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The New England Journal of Medicine Jan 2017Patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options.... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 (Lu)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors.
METHODS
We randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either Lu-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) (Lu-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here.
RESULTS
At the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the Lu-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the Lu-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the Lu-Dotatate group and 26 in the control group (P=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the Lu-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame.
CONCLUSIONS
Treatment with Lu-Dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the Lu-Dotatate group. (Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials.gov number, NCT01578239 ; EudraCT number 2011-005049-11 .).
Topics: Aged; Antineoplastic Agents; Delayed-Action Preparations; Disease-Free Survival; Drug Administration Schedule; Female; Gastrointestinal Neoplasms; Humans; Infusions, Intravenous; Kaplan-Meier Estimate; Male; Middle Aged; Nausea; Neuroendocrine Tumors; Octreotide; Organometallic Compounds
PubMed: 28076709
DOI: 10.1056/NEJMoa1607427 -
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 -
International Journal of Molecular... Jun 2019In recent decades, the incidence of neuroendocrine tumors (NETs) has steadily increased. Due to the slow-growing nature of these tumors and the lack of early symptoms,... (Review)
Review
In recent decades, the incidence of neuroendocrine tumors (NETs) has steadily increased. Due to the slow-growing nature of these tumors and the lack of early symptoms, most cases are diagnosed at advanced stages, when curative treatment options are no longer available. Prognosis and survival of patients with NETs are determined by the location of the primary lesion, biochemical functional status, differentiation, initial staging, and response to treatment. Somatostatin analogue (SSA) therapy has been a mainstay of antisecretory therapy in functioning neuroendocrine tumors, which cause various clinical symptoms depending on hormonal hypersecretion. Beyond symptomatic management, recent research demonstrates that SSAs exert antiproliferative effects and inhibit tumor growth via the somatostatin receptor 2 (SSTR2). Both the PROMID (placebo-controlled, prospective, randomized study in patients with metastatic neuroendocrine midgut tumors) and the CLARINET (controlled study of lanreotide antiproliferative response in neuroendocrine tumors) trial showed a statistically significant prolongation of time to progression/progression-free survival (TTP/PFS) upon SSA treatment, compared to placebo. Moreover, the combination of SSA with peptide receptor radionuclide therapy (PRRT) in small intestinal NETs has proven efficacy in the phase 3 neuroendocrine tumours therapy (NETTER 1) trial. PRRT is currently being tested for enteropancreatic NETs versus everolimus in the COMPETE trial, and the potential of SSTR-antagonists in PRRT is now being evaluated in early phase I/II clinical trials. This review provides a synopsis on the pharmacological development of SSAs and their use as antisecretory drugs. Moreover, this review highlights the clinical evidence of SSAs in monotherapy, and in combination with other treatment modalities, as applied to the antiproliferative management of neuroendocrine tumors with special attention to recent high-quality phase III trials.
Topics: Animals; Antineoplastic Agents, Hormonal; Clinical Trials as Topic; Disease-Free Survival; Humans; Neuroendocrine Tumors; Octreotide; Peptides, Cyclic; Receptors, Somatostatin; Signal Transduction; Somatostatin
PubMed: 31234481
DOI: 10.3390/ijms20123049 -
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 -
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 -
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 -
AJR. American Journal of Roentgenology Aug 2018The purposes of this article are to increase understanding of the concepts of theranostics and peptide receptor radionuclide therapy (PRRT) as they apply to... (Review)
Review
OBJECTIVE
The purposes of this article are to increase understanding of the concepts of theranostics and peptide receptor radionuclide therapy (PRRT) as they apply to neuroendocrine tumors (NETs); review the key 1, 2, and 3 clinical trial data leading to the approval of Lu-tetraazacyclododecanetetraacetic acid-octreotide (Lu-DOTATATE); and foster understanding of the practical aspects and future directions of PRRT for NETs.
CONCLUSION
In January 2018, Lu-DOTATATE therapy was approved in the United States (previously approved in Europe in September 2017) for adult patients with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors, including those of the foregut, midgut, and hindgut. The results of the phase 3 Neuroendocrine Tumors Therapy (NETTER-1) trial show favorable outcomes with respect to the primary endpoint of progression-free survival and a host of secondary objectives, including overall survival, objective response rate, and quality of life measures. Patient selection is based on a number of specific factors and should be sequenced carefully with respect to other available therapies, ideally in multidisciplinary cancer conferences. Establishing the therapy at a new institution can be somewhat involved, but once it is established, the therapy is fairly straightforward to administer and is well tolerated with limited side-effects and toxicity. A number of approaches and issues are still to be worked out, and this therapy will continue to be studied and optimized.
Topics: Gastrointestinal Neoplasms; Humans; Neuroendocrine Tumors; Octreotide; Organometallic Compounds; Patient Selection
PubMed: 29949416
DOI: 10.2214/AJR.18.19953 -
Current Oncology Reports May 2024This paper aims to address the latest findings in neuroendocrine tumor (NET) theranostics, focusing on new evidence and future directions of combined diagnosis with... (Review)
Review
PURPOSE OF REVIEW
This paper aims to address the latest findings in neuroendocrine tumor (NET) theranostics, focusing on new evidence and future directions of combined diagnosis with positron emission tomography (PET) and treatment with peptide receptor radionuclide therapy (PRRT).
RECENT FINDINGS
Following NETTER-1 trial, PRRT with [177Lu]Lu-DOTATATE was approved by FDA and EMA and is routinely employed in advanced G1 and G2 SST (somatostatin receptor)-expressing NET. Different approaches have been proposed so far to improve the PRRT therapeutic index, encompassing re-treatment protocols, combinations with other therapies and novel indications. Molecular imaging holds a potential added value in characterizing disease biology and heterogeneity using different radiopharmaceuticals (e.g., SST and FDG) and may provide predictive and prognostic parameters. Response assessment criteria are still an unmet need and new theranostic pairs showed preliminary encouraging results. PRRT for NET has become a paradigm of modern theranostics. PRRT holds a favorable toxicity profile, and it is associated with a prolonged time to progression, reduction of symptoms, and improved patients' quality of life. In light of further optimization, different new strategies have been investigated, along with the development of new radiopharmaceuticals.
Topics: Humans; Neuroendocrine Tumors; Radiopharmaceuticals; Octreotide; Positron-Emission Tomography; Receptors, Peptide; Theranostic Nanomedicine; Radioisotopes; Organometallic Compounds
PubMed: 38581469
DOI: 10.1007/s11912-024-01526-5 -
Best Practice & Research. Clinical... Jan 2016Somatostatin analogues (SSA) are well established antisecretory drugs that have been used as first line treatment for symptomatic control in hormonally active... (Review)
Review
Somatostatin analogues (SSA) are well established antisecretory drugs that have been used as first line treatment for symptomatic control in hormonally active neuroendocrine tumours (NET) for three decades. Both available depot formulations of SSA, long-acting repeatable (LAR) octreotide and lanreotide autogel, seem similarly effective and well tolerated, although comparative trials in NET have not been performed. The importance of SSA as antiproliferative treatment has been increasingly recognized during recent years. Two placebo-controlled trials demonstrated significant prolongation of progression free survival under SSA treatment. However, objective response as assessed by imaging is rare. Interferon-α (IFNα) also has antisecretory and antiproliferative efficacy in NET. Due to the less favourable toxicity profile it mainly has a role as add-on option in the refractory setting, especially in carcinoid syndrome patients. Further studies are needed to evaluate the antiproliferative efficacy of the multiligand SSA pasireotide and the role of pegylated IFNα.
Topics: Animals; Antineoplastic Agents, Hormonal; Cell Proliferation; Clinical Trials as Topic; Humans; Molecular Targeted Therapy; Neuroendocrine Tumors; Octreotide; Receptors, Somatostatin
PubMed: 26971845
DOI: 10.1016/j.beem.2015.09.004 -
Giornale Italiano Di Nefrologia :... Dec 2019Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most frequent monogenic hereditary disease as well as the most studied inherited kidney disease. Two drugs... (Review)
Review
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most frequent monogenic hereditary disease as well as the most studied inherited kidney disease. Two drugs have recently been authorized that can slow down the progression of the disease: Tolvaptan (vasopressin receptor antagonist) and Octreotide-LAR (long-acting somatostatin analogue); they both are able to reduce the activity of cyclic adenosine monophosphate (cAMP) and therefore have anti-proliferative and anti-secretory effects. This review analyzes the main trials published to date demonstrating the effects on disease progression in patients with ADPKD and illustrates the indications for identifying subjects eligible for therapy.
Topics: Antidiuretic Hormone Receptor Antagonists; Humans; Octreotide; Polycystic Kidney, Autosomal Dominant; Tolvaptan
PubMed: 31830392
DOI: No ID Found