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The Lancet. Oncology Dec 2021The primary analysis of the phase 3 NETTER-1 trial showed significant improvement in progression-free survival with Lu-Dotatate plus long-acting octreotide versus... (Randomized Controlled Trial)
Randomized Controlled Trial
Lu-Dotatate plus long-acting octreotide versus high‑dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial.
BACKGROUND
The primary analysis of the phase 3 NETTER-1 trial showed significant improvement in progression-free survival with Lu-Dotatate plus long-acting octreotide versus high-dose long-acting octreotide alone in patients with advanced midgut neuroendocrine tumours. Here, we report the prespecified final analysis of overall survival and long-term safety results.
METHODS
This open-label, randomised, phase 3 trial enrolled patients from 41 sites in eight countries across Europe and the USA. Patients were 18 years and older with locally advanced or metastatic, well differentiated, somatostatin receptor-positive midgut neuroendocrine tumours (Karnofsky performance status score ≥60) and disease progression on fixed-dose long-acting octreotide. Patients were randomly assigned (1:1) via an interactive web-based response system to intravenous Lu-Dotatate 7·4 GBq (200 mCi) every 8 weeks (four cycles) plus intramuscular long-acting octreotide 30 mg (Lu-Dotatate group) or high-dose long-acting octreotide 60 mg every 4 weeks (control group). The primary endpoint of progression-free survival has been previously reported; here, we report the key secondary endpoint of overall survival in the intention-to-treat population. Final overall survival analysis was prespecified to occur either after 158 deaths or 5 years after the last patient was randomised, whichever occurred first. During long-term follow-up, adverse events of special interest were reported in the Lu-Dotatate group only. This trial is registered with ClinicalTrials.gov, NCT01578239.
FINDINGS
From Sept 6, 2012, to Jan 14, 2016, 231 patients were enrolled and randomly assigned for treatment. The prespecified final analysis occurred 5 years after the last patient was randomly assigned (when 142 deaths had occurred); median follow-up was 76·3 months (range 0·4-95·0) in the Lu-Dotatate group and 76·5 months (0·1-92·3) in the control group. The secondary endpoint of overall survival was not met: median overall survival was 48·0 months (95% CI 37·4-55·2) in the Lu-Dotatate group and 36·3 months (25·9-51·7) in the control group (HR 0·84 [95% CI 0·60-1·17]; two-sided p=0·30). During long-term follow-up, treatment-related serious adverse events of grade 3 or worse were recorded in three (3%) of 111 patients in the Lu-Dotatate group, but no new treatment-related serious adverse events were reported after the safety analysis cutoff. Two (2%) of 111 patients given Lu-Dotatate developed myelodysplastic syndrome, one of whom died 33 months after randomisation (this person was the only the only reported Lu-Dotatate treatment-related death). No new cases of myelodysplastic syndrome or acute myeloid leukaemia were reported during long-term follow-up.
INTERPRETATION
Lu-Dotatate treatment did not significantly improve median overall survival versus high-dose long-acting octreotide. Despite final overall survival not reaching statistical significance, the 11·7 month difference in median overall survival with Lu-Dotatate treatment versus high-dose long-acting octreotide alone might be considered clinically relevant. No new safety signals were reported during long-term follow-up.
FUNDING
Advanced Accelerator Applications, a Novartis company.
Topics: Aged; Antineoplastic Agents, Hormonal; Chemoradiotherapy; Digestive System Neoplasms; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Male; Neuroendocrine Tumors; Octreotide; Organometallic Compounds; Prognosis; Radiopharmaceuticals; Survival Rate
PubMed: 34793718
DOI: 10.1016/S1470-2045(21)00572-6 -
Frontiers in Endocrinology 2022Lu-177 has been developed for the treatment of patients with peptide receptor radionuclide therapy (PRRT). A second generation pure no-carrier-added Lu-177 has a high... (Review)
Review
Lu-177 has been developed for the treatment of patients with peptide receptor radionuclide therapy (PRRT). A second generation pure no-carrier-added Lu-177 has a high specific activity and has waste disposal advantages over the first generation carrier-added Lu-177. PRRT has recently been developed for the treatment of neuroendocrine tumors (NETs). The majority of pancreatic and gastroenteric NETs (GEP-NETs) express the somatostatin receptors (SSTRs) 2 and 5. These receptors can be specifically targeted with a somatostatin peptide analogue (DOTATOC/DOTATATE) which can be chelated to a positron emission tomography (PET) emitting radioisotope such as Ga-68 for imaging or to a β-emitting radioisotope Lu-177 for therapy. A key advantage of this approach is that the receptor expression can be demonstrated by PET imaging before the patient is treated. Clinical studies in G1 and G2 GEP-NETS have demonstrated that PRRT is extremely effective in terms of progression free survival (PFS), symptom control and quality of life, with a well-established safety profile. A beneficial effect on outcome survival awaits to be confirmed. The first commercially available product Lu-177-DOTATATE was approved following the NETTER-1 trial in G1 and G2 GE-NETS. Lu-177-DOTATATE 7,4 GBq every 8 weeks for 4 cycles, together with octreotide LAR 30 mg monthly, demonstrated a median PFS of 28,4 months compared to 8,5 months for octreotide LAR 60 mg monthly. A second pivotal study COMPETE is currently in progress, comparing no carrier-added (n.c.a.) Lu-177-DOTATOC to the m-TOR inhibitor Everolimus in both GE-NETs and PNETs. Two studies, NETTER-2 and COMPOSE are currently underway in patients with high grade G2 and G3 NETs. Novel SSTR antagonists are being developed as next generation targeting molecules for SSTR2-expressing tumors. Antagonists have a higher tumor binding to receptors than agonists, opening up the potential indications for SSTR2 targeting to tumors which have a relatively lower expression of SSTR2 compared to NET such as small cell lung cancer, hepatocellular carcinoma and breast cancer. In addition to Lu-177, radioisotopes with different radiation properties such as Tb-161 and the α-emitter Ac-225 are being developed which have the potential to improve treatment efficacy across the range of G1 to G3 NETs.
Topics: Humans; Neuroendocrine Tumors; Octreotide; Gallium Radioisotopes; Actinium; Quality of Life; Radioisotopes; Radiopharmaceuticals
PubMed: 36387893
DOI: 10.3389/fendo.2022.941832 -
Expert Review of Gastroenterology &... Nov 2019: Lutetium-[DOTA°,Tyr]octreotate (Lu-DOTATATE) is a type of peptide receptor radionuclide therapy that garnered FDA approval in January 2018 for the treatment of... (Review)
Review
: Lutetium-[DOTA°,Tyr]octreotate (Lu-DOTATATE) is a type of peptide receptor radionuclide therapy that garnered FDA approval in January 2018 for the treatment of somatostatin receptor-positive gastroenteropancreatic (GEP) neuroendocrine tumor (NET) patients. The therapy approval was based on findings from the randomized international phase III NETTER-1 trial as well as outcome data from a large European registry. The mechanism of the drug stems directly from its structure: a somatostatin analog (octreotate) selectively binding to somatostatin receptor expressing cells and being internalized, along with a chelated beta-emitting isotope Lu.: Herein we describe the pharmacology, clinical efficacy and adverse event data from prospective and retrospective studies with Lu-DOTATATE. We discuss the role of Lu-DOTATATE within the current treatment landscape for GEP NET patients.: Lu-DOTATATE represents a unique addition to the treatment armamentarium for GEP NETs because of its potential to elicit tumor cytoreduction, which is rare among other existing treatment options, and prolonged disease control. Where Lu-DOTATATE fits into the treatment sequence for GEP NET patients remains an area of active investigation.
Topics: Animals; Gastrointestinal Neoplasms; Humans; Neuroendocrine Tumors; Octreotide; Organometallic Compounds; Pancreatic Neoplasms; Radiopharmaceuticals; Treatment Outcome
PubMed: 31652074
DOI: 10.1080/17474124.2019.1685381 -
Gastroenterology Apr 2024Gastrointestinal angiodysplasias are vascular anomalies that may result in transfusion-dependent anemia despite endoscopic therapy. An individual patient data... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND & AIMS
Gastrointestinal angiodysplasias are vascular anomalies that may result in transfusion-dependent anemia despite endoscopic therapy. An individual patient data meta-analysis of cohort studies suggests that octreotide decreases rebleeding rates, but component studies possessed a high risk of bias. We investigated the efficacy of octreotide in reducing the transfusion requirements of patients with angiodysplasia-related anemia in a clinical trial setting.
METHODS
The study was designed as a multicenter, open-label, randomized controlled trial. Patients with angiodysplasia bleeding were required to have had at least 4 red blood cell (RBC) units or parental iron infusions, or both, in the year preceding randomization. Patients were allocated (1:1) to 40-mg octreotide long-acting release intramuscular every 28 days or standard of care, including endoscopic therapy. The treatment duration was 1 year. The primary outcome was the mean difference in the number of transfusion units (RBC + parental iron) between the octreotide and standard of care groups. Patients who received at least 1 octreotide injection or followed standard of care for at least 1 month were included in the intention-to-treat analyses. Analyses of covariance were used to adjust for baseline transfusion requirements and incomplete follow-up.
RESULTS
We enrolled 62 patients (mean age, 72 years; 32 men) from 17 Dutch hospitals in the octreotide (n = 31) and standard of care (n = 31) groups. Patients required a mean number of 20.3 (standard deviation, 15.6) transfusion units and 2.4 (standard deviation, 2.0) endoscopic procedures in the year before enrollment. The total number of transfusions was lower with octreotide (11.0; 95% confidence interval [CI], 5.5-16.5) compared with standard of care (21.2; 95% CI, 15.7-26.7). Octreotide reduced the mean number of transfusion units by 10.2 (95% CI, 2.4-18.1; P = .012). Octreotide reduced the annual volume of endoscopic procedures by 0.9 (95% CI, 0.3-1.5).
CONCLUSIONS
Octreotide effectively reduces transfusion requirements and the need for endoscopic therapy in patients with angiodysplasia-related anemia.
CLINICALTRIALS
gov, NCT02384122.
Topics: Aged; Humans; Male; Anemia; Angiodysplasia; Colonic Diseases; Gastrointestinal Hemorrhage; Iron; Multicenter Studies as Topic; Octreotide; Randomized Controlled Trials as Topic; Standard of Care; Female
PubMed: 38158089
DOI: 10.1053/j.gastro.2023.12.020 -
Respiration; International Review of... 2022Congenital chylothorax (CCT) of the newborn is a rare entity but the most common cause of pleural effusion in this age-group. We aimed to find the optimal treatment...
BACKGROUND
Congenital chylothorax (CCT) of the newborn is a rare entity but the most common cause of pleural effusion in this age-group. We aimed to find the optimal treatment strategy.
MATERIAL AND METHODS
A PubMed search was performed according to the PRISMA criteria. All cases were analyzed according to prenatal, perinatal, and postnatal treatment modalities and follow-ups.
RESULTS
We identified 753 cases from 157 studies published between 1990 and 2018. The all-cause mortality rate was 28%. Prematurity was present in 71%, male gender dominated 57%, mean gestational age was 34 weeks, and birth weight was 2,654 g. Seventy-nine percent of newborns had bilateral CCT, the most common associated congenital anomalies with CCT were pulmonary lymphangiectasia and pulmonary hypoplasia, and the most common chromosomal aberrations were Down, Noonan, and Turner syndromes, respectively. Mechanical ventilation was reported in 381 cases for mean 17 (range 1-120) days; pleural punctuations and drainages were performed in 32% and 64%, respectively. Forty-four percent received total parenteral nutrition (TPN) for mean 21 days, 46% medium-chain triglyceride (MCT) diet for mean 37 days, 20% octreotide, and 3% somatostatin; chemical pleurodesis was performed in 116 cases, and surgery was reported in 48 cases with a success rate of 69%. In 462 cases (68%), complete restitution was reported; in 34 of 44 cases (77%), intrauterine intervention was carried out.
CONCLUSION
Respiratory support, pleural drainages, TPN, and MCT diet as octreotide remain to be the cornerstones of CCT management. Pleurodesis with OK-432 done prenatally and povidone-iodine postnatally might be discussed for use in life-threatening CCT.
Topics: Chylothorax; Female; Humans; Infant; Infant, Newborn; Male; Octreotide; Pleural Effusion; Pleurodesis
PubMed: 34515211
DOI: 10.1159/000518217 -
Ceska a Slovenska Farmacie : Casopis... 2021The radiopharmaceutical 68Ga-DOTATOC represents the latest radiopharmaceutical in the diagnosis of a neuroendocrine tumor with somatostatin receptor overexpression....
The radiopharmaceutical 68Ga-DOTATOC represents the latest radiopharmaceutical in the diagnosis of a neuroendocrine tumor with somatostatin receptor overexpression. Technological and economic difficulties of preparing and quality control of the radiopharmaceutical limit its use to specialised departments. Background of the department with rich experience with radiopharmaceuticals for positron emission tomography allows handling more difficult 68Ga-radiopharmacy and may increase and improve the care of oncology patients.
Topics: Humans; Neuroendocrine Tumors; Octreotide; Organometallic Compounds; Positron-Emission Tomography; Radiopharmaceuticals
PubMed: 35045714
DOI: 10.5817/CSF2021-4-136 -
ESMO Open Aug 2020Neuroendocrine tumours (NETs) constitute a heterogeneous group of neoplasms characterised by variable endocrine activity and somatostatin receptor expression, with the... (Review)
Review
Neuroendocrine tumours (NETs) constitute a heterogeneous group of neoplasms characterised by variable endocrine activity and somatostatin receptor expression, with the latter allowing the use of targeted therapeutic concepts. Currently accepted treatment strategies for advanced well-differentiated NET include somatostatin analogues octreotide and lanreotide, peptide receptor radionuclide therapy using radiolabelled somatostatin analogues, mammalian target of Rapamycin inhibitor everolimus, tyrosine kinase inhibitor sunitinib, interferon alpha and classical cytostatic, such as streptozotocin-based and temozolomide-based treatment. Indication, use and approval of these treatments differ based on primary tumour origin, grading and symptomatic burden and require an optimised multidisciplinary cooperation of medical oncologists, endocrinologists and nuclear medicine specialists. Interestingly, hot topics in oncology including immunotherapy and use of next-generation-sequencing techniques currently play a minor role for the treatment of NETs. The recent revision of the WHO classification including the recognition of the novel NET G3 category allows for potentially more tailored treatment strategies in the near future. However, this new entity also poses a therapeutic challenge as only limited data are currently available. The present article aims to provide an overview on our personal treatment concepts for advanced NETs with a focus on tumours of gastroenteropancreatic origin.
Topics: Everolimus; Humans; Neuroendocrine Tumors; Octreotide; Receptors, Somatostatin; Sunitinib
PubMed: 32817134
DOI: 10.1136/esmoopen-2020-000811 -
Surgical Oncology Clinics of North... Apr 2020To better understand developments in treatment of neuroendocrine tumors of the gastroenteropancreatic system, and the pivotal roles of native somatostatin and its... (Review)
Review
To better understand developments in treatment of neuroendocrine tumors of the gastroenteropancreatic system, and the pivotal roles of native somatostatin and its long-acting analogues play in normal peptide regulation and neuropeptide excess associated with neuroendocrine tumors (NETs), this article delineates and defines distinct eras in the history and discovery of gastrointestinal endocrinology. We highlight the collaboration between academia and industry in basic science and the clinical research that advanced Lu-177-DOTATATE to approval as standard of care therapy for low-grade NETs. Examples of new radioisotopes and therapy compounds currently in development for diagnosis and therapy for high-grade NETs are also discussed.
Topics: Animals; Humans; Neuroendocrine Tumors; Octreotide; Organometallic Compounds; Prognosis; Radiopharmaceuticals
PubMed: 32151353
DOI: 10.1016/j.soc.2019.11.002 -
Practical Radiation Oncology 2022Neuroendocrine tumors (NETs) are a heterogeneous group of tumors that originate in endocrine tissues throughout the body. Though most are indolent, clinical outcomes... (Review)
Review
Neuroendocrine tumors (NETs) are a heterogeneous group of tumors that originate in endocrine tissues throughout the body. Though most are indolent, clinical outcomes vary greatly based on histologic differentiation and grade. Peptide receptor radionuclide therapy has emerged as a promising treatment for patients with locally advanced and/or metastatic disease refractory to standard of care treatment. The phase III NETTER-1 trial found that [Lu] Lu-DOTA-[Tyr]-octreotate improved disease-free survival versus octreotide alone for somatostatin receptor-positive gastroenteropancreatic NETs and had a favorable toxicity profile, leading to Food and Drug Administration approval. [Lu] Lu-DOTA-[Tyr]-octreotate is an important new treatment that expands the role of radiation in the treatment of NETs. Several important trials are ongoing to better elucidate the role of this treatment.
Topics: Humans; Lutetium; Neuroendocrine Tumors; Octreotide; Positron-Emission Tomography; Radioisotopes; Radionuclide Imaging; Radiopharmaceuticals
PubMed: 35717045
DOI: 10.1016/j.prro.2022.02.002 -
Revista Da Associacao Medica Brasileira... Apr 2022Long-acting depot formulations of somatostatin analogs, i.e., octreotide and lanreotide, are the first-line medical therapies for patients with acromegaly to whom...
OBJECTIVE
Long-acting depot formulations of somatostatin analogs, i.e., octreotide and lanreotide, are the first-line medical therapies for patients with acromegaly to whom surgery/radiotherapy cannot be performed or who have inadequate response. In this study, we aimed to evaluate the short-term local and systemic adverse reactions developed after the somatostatin analogs injections in the patients with acromegaly, in order to compare the side effects of somatostatin analogs injections.
METHODS
Patients diagnosed with acromegaly who were referred to our endocrinology clinic for monthly somatostatin analogs injections were questionnaired. Wong-Baker Faces Pain Rating Scale was used to evaluate the injection-site pain at the time of injection. The existence of leg pain, nausea, diarrhea, and abdominal pain following the previous injection was also investigated during the next injection.
RESULTS
A total of 49 patients were included in the study. The statistical difference could not be shown between the injection-site pain, anorexia, and leg pain frequencies of the groups, while the frequency of gastrointestinal disturbances, i.e., diarrhea and abdominal pain, was significantly lower in the octreotide group (p<0.001 and p=0.015, respectively).
CONCLUSIONS
This is the first prospective study that compared the severity of the injection-site pain by using a scoring scale, following the long-acting somatostatin analogs injections. We have shown that there was no significant association of the injection-site pain severity with the somatostatin analogs regimen nor the dose differences within each somatostatin analogs treatment.
Topics: Abdominal Pain; Acromegaly; Diarrhea; Humans; Octreotide; Prospective Studies; Somatostatin
PubMed: 35649076
DOI: 10.1590/1806-9282.20211224