Octreotide Long-acting Repeatable Research Articles

[177Lu]Lu-DOTA-TATE plus long-acting octreotide versus high‑dose long-acting octreotide for the treatment of newly diagnosed, advanced grade 2–3, well-differentiated, gastroenteropancreatic neuroendocrine tumours (NETTER-2): an open-label, randomised, phase 3 study

There are currently no standard first-line treatment options for patients with higher grade 2-3, well-differentiated, advanced, gastroenteropancreatic neuroendocrine tumours. We aimed to investigate the efficacy and safety of first-line [177Lu]Lu-DOTA-TATE (177Lu-Dotatate) treatment. NETTER-2 was an open-label, randomised, parallel-group, superiority, phase 3 trial. We enrolled patients (aged ≥15 years) with newly diagnosed higher grade 2 (Ki67 ≥10% and ≤20%) and grade 3 (Ki67 >20% and ≤55%), somatostatin receptor-positive (in all target lesions), advanced gastroenteropancreatic neuroendocrine tumours from 45 centres across nine countries in North America, Europe, and Asia. We used interactive response technologies to randomly assign (2:1) patients to receive four cycles (cycle interval was 8 weeks ± 1 week) of intravenous 177Lu-Dotatate plus intramuscular octreotide 30 mg long-acting repeatable (LAR) then octreotide 30 mg LAR every 4 weeks (177Lu-Dotatate group) or high-dose octreotide 60 mg LAR every 4 weeks (control group), stratified by neuroendocrine tumour grade (2 vs 3) and origin (pancreas vs other). Tumour assessments were done at baseline, week 16, and week 24, and then every 12 weeks until disease progression or death. The primary endpoint was progression-free survival by blinded, independent, central radiology assessment. We did the primary analysis at 101 progression-free survival events as the final progression-free survival analysis. NETTER-2 is registered with ClinicalTrials.gov, NCT03972488, and is active and not recruiting. Between Jan 22, 2020, and Oct 13, 2022, we screened 261 patients, 35 (13%) of whom were excluded. We randomly assigned 226 (87%) patients (121 [54%] male and 105 [46%] female) to the 177Lu-Dotatate group (n=151 [67%]) and control group (n=75 [33%]). Median progression-free survival was 8·5 months (95% CI 7·7-13·8) in the control group and 22·8 months (19·4-not estimated) in the 177Lu-Dotatate group (stratified hazard ratio 0·276 [0·182-0·418]; p<0·0001). During the treatment period, adverse events (of any grade) occurred in 136 (93%) of 147 treated patients in the 177Lu-Dotatate group and 69 (95%) of 73 treated patients in the control group. There were no study drug-related deaths during the treatment period. First-line 177Lu-Dotatate plus octreotide LAR significantly extended median progression-free survival (by 14 months) in patients with grade 2 or 3 advanced gastroenteropancreatic neuroendocrine tumours. 177Lu-Dotatate should be considered a new standard of care in first-line therapy in this population. Advanced Accelerator Applications, a Novartis Company.

The role of quantitative tumor burden based on [68Ga]Ga-DOTA-NOC PET/CT in well-differentiated neuroendocrine tumors: beyond prognosis.

We aimed to elucidate the role of quantitative tumor burden based on PET/CT of somatostatin receptors in well-differentiated neuroendocrine tumors (NETs). This study enrolled patients with [68Ga]Ga-DOTA-NOC PET/CT-positive advanced NETs who did not receive medical treatment prior to PET/CT. Tumor burden was calculated using methods based on the background threshold and relative fixed threshold values (30%, 40%, and 50%). The prognostic value of the measured tumor burden in reference to overall survival (OS) and progression-free survival (PFS) on treatment with octreotide long-acting repeatable (LAR) was assessed using Cox regression analysis, Harrell's C-index, and survival analysis. A classification and regression tree (CART) was used to determine the optimal threshold for tumor burden. A total of 204 patients were included. Somatostatin receptor-expressing tumor volume (SRETV) and liver SRETV derived from a relative fixed threshold of 30% (SRETV30 and liver SRETV30) were statistically significantly associated with OS (C-index: 0.802 [95% confidence interval (CI), 0.658-0.946] and 0.806 [95% CI, 0.664-0.948], respectively). Extrahepatic tumor burden was not correlated with OS (hazard ratio: 0.617, 95% CI: 0.241-1.574, P = 0.312). Among 155 patients with non-functional NETs with a ki-67 index of ≤ 10%, those with a high SRETV30 (P = 0.016) or high liver SRETV30 (P = 0.014) showed statistically significantly worse PFS on treatment with octreotide LAR. Patients receiving a higher dose of octreotide LAR normalized by SRETV30 or liver SRETV30 (a normalized dose or a liver normalized dose) showed prolonged PFS on treatment with octreotide LAR and a prolonged OS. Quantitative tumor burden based on [68Ga]Ga-DOTA-NOC PET/CT was correlated with OS and PFS in patients with non-functional NETs with a ki-67 index of ≤ 10% who received octreotide LAR. Calculating normalized and liver normalized doses may help in selecting the starting dose of octreotide LAR.

Prolonged progression-free survival achieved by octreotide LAR plus transarterial embolization in low-to-intermediate grade neuroendocrine tumor liver metastases with high hepatic tumor burden.

ObjectiveTo evaluate the efficacy and outcome of transarterial embolization (TAE) plus octreotide long‐acting repeatable (LAR) on patients with low‐to‐intermediate neuroendocrine tumor liver metastases (NETLM).MethodsOne hundred and sixteen patients with G1/G2 NETLM treated with TAE plus octreotide LAR at the First Affiliated Hospital, Sun Yat‐sen University between January 12, 2016 and September 24, 2020 were reviewed. Radiological response was evaluated according to response evaluation criterion in solid tumor version 1.1. Overall progression‐free survival (PFS) was assessed. Intrahepatic and extrahepatic PFS were evaluated in the whole cohort and in patients with the extrahepatic disease (EHD), respectively. Factors affecting treatment response and overall PFS were analyzed using the logistic regression model and Cox proportional hazard model. Adverse events were recorded and evaluated according to Common Terminology Criteria for Adverse Events 5.0.ResultsThe median overall PFS of the whole cohort was 13.6 months. For the patients with EHD, the median intrahepatic PFS and extrahepatic PFS were 13.6 and 26.1 months, respectively. The median overall PFS of patients with hepatic tumor burden (HTB) <10%, 10%–25%, 25%–50%, and >50% were 25.2, 13.6, 11.2, and 12.3 months, respectively. Ki67 >10%, HTB >50%, and bone metastasis were independently associated with overall PFS. The objective response rate was 78.4%. In patients with HTB 25%–50% and >50%, responders (complete response or partial response) had significant prolonged PFS compared with nonresponders (stable disease or progression disease). Ki67 >10%, bone metastasis, and clear tumor margin were independently associated with response to TAE. The most frequent adverse events that occurred after TAE were postembolization syndrome, and no treatment‐associated death occurred during the perioperative period.ConclusionTransarterial embolization plus octreotide LAR can significantly prolong the PFS of neuroendocrine tumor liver metastases, especially with high HTB over 50%. Selected patients with HTB >25% (ki67 ≤10%, absence of bone metastasis, clear tumor margin) could derive prognostic advantage from the combined treatment.

Population Pharmacokinetic Modelling of the Complex Release Kinetics of Octreotide LAR: Defining Sub-Populations by Cluster Analysis.

The aim of the study is to develop a population pharmacokinetic (PPK) model, of Octreotide long acting repeatable (LAR) formulation in healthy volunteers, which describes the highly variable, multiple peak absorption pattern of the pharmacokinetics of the drug, in individual and population levels. An empirical absorption model, coupled with a one-compartment distribution model with linear elimination was found to describe the data well. Absorption was modelled as a weighted sum of a first order and three transit compartment absorption processes, with delays and appropriately constrained model parameters. Identifiability analysis verified that all twelve parameters of the structural model are identifiable. A machine learning method, i.e., cluster analysis, was performed as pre-processing of the PK profiles, to define subpopulations, before PPK modelling. It revealed that 13% of the patients deviated considerably from the typical absorption pattern and allowed better characterization of the observed heterogeneity and variability of the study, while the approach may have wider applicability in building PPK models. The final model was evaluated by goodness of fit plots, Visual Predictive Check plots and bootstrap. The present model is the first to describe the multiple-peak absorption pattern observed after octreotide LAR administration and may be useful to provide insights and validate hypotheses regarding release from PLGA-based formulations.

Opportunities to Improve Symptom Control with Somatostatin Congeners in GEP-NETs: A Review of Key Issues.

Octreotide acetate (octreotide) is the most prescribed and most studied somatostatin congener, or analog, for gastroenteropancreatic neuroendocrine tumors (GEP‐NETs) and carcinoid syndrome, the latter of which may be characterized by debilitating diarrhea and flushing. Approved in the U.S. more than 30 years ago, octreotide is widely used to control the symptoms of carcinoid syndrome and has been shown to demonstrate antiproliferative activity. The two formulations available in the U.S. include a subcutaneous immediate‐release (IR) injection introduced in 1989 and a long‐acting repeatable (LAR) intramuscular injection approved in 1999. Lanreotide depot (lanreotide), a more recent somatostatin congener, has been available in the U.S. since 2014.Despite widespread use of octreotide LAR, several key challenges exist with the current depot‐based treatment paradigm. Studies indicate that LAR formulations are associated with continued unmet patient needs, owing in part to a loss of bioactivity over time that may necessitate progressive supplemental treatment with IR octreotide to adequately control symptoms. Clinicians should understand the key differences in the pharmacokinetic profiles of the LAR and IR formulations that may contribute to bioactivity loss and somatostatin receptor desensitization. In addition, there is a need to re‐evaluate the role of IR octreotide in combination with depot therapy to provide consistent bioavailability and better control of carcinoid syndrome symptoms.The purpose of this review is to explore all these issues and to re‐establish a rationale for the IR formulation, particularly with respect to novel use cases and its use during the COVID‐19 pandemic.Implications for PracticeThere is a need to re‐evaluate the role of immediate‐release octreotide in combination with depot therapy to provide consistent bioavailability and better control of carcinoid syndrome symptoms.

Use of octreotide long acting repeatable (LAR) as second-line therapy in advanced neuroendocrine tumors in different clinical settings: an Italian Delphi survey

ABSTRACT Background Somatostatin receptor ligands including octreotide LAR are first-line therapy in locally advanced or metastatic NETs that are nonresectable and well differentiated and are recommended as first-line therapy in functioning and in G1/low G2 nonfunctioning NETs. However, several questions remain that are not adequately addressed in current guidelines regarding its use in clinical scenarios in which the tumor progresses. These include use of nonconventional doses or schedules of octreotide LAR in tumors with hormonal symptoms or showing clinical-radiological progression, administration in combination with everolimus, peptide receptor radionuclide therapy, and chemotherapy, following first-line treatment with octreotide LAR. Methods An expert panel was gathered to obtain consensus using Delphi methodology on a series of statements regarding further administration of octreotide LAR after its use in first-line therapy in these settings in patients who experience disease progression. Results Consensus was reached for 8 of the 10 statements proposed in the above clinical scenarios; consensus was not achieved for two statements. Conclusions The present statements aim to fill current gaps in treatment guidelines by providing recommendations based on expert consensus in clinical settings in which patients progress following first-line therapy with octreotide LAR.

Effect of Octreotide Long-Acting Release on Tregs and MDSC Cells in Neuroendocrine Tumour Patients: A Pivotal Prospective Study.

Octreotide long-acting repeatable (LAR) is largely used to treat functional and/or metastatic neuroendocrine neoplasms (NENs). Its effect in controlling carcinoid syndrome and partially reduce tumour burden is attributable to the ability of octreotide to bind somatostatin receptors (SSTRs) on the tumour and metastasis, regulating growth hormone secretion and cell growth. Notably, SSTRs are also expressed, at different levels, on Tregs. Tregs, together with myeloid-derived suppressor cells (MDSCs), are key components in the anti-tumour immunoregulation. This is the first prospective study aimed to explore the impact of Octreotide (OCT) LAR on the immune system, with a particular focus on Tregs and MDSC cells. Here, we show that circulating Tregs are elevated in NENs patients compared to healthy donors and that treatment with OCT LAR significantly decrease the level of total Tregs and of the three functional Tregs populations: nTregs, eTregs and non-Tregs. Furthermore, OCT LAR treatment induces a functional impairment of the remaining circulating Tregs, significantly decreasing the expression of PD1, CTLA4 and ENTPD1. A trend in circulating MDSC cells is reported in patients treated with OCT LAR. The results reported here suggest that the effect of OCT LAR on Tregs could tip the balance of the patients’ immune-system towards a durable anti-tumour immunosurveillance with consequent long-term control of the NENs disease.

Efficacy of everolimus plus octreotide LAR in patients with advanced neuroendocrine tumor and carcinoid syndrome: final overall survival from the randomized, placebo-controlled phase 3 RADIANT-2 study.

Ann Oncol 2017; 28(7): 1569–1575 (doi: 10.1093/annonc/mdx193) The following funding information has been added: “This work was supported in part by The University of Texas MD Anderson Cancer Center Support Grant P30 CA016672.” Efficacy of everolimus plus octreotide LAR in patients with advanced neuroendocrine tumor and carcinoid syndrome: final overall survival from the randomized, placebo-controlled phase 3 RADIANT-2 studyAnnals of OncologyVol. 28Issue 7PreviewIn the phase 3 RADIANT-2 study, everolimus plus octreotide long-acting repeatable (LAR) showed improvement of 5.1 months in median progression-free survival versus placebo plus octreotide LAR among patients with advanced neuroendocrine tumors associated with carcinoid syndrome. The progression-free survival P-value was marginally above the prespecified threshold for statistical significance. Here, we report final overall survival (OS) and key safety update from RADIANT-2. Full-Text PDF Open Archive

CT evaluation of response in advanced gastroenteropancreatic neuroendocrine tumors treated with long-acting-repeatable octreotide: what is the optimal size variation threshold?

To identify a reliable early indicator of deriving progression-free survival (PFS) benefit in patients with advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs) treated with octreotide long-acting repeatable (LAR). We investigated the images of 50 patients with well-differentiated advanced GEP-NETs treated with LAR octreotide and underwent baseline and follow-up thoracic, abdominal, and pelvic computed tomography. Receiver-operating characteristic (ROC) analysis and the Kaplan-Meier method were used to identify the optimal threshold to distinguish between those with and without significant improvement of PFS. The optimal threshold for determining a response to octreotide LAR was -10% ΔSLD, with a sensitivity and specificity of 85.7% and 80%, respectively. At this threshold, 19 patients were responders and 31 were non-responders; the median PFS was 20.2 and 7.6 months in responders and non-responders (hazard ratio, 2.66; 95% confidence interval, 1.32-5.36). A 10% shrinkage in tumor size is an optimal early predictor of response to octreotide LAR in advanced GEP-NETs. • Octreotide LAR can significantly prolong PFS among patients with well-differentiated advanced GEP-NETs. • No optimal tumor size-based response criteria are reported in GEP-NETs with octreotide. • Ten percent tumor shrinkage is a reliable indicator of the response to octreotide for advanced GEP-NETs.

Octreotide long-acting repeatable in the treatment of neuroendocrine tumors: patient selection and perspectives.

Over the past three decades, the incidence and prevalence of neuroendocrine tumors have gradually increased. Due to the slow-growing nature of these tumors, most cases are diagnosed at advanced stages. Prognosis and survival are associated with location of primary lesion, biochemical functional status, differentiation, initial staging, and response to therapy. Octreotide, the first synthetic somatostatin analog, was initially used for the management of gastrointestinal symptoms associated with functional carcinoid tumors. Its commercial development over time led to long-acting repeatable octreotide acetate, a long-acting version that provided greater administration convenience. Recent research demonstrates that octreotide’s efficacy has evolved beyond symptomatic management to targeted therapy with antitumoral effects. This review examines the history and development of octreotide, provides a synopsis on the classification, grading, and staging of neuroendocrine tumors, and reviews the evidence of long-acting repeatable octreotide acetate as monotherapy and in combination with other treatment modalities in the management of non-pituitary neuroendocrine tumors with special attention to recent high-quality Phase III trials.

Everolimus in Combination with Octreotide Long-Acting Repeatable in a First-Line Setting for Patients with Neuroendocrine Tumors: A 5-Year Update

Background: We previously presented data of this multicentric, phase II study showing that everolimus plus octreotide long-acting repeatable (LAR) for advanced neuroendocrine neoplasms (NENs), in the first line setting, is an active and safe treatment. We now present updated data at 5 years. Methods: Patients with advanced well-differentiated, previously untreated neuroendocrine tumors of the gastroenteropancreatic tract and of the lung received octreotide LAR 30 mg plus everolimus 10 mg/day. The primary endpoint was the objective response rate (ORR). We performed an analysis of “long responder” patients and of time to progression (TTP) and overall survival (OS) at 5 years. Results: Fifty patients were enrolled; the primary tumor site was: pancreas (14 patients), lung (11 patients), ileum (9 patients), jejunum/duodenum (2 patients), and unknown (14 patients). Seventeen (34%) of these patients have received treatment for more than 2 years. The median exposure to study drugs was 519.5 days (range 48-2,024). Currently 3 patients are still in treatment. The ORR (partial response + complete response) was 18% (95% confidence interval [CI] 7.4-28.6): complete response 1 patient (2%), partial response 8 patients (16%), stable disease 37 patients (74%). The median TTP was 33.6 months (95% CI 18.7-41.2) and the median OS was 61.0 months (95% CI 49.8-not reached). Conclusion: In this update of clinical outcome at 5-year follow-up, everolimus plus octreotide has been shown to be active in advanced NENs. The current analysis showed a further prolongation of TTP and a long exposure to the study drug without major side effects in the long term.

Long-Acting Somatostatin Analog Therapy Differentially Alters 68Ga-DOTATATE Uptake in Normal Tissues Compared with Primary Tumors and Metastatic Lesions.

Synthetic somatostatin analogs have been posed as a potential source of error in somatostatin receptor imaging through interference with tumor detection; however, experimental models and clinical studies have shown a complex mechanism of the effect of octreotide on tumors. The aim of this study was to assess whether 68Ga-DOTATATE uptake before treatment with long-acting somatostatin analogs differs from that after treatment. Methods: Thirty patients (15 men; age [mean ± SD], 64.6 ± 13.4 y) who had intermediately differentiated to well-differentiated neuroendocrine tumors and who underwent 68Ga-DOTATATE PET/CT scanning before and after receiving long-acting repeatable octreotide (Sandostatin LAR) were included in the study. The SUVmax and SUVmean of healthy target organs, residual primary tumor, and up to 5 lesions with the highest SUVmax in each organ were compared before and after octreotide treatment. Results: The mean time interval between the 2 68Ga-DOTATATE studies was 9.6 ± 7.2 mo, and the mean time gap between the last Sandostatin LAR injection and the second 68Ga-DOTATATE study was 25.1 ± 14.8 d. The pretreatment mean SUVmax and SUVmean were both significantly higher in the thyroid, liver, and spleen (P < 0.05) than the values measured after the administration of Sandostatin LAR. No significant differences were found among the uptake indices for residual primary tumor or any metastatic lesions in the liver, bone, lung, or lymph nodes before and after Sandostatin LAR administration (P > 0.05). Conclusion: Long-acting octreotide treatment diminished 68Ga-DOTATATE uptake in the liver, spleen, and thyroid but did not compromise tracer uptake in residual primary tumor and metastatic lesions. These findings have a direct impact on the interpretation of 68Ga-DOTATATE PET/CT scans.

Efficacy of everolimus plus octreotide LAR in patients with advanced neuroendocrine tumor and carcinoid syndrome: final overall survival from the randomized, placebo-controlled phase 3 RADIANT-2 study

In the phase 3 RADIANT-2 study, everolimus plus octreotide long-acting repeatable (LAR) showed improvement of 5.1 months in median progression-free survival versus placebo plus octreotide LAR among patients with advanced neuroendocrine tumors associated with carcinoid syndrome. The progression-free survival P-value was marginally above the prespecified threshold for statistical significance. Here, we report final overall survival (OS) and key safety update from RADIANT-2. The RADIANT-2 trial compared everolimus (10 mg/day, orally; n = 216) versus placebo (n = 213), both in conjunction with octreotide LAR (30 mg, intramuscularly, every 28 days). Patients, unblinded at the time of progression or after end of double-blind core phase following primary analysis, were offered open-label everolimus with octreotide LAR (open-label phase). In the open-label phase, patients had similar safety and efficacy assessments as those in the core phase. For OS, hazard ratios (HRs) with 95% CIs using unadjusted Cox model and a Cox model adjusted for prespecified baseline covariates were calculated. A total of 170 patients received open-label everolimus (143 crossed over from the placebo arm; 27 in the everolimus arm continued to receive the same treatment after unblinding). The median OS (95% CI) after 271 events was 29.2 months (23.8-35.9) for the everolimus arm and 35.2 months (30.0-44.7) for the placebo arm (HR, 1.17; 95% CI, 0.92-1.49). HR adjusted for baseline covariates was 1.08 (95% CI, 0.84-1.38). The most frequent drug-related grade 3 or 4 AEs reported during the open-label phase were diarrhea (5.3%), fatigue (4.7%), and stomatitis (4.1%). Deaths related to pulmonary or cardiac failure were observed more frequently in the everolimus arm. No significant difference in OS was observed for the everolimus plus octreotide LAR and placebo plus octreotide LAR arms of the RADIANT-2 study, even after adjusting for imbalances in the baseline covariates. NCT00412061, www.clinicaltrials.gov.

S25 - Real-word analysis on the use of somatostatin analogs (SSAs) in patients with neuroendocrine neoplasms (NENs): results of a survey conducted by the Italian Society of Medical Oncology (AIOM)

Background: In neuroendocrine neoplasms (NENs) two somatostatin analogs (SSAs), octreotide and lanreotide, were approved for carcinoid syndrome control in functioning and for tumor growth control in well differentiated non functioning advanced NENs. The full labeled schedule is 30 mg every 4 weeks (/4w) for octreotide long acting repeatable (LAR) and 120 mg/4w for lanreotide depot. We investigated the real-world use of SSAs in NEN patients among the Italian medical oncological community about several aspects. Dose and schedule- related results are reported in the present analysis. Methods: In September 2014 a 27-item online questionnaire was administered to all Italian Association of Medical Oncology (AIOM) members. Results: One hundred and ten members filled out the questionnaire. Almost all were medical oncologists and around two third of them had seen < 20 NEN patients over the latest year. A full labeled dose was used upfront by 43% for lanreotide depot and 69% for octreotide LAR. In functioning NENs while the vast majority of participants had used 30 mg/4w octreotide LAR and 120 mg/4w lanreotide depot as the most dose per administration, more than 70% had used a shorter interval between administrations, up to 3 or even 2 weeks. In non functioning NETs again around 90% of participants had used 30 mg/4w octreotide LAR and 120 mg/4w lanreotide depot as the highest dose per administration, but 62% had used a shorter interval than /4w for octreotide LAR and 43% for lanreotide depot. While in case of incomplete syndrome control at full labeled dose, around 40% of responders shortened administrations interval without changing the total dose per administration both for octreotide and lanreotide, in case of non functioning NETs progressing on full labeled dose the percentage of responders who had shortened the interval was 30-40% for both SSA. This percentage was almost equivalent to that of whom stopped SSA and started other therapies. Conclusions: We presented the results regarding SSA schedule management in NEN patients among Italian medical oncological community. Above-label dose of SSA was applied in both functioning and non functioning NENs. Particularly shortening interval between administrations rather than increasing dose of the single administration was applied. This same survey is currently ongoing among other Italian scientific societes involved in NETs, such as endocrinological and gastroenterological ones.

Antiproliferative Effect of Somatostatin Analogs - Data Analyses and Clinical Applications in the Context of the CLARINET Study

Somatostatin analogs (SSAs) are antisecretory agents that have been used to control hormonal syndromes associated with neuroendocrine tumors for more than 20 years. Recent phase III randomized, placebo controlled trials demonstrated their antiproliferative effects. The PROMID study showed that octreotide LAR (long-acting repeatable) treatment had anti-tumor effects. CLARINET, an international multicenter controlled study, provides new evidence that lanreotide has antiproliferative effects. Depot lanreotide significantly prolonged progression-free survival among patients with metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Because GEP-NETs are biologically diverse in terms of primary tumor site and functional status, preventing progression can be difficult. This review summarizes data supporting the role of SSAs, in particular lanreotide, as antiproliferative agents for the treatment of patients with GEP-NETs. The CLARINET study is the most powerful (in sence of data, results, clinical aplication) randomized study of the antiproliferative effects of SSA in GEP-NET patients. The median lanreotide-associated progression-free survival in the CLARINET core study or in open-label extension study was 32.8 vs. 18 months for placebo. Thus, early treatment with lanreotide is expected to prolong progression-free survival. Lanreotide is now recommended for the treatment of patients with well-differentiated metastatic grade 1 and grade 2 GEP-NETs (i.e., those with a Ki-67 proliferative index < 10%) located in the pancreas, small intestine, or in cases where the location of the primary tumor is unknown, regardless of the degree of liver involvement. somatostatin - neuroendocrine tumors - angiogenesis - apoptosis - antiproliferative effectThis work was supported by MEYS-NPS I-LO1413.The author declares she has no potential conflicts of interest concerning drugs, products, or services used in the study.The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 2. 12. 2015Accepted: 20. 3. 2016.

Octreotide LAR Dosage and Survival Among Elderly Patients With Distant-Stage Neuroendocrine Tumors.

Octreotide long-acting repeatable (LAR) is approved for the management of carcinoid syndromes and may improve progression-free survival of patients with well-differentiated neuroendocrine tumors (NETs). It is unknown whether the dosage of octreotide LAR affects survival. This paper evaluates the association between initial octreotide LAR dosage and overall survival of elderly patients with NETs. Patients with distant-stage NET diagnosed between January 1999 and December 2009 who received octreotide LAR treatment within 12 months of diagnosis were identified from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Those under age 65 years, enrolled in health maintenance organizations, or without continuous enrollment in Medicare Parts A and B were excluded. We compared the 5-year survival of patients with NET based on dose per 28 days averaged over the initial 3 months: low (≤20 mg); medium (21-30 mg); high (>30 mg). Kaplan-Meier estimations and Cox proportional hazard modeling were used to examine the association between octreotide LAR dose and survival. Among 222 patients with distant-stage NET who received octreotide LAR treatment, 81 (36%) received a low dosage, 82 (37%) received a medium dosage, and only 59 (27%) received a high dosage. Multivariate analysis showed that compared with a medium octreotide LAR dose, a low dosage was associated with significantly worse survival (hazard ratio [HR]: 2.00; p = .001), whereas a high initial dosage (HR: 1.09; p = .719) did not show additional survival benefits over that observed with a medium dosage. This population-based study suggests potential survival benefits for octreotide LAR provided within 12 months of diagnosis at a dosage of 21-30 mg among elderly patients with distant-stage NET.

Octreotide long-acting repeatable among elderly patients with neuroendocrine tumors: a survival analysis of SEER-Medicare data.

Octreotide long-acting repeatable (LAR) is approved in the United States for the management of carcinoid syndromes among patients with neuroendocrine tumors (NET). The objective of our study is to evaluate the impact of octreotide LAR on overall survival (OS), as it has not been established. NET patients of 65 years and older diagnosed between January 1999 and December 2009 were identified from the SEER-Medicare database. We compared the OS of NET patients who started octreotide LAR within 12 months of diagnosis with those who did not receive it during the same period. We conducted Kaplan-Meier estimations and Cox proportional hazard models to examine the association between octreotide LAR and OS. Among 1,176 distant stage patients, 233 (20%) received octreotide LAR within 12 months of diagnosis, compared with 2% (96 in 5,764) of local/regional stage patients. Median OS for patients who started octreotide LAR within 12 months was 35.22 months [95% confidence interval (CI), 27.96-47.77], longer than those who did not receive it (19.15 months; 95% CI, 16.36-22.80; P < 0.0001). Multivariate analysis showed that octreotide LAR was associated with significant survival improvement for distant stage patients (HR, 0.68; P < 0.001) and in the subgroups with (HR, 0.65; P, 0.003) and without (HR, 0.55; P, 0.002) carcinoid syndrome. No survival benefit was found among local/regional stage patients. This population-based study suggests potential survival benefits of octreotide LAR among elderly distant stage NET patients, both with or without carcinoid syndrome. The study provides population-based evidence of a positive association between octreotide LAR and overall survival among elderly distant stage NET patients.

Impact of Previous Somatostatin Analogue Use on the Activity of Everolimus in Patients with Advanced Neuroendocrine Tumors: Analysis from the Phase III RADIANT-2 Trial

Background/Aims: The phase III placebo-controlled RADIANT-2 trial investigated the efficacy of everolimus plus octreotide long-acting repeatable (LAR) in patients with advanced neuroendocrine tumors (NET) associated with carcinoid syndrome. Here we report a secondary analysis based on the previous somatostatin analogue (SSA) exposure status of patients enrolled in RADIANT-2. Methods: Patients were randomly assigned to receive oral everolimus 10 mg/day plus octreotide LAR 30 mg intramuscularly (i.m.) or to receive matching placebo plus octreotide LAR 30 mg i.m. every 28 days. SSA treatment before study enrollment was permitted. Patient characteristics and progression-free survival (PFS) were analyzed by treatment arm and previous SSA exposure status. Results: Of the 429 patients enrolled in RADIANT-2, 339 were previously exposed to SSA (95% received octreotide); 173 of 339 patients were in the everolimus plus octreotide LAR arm. All patients had a protocol-specified history of secretory symptoms, but analysis by type showed that more patients who previously received SSA therapy had a history of flushing symptoms (77%), diarrhea (86%), or both (63%) compared with SSA-naive patients (62, 62, and 24%, respectively). Patients who received everolimus plus octreotide LAR had longer median PFS regardless of previous SSA exposure (with: PFS 14.3 months, 95% confidence interval, CI, 12.0-20.1; without: 25.2 months, 95% CI, 12.0-not reached) compared with patients who received placebo plus octreotide LAR (with: 11.1 months, 95% CI, 8.4-14.6; without: 13.6 months, 95% CI, 8.2-22.7). Conclusion: Everolimus in combination with octreotide improves PFS in patients with advanced NET associated with carcinoid syndrome, regardless of previous SSA exposure.

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, &lt;= 20 mg; B, 21 to 30 mg; C, &gt; 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 &lt;= 20 mg, 82 (38%) received 21 – 30 mg, while 59 (28%) received &gt;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.