrhea. Treatment choices for diarrhea management included loperamide in the majority of participants. The authors concluded this study could not prove the efficacy of octreotide LAR in the prevention of chemotherapy-induced diarrhea.

The NCCN CPGs for palliative care (V2.2017) include a category 2A off-label recommendation for use of octreotide acetate as an antidiarrheal intervention for persistent grades 3 or 4 diarrhea in individuals with a “1 year; year to months; and months to weeks” estimated life expectancy. For grades 3 or 4 diarrhea (inpatient hospitalization with ICU for grade 4), the CPG recommends to “consider octreotide 100-200 mcg/day SC, q8 hr or by continuous infusion.”

A category 2A off-label recommendation for use of octreotide acetate, administered at 100-200 mcg SC every 8 hours, is included as an antidiarrheal option for those individuals with an estimated life expectancy of weeks to days (“dying patient”).

Malignant Bowel Obstruction

Octreotide acetate has been effective in controlling GE symptoms in individuals with inoperable malignant bowel obstruction. The peer-reviewed published medical literature consists of a systematic review and several small RCTs that confirm the efficacy of octreotide acetate in controlling symptoms of nausea, vomiting, and pain associated with malignant bowel obstruction in individuals with advanced or terminal cancer (Berger, 2016; Hisanaga, 2010; Laval, 2012; Mystakidou, 2002; Peng, 2015; Ripamonti, 2000; Watari, 2012).

The NCCN CPGs for palliative care (V2.2017) include a category 2A off-label recommendation for use of octreotide acetate (Sandostatin, Sandostatin LAR Depot) as a pharmacologic intervention for the management of malignant bowel obstruction when gut function cannot be maintained because of its efficacy and tolerability. Octreotide acetate is administered for this indication at 100-300 mcg SC, 2 to 3 times daily, or 10-40 mcg/hour continuous SC/IV infusion “if prognosis > 8 weeks, consider long-acting release (LAR) or depot injection.” 

Other Neuroendocrine Tumors (NETs)

NETs comprise a broad group of tumors that are thought to arise from cells throughout the endocrine system. The most common NETs are carcinoid tumors and pancreatic NETs. Other less common NETs include those arising in the adrenal, pituitary, parathyroid, and thyroid glands. The NCCN CPGs for neuroendocrine tumors (2017) state:

Patients with neuroendocrine tumors may or may not have symptoms attributable to hormonal hypersecretion. These symptoms include intermittent flushing and diarrhea in patients with carcinoid syndrome, hypertension in patients with pheochromocytoma, and symptoms attributable to secretion of insulin, glucagon, gastrin, and other peptides in patients with pancreatic neuroendocrine tumors. Patients with hormonal symptoms are considered to have “functional” tumors, and those without symptoms are considered to have “nonfunctional” tumors.

Most NETs fall into three broad histologic categories: well-differentiated, low-grade; well-differentiated, intermediate grade; and, poorly differentiated, high-grade. Octreotide acetate is a synthetic somatostatin analog that can control symptoms in individuals with NETs and has been reported to alleviate symptoms in 30% to 70% of individuals, mainly through a direct inhibitory effect on hormone production from the tumors. For some NETs, octreotide acetate therapy has shown minimal or no effect on controlling tumor growth; however, one study reported a clinical response when octreotide acetate was compared to placebo (in the median time to tumor progression) for individuals with locally inoperable or metastasized well-differentiated midgut NETs (Rinke, 2009).

GI Tract, Lung, and Thymus NETs (Carcinoid Tumors)

Gastric NETs are generally recognized as 3 types: type 1 (associated with chronic atrophic gastritis, type 2 (associated with antrum sparing type A Zollinger-Ellison syndrome), and type 3 (sporadic). Type 2 gastric NETs have evidence of acid hypersecretion secondary to gastrinoma (Zollinger-Ellison syndrome). The off-label use of octreotide acetate has been effective in symptom control as primary treatment of non-metastatic, unresected gastric NET in individuals with hypergastrinemic/Type 2 Zollinger-Ellison syndrome. The NCCN category 2A off-label recommendation is based upon uniform consensus that the intervention is appropriate and lower-level evidence from two small case series (Ellison, 1986; Vinik, 1988) where octreotide acetate significantly reduced hypersecretion of gastrin and gastric acid over the long-term.

The NCCN CPG for NETs (2017) recommends the initiation of octreotide acetate in the management of locoregional unresectable and/or distant metastatic GI tract NETs (asymptomatic with low tumor burden, locally symptomatic from primary tumor, or those with clinically significant tumor burden). For individuals with GI tract primary tumors who have clinically significant tumor burden or progressive disease, initiation of octreotide acetate “is recommended to potentially control tumor growth if they are not already receiving it.” The NCCN category 2A off-label recommendation for use is based on uniform consensus and the results of the prospective, double-blind, randomized, placebo-controlled, phase III PROMID study of 85 individuals with functionally active and inactive metastatic midgut NETs (Rinke, 2009). Treatment-naive individuals (median age, 62 years) with locally inoperable or metastasized well-differentiated midgut NETs and a Karnofsky performance status > 60% were randomized to octreotide LAR 30 mg (n=42) IM every 28 days or placebo (n=43). The primary endpoint was time to tumor progression. After 6 months of treatment, the median time to tumor progression was 14.3 months and 6 months in the octreotide acetate and placebo groups, respectively (95% CI, 0.2 to 5.9; p=0.000072). Stable disease was observed in 66.7% of participants treated with octreotide acetate and 37.2% of participants in the placebo group.

Rinke and colleagues (2017) reported on the long-term survival of participants from the PROMID study. Post study treatment was at the discretion of the investigator. Upon disease progression, 38 of 43 placebo-treated participants (88.4%) received octreotide LAR. Participants who survived were followed until May 2014. A total of 48 of 85 (56.5%) participants died; tumor related death occurred in 38 of the 48 participants (79.2%). The median overall survival (OS) was only slightly different in participants assigned to octreotide LAR and placebo (84.7 and 83.7 months, respectively; hazard ratio [HR], 0.83 [95% CI, 0.47-1.46]; p=0.51). Median OS for all 85 participants was 84.7 months, 107.6 months in the low tumor load (n=64) and 57.5 months in the high tumor load (n=21) subgroup (HR, 2.49 [1.36-4.55]; p=0.002). There was a trend towards improved OS in participants with low hepatic tumor load receiving octreotide LAR compared to placebo (median not reached; 87.2 months; HR, 0.59 [0.29-1.2]; p=0.142). The authors suggested that the extent of tumor burden may be a predictor for shorter survival. A limitation of this study was that the majority of placebo-treated participants crossed over to octreotide LAR, resulting in the potential to confound the reported OS data.

Octreotide acetate is also used for individuals with metastatic NETs of the GI tract and carcinoid syndrome. Octreotide LAR is “commonly used for the chronic management of symptoms in patients with carcinoid syndrome.” The NCCN CPG for NETs (2017) recommends use of the LAR formulation of octreotide acetate in standard doses of 20 mg to 30 mg IM every 4 weeks. The dose and frequency may be increased for the chronic management of symptoms in individuals with carcinoid syndrome. For rapid relief of symptoms or for breakthrough symptoms, short-acting octreotide acetate can be added to octreotide LAR, usually administered SC 3 times daily. Octreotide or lanreotide, in combination with oral telotristat, is recommended for persistent diarrhea from poorly controlled carcinoid syndrome.

The NCCN CPG for NETs (2017) includes a category 2A off-label recommendation for use of octreotide acetate (including LAR) for the treatment of advanced NETs of the GI tract, lung, and thymus when given in combination with everolimus for individuals with advanced carcinoid tumors. This recommendation is based on uniform consensus that the intervention is appropriate and the results of the phase III, randomized, placebo-controlled RADIANT-2 trial (Yao, 2008; Fazio, 2013; Pavel, 2011) that evaluated the efficacy and safety of octreotide LAR with everolimus as combination therapy for individuals with advanced NETs and carcinoid syndrome. In the exploratory subgroup analysis of the trial, the primary outcome measure of PFS was reported as 13.63 months (median PFS) in the everolimus plus octreotide LAR arm compared with 5.59 months in the placebo plus octreotide LAR arm (relative risk [RR] for progression: HR, 0.72; 95% CI, 0.31-1.68; p=0.228). The investigators reported that more participants receiving everolimus plus octreotide LAR (67%) experienced minor tumor shrinkage (not partial response as per RECIST [Response Evaluation Criteria in Solid Tumors]) than those receiving placebo plus octreotide LAR (27%). The most frequently reported AEs included asthenia, diarrhea, rash, and stomatitis.

Strosberg and colleagues (2015) performed a post hoc analysis of the placebo arm of the RADIANT-2 trial to estimate the efficacy of octreotide acetate LAR on PFS and OS using the Kaplan-Meier method. A total of 196 of 213 participants randomized to placebo plus octreotide acetate LAR in RADIANT-2 with foregut, midgut, or hindgut NET were considered for the analysis. Of the 196 participants, 41 were somatostatin analog (SSA)-treatment naïve and 155 had received SSA therapy before study entry. For SSA-naïve participants, median PFS was 13.6 (95% CI, 8.2-22.7) months. For SSA-naïve participants with midgut NET (n=24), median PFS was 22.2 (95% CI, 8.3-29.5) months. For participants who had received SSA previously, the median PFS was 11.1 (95% CI, 8.4-14.3) months. Among the SSA-pretreated participants who had midgut NET (n=119), the median PFS was 12.0 (95% CI, 8.4-19.3) months. Median OS was 35.8 (95% CI, 32.5-48.9) months for participants in the placebo plus octreotide acetate LAR arm; 50.6 months for SSA-naïve participants and 33.5 (95% CI, 27.5-44.7) months for those who had received prior SSA. This post hoc analysis of the phase III RADIANT-2 study demonstrates longer survival in SSA-naïve participants treated with octreotide acetate LAR for progressive NET.

The NCCN CPG for NETs (2017) includes a category 2A recommendation for use of octreotide or lanreotide in combination with temozolomide as systemic therapy for advanced NETs to manage tumor burden and any associated symptoms in individuals with clinically significant bronchopulmonary or thymic tumor burden (low or intermediate grade).

For the management of locoregional unresectable and/or distant metastatic bronchopulmonary or thymic NETs, asymptomatic individuals with low tumor burden may be initiated on treatment with octreotide or lanreotide. “Deferring initiation until evidence of tumor progression is seen may also be appropriate in selected patients.” For lung NETs, the NCCN CPG for NETs (2017) recommends treatment with octreotide or lanreotide if the individual presents with asymptomatic, low tumor burden that is low grade. As with GI primary tumors, the NCCN states that no clear consensus exists on the timing of octreotide or lanreotide initiation in asymptomatic individuals with metastatic NETs and low tumor burden. If an individual with advanced low-grade lung or thymic NETs presents with clinically significant tumor burden, initiation of octreotide or lanreotide may be considered in combination with everolimus or temozolomide. For advanced low-grade lung or thymic NETs, systemic therapy should be initiated with octreotide or lanreotide and other chemotherapeutic options (that is, everolimus, temozolomide). Carboplatin, cisplatin, or etoposide may be given with or without octreotide or lanreotide “…for tumors on the higher end of the atypical category with respect to Ki-67 and grade.”

Poorly Differentiated Neuroendocrine Carcinoma/Large or Small Cell Carcinomas

Small cell NETs are poorly differentiated (high grade/G3) tumors that occur in the lungs. Though rare, extrapulmonary large or small cell carcinomas present as aggressive tumors that may occur in a wide variety of organs, require combined multimodality treatment, and are infrequently associated with a hormonal syndrome (NCCN, 2017). The NCCN CPG for NETs (2017) category 2A off-label recommendation to consider use of octreotide acetate “…for symptom control in the rare cases of hormone-secreting, poorly differentiated tumors that are unresectable or metastatic if somatostatin scintigraphy is positive” is based on uniform consensus that the intervention is appropriate.

Pancreatic NETs

Pancreatic NETs (or islet cell tumors) are uncommon cancers with about 1000 new cases per year in the United States. They account for 3% to 5% of pancreatic malignancies with an overall prognosis that is better than the more common pancreatic exocrine tumors. The 5-year survival is about 55% when the tumors are localized and resected, but only about 15% when the tumors are not resectable; thus, the overall 5-year survival rate is about 42%. Most pancreatic NETs are sporadic, but some occur as part of an autosomal dominant multiple endocrine neoplasia type-1 (MEN-1) inherited syndrome consisting of tumors of the anterior pituitary, parathyroid, and endocrine pancreas glands. When part of the MEN-1 syndrome, there may be multiple pancreatic tumors (NCI, 2015).

Pancreatic NETs are categorized as functional (produce one or more active hormones) or nonfunctional. Functional pancreatic NETs, which usually present with symptoms of hormone hypersecretion, include insulinomas, glucagonomas, gastrinomas, and somatostatinomas. The remaining rare pancreatic NETs include VIPomas (previously discussed in this document) and cholecystokininoma (CCKoma) (NCCN, 2017).

Insulinomas (also called beta cell neoplasm, beta cell tumor of the pancreas) are abnormal masses that grow in the beta cells of the pancreas that make insulin, accounting for up to 70% of pancreatic NETs, with 90% being benign. Insulinomas are also the most common pancreatic NETs in individuals with MEN-1. Glucagonomas are rare pancreatic tumors that produce a hormone called glucagon, accounting for 15% of pancreatic NETs. Glucagonomas can produce symptoms similar to diabetes. Most glucagonomas are malignant, calcified tumors located in the tail of the pancreas. Regional node involvement is present in most malignant tumors. Gastrinomas are a type of pancreatic NET that occurs sporadically as well as part of inherited familial endocrine syndromes such as MEN-1. Gastrinomas and somatostatinomas account for another 10% of pancreatic NETs with 80% to 90% associated with a high risk for metastases. Gastrinomas are usually found in the duodenal or head of the pancreas, secret gastrin (stomach acid), and are associated with Zollinger-Ellison syndrome. Severe gastroduodenal ulcer symptoms, such as dyspepsia accompanied by diarrhea, may be present in an individual with suspected gastrinoma (NCI, 2015; NCCN, 2017).

The NCCN CPG for NETs (2017) states that surgical resection is the optimal treatment approach for locoregional pancreatic NETS; however, before excision, “any symptoms of hormonal excess must be treated. Octreotide or lanreotide can be considered for symptom control in most pancreatic neuroendocrine tumor subtypes (Oberg, 2004).” Ramage and colleagues (2004) published guidelines for the management of gastroenteropancreatic NETs, recommending the prophylactic use of octreotide acetate prior surgical resection of pancreatic and periampullary NETs (including IV octreotide acetate for gastrinoma).

Both formulations of octreotide acetate are recommended for use in the treatment of symptoms related to hormone hypersecretion in pancreatic NETs and its subtypes (Oberg, 2004; Toumpanakis, 2013). Short-acting octreotide acetate (150-250 mcg) is administered SC 3 times per day or octreotide LAR (20-30 mg) administered IM every 4 weeks. Dose and frequency may be increased for symptom control. Therapeutic levels after octreotide LAR would not be expected to be reached for 10 to 14 days; therefore, short-acting octreotide can be added to an octreotide LAR regimen for rapid relief of symptoms or for breakthrough symptoms.

The NCCN CPG for NETs (2017) includes a category 2A off-label recommendation for use of octreotide acetate for the management of primary gastrinomas. The treatment algorithm recommends to consider endoscopic surveillance and endoscopic resection of prominent tumors and/or consider use of octreotide or lanreotide. Octreotide or lanreotide are also recommended for treatment of primary, nonmetastatic/locoregional glucagonoma (usually tail). Octreotide acetate has been shown to be effective as palliative treatment of hyperinsulinemia from severe refractory metastatic insulinomas. The level of evidence to support the use of octreotide acetate for these indications is limited to data from single and small case studies. In addition, the NCCN CPG for preoperative management of primary locoregional, resectable NETs of the pancreas states:

Octreotide or lanreotide should be used with caution in patients with insulinomas, because they can also suppress counterregulatory hormones such as growth hormone (GH), glucagon, and catecholamines. In this situation, octreotide and lanreotide can precipitously worsen hypoglycemia, and can result in fatal complications. Octreotide (and lanreotide) should not be used in patients with insulinoma who have a negative result by somatostatin receptor-based imaging.

The NCCN CPG for NETs (2017) recommend the off-label use of octreotide for tumor control in individuals with unresectable locoregional disease and/or distant metastatic pancreatic NETs who initially present with clinically significant tumor burden, or those with clinically significant disease progression. The NCCN category 2A off-label recommendation is based on uniform consensus that the intervention is appropriate and results of the PROMID trial (Rinke, 2009), which states:

Although no randomized studies to date have directly shown an antitumor effect of octreotide in pancreatic neuroendocrine tumors, the PROMID trial showed an improvement in its primary endpoint of time to tumor progression (14.3 vs. 6 months; p=.000072) in carcinoid tumors of the midgut. Lanreotide and octreotide share the same mechanism of action, and the panel believes that either lanreotide or octreotide are appropriate options for tumor control in this setting.

Octreotide should be considered for individuals with unresectable locoregional disease and/or distant metastatic pancreatic NETs that are asymptomatic and have low tumor burden and stable disease. For those individuals with disease progression, treatment with octreotide or lanreotide may be continued in combination with everolimus, sunitinib, cytotoxic chemotherapy, or a hepatic-directed therapy for hepatic-predominant disease.

Thymic Carcinomas and Thymomas

Thymic carcinomas and thymomas are rare, invasive epithelial tumors that originate in the thymus gland. Thymic carcinomas are aggressive tumors that often metastasize to regional lymph nodes and distant sites, account for only 0.06% of all thymic neoplasms, and have 5-year survival rates of 30% to 50% (NCI, 2015).

Total thymectomy and complete excision of tumor is the treatment of choice for individuals with thymomas and thymic carcinoma who can tolerate surgery. Postoperative radiation is recommended for incompletely resected thymomas. Chemotherapy, with or without radiation therapy, is recommended for advanced disease. The NCCN CPGs for thymomas and thymic carcinoma (NCCN, 2017) recommend off-label use of octreotide acetate, with or without prednisone, as second-line systemic therapy for individuals who have a positive octreotide scan or symptoms of carcinoid syndrome. Two small phase II clinical trials and a pilot study have shown modest activity of octreotide acetate in individuals with octreotide scan-positive thymomas (Loehrer, 2004) and in those with recurrent and metastatic thymic tumors refractory to standard therapeutic options (Longo, 2012; Palmieri, 2002).

Bleeding Gastroesophageal Varices

Evidence in the peer-reviewed published medical literature supports the off-label use of octreotide acetate for the treatment of acutely bleeding gastroesophageal (GE) varices associated with liver disease when used in combination with endoscopic therapy (that is, band ligation or sclerotherapy) or alone if endoscopic therapy is not immediately available (Abid, 2009; Freitas, 2000; Rengasamy, 2015; Shah, 2005; Sung, 1995). Two early meta-analyses reported the safety and efficacy of octreotide acetate for GE variceal hemorrhage when compared with combined alternative therapies without differences in mortality or severe AEs (Banares, 2002; Corley, 2001). Gotzsche and Hrobjartsson (2008) performed a meta-analysis of RCTs to determine whether somatostatin or its analogues improved survival or reduced the need for blood transfusions in individuals with bleeding esophageal varices. In the 21 trials (2588 subjects), somatostatin and its analogues (including octreotide acetate injection) did not reduce mortality significantly but the units of blood transfused were less in the trials with a low risk of bias; in addition, there was a reduction in number of subjects failing initial hemostasis. D'Amico and colleagues (2010) performed a meta-analysis including a search of trials in the Cochrane Hepato-Biliary Group Controlled Trials Register to evaluate emergency sclerotherapy versus medical interventions for bleeding esophageal varices in individuals with cirrhosis. Of the 17 trials using vasoactive drugs, 10 trials involved the use of octreotide acetate. The authors reported no significant differences were found comparing sclerotherapy with octreotide acetate (and all other vasoactive drug) for any outcome and no convincing evidence to support the use of emergency sclerotherapy for variceal bleeding in cirrhosis as the first, single treatment when compared with vasoactive drugs. The authors suggested that vasoactive drugs may be safe and effective whenever endoscopic therapy is not promptly available and “seems to be associated with less adverse events than emergency sclerotherapy.”

The American Association for the Study of Liver Diseases and Practice Parameters Committee of the American College of Gastroenterology’s Practice Guidelines for the Prevention and Management of Gastroesophageal Varices and Variceal Hemorrhage in Cirrhosis (Garcia-Tsao, 2007) recommend octreotide acetate as a useful clinical adjunct to endoscopic therapy. The Class I, Level A recommendations states that somatostatin or its analogues should be initiated as soon as variceal hemorrhage is suspected and continued for 3 to 5 days after the diagnosis is confirmed (Class I: Conditions for which there is evidence and/or general agreement that a given diagnostic evaluation, procedure or treatment is beneficial, useful, and effective. Level A: Data derived from multiple randomized clinical trials or meta-analyses)

Other Proposed Uses of Octreotide Acetate

The safety and/or efficacy of octreotide acetate have not been established for treating conditions other than those previously discussed. There is a paucity of high quality clinical evidence evaluating the use of octreotide acetate for other off-label uses. The peer-reviewed published medical literature consists of case reports, small case series, RCTs of small sample sizes, and non-randomized or uncontrolled trials which precludes drawing reliable conclusions on the safety and net health benefit of octreotide acetate for other conditions, including but not limited to:

  1. AIDs-related diarrhea (Kaplan, 2009; Simon, 1995);
  2. Chyle fistula management following neck dissection surgery (Swanson, 2015);
  3. Chylothorax in adults (Fujita, 2014; Ismail, 2015) and neonates (Das and Shah, 2010; Testoni, 2015);
  4. Graves' ophthalmopathy (thyroid eye disease) (Stan, 2006);
  5. Hypothalamic obesity (insulin hypersecretion) (Lustig, 2003; Michalsky, 2012);
  6. Other carcinomas, such as:
    • advanced, metastatic breast cancer (Bajetta, 2002; Chapman, 2015);
    • hepatocellular cancer (Jia, 2010);
    • prostate cancer (including castration-resistant) (Friedlander, 2012);
  7. Other GI tract conditions, such as:
    • bleeding from vascular malformations (such as, angiodysplasias, angioectasias, or/GI tract AVM (Brown, 2010; Junquera, 2007; Loyaga-Rendon, 2015, Szilagyi and Ghali, 2006);
    • gastroparesis (Edmunds, 1998);
    • non-variceal upper GI bleeding (Archimandritis, 2000);
    • pancreatitis (Xu, 2013);
    • short bowel syndrome (Nehra, 2001);
    • small intestinal dysmotility associated with systemic sclerosis (scleroderma) (Nikou, 2007; Perlemuter, 1999; Soudah, 1991; Verne, 1995); and
  8. Polycystic kidney or liver disease (Caroli, 2013; Hogan, 2010; Ruggenenti, 2005).

The evidence in the available RCTs or open-label trials, large case series, and other comparative studies of octreotide acetate for the prophylactic or symptomatic treatment of other conditions is limited, in part, by variations in the octreotide formulation (short-acting, long-acting, or both), dosage schedule, and disease severity of the study populations which make meaningful comparisons difficult. Inconclusive or mixed results have been reported in some of the peer-reviewed published meta-analyses and systematic reviews. For example, a meta-analysis by Jia and colleagues (2010) evaluated two double-blind, placebo-controlled trials that reported mixed or no survival benefit using octreotide acetate in individuals with advanced HCC (Becker, 2007; Dimitroulopoulos, 2007).

Adrenal Gland NETs

Adrenocortical carcinoma (ACC) is a rare tumor that affects only 0.72 persons per 1 million population with peak incidences in early childhood and middle-age adults (median age at diagnosis, 46 years). Approximately 60% of individuals present with evidence of adrenal steroid hormone excess. The signs and symptoms associated with hypersecretion of cortisol, called Cushing’s syndrome include, but are not limited to, “buffalo hump”, hirsutism, hypertension, weight gain, weakness in the proximal muscles, and hyperglycemia and hypokalemia (NCCN, 2014; NCI, 2015). The primary treatment of individuals with non-adrenocorticotropic hormone-dependent (ACTH-independent) Cushing’s syndrome includes management of hypercortisolism from presumed multinodular hyperplasia of the adrenal gland.

The NCCN Drugs and Biologics Compendium for octreotide acetate and octreotide acetate LAR (NCCN, 2017) includes a category 2A off-label recommendation for use of octreotide acetate for symptom control in adrenal gland tumors. The recommendation (with criteria) is based on uniform consensus that the intervention is appropriate. The NCCN CPG for NETs (2017) treatment algorithm for adrenal gland tumors does not include a specific recommendation for use of octreotide acetate, but states, “consider octreotide or lanreotide for symptom control, if somatostatin receptor scintigraphy is positive.” In the Discussion section, the NCCN CPG states that in cases of bilateral adrenal multinodular hyperplasia “when the tumor appears benign but the contralateral gland appears abnormal, adrenal vein sampling of cortisol production determines treatment. If cortisol production is asymmetric, laparoscopic unilateral adrenalectomy...is recommended with postoperative corticosteroid supplementation.” Medical management is achieved with adrenostatic agents, including ketoconazole, mitotane, and/or mifepristone. “The data supporting individual drugs for management of Cushing’s disease are limited” (Gadelha, 2014). Use of octreotide acetate is only “...considered for ectopic Cushing’s syndrome if the tumor is somatostatin scintigraphy-positive, although it may be less effective in controlling ectopic ACTH secretion than it is in other contexts.” No additional data or evidence in the peer-reviewed published medical literature was cited to support this statement (NCCN, 2017).

The Endocrine Society (Nieman, 2015) has published a CPG for the treatment of Cushing’s syndrome, recommending first-line treatment as “initial resection of primary lesions(s) underlying Cushing’s disease, ectopic, and adrenal (cancer, adenoma, and bilateral disease) etiologies, unless surgery is not possible or is unlikely to significantly reduce glucocorticoid excess.” Second-line treatment options include medical management with ketoconazole or combination therapy with metyrapone and ketoconazole to enhance the control of severe hypercortisolemia. Mitotane is primarily used to treat adrenal carcinoma. Concerning the use of octreotide acetate, the CPG states that several case reports show that octreotide “...may control ACTH and cortisol secretion for a short- to midterm period in patients with recurrent or unresectable ectopic ACTH-secreting tumors. However, octreotide treatment usually had little or no effect on tumor growth.”

Chylothorax

Das and Shah (2010) conducted a systematic review of the peer-reviewed literature to assess the efficacy and safety of octreotide acetate in the treatment of chylothorax in neonates. In this Cochrane review, the authors state that no practice recommendation could be made based on analysis of the available evidence. No RCTs were identified. In 14 of 19 case reports, neonates with chylothorax were successfully treated with octreotide acetate (SC or IV); however, the timing of initiation, dose, duration, and frequency of doses varied markedly. Tatar and colleagues (2011) described a small case series where continuous IV infusion of octreotide acetate was administered to 12 pediatric subjects for the treatment of chylothorax after congenital heart surgery. Chylothorax was successfully resolved in an average of 10.3 days (7-14 days) with octreotide acetate infusion; however, these children were also treated with daily pleural drainage and a strict oral diet containing medium-chain triglycerides. Das and Shah (2010) suggest “a prospective registry and a subsequent multicenter randomised controlled trial are needed to assess the safety and efficacy of octreotide in the treatment of chylothorax in neonates.”

Testoni and colleagues (2015) evaluated the off-label use and safety profile of octreotide in the treatment of hospitalized infants with chylothorax. A total of 428 infants discharged from 333 neonatal intensive care units between 1997 and 2012 received at least 1 dose of octreotide for chylothorax (50%), pleural effusion (32%), and hypoglycemia (22%). Laboratory and clinical information was collected to describe the frequency of baseline diagnoses, laboratory abnormalities, and clinical AEs. The most common laboratory AEs that occurred during exposure to octreotide were thrombocytopenia (47/1000 infant-days), hyperkalemia (21/1000 infant-days), and leukocytosis (20/1000 infant-days). Hyperglycemia occurred in 1/1000 infant-days and hypoglycemia in 3/1000 infant-days. Hypotension requiring pressors (12%) was the most common clinical AE that occurred during exposure to octreotide. Necrotizing enterocolitis was observed in 9/490 (2%) courses, and death occurred in 11 (3%) infants during octreotide administration. The authors concluded that in this cohort of hospitalized infants, relatively few AEs occurred during off-label use of octreotide. Additional studies are needed to evaluate the safety, dosing, and efficacy of octreotide in similar groups of hospitalized infants.

The efficacy of octreotide acetate has been evaluated in the treatment of chylothorax following thoracic esophagectomy for esophageal cancer (Fujita, 2014) and following cardiothoracic surgery (post-operative or traumatic) as part of conservative management to reduce lymphorrhagia (Ismail, 2015). Fujita and colleagues (2014) retrospectively reported that high-output chylothorax (>1 liter/day) persisting for 2 days after 48 hours of treatment with octreotide acetate was “the predicting factor for failure of treatment” with octreotide. A total of 13 of 15 (86.6%) individuals treated with octreotide acetate in combination with total parenteral nutrition (TPN) and no oral intake did not require surgical intervention for chylothorax when compared to 2 of 5 individuals (40%) treated with TPN and no oral intake (p=0.003). Limitations of this review include the small sample size, lack of randomization, and use of concomitant treatments. A “best evidence” review by Ismail and colleagues (2015) (which included the retrospective case series by Fujita and colleagues) reported no RCTs in humans are available to evaluate the use of octreotide acetate in chylothorax. The authors selected 16 of 19 papers for review, finding octreotide acetate “to be effective” in the treatment of chylothorax; however, octreotide acetate was found to have no complementary effect in three reports, two papers were retrospective studies, one RCT studied canines, and the remainder were case reports and case series. The small retrospective studies reported a success rate of 87% to 90% when octreotide acetate was used as an adjunct to conservative management for the treatment of chylothorax, thus preventing the need for further surgery. The “general consensus” from this review suggested that conservative management of chylothorax should consider administration of octreotide acetate for 1 week prior to surgical intervention; however, some of the reviewed articles advocated for additional surgical intervention for large volume chylothorax, especially after esophageal surgery with no response to conservative management with octreotide acetate. Limitations of this review include the retrospective design, inclusion of heterogeneous study populations, and treatment with concomitant therapies.  

Diarrhea - AIDS-related

The Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH) and HIV Medicine Association of the Infectious Diseases Society of America have published guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents (Kaplan, 2009). The recommendations state that treatment with antimotility agents (for example, loperamide or tincture of opium) can palliate symptoms of AIDS-related diarrhea by reducing diarrheal frequency and volume, but these agents are not consistently effective (Level of Evidence: BIII). Octreotide acetate is approved for the treatment of secreting tumor-induced diarrhea (that is, VIPomas), however, it is no more effective than other oral antidiarrheal agents and is usually not recommended (Level of Evidence: DII) (Kaplan, 2009; Simon, 1995).

Moderate-to-Severe Acute Pancreatitis

Xu and colleagues (2013) performed a meta-analysis to evaluate the safety and effectiveness of octreotide acetate on primary moderate-to-severe acute pancreatitis. A total of 11 randomized clinical trials with 720 participants were evaluated; however, only two trials of high quality were analyzed in the meta-analysis. The pooled estimate of RR of mortality was 0.88 (95% confidence interval [CI], 0.53 to 1.45) and the incidence rate of complication was 1.08 (95% CI, 0.94 to 1.26); both of which had no significant difference. The authors concluded that the evidence does not confirm the clinical benefit of octreotide acetate in improvement of major health outcomes of mortality, incidence rate of complications, rate of surgical intervention, and length of hospital stay for moderate-to-severe acute pancreatitis.

Pancreatic Surgery

The peer-reviewed published medical literature consists of Cochrane reviews, meta-analyses and systematic reviews evaluating the clinical utility of octreotide acetate for other GI conditions. Gurusamy and colleagues (2013) identified twenty-one RCTs involving 2348 subjects evaluating prophylactic somatostatin or one of its analogues to “no drug” or placebo during pancreatic surgery. The authors found no significant difference between groups in perioperative mortality or in the number of subjects who experienced drug-related AEs. The number of subjects who experienced postoperative complications was significantly reduced in the somatostatin analogue group; however, significant differences were not seen between groups in the re-operation rate or in hospital length of stay. Participants in the somatostatin analogue group experienced lower rates of pancreatic fistula, but the proportion of fistulas that were clinically significant was not noted in most of the studies. In studies that did make a distinction in clinically significant fistulas, no significant difference was found between the 2 groups. The authors concluded that while somatostatin analogues may reduce perioperative complications, they do not reduce perioperative mortality. Drymousis and colleagues (2013) examined whether the prophylactic administration of somatostatin or somatostatin analogues in individuals undergoing pancreaticoduodenectomy (Whipple's procedure) is beneficial in terms of improved surgical outcomes, reduced morbidity, or reduced mortality. The “best evidence” was found represented in 5 of a total of 118 papers (one meta-analysis, one systematic review and three RCTs). The authors reported there is evidence that the perioperative administration of somatostatin or somatostatin analogues reduces biochemical incidence of pancreatic fistula; however, it is still unclear if there is a beneficial effect in the incidence of clinically significant pancreatic fistula. In conclusion, the authors stated “from the available data, somatostatin or somatostatin analogues have no effect on mortality post Whipple's.”

Kurumboor and colleagues (2015) assessed the potential benefit of octreotide acetate in preventing pancreatic fistula following elective pancreatoduodenectomy in a prospective randomized controlled trial of 109 individuals with soft pancreas and non-dilated duct. The investigators reported no statistical difference in the post-operative development of pancreatic fistula. Of the 55 participants randomized to receive octreotide acetate versus 54 controls, the rates of clinically significant pancreatic fistulae (grades B and C) were 10.9 and 18.5 % (p=not significant), and morbidity was 18 and 29.6 % (p=not significant), respectively; however, participants who received octreotide acetate were reported as resuming an oral diet earlier and had a shorter hospital stay.

Common Symptoms and AEs

In the data reported in the clinical trials of octreotide acetate, AEs in individuals with acromegaly treated for 12 months or longer included new biliary tract abnormalities (52%) such as gallstones, sludge without stones, microlithiasis and biliary duct dilatation. Across all trials, a few individuals developed acute cholecystitis, ascending cholangitis, biliary obstruction, cholestatic hepatitis, or pancreatitis during octreotide acetate therapy or following its withdrawal. Cardiac events developing during octreotide acetate injection therapy included sinus bradycardia (< 50 beats per minute (25% of participants), conduction abnormalities (10%) and arrhythmias (9%). The relationship of these events to octreotide acetate is not established because many of these participants had underlying cardiac disease. Other AEs in study participants treated with octreotide acetate included hypoglycemia, hyperglycemia, biochemical hypothyroidism, goiter, or required initiation of thyroid replacement therapy.

The most common symptoms reported were gastrointestinal, with the overall incidence of the most frequent of these symptoms in clinical trials of acromegalic individuals treated for approximately 1 to 4 years, included diarrhea, abdominal pain or discomfort, and nausea.

Warnings, Precautions, and Drug Interactions from the FDA Product Information (PI) Labels for Sandostatin (2012) and Sandostatin LAR Depot (2016)

There are currently no black box warnings on the FDA PI labels for either formulation of octreotide acetate.

Sandostatin

WARNINGS

Single doses of Sandostatin (octreotide acetate) have been shown to inhibit gallbladder contractility and decrease bile secretion in normal volunteers. In clinical trials (primarily patients with acromegaly or psoriasis), the incidence of biliary tract abnormalities was 63 (27% gallstones, 24% sludge without stones, 12% biliary duct dilatation). The incidence of stones or sludge in patients who received Sandostatin for 12 months or longer was 52%. Less than 2% of patients treated with Sandostatin for 1 month or less developed gallstones. The incidence of gallstones did not appear related to age, sex or dose. Like patients without gallbladder abnormalities, the majority of patients developing gallbladder abnormalities on ultrasound had gastrointestinal symptoms. The symptoms were not specific for gallbladder disease. A few patients developed acute cholecystitis, ascending cholangitis, biliary obstruction, cholestatic hepatitis, or pancreatitis during Sandostatin therapy or following its withdrawal. One patient developed ascending cholangitis during Sandostatin therapy and died.

Sandostatin LAR Depot

WARNINGS AND PRECAUTIONS

DRUG INTERACTIONS

Definitions

Line of therapy:

Metastasis: A cancer that has spread from one part of the body to another; a metastatic tumor contain cells that are like those in the original (primary) tumor that has spread beyond the local lymph nodes.

Neuroendocrine tumors (NETs): A tumor that forms from cells that release hormones into the blood in response to a signal from the nervous system. Neuroendocrine tumors may make higher-than-normal amounts of hormones, which can cause many different symptoms. These tumors may be benign (not cancer) or malignant (cancer) (NCI, 2015). The following are Clinical Presentations and Diagnosis for neuroendocrine tumors as described by the NCCN (NCCN CPG Neuroendocrine Tumors, 2017):

Off-label: Utilization of an FDA approved drug for uses other than those listed in the FDA approved label.

Relapse or recurrence: After a period of improvement, during which time a disease (for example, cancer) could not be detected, the return of signs and symptoms of illness or disease. For cancer, it may come back to the same place as the original (primary) tumor or to another place in the body.

Somatostatin-receptor scintography (SRS): A type of radionuclide scan used to find carcinoid and other types of tumors. Radioactive octreotide, a drug similar to somatostatin, is injected into a vein and travels through the bloodstream. The radioactive octreotide attaches to tumor cells that have receptors for somatostatin. A radiation-measuring device detects the radioactive octreotide, and makes pictures showing where the tumor cells are in the body; also called octreotide scan and SRS (NCI, 2015).

References

Peer Reviewed Publications:

  1. Abid S, Jafri W, Hamid S, et al. Terlipressin vs. octreotide in bleeding esophageal varices as an adjuvant therapy with endoscopic band ligation: a randomized double-blind placebo-controlled trial. Am J Gastroenterol. 2009; 104(3):617-623.
  2. Archimandritis A, Tsirantonaki M, Tryphonos M, et al. Ranitidine versus ranitidine plus octreotide in the treatment of acute non-variceal upper gastrointestinal bleeding: a prospective randomised study. Curr Med Res Opin. 2000; 16(3):178-183.
  3. Ayuk J, Stewart SE, Stewart PM, Sheppard MC. Efficacy of Sandostatin LAR (long-acting somatostatin analogue) is similar in patients with untreated acromegaly and in those previously treated with surgery and/or radiotherapy. Clin Endocrinol (Oxf). 2004; 60(3):375-381.
  4. Bajetta E, Procopio G, Ferrari L, et al. A randomized, multicenter prospective trial assessing long-acting release octreotide pamoate plus tamoxifen as a first line therapy for advanced breast carcinoma. Cancer. 2002; 94(2):299-304.
  5. Banares R, Albillos A, Rincon D, et al. Endoscopic treatment versus endoscopic plus pharmacologic treatment for acute variceal bleeding: a meta-analysis. Hepatology. 2002; 35(3):609-615.
  6. Becker G, Allgaier HP, Olschewski M, et al. Long-acting octreotide versus placebo for treatment of advanced HCC: a randomized controlled double-blind study. Hepatology. 2007; 45(1):9-15.
  7. Benson AB III, Ajani JA, Catalano RB, et al. Recommended guidelines for the treatment of cancer treatment-induced diarrhea. J Clin Oncol. 2004; 22(14):2918-2926.
  8. Berger J, Lester P, Rodrigues L. Medical therapy of malignant bowel obstruction with octreotide, dexamethasone, and metoclopramide. Am J Hosp Palliat Care. 2016; 33(4):407-410.
  9. Brown C, Subramanian V, Wilcox CM, Peter S. Somatostatin analogues in the treatment of recurrent bleeding from gastrointestinal vascular malformations: an overview and systematic review of prospective observational studies. Dig Dis Sci. 2010; 55(8):2129-2134.
  10. Caroli A, Perico N, Perna A, et al. Effect of longacting somatostatin analogue on kidney and cyst growth in autosomal dominant polycystic kidney disease (ALADIN): a randomised, placebo-controlled, multicentre trial. Lancet. 2013; 382(9903):1485-1495.
  11. Chamberlain MC, Glantz MJ, Fadul CE. Recurrent meningioma: salvage therapy with long-acting somatostatin analogue. Neurology. 2007; 69(10):969-973. Erratum in: Neurology. 2008; 70(4):325.
  12. Chapman JA, Costantino JP, Dong B, et al. Octreotide LAR and tamoxifen versus tamoxifen in phase III randomize early breast cancer trials: NCIC CTG MA.14 and NSABP B-29. Breast Cancer Res Treat. 2015; 153(2):353-360.
  13. Corley DA, Cello JP, Adkisson W, et al. Octreotide for acute esophageal variceal bleeding: a meta-analysis. Gastroenterology. 2001; 120(4):946-954.
  14. Cozzi R, Montini M, Attanasio R, et al. Primary treatment of acromegaly with octreotide LAR: a long-term (up to nine years) prospective study of its efficacy in the control of  disease activity and tumor shrinkage. J Clin Endocrinol Metab. 2006; 91(4):1397-1403.
  15. Dimitroulopoulos D, Xinopoulos D, Tsamakidis K, et al. Long acting octreotide in the treatment of advanced hepatocellular cancer and overexpression of somatostatin receptors: randomized placebo-controlled trial. World J Gastroenterol. 2007; 13(23):3164-3170.
  16. Drymousis P, Pai M, Spalding D, et al. Is octreotide beneficial in patients undergoing pancreaticoduodenectomy? Best evidence topic (BET). Int J Surg. 2013; 11(9):779-782.
  17. Edmunds MC, Chen JD, Soykan I, et al. Effect of octreotide on gastric and small bowel motility in patients with gastroparesis. Aliment Pharmacol Ther. 1998; 12(2):167-174.
  18. Ellison EC, O'Dorisio TM, Sparks J, et al. Observations on the effect of a somatostatin analog in the Zollinger-Ellison syndrome: implications for the treatment of apudomas. Surgery. 1986; 100(2):437-444.
  19. Ezzat S, Snyder PJ, Young WF, et al. Octreotide treatment of acromegaly. A randomized, multicenter study. Ann Intern Med. 1992; 117(9):711-718.
  20. Fazio N, Granberg D, Grossman A, et al. Everolimus plus octreotide long-acting repeatable in patients with advanced lung neuroendocrine tumors: analysis of the phase 3, randomized, placebo-controlled RADIANT-2 study. Chest. 2013; 143(4):955-962.
  21. Friedlander TW, Weinberg VK, Small EJ, et al. Effect of the somatostatin analog octreotide acetate on circulating insulin-like growth factor-1 and related peptides in patients with non-metastatic castration-resistant prostate cancer: results of a phase II study. Urol Oncol. 2012; 30(4):408-414.
  22. Freitas DS, Sofia C, Pontes JM, et al. Octreotide in acute bleeding esophageal varices: a prospective randomized study. Hepatogastroenterology. 2000; 47(35):1310-1314.
  23. Fujita T, Daiko H. Efficacy and predictor of octreotide treatment for postoperative chylothorax after thoracic esophagectomy. World J Surg. 2014; 38(8):2039-2045.
  24. Gadelha MR, Vieira Neto L. Efficacy of medical treatment in Cushing's disease: a systematic review. Clin Endocrinol (Oxf). 2014: 80(1):1-12.
  25. Garland J, Buscombe JR, Bouvier C, et al. Sandostatin LAR (long-acting octreotide acetate) for malignant carcinoid syndrome: a 3-year experience. Aliment Pharmacol Ther. 2003; 17(3):437-444.
  26. Giustina A, Mazziotti G, Torri V, et al. Meta-analysis on the effects of octreotide on tumor mass in acromegaly. PLoS One. 2012; 7(5):e36411.
  27. Hisanaga T, Shinjo T, Morita T, et al. Multicenter prospective study on efficacy and safety of octreotide for inoperable malignant bowel obstruction. Jpn J Clin Oncol. 2010; 40(8):739-745.
  28. Hoff PM, Saragiotto DF, Barrios CH, et al. Randomized phase III trial exploring the use of long-acting release octreotide in the prevention of chemotherapy-induced diarrhea in patients with colorectal cancer: the LARCID trial. J Clin Oncol. 2014; 32(10):1006-1011.
  29. Hogan MC, Masyuk T, Bergstralh E, et al. Efficacy of 4 years of octreotide long-acting release therapy in patients with severe polycystic liver disease. Mayo Clin Proc. 2015; 90(8):1030-1037.
  30. Hogan MC, Masyuk TV, Page LJ, et al. Randomized clinical trial of long-acting somatostatin for autosomal dominant polycystic kidney and liver disease. J Am Soc Nephrol. 2010; 21(6):1052-1061.
  31. Ismail NA, Gordon J, Dunning J. The use of octreotide in the treatment of chylothorax following cardiothoracic surgery. Interact Cardiovasc Thorac Surg. 2015; 20(6):848-854.
  32. Jia WD, Zhang CH, Xu GL, et al. Octreotide therapy for hepatocellular carcinoma: a systemic review of the evidence from randomized controlled trials. Hepatogastroenterology. 2010; 57(98):292-299.
  33. Johnson DR, Kimmel DW, Burch PA, et al. Phase II study of subcutaneous octreotide in adults with recurrent or progressive meningioma and meningeal hemangiopericytoma. Neuro Oncol. 2011; 13(5):530-535.
  34. Junquera F, Saperas E, Videla S, et al. Long-term efficacy of octreotide in the prevention of recurrent bleeding from gastrointestinal angiodysplasia. Am J Gastroenterol. 2007; 102(2):254-260.
  35. Kinney MA, Warner ME, Nagorney DM, et al. Perianaesthetic risks and outcomes of abdominal surgery for metastatic carcinoid tumours. Br J Anaesth. 2001; 87(3):447-452.
  36. Kurumboor P, Palaniswami KN, Pramil K, et al. Octreotide does not prevent pancreatic fistula following pancreatoduodenectomy in patients with soft pancreas and non-dilated duct: a prospective randomized controlled trial. J Gastrointest Surg. 2015; 19(11):2038-2044.
  37. Kvols LK, Moertel CG, O'Connell MJ, et al. Treatment of the malignant carcinoid syndrome. Evaluation of a long-acting somatostatin analogue. N Engl J Med. 1986; 315(11):663-666.
  38. Laval G, Rousselot H, Toussaint-Martel S, et al. SALTO: a randomized, multicenter study assessing octreotide LAR in inoperable bowel obstruction. Bull Cancer. 2012; 99(2):E1-E9.
  39. Loehrer PJ Sr, Wang W, Johnson DH, et al. Octreotide alone or with prednisone in patients with advanced thymoma and thymic carcinoma: an Eastern Cooperative Oncology Group Phase II Trial. J Clin Oncol. 2004; 22(2):293-299.
  40. Longo F, De Filippis L, Zivi A, et al. Efficacy and tolerability of long-acting octreotide in the treatment of thymic tumors: results of a pilot trial. Am J Clin Oncol. 2012; 35(2):105-109.
  41. Loyaga-Rendon RY, Hashim T, Tallaj JA, et al. Octreotide in the management of recurrent gastrointestinal bleed in patients supported by continuous flow left ventricular assist devices. ASAIO J. 2015; 61(1):107-109.
  42. Lustig RH, Hinds PS, Ringwald-Smith K, et al. Octreotide therapy of pediatric hypothalamic obesity: a double-blind, placebo-controlled trial. J Clin Endocrinol Metab. 2003; 88(6):2586-2592.
  43. Mercadante S, Porzio G. Octreotide for malignant bowel obstruction: twenty years after. Crit Rev Oncol Hematol. 2012; 83(3):388-392.
  44. Mercado M, Borges F, Bouterfa H, et al. A prospective, multicentre study to investigate the efficacy, safety and tolerability of octreotide LAR (long-acting repeatable octreotide) in the primary therapy of patients with acromegaly. Clin Endocrinol (Oxf). 2007; 66(6):859-868.
  45. Murakami H, Matsumoto H, Nakamura M, et al. Octreotide acetate-steroid combination therapy for malignant gastrointestinal obstruction. Anticancer Res. 2013; 33(12):5557-5560.
  46. Mystakidou K, Tsilika E, Kalaidopoulou O, et al. Comparison of octreotide administration vs conservative treatment in the management of inoperable bowel obstruction in patients with far advanced cancer: a randomized, double-blind, controlled clinical trial. Anticancer Res. 2002; 22(2B):1187-1192.
  47. Nehra V, Camilleri M, Burton D, et al. An open trial of octreotide long-acting release in the management of short bowel syndrome. Am J Gastroenterol. 2001; 96(5):1494-1498.
  48. Newman CB, Melmed S, Snyder PJ, et al. Safety and efficacy of long-term octreotide therapy of acromegaly: results of a multicenter trial in 103 patients--a clinical research center study. J Clin Endocrinol Metab. 1995; 80(9):2768-2775. Erratum in: J Clin Endocrinol Metab 1995; 80(11):3238.
  49. Nikou GC, Toumpanakis C, Katsiari C, et al. Treatment of small intestinal disease in systemic sclerosis with octreotide: a prospective study in seven patients. J Clin Rheumatol. 2007; 13(3):119-123.
  50. Palmieri, G, Montella L, Martignetti A, et al. Somatostatin analogs and prednisone in advanced refractory thymic tumors. Cancer. 2002; 94(5):1414-1420.
  51. Pavel ME, Hainsworth JD, Baudin E, et al. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet. 2011; 378(9808):2005-2012.
  52. Peng X, Wang P, Li S, et al. Randomized clinical trial comparing octreotide and scopolamine butylbromide in symptom control of patients with inoperable bowel obstruction due to advanced ovarian cancer. World J Surg Oncol. 2015; 13(1):455.
  53. Perlemuter G, Cacoub P, Chaussade S, et al. Octreotide treatment of chronic intestinal pseudoobstruction secondary to connective tissue diseases. Arthritis Rheum. 1999; 42(7):1545-1549.
  54. Rengasamy S, Ali SM, Sistla SC, et al. Comparison of 2 days versus 5 days of octreotide infusion along with endoscopic therapy in preventing early rebleed from esophageal varices: a randomized clinical study. Eur J Gastroenterol Hepatol. 2015; 27(4):386-392.
  55. Rinke A, Muller HH, Schade-Brittinger C, et al. 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: a report from the PROMID Study Group. J Clin Oncol. 2009; 27(28):4656-4663.
  56. Rinke A, Wittenberg M, Schade-Brittinger C, et al. 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 (PROMID): results on long term survival. Neuroendocrinology. 2017; 104(1):26-32.
  57. Ripamonti C, Mercadante S, Groff L, et al. Role of octreotide, scopolamine butylbromide, and hydration in symptom control of patients with inoperable bowel obstruction and nasogastric tubes: a prospective randomized trial. J Pain Symptom Manage. 2000; 19(1):23-34.
  58. Rosenoff SH, Gabrail NY, Conklin R, et al. A multicenter, randomized trial of long-acting octreotide for the optimum prevention of chemotherapy-induced diarrhea: results of the STOP trial. J Support Oncol. 2006; 4(6):289-294.
  59. Rubin J, Ajani J, Schirmer W, et al. Octreotide acetate long-acting formulation versus open-label subcutaneous octreotide acetate in malignant carcinoid syndrome. J Clin Oncol. 1999; 17(2):600-606.
  60. Ruggenenti P, Remuzzi A, Ondei P, et al. Safety and efficacy of long-acting somatostatin treatment in autosomal-dominant polycystic kidney disease. Kidney Int. 2005; 68(1):206-216.
  61. Shah HA, Mumatz K, Jafri W, et al. Sclerotherapy plus octreotide versus sclerotherapy alone in the management of gastro-oesophageal variceal hemorrhage. J Ayub Med Coll Abbottabad. 2005; 17(1): 10-14.
  62. Simon DM, Cello JP, Valenzuela J, et al. Multicenter trial of octreotide in patients with refractory acquired immunodeficiency syndrome-associated diarrhea. Gastroenterology. 1995; 108(6):1753-1760.
  63. Soudah HC, Hasler WL, Owyang C. Effect of octreotide on intestinal motility and bacterial overgrowth in scleroderma. N Engl J Med. 1991; 325(21):1461-1467.
  64. Stan MN, Garrity JA, Bradley EA, et al. Randomized, double-blind, placebo-controlled trial of long-acting release octreotide for treatment of Graves' ophthalmopathy. J Clin Endocrinol Metab. 2006; 91(12):4817-4824.
  65. Strosberg JR, Yao JC, Bajetta E, et al. Efficacy of octreotide long-acting repeatable in neuroendocrine tumors: RADIANT-2 placebo arm post hoc analysis. Endocr Relat Cancer. 2015; 22(6):933-940.
  66. Sung JJ, Chung SC, Yung MY, et al. Prospective randomized study of effect of octreotide on rebleeding from oesophageal varices after endoscopic ligation. Lancet. 1995; 346(8991-8992):1666-1669.
  67. Swanson MS, Hudson RL, Bhandari N, et al. Use of octreotide for the management of chyle fistula following neck dissection. JAMA Otolaryngol Head Neck Surg. 2015; 141(8):723-727.
  68. Szilagyi A, Ghali MP. Pharmacological therapy of vascular malformations of the gastrointestinal tract. Can J Gastroenterol. 2006; 20(3):171-178.
  69. Tatar T, Kilic D, Ozkan M, et al. Management of chylothorax with octreotide after congenital heart surgery. Thorac Cardiovasc Surg. 2011; 59(5):298-301.
  70. Testoni D, Hornik CP, Neely ML, et al. Best Pharmaceuticals for Children Act - Pediatric Trials Network Administrative Core Committee. Safety of octreotide in hospitalized infants. Early Hum Dev. 2015; 91(7):387-392.
  71. Toumpanakis C, Caplin ME. Update on the role of somatostatin analogs for the treatment of patients with gastroenteropancreatic neuroendocrine tumors. Semin Oncol. 2013; 40(1):56-68.
  72. Toumpanakis C, Garland J, Marelli L, et al. Long-term results of patients with malignant carcinoid syndrome receiving octreotide LAR. Aliment Pharmacol Ther. 2009; 30(7):733-740.
  73. Verne GN, Eaker EY, Hardy E, Sninsky CA. Effect of octreotide and erythromycin on idiopathic and scleroderma-associated intestinal pseudoobstruction. Dig Dis Sci. 1995; 40(9):1892-1901.
  74. Vinik AI, Tsai S, Moattari AR, Cheung P. Somatostatin analogue (SMS 201-995) in patients with gastrinomas. Surgery. 1988; 104(5):834-842.
  75. Watari H, Hosaka M, Wakui Y, et al. A prospective study on the efficacy of octreotide in the management of malignant bowel obstruction in gynecologic cancer. Int J Gynecol Cancer. 2012; 22(4):692-626.
  76. Xu W, Zhou YF, Xia SH. Octreotide for primary moderate to severe acute pancreatitis: a meta-analysis. Hepatogastroenterology. 2013; 60(126):1504-1508.
  77. Yao JC, Phan AT, Chang DZ, et al. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol. 2008; 26(26):4311-4318.
  78. Yavuz MN, Yavuz AA, Aydin F, et al. The efficacy of octreotide in the therapy of acute radiation-induced diarrhea: a randomized controlled study. Int J Radiat Oncol Biol Phys. 2002; 54(1):195-202.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Boudreaux JP, Klimstra DS, Hassan MM, et al. The NANETS consensus guideline for the diagnosis and management of neuroendocrine tumors: well-differentiated neuroendocrine tumors of the jejunum, ileum, appendix, and cecum. Pancreas. 2010; 39(6):753-766.
  2. D'Amico G, Pagliaro L, Pietrosi G, Tarantino I. Emergency sclerotherapy versus medical interventions for bleeding oesophageal varices in cirrhotic patients. Cochrane Database Syst Rev. 2010;(3):CD002233.
  3. Das A, Shah PS. Octreotide for the treatment of chylothorax in neonates. Cochrane Database Syst Rev. 2010;(9):CD006388.
  4. Garcia-Tsao G, Sanyal AJ, Grace ND, et al. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Am J Gastroenterol. 2007; 102(9):2086-2102.
  5. Gotzsche PC, Hrobjartsson A. Somatostatin analogues for acute bleeding oesophageal varices. Cochrane Database Syst Rev. 2008;(3):CD000193.
  6. Gurusamy KS, Koti R, Fusai G, Davidson BR. Somatostatin analogues for pancreatic surgery. Cochrane Database Syst Rev. 2013;4:CD008370.
  7. Kaplan JE, Benson C, Holmes KK, et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep. 2009; 58(RR-4):1-207.
  8. Katznelson L, Laws ER Jr, Melmed S, et al.; Endocrine Society. Acromegaly: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014; 99(11):3933-3951.
  9. Katznelson L, Atkinson JL, Cook DM, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of acromegaly--2011 update. Endocr Pract. 2011; 17(Suppl 4):1-44.
  10. Moggia E, Koti R, Belgaumkar AP, et al. Pharmacological interventions for acute pancreatitis. Cochrane Database Syst Rev. 2017;(4):CD011384.
  11. National Comprehensive Cancer Network®. NCCN Drugs & Biologic Compendium® (electronic version). For additional information visit the NCCN website: http://www.nccn.org. Accessed on September 25, 2017.
  12. NCCN Clinical Practice Guidelines in Oncology® (NCCN). © 2017 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org. Accessed on September 25, 2017.
    • Central Nervous System (CNS) Cancers (Meningiomas) (V1.2017). Revised August 18, 2017.
    • Neuroendocrine Tumors (V3.2017). Revised June 13, 2017.
    • Palliative Care (V2.2017). Revised June 1, 2017.
    • Thymomas and Thymic Carcinomas (V2.2017). Revised June 1, 2017.
  13. Nieman LK, Biller BM, Findling JW, et al. Treatment of Cushing's Syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2015; 100(8):2807-2831.
  14. Oberg K, Kvols L, Caplin M, et al. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol. 2004; 15(6):966-973.
  15. Octreotide. In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated August 17, 2017. Available at: http://www.micromedexsolutions.com. Accessed on September 25, 2017.
  16. Octreotide Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised August 1, 2008. Accessed on September 25, 2017.
  17. Plockinger U, Rindi G, Arnold R, et al. Guidelines for the diagnosis and treatment of neuroendocrine gastrointestinal tumours. A consensus statement on behalf of the European Neuroendocrine Tumour Society (ENETS). Neuroendocrinology. 2004; 80(6):394-424.
  18. Ramage JK, Davies AH, Ardill J, et al. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours. Gut. 2005; 54 Suppl 4:iv1-16.
  19. Sandostatin [Product Information], Schaftenau, Austria. Sandoz GmbH (Novartis Pharmaceuticals Corporation, East Hanover, NY, USA); February 2012. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019667s061lbl.pdf. Accessed on September 25, 2017.
  20. Sandostatin LAR Depot [Product Information], Schaftenau, Austria. Sandoz GmbH (Novartis Pharmaceuticals Corporation, East Hanover, NY, USA); July 2016. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021008s035lbl.pdf. Accessed on September 25, 2017.
Websites for Additional Information
  1. National Cancer Institute (NCI). Cancer Topics. Available at: http://www.cancer.gov/cancertopics. Accessed on September 25, 2017.
    • Adrenocortical Carcinoma Treatment (PDQ®). Updated June 2, 2015.
    • Gastrointestinal Carcinoid Tumors Treatment (PDQ®). Updated July 8, 2015.
    • Pancreatic Neuroendocrine Tumors (Islet Cell Tumors) Treatment (PDQ®). Updated April 30, 2015.
    • Thymoma and Thymic Carcinoma Treatment (PDQ®). Updated February 4, 2015.
Index

Somatostatin analogue

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History

Status

Date

Action

Revised

11/02/2017

Medical Policy & Technology Assessment Committee (MPTAC) review. Clarified MN statement for use of octreotide acetate in the treatment of acromegaly when criteria are met.

Revised

11/01/2017

Hematology/Oncology Subcommittee review. The document header wording updated from “Current Effective Date” to “Publish Date.” Clarified MN statement for use of octreotide acetate in “Other Neuroendocrine Tumors,” adding “hypergastrinemic” to the statement for Zollinger-Ellison syndrome. Updated Discussion, References, and Websites for Additional Information sections.

 

10/01/2017

Updated Coding section with 10/01/2017 ICD-10-CM diagnosis code changes.

Revised

11/03/2016

MPTAC review.

Revised

11/02/3016

Hematology/Oncology Subcommittee review. Updated formatting in the Clinical Indications section. Added “or” between conditions in the NMN statement. Updated Discussion, Definitions, References, and Websites for Additional Information sections.

Revised

11/05/2015

MPTAC review.

Revised

11/04/2015

Hematology/Oncology Subcommittee review. Revised Clinical Indications, removing medically necessary statement for use of octreotide acetate for the treatment of adrenal gland tumors, now considered as not medically necessary. Updated Discussion, References, and Websites for Additional Information sections. Removed ICD-9 codes from Coding section.

Revised

08/06/2015

MPTAC review. Clarifications to medically necessary sections II and III (categories) for carcinoid and other neuroendocrine tumors. Clarified not medically necessary statement for the following conditions: chylothorax, GI tract bleeding from vascular malformations (including examples), and AIDS-associated diarrhea. Other updates to Discussion, References, and Websites for Additional Information sections.

New

05/07/2015

MPTAC review.

New

05/06/2015

Hematology/Oncology Subcommittee review. Initial document development.