Octreotide Long-acting Repeatable Research Articles

Biotherapy of pancreatic neuroendocrine tumors using somatostatin analogs.

Basically, pancreatic neuroendocrine tumor (PNET) should be treated surgically; however, in unresectable cases, a treatment that aims to improve the prognosis by inhibiting the growth of the tumor and control the clinical symptoms becomes necessary. In the case of functional tumors, the quality of life of patients is decreased by not only the symptoms with tumor invasion and/or metastasis but also by the symptoms of hormone excess. The efficacy of somatostatin analogs against the latter has been previously reported, and their sustained release formulations have been developed. Somatostatin analogs are recommended to treat the endocrine symptoms of functional PNET; however, in case they can cause hypoglycemia in patients with insulinoma. On the other hand, results from the PROMID study demonstrated a tumor-stabilizing effect when octreotide LAR (long acting repeatable) was used to treat patients with advanced midgut NET; however, there has been no consensus regarding its antitumor effect for PNET. Additionally, a recent result from the CLARINET study suggests that lanreotide autogel has an antitumor effect against nonfunctional NET including PNET. Further clinical study results are awaited.

Octreotide LAR dosage and survival among elderly patients with distant-stage neuroendocrine tumors.

392 Background: Octreotide long-acting repeatable (LAR) is approved for the management of symptoms due to carcinoid syndrome and may delay tumor progression among patients with neuroendocrine tumors (NETs). It is unknown whether dosage of octreotide LAR has an impact on survival. The current analysis evaluates the impact of initial octreotide LAR dosage on survival of elderly patients with NETs. Methods: Distant stage NET patients diagnosed between 1/1999 and 12/2009 who had received octreotide LAR treatment within 12 months of diagnosis were identified from the SEER-Medicare database. Those under age 65, enrolled in HMOs, or without continuous enrollment in Medicare Parts A and B were excluded. We compared the five-year survival of NET patients based on dose per 28 days averaged over the initial 3 months: Group A, <= 20 mg; B, 21 to 30 mg; C, > 30 mg. Kaplan-Meier estimations and Cox proportional hazard modeling were used to examine the association between octreotide LAR dose and survival. Results: Among 214 distant stage patients (mean and median age at 74 years old) with octreotide LAR treatment, 73 (34%) received <= 20 mg, 82 (38%) received 21 – 30 mg, while 59 (28%) received >30 mg. Median survival for patients who received low, medium and high dosage levels were 20.8 (95% CI: 13.2 – 31.5), 32.6 (95% CI: 20.5 – 51.1), and 36.3 (95% CI: 24.8 – N/A) months respectively. The log rank test had a p-value of 0.006. Multivariate analyses showed that higher octreotide LAR dosage levels were associated with significant survival improvement for distant stage patients. Compared to patients with the low dosage level, patients with medium dosage (HR=0.52, P=0.002) and patients with high dosage (HR=0.48, P=0.004) had better five-year survival. The difference in survival between Groups B and C was not statistically significant. Conclusions: This population-based study suggests potential survival benefits for octreotide LAR 30 mg dosage level among elderly distant stage NET patients.

Everolimus plus octreotide long-acting repeatable in advanced neuroendocrine tumors in the routine tertiary cancer care setting: An Indian experience.

Neuroendocrine tumors (NETs) are rare, heterogeneous, indolent tumors that are relatively insensitive to systemic chemotherapy. Therapeutic strategies for NETs broadly include somatostatin analogs, antiangiogenic therapy, and most recently, mammalian target of rapamycin inhibition. Combination therapy has shown promising antitumor activity and good tolerability in the randomized phase III trials. The aim was to evaluate the safety and efficacy of Everolimus plus Octreotide long-acting repeatable (LAR) in patients with advanced NETs in the routine tertiary cancer care setting in India in this postapproval, noninterventional trial. Patients presenting to selected centers between 2011 and 2013 with histologically confirmed low-, intermediate- or high-grade advanced NETs who may have had prior exposure to cytotoxic chemotherapy (≤2 lines) were treated with oral Everolimus (10 mg/day) plus intramuscular Octreotide LAR (30 mg once every 28 days) until disease progression or unacceptable toxicity was seen. Patients were evaluated every 3 months for a response to therapy as per Response Evaluation Criteria in Solid Tumors. Everolimus plus Octreotide LAR was associated with a clinical benefit rate of 69% (best evaluable responses: Stable disease [SD] in 10 patients [63%], partial response in 1 patient [6%]). The average duration of therapy was 4.8 cycles, and 3 (17%) patients continued therapy for ≥12 cycles (all achieved SD). The therapy was found to be well-tolerated in all patients. Everolimus plus Octreotide LAR appears to be safe and efficacious in patients with advanced NETs who may have had prior exposure to chemotherapy - a finding consistent with recently conducted major trials.

Hormonal Secretion and Quality Of Life in Nelson Syndrome and Cushing Disease After Long Acting Repeatable Octreotide

Clinical management of persistent adrenocorticotropin hormone (ACTH) excess in Nelson syndrome (NS) and Cushing disease (CD) remains a challenge. Somatostatin and its analogs as octreotide decrease ACTH secretion through somatostatin receptors of pituitary cells. To our knowledge, there are no reports on the effect of long-acting repeatable octreotide (oct-lar) on hormonal secretion and quality of life in patients with NS and CD who failed conventional therapy. Herein, we describe the effects of treatment with oct-lar (20 mg/month intramurally) in 1 woman with NS and 2 women with persistent CD. Oct-lar therapy reduced ACTH secretion and improved the quality of life in NS patient. By contrast, in CD patients, it failed to control ACTH and cortisol secretion, and the quality of life remained unchanged.

Octreotide long-acting repeatable use among elderly patients with carcinoid syndrome and survival outcomes: a population-based analysis.

Octreotide long-acting repeatable (LAR) is indicated for the treatment of carcinoid syndrome and diarrhea related to VIPoma, and may delay tumor growth in patients with neuroendocrine tumors (NETs). To the authors' knowledge, the pattern of octreotide LAR use in clinical practice and its impact on survival outcomes has not been well documented. Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, the authors identified patients with NET aged ≥ 65 years who were diagnosed between July 1999 and December 2007. Patients with US Food and Drug Administration-approved indications for octreotide LAR were identified from Medicare claims. Multivariate logistic regression was performed to ascertain factors associated with octreotide LAR use, whereas the Cox proportional hazards model was used to evaluate the impact of octreotide LAR on survival. Among those with Food and Drug Administration-approved indications, 245 of 4848 patients with distant-stage disease (51%) and 81 of 807 patients with local/regional disease (10%) initiated treatment with octreotide LAR within 6 months of diagnosis. Multivariate logistic regression indicated that among those with distant-stage disease, older age (≥ 80 years vs 65-69 years) (odds ratio [OR], 0.43; 95% confidence interval [95% CI], 0.23-0.81), female sex (OR, 0.62; 95% CI, 0.40-0.97), and living in the South (vs Northeast) (OR, 0.36; 95% CI, 0.18-0.72) were associated with a lower likelihood of using octreotide LAR. The multivariate proportional hazards model showed that octreotide LAR provided a significant 5-year survival benefit for patients with distant-stage disease (hazards ratio, 0.61; P ≤ .001), whereas this survival benefit was not shown for the patients with local/regional stage (hazards ratio, 0.88; P = .563). The results of this retrospective study suggest a possible survival benefit for the use of octreotide LAR in elderly patients with distant-stage NET with carcinoid syndrome. The results of the current study also suggest that octreotide LAR is underused in this population despite recommended guidelines.

Everolimus in combination with octreotide LAR as the first-line treatment for advanced neuroendocrine tumors: A phase II trial of the I.T.M.O. (Italian Trials in Medical Oncology) group.

4136^ Background: Everolimus has shown antitumor activity in patients (pts) with advanced pancreatic neuroendocrine tumors (NETs). We aimed to assess efficacy and safety of everolimus in combination with octreotide long-acting repeatable (LAR) in patients with well differentiated NETs of gastroenteropancreatic and of lung origin. Methods: We performed a phase II, multicenter trial using a Simon two-stage minmax design. Pts with advanced well differentiated, previously untreated NETs of the gastroenteropancreatic tract and of the lung received octreotide LAR 30 mg every 28 days in conjunction with everolimus 10 mg per day continuously. The primary endpoint was objective response rate (ORR). Results: A total of 50 pts (58% males) were enrolled. The median age was 60.5 years (range 25-76). Primary tumor site was pancreas in 14 (28%), unknown in 14 (28%), lung in 11 (22%), ileum in 9 (18%) and jejunum and duodenum in 2 (4%) of pts. 13 (26%) pts had carcinoid syndrome. The ORR, calculated on the ITT population, was 20.0% (95% CI 8.9-31.1): 2 patients (4%) had a complete response (CR), 8 (16%) a partial response (PR). Thirty-six patients (72%) achieved stable disease (SD). All CR and all PR as well as 91.7% of SD had a duration ≥ 6 months. Clinical benefit (CR+PR+SD) was 92%. At a median follow-up of 277 days, the median time to progression (TTP) was 16.3 months (95% CI 10.7-20.1). Overall survival could not be assessed. Treatment-related adverse events (AEs) were mostly of grade 1 or 2; the only grade 4 AE was mucositis in 1 patient, while grade 3 AEs included skin rash in 1 case, stomatitis in 4 cases (8%) and diarrhea in 11 cases (22%). Conclusions: Everolimus in combination with octreotide LAR has shown to be active and well tolerated in advanced NETs and, in this study, not only in primary pancreatic tumors. Compared to other clinical trials with everolimus in NETs, the observed ORR in this study was higher. Aknowledgements: The Authors thank the Italian Trials in Medical Oncology (I.T.M.O.) group and Novartis Pharma for the support provided. Clinical trial information: 2008-007153-13.

Everolimus Plus Octreotide Long-Acting Repeatable in Patients With Advanced Lung Neuroendocrine Tumors: Analysis of the Phase 3, Randomized, Placebo-Controlled RADIANT-2 Study

The incidence of neuroendocrine tumors (NETs) has increased approximately fivefold since the 1980s. A similar increase in the incidence of lung NETs has been reported, but therapy has not been optimized. This exploratory subanalysis evaluated the efficacy and safety of everolimus plus octreotide long-acting repeatable (LAR) in a cohort of patients with low- to intermediate-grade advanced lung NET from the phase 3, randomized, placebo-controlled RADIANT-2 (RAD001 in Advanced Neuroendocrine Tumors) study. The primary end point was progression-free survival (PFS). Secondary end points included objective response rate, overall survival, change from baseline in biomarker levels, and safety outcomes. Patients were randomly assigned to everolimus plus octreotide LAR (n 5 33) or placebo plus octreotide LAR (n 5 11). Median PFS was 13.63 months in the everolimus plus octreotide LAR arm compared with 5.59 months in the placebo plus octreotide LAR arm (relative risk for progression: HR, 0.72; 95% CI, 0.31–1.68; P 5 .228). More patients 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%). Most frequently reported adverse events (AEs) included stomatitis, rash, diarrhea, and asthenia. This was consistent with the overall RADIANT-2 trial and the safety profile of everolimus. This exploratory subgroup analysis of the RADIANT-2 trial indicates that in patients with advanced lung NET, the addition of everolimus to octreotide LAR improves median PFS by 2.4-fold compared with placebo plus octreotide LAR. These clinically significant observations support the continued evaluation of everolimus treatment regimens in this patient population. ClinicalTrials.gov; No.: NCT00412061

A case of malignant insulinoma: successful control of glycemic fluctuation by replacing octreotide injections with octreotide LAR injections

A 73-year-old woman with malignant insulinoma was treated with 100 μg/day octreotide for unresected insulinoma and liver metastases. The daily administration of the drug induced hyperglycemia after dinner in addition to existing fasting hypoglycemia possibly because this drug suppressed both insulin and glucagon secretion and its blood concentration was unstable. After replacing a daily injection of octreotide with a monthly injection of octreotide long-acting repeatable (LAR), blood glucose levels stabilized within the normal range. The findings of the present study showed that octreotide LAR could be useful for the long-term treatment of unresectable insulinomas.

Everolimus plus octreotide long-acting repeatable in patients with colorectal neuroendocrine tumors: a subgroup analysis of the phase III RADIANT-2 study.

The incidence of colorectal neuroendocrine tumors (NETs) is increasing, and patients with this disease have particularly poor prognoses. Treatment options are limited, and survival times have not improved in the past decade. A post hoc analysis of the efficacy and tolerability of everolimus plus octreotide long-acting repeatable (LAR) was conducted in patients with colorectal NETs enrolled in the phase III RAD001 in Advanced Neuroendocrine Tumors, Second Trial (RADIANT-2) study. The primary endpoint (progression-free survival [PFS]), secondary endpoints (including objective response rate), and safety were assessed. Patients with colorectal NETs receiving everolimus plus octreotide LAR had a significantly longer median PFS (29.9 months; n = 19) than did those receiving placebo plus octreotide LAR (6.6 months; n = 20). Everolimus plus octreotide LAR treatment also significantly reduced the risk for disease progression (hazard ratio: 0.34; 95% confidence interval: 0.13-0.89; p = .011). Although no objective responses were observed, tumor shrinkage was more frequently noted in the everolimus plus octreotide LAR arm than in the placebo plus octreotide LAR arm (67% vs. 37%, respectively). The combination of everolimus plus octreotide LAR was generally well tolerated by patients with colorectal NETs; rash and stomatitis were the most commonly reported adverse events. Everolimus plus octreotide LAR treatment had significant benefits and improved outcomes for patients with advanced colorectal NETs compared with placebo plus octreotide LAR treatment. Results of this exploratory analysis are consistent with those reported from the RADIANT-2 primary analysis. These findings support additional investigations of everolimus plus octreotide LAR in patients with colorectal NETs.

Antitumor Effects of Somatostatin Analogs in Neuroendocrine Tumors

For decades, somatostatin analogs (including octreotide and lanreotide) have been indicated for relief of the symptoms of flushing, diarrhea, and wheezing associated with secretory neuroendocrine tumors (NETs). Recently, it has been suggested that somatostatin analogs may provide direct and indirect antitumor effects in secretory and nonsecretory NETs in addition to symptom control in secretory NETs. A systematic review of MEDLINE was conducted to identify studies that investigated the antitumor effects of octreotide or lanreotide for patients with NETs. Additional studies not published in the peer-reviewed literature were identified by searching online abstracts. Results. In all, 17 octreotide trials and 11 lanreotide trials that included antitumor effects were identified. Partial response rates were between 0% and 31%, and stable disease rates were between 15% and 89%. Octreotide was the only somatostatin analog for which results of a phase III, randomized, placebo-controlled clinical trial that investigated antitumor effects were published. After 6 months of treatment in this randomized phase III trial, stable disease was observed in 67% of patients (hazard ratio for time to disease progression: 0.34; 95% confidence interval: 0.20-0.59; p = .000072). In addition to symptom control for NETs, the data support an antitumor effect of somatostatin analogs and suggest that they may slow tumor growth. Long-acting repeatable octreotide has been shown to have an antitumor effect in a randomized phase III trial in midgut NETs, whereas results are pending in a corresponding controlled trial with lanreotide for patients with intestinal and pancreatic primary NETs.

Effect of octreotide LAR on quality of life of 93 Hungarian patients with neuroendocrine tumors.

362 Background: Studies have shown that health-related quality of life (HRQoL) of patients with neuroendocrine tumors (NET) is lower compared to the general population in the US and Norway. Secretory symptoms associated with functional NET (diarrhea/flushing) contribute to worsened HRQoL but may be controlled with the somatostatin analog octreotide long-acting repeatable (LAR). To date, there have been limited assessments of specific drug effects on HRQoL in patients with NET. The purpose of this study was to assess the effect of octreotide LAR treatment on HRQoL. Methods: 93 Hungarian patients with gastroenteropancreatic NET who were treated with octreotide LAR participated in a multicenter observational study from 2005 to 2007. At study entry and 4 quarterly follow-up visits, patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) questionnaire. A mixed model was used to analyze the data and confirm significance. Results: 91 patients (mean age = 61 years) were evaluable for QoL assessments. Overall, patients reported improvements in diarrhea, global health status, emotional functioning, and financial difficulties but worsening in role functioning, pain, and insomnia. There were some differences in trends, depending on the tumor site, but diarrhea still improved in all patient categories. Women reported lower global health status compared to men, including more fatigue, nausea/vomiting, pain, dyspnea, and constipation. Elderly patients >70 years did not report any lessening of overall global health status scores compared to younger patients; older patients did experience less nausea/vomiting and pain but more constipation and diarrhea. In addition, patients diagnosed <2 years had slightly lower global health status than patients diagnosed >2 years earlier. Conclusions: Patients with NET who were treated with octreotide LAR had improvements in global health status and diarrhea. Interesting trends were noted in different patient populations, depending on tumor site, gender, or age. Additional analysis is planned to assess changes as measured by the GI NET disease-specific module of EORTC that was also applied to patients.

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

Everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), has shown antitumour activity in patients with advanced pancreatic neuroendocrine tumours. We aimed to assess the combination of everolimus plus octreotide long-acting repeatable (LAR) in patients with low-grade or intermediate-grade neuroendocrine tumours (carcinoid). We did a randomised, double-blind, placebo-controlled, phase 3 study comparing 10 mg per day oral everolimus with placebo, both in conjunction with 30 mg intramuscular octreotide LAR every 28 days. Randomisation was by interactive voice response systems. Participants were aged 18 years or older, with low-grade or intermediate-grade advanced (unresectable locally advanced or distant metastatic) neuroendocrine tumours, and disease progression established by radiological assessment within the past 12 months. Our primary endpoint was progression-free survival. Adjusted for two interim analyses, the prespecified boundary at final analysis was p≤0·0246. This study is registered at ClinicalTrials.gov, number NCT00412061. 429 individuals were randomly assigned to study groups; 357 participants discontinued study treatment and one was lost to follow-up. Median progression-free survival by central review was 16·4 (95% CI 13·7-21·2) months in the everolimus plus octreotide LAR group and 11·3 (8·4-14·6) months in the placebo plus octreotide LAR group (hazard ratio 0·77, 95% CI 0·59-1·00; one-sided log-rank test p=0·026). Drug-related adverse events (everolimus plus octreotide LAR vs placebo plus octreotide LAR) were mostly grade 1 or 2, and adverse events of all grades included stomatitis (62%vs 14%), rash (37%vs 12%), fatigue (31%vs 23%), and diarrhoea (27%vs 16%). Everolimus plus octreotide LAR, compared with placebo plus octreotide LAR, improved progression-free survival in patients with advanced neuroendocrine tumours associated with carcinoid syndrome. Novartis Pharmaceuticals.

Safety review: Dose optimization of somatostatin analogs in patients with acromegaly and neuroendocrine tumors

Patients with either acromegaly or neuroendocrine tumors (NET) can be treated with somatostatin analogs to relieve symptoms and improve disease control. However, there is an absence of large clinical trials specifically designed to document the safety when increases in somatostatin analog dosing are needed in patients who do not achieve their treatment goals. To fully explore and communicate any potential risks, we conducted a literature review and present a summary of the studies documenting the safety and tolerability of dose optimization with somatostatin analogs in patients with acromegaly and NET. A literature search was undertaken to find clinical studies specifically reporting the effects of dose titration using the depot formulations of the somatostatin analogs, octreotide long-acting repeatable (LAR) or lanreotide, in patients with acromegaly and NET. Publications that described the treatment and management of patients with acromegaly and NET were reviewed. The rationale for dose optimization, including high-dose treatment in patients who are inadequately controlled on conventional doses and the safety and tolerability of somatostatin analogs, is discussed. A review of published clinical studies demonstrates that dose optimization provides additional biochemical control in patients with acromegaly and NET who are inadequately controlled with conventional starting doses of octreotide LAR and lanreotide ATG. The benefits of dose optimization include improved efficacy without a significant change in the recorded adverse events and the tolerability of the treatment. Therefore, patient response to treatment should be routinely monitored and their somatostatin analog dose increased or decreased thereafter according to their individual response.

The Management of Neuroendocrine Tumours: Current and Future Medical Therapy Options

Neuroendocrine tumours (NETs) are a genetically diverse group of malignancies that sometimes produce peptides causing characteristic hormonal syndromes. NETs can be clinically symptomatic (functioning) or silent (non-functioning); both types frequently synthesise more than one peptide, although often these are not associated with specific syndromes. Based on data from various sources, the incidence and prevalence of NETs is increasing. The primary treatment goal for patients with NETs is curative, with symptom control and the limitation of tumour progression as secondary goals. Surgery is the only possible curative approach and so represents the traditional first-line therapy. However, as most patients with NETs are diagnosed once metastases have occurred, curative surgery is generally not possible. Patients therefore require chronic postoperative medical management with the aim of relieving symptoms and, in recent years, suppressing tumour growth and spread. Somatostatin analogues, such as octreotide long-acting repeatable (LAR), can improve the symptoms of carcinoid syndrome and stabilise tumour growth in many patients. Results from the PROMID study show that octreotide LAR 30mg is an effective antiproliferative treatment in patients with newly diagnosed, functionally active or inactive, well-differentiated metastatic midgut NETs. An antiproliferative effect can also be achieved with everolimus, and combination therapy with octreotide LAR has shown synergistic antiproliferative activity. In the future, pasireotide, the multi-receptor targeted somatostatin analogue, has the potential to be an effective therapy for de novo or octreotide-refractory carcinoid syndrome and for inhibiting tumour cell proliferation. Peptide receptor radiotherapy with [90]yttrium-DOTATOC or [177]lutetium-DOTATE is also a new interesting treatment option for NETs.

Six-month preoperative octreotide treatment in unselected, de novo patients with acromegaly: effect on biochemistry, tumour volume, and postoperative cure

Treatment with somatostatin analogues is the primary medical treatment of acromegaly. Controversies still exist whether acute octreotide effect predicts long-term biochemical effects, tumour regression or surgical cure. This prospective study investigates effect of 6-month treatment with octreotide long-acting repeatable (LAR) on insulin-like growth factor-1 (IGF-1) and growth hormone (GH) levels, pituitary function, tumour regression and postoperative cure in de novo acromegalic patients. After a baseline evaluation including fasting hormone levels, MRI scan and an acute 50 μg octreotide test, 32 patients were treated with octreotide LAR 20 mg every 28th day for 6 months before surgery. Treatment effects on IGF-1 and GH levels, serum hormone levels and tumour volume were monitored. Surgical cure was evaluated 3 months postoperatively. Mean tumour volume reduction was 35%, in one-third of the patients more than 50%, while approximately one-third achieved biochemical remission evaluated by normalized IGF-1 levels. The GH reduction following an acute octreotide test was 81 ± 19% and associated with long-term GH reduction (r = 0·78, P < 0·0005). However, neither acute (r = 0·29, P = 0·12) nor the long-term octreotide effect (r = 0·11, P = 0·58) on GH levels was associated with tumour volume reduction and did not predict subsequent surgical cure. Six months of long-acting octreotide using a fixed dose, 1/3 of the patients came in biochemical remission, while 2/3 had significant tumour reduction. Moreover, an acute effect of octreotide seemed to be a prerequisite for long-term effect.

Management of neuroendocrine tumors: current and future therapies

Neuroendocrine tumors (NETs) are a genetically diverse group of malignancies that sometimes produce peptides that cause characteristic hormonal syndromes. NETs can be clinically symptomatic (functioning) or silent (nonfunctioning); both types frequently synthesize more than one peptide, although often these are not associated with specific syndromes. Based on data from various sources, the incidence and prevalence of NETs is increasing. The primary treatment goal for patients with NETs is curative, with symptom control and the limitation of tumor progression as secondary goals. Surgery is the only possible curative approach and so represents the traditional first-line therapy. However, as most patients with NETs are diagnosed once metastases have occurred, curative surgery is generally not possible. Patients therefore require chronic postoperative medical management with the aim of relieving symptoms and, in recent years, suppressing tumor growth and spread. Somatostatin analogues, such as octreotide long-acting repeatable (LAR), can improve the symptoms of carcinoid syndrome and stabilize tumor growth in many patients. Results from the 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 study) demonstrate that octreotide LAR 30 mg is an effective antiproliferative treatment in patients with newly diagnosed, functionally active or inactive, well-differentiated metastatic midgut NETs. An antiproliferative effect can also be achieved with everolimus, and combination therapy with octreotide LAR has shown synergistic antiproliferative activity. Sunitinib, a tyrosine kinase inhibitor, is active in pancreatic NETs. In the future, pasireotide, the multireceptor targeted somatostatin analogue, has the potential to be an effective therapy for de novo or octreotide-refractory carcinoid syndrome and for inhibiting tumor cell proliferation. Peptide receptor radiotherapy with 90Yttrium-DOTATOC or 177Lutetium-DOTATE is also a new interesting treatment option for NETs.

A Prospective Trial on the Effect of Body Mass Index and Sex on Plasma Octreotide Levels in Patients Undergoing Long-Term Octreotide LAR Therapy

Octreotide long acting repeatable (LAR) is commonly used to control the symptoms of patients with functional neuroendocrine tumors. Unfortunately, most patients escape control over time and require higher LAR doses or more frequent rescue therapy to remain asymptomatic. Previous work has shown that body weight and monthly LAR dose will significantly affect circulating plasma octreotide levels in patients undergoing therapy. To determine if other parameters change circulating plasma octreotide levels, we prospectively studied 82 patients undergoing long-term LAR therapy. Multivariate analysis demonstrated that the plasma octreotide levels decrease by approximately 3.4% for each unit of body mass index (BMI) increase (P = 0.03), adjusting for sex and monthly LAR dose. Plasma octreotide levels for females were approximately 47.6% higher than those for males (P = 0.045), adjusting for BMI and monthly LAR dose. Initial and subsequent octreotide LAR doses should take into consideration sex and BMI. Males are estimated to require 14.1-mg (SD, 7.25) higher monthly LAR doses than females with the same BMI. We have shown that plasma octreotide levels are affected by not only monthly LAR dose but also BMI and sex. We hope these observations will make choosing initial and subsequent octreotide LAR doses easier for physicians.

Comparison of the Efficacy of Octreotide Long-acting Repeatable and Lanreotide Autogel in Acromegalic Patients

Background: Somatostatin analogues have been used as the first-line medical therapy for active acromegaly that is not completely cured, or which recurs after surgery. The aim of this study was to compare the effects of octreotide long-acting repeatable (LAR) and lanreotide Autogel. Such a comparison has not been reported in Korea. Methods: Twenty-seven patients who had previously undergone surgery for acromegaly from December 2003 to March 2005 were included. We retrospectively investigated eight patients who underwent operation only and 19 patients who additionally received medical treatment after surgery (octreotide LAR, n = 5; lanreotide Autogel, n = 5). Growth hormone (GH) and insulin-like growth factor-I (IGF-I) levels were measured. Results: The mean pre-operative and post-operative levels of GH were lower in patients who underwent surgery only than in those who received adjuvant therapy, but IGF-I levels were not significantly different. In the 19 patients receiving medical treatment after unsuccessful surgery, the mean baseline GH levels were 24.2 g/L for octreotide LAR and 22.8 g/L for lanreotide Autogel (P = 0.711), and the mean GH levels 36 months post-treatment were 4.1 g/L and 2.5 g/L, respectively (P = 0.794). GH g/L represented 30% of octreotide LAR patients and 33.3% of lanreotide Autogel patients (P = 0.91). Patients with normal IGF-I levels represented 54.5% and 66.7%, respectively (P = 0.71). Conclusion: No significant difference in therapeutic effect of octreotide LAR and lanreotide Autogel was evident in 19 Korean acromegalic patients who were not completely cured by surgery and radiation therapy.

Antiproliferative effect of somatostatin analogs in gastroenteropancreatic neuroendocrine tumors

Somatostatin analogs were initially developed for the control of hormonal syndromes associated with neuroendocrine tumors (NETs). In recent years, accumulating data has supported their role as antiproliferative agents, capable of stabilizing tumor growth in patients with metastatic neuroendocrine malignancies, including carcinoid and pancreatic endocrine tumors. A phase III, randomized, placebo-controlled trial has now demonstrated that octreotide long-acting repeatable (LAR) 30 mg can significantly prolong time to tumor progression among patients with metastatic midgut NETs regardless of functional status, chromogranin A level or age. In addition to significantly lengthening time to tumor progression in the overall study population, subset analysis suggests that patients with low tumor burden are most likely to experience disease stabilization with octreotide LAR 30 mg, supporting the early use of octreotide LAR in patients with metastatic disease. Further research efforts are underway to evaluate the use of somatostatin analogs as antiproliferative agents in other types of gastroenteropancreatic-NETs. Ongoing studies are also evaluating novel somatostatin analogs and somatostatin analogs in combination with other anti-tumor therapies.

Octreotide Long-Acting Repeatable in Acromegaly

Abstract: Treatment modalities for acromegaly include transsphenoidal surgery, medical therapy, and radiotherapy. Somatostatin analogs are the medical therapy of choice in acromegaly, with octreotide long-acting repeatable (LAR) the current global leader for patients with growth hormone (GH)-secreting pituitary adenomas. In patients with acromegaly, octreotide LAR is traditionally used as postsurgical therapy in patients with persistent disease. Although surgery remains the first-line treatment option in patients with tumors likely to be completely resected, there is a growing consensus that octreotide LAR could be used as first-line therapy in select patients. Octreotide LAR has been used in the treatment of acromegaly for over 10 years, and there are a wealth of data demonstrating that it is an effective, convenient, and well-tolerated treatment for the majority of patients with this disorder. Most patients initiating treatment with somatostatin analogs begin with octreotide LAR 20 mg every 28 days. On average, 60% of patients can safely achieve normal GH and insulin-like growth factor-I levels during octreotide LAR therapy, as well as experience significant reduction in pituitary tumor volume. However, recent studies have shown that up to 80% of patients can attain biochemical control. This can be attained by regularly monitoring GH and insulin-like growth factor-I levels and by escalating the dose of octreotide LAR to 30 mg or 40 mg every 28 days. By optimizing the control of acromegaly, the comorbidities and increased risk of premature mortality associated with this disorder can be reversed in most patients.