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

   1. Treatment of acromegaly for any of the following conditions:

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

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

   2. Treatment of severe diarrhea and flushing episodes associated with carcinoid tumors.
   3. Prophylactic treatment to prevent carcinoid crises prior to surgery of carcinoid tumor.
   4. Prophylactic treatment prior to surgery for gastrinoma.
   5. Prophylactic treatment prior to hepatic artery embolization for nonresectable multiple and hormone-secreting neuroendocrine tumors.
   6. Treatment of profuse watery diarrhea associated with vasoactive intestinal polypeptide (VIP)-secreting tumors.
   7. Stabilization of blood glucose levels in persons with functioning islet cell tumors (insulinomas or glucagonomas).
   8. Treatment of functioning gastrinomas (Zollinger Ellison syndrome).
   9. Treatment of chemotherapy and/or radiation therapy-induced diarrhea when oral anti-diarrheal medications such as loperimide have become ineffective.
   10. Treatment of severe secretory diarrhea associated with acquired immunodeficiency syndrome (AIDS) when anti-microbial or anti-motility agents have become ineffective.
   11. Treatment of acute bleeding of gastroesophageal varices associated with cirrhosis when used in conjunction with endoscopic band ligation or sclerotherapy, OR alone if ligation/sclerotherapy is not immediately available.
   12. Management of gastrointestinal symptoms (e.g., nausea, vomiting, and pain) of in-operable bowel obstruction in persons with terminal cancer.
   13. Management of persons with short bowel syndrome if daily intravenous fluid requirements are greater than 3 liters.

   14. Treatment of unresectable malignant thymoma that is refractory to standard chemotherapy.

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

   1. Treatment of acute pancreatitis; or
   2. Treatment of acute non-variceal upper gastrointestinal bleeding; or
   3. Treatment of advanced breast carcinoma; or
   4. Management of diabetes mellitus (e.g., control of an excess of pro-angiogenic factors in diabetes-associated retinal complications); or
   5. Treatment of gastric paresis; or
   6. Treatment of hepatocellular carcinoma; or
   7. Management of hormone refractory prostate cancer; or
   8. Management of obesity (e.g., control of hyperinsulinemia); or
   9. Treatment of post-operative enterocutaneous pancreatic fistulas; or
   10. Treatment of protein-losing enteropathy following the Fontan operation; or
   11. Treatment of thyroid cancer; or
   12. Treatment of thyroid eye disease; or
   13. Treatment of vascular malformations of the gastrointestinal tract; or
   14. Salvage therapy for small cell lung cancer; or

   15. Treatment of biliary fistulae or leak.

Note: Octreotide is not coverd for constitutional (idiopathic) tall stature because such use is not considered treatment of disease.

For Aetna's CPB on OctreoScan, please see CPB 168 - Tumor Scintigraphy.

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

Neuroendocrine tumors are rare, occurring in less than 1 % of the general population. Clinically, these tumors are divided into 2 groups: (i) functionally active, and (ii) functionally non-active. The former produces a variety of substances (e.g., peptides or serotonin) that are responsible for symptoms and sometimes can lead to the death of the patient independently from tumor proliferation. The most effective compounds that can control symptoms in these patients are somatostatin analogs since native somatostatin is unsuitable for long-term clinical application because of its short half-life. Octreotide is one of these synthetic agents with improved pharmacokinetic characteristics compared to native somatostatin. It has been reported to alleviate symptoms in 30 to 70 % of the patients, mainly through a direct inhibitory effect on hormone production from the tumors. There is little or no effect on tumor growth during octreotide therapy; clinical responses were recorded in only 10 to 30 % of the patients. Recently, significant improvement in the management of the disease has been demonstrated with long-acting repeatable (LAR) octreotide. This new formulation requires only once-monthly intramuscular injection, and has been reported to demonstrate better acceptability and patient compliance to therapy. Available evidence show super-imposable results of both standard octreotide and LAR octreotide in controlling symptoms, lowering hormone and tumor marker levels, and in reducing tumor growth.

Carcinoid tumors are extremely rare and originate primarily from the gastrointestinal (GI) tract. The tumor histology is ambiguous and malignancy is determined by metastases. Many carcinoid tumors are found incidentally or from symptoms related to the hormones that the tumor secretes. Carcinoid syndrome occurs when an abundance of hormones are produced from GI carcinoid metastases or a non-GI primary tumor. The hallmark carcinoid symptoms include flushing, diarrhea, and cardiac involvement. Treatment consists of a wide resection for local primaries and usually palliative, medical support for patients with metastases. The tumors are very slow-growing and patients have lived for up to 30 years after metastasis is diagnosed. Administration of somatostatin analogs (e.g., octreotide) controls many of the carcinoid symptoms.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

There is currently insufficient evidence to support the use of octreotide in the treatment of biliary leak/fistulae. Dorta (1999) stated that "octreotide and somatostatin actually cannot be recommended in the treatment of intestinal fistulae in settings outside of controlled trials". A subsequent randomized controlled trial of the use of somatostatin in enterocutaneous fistulae by Jamil et al (2004) concluded that "[s]omatostatin and its analogues have shown some beneficial effects with regard to fistula closure rate and hospital stay, but the effects are statistically insignificant....Thus the role of somatostatin is not established in the closure of enterocutaneous fistula". Furthermore, Leandros et al (2004) evaluated and compared the potential clinical benefit and cost effectiveness of pharmacotherapy (somatostatin versus octreotide) versus conventional therapy. A toal of 51 patients with gastrointestinal or pancreatic fistulas were randomized to 3 treatment groups: (i) 19 received 6000 IU/day of somatostatin intravenously, (ii) 17 received 100 microg of octreotide three times daily subcutaneously, and (iii) 15 received only standard medical treatment. The fistula closure rate was 84 % in the somatostatin group, 65 % in the octreotide group and 27 % in the control group. These differences were of statistical significance (p = 0.007). Overall mortality rate was less than 5 % and statistically significant differences in mortality among the 3 groups could not be established. Overall, treatment with somatostatin and octreotide was more cost effective than conventional therapy (control group), and somatostatin was more cost effective than octreotide. The average hospital stay was 21.6 days, 27.0 and 31.5 days for the somatostatin, octreotide and control groups, respectively. The authors concluded that these findings suggested that pharmacotherapy reduces the costs involved in fistula management by reducing hospitalization and also offered increased spontaneous closure rate. They stated that further prospective studies focusing on the above parameters are needed to demonstrate the clinico-economic benefits.