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JAMA Network Open Jan 2022Despite the benefit of peptide receptor radionuclide therapy (PRRT) for patients with well-differentiated neuroendocrine tumors (WD NETs), no clinical metric to...
IMPORTANCE
Despite the benefit of peptide receptor radionuclide therapy (PRRT) for patients with well-differentiated neuroendocrine tumors (WD NETs), no clinical metric to anticipate benefit from the therapy for individual patients has been previously defined.
OBJECTIVE
To assess whether the prognostic ability of the clinical score (CS) could be validated in an external cohort of patients with WD NETs.
DESIGN, SETTING, AND PARTICIPANTS
This multicenter cohort study's analysis included patients with WD NETs who were under consideration for peptide receptor radionuclide therapy (PRRT) with lutetium-177 (177Lu)-dotatate between March 1, 2016, and March 17, 2020. The original cohort included patients from Vanderbilt-Ingram Cancer Center. The validation cohort included patients from Ochsner Medical Center, Markey Cancer Center, and Rush Medical Center. Patients with paragangliomas, pheochromocytomas and neuroblastomas were excluded. Statistical analysis was performed from June to November 2021.
EXPOSURES
PRRT with 177Lu-dotatate or alternate therapies such as everolimus, sunitinib, or capecitabine plus temozolomide.
MAIN OUTCOMES AND MEASURES
The primary outcome was progression-free survival (PFS) and was estimated by the Kaplan-Meier method; a Cox proportional-hazards model adjusting for primary tumor site, tumor grade, and number of PRRT doses administered was used to analyze association between CS and outcomes.
RESULTS
A total of 126 patients (median age [IQR] age: 63.6 [52.9-70.7] years; 64 male individuals) were included in the validation cohort, and the combined cohort (validation and original cohorts combined) had a total of 248 patients (median [IQR] patient age: 63.3 [53.3-70.3] years; 126 male individuals). In the validation cohort, on multivariable analysis, for each 2-point increase in CS, PFS decreased significantly (hazard ratio, 2.61; 95% CI, 1.64-4.16). After finding an association of the CS with PFS in the validation cohort, the original and validation cohorts were combined into the cohort for this analysis. On multivariable analysis, for each 2-point increase in CS, PFS decreased significantly (hazard ratio, 2.52; 95% CI, 1.89-3.36).
CONCLUSIONS AND RELEVANCE
Increases in CS were associated with worsening PFS in the validation cohort, validating findings from the original cohort. These findings suggest that the CS, to our knowledge, represents the first clinical metric to estimate anticipated benefit from PRRT for patients with WD NETs and may be a clinical tool for patients being considered for PRRT.
Topics: Aged; Cohort Studies; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neuroendocrine Tumors; Octreotide; Organometallic Compounds; Predictive Value of Tests; Prognosis; Progression-Free Survival; Proportional Hazards Models; Prospective Studies; Radioisotopes; Radionuclide Imaging; Receptors, Peptide; Severity of Illness Index; Treatment Outcome
PubMed: 35044469
DOI: 10.1001/jamanetworkopen.2021.44170 -
Journal of Nuclear Medicine : Official... Jul 1997Ten dogs with hypoglycemia due to insulinomas were studied to assess the expression of somatostatin receptors (SSTRs) in canine insulinomas and its potential diagnostic...
UNLABELLED
Ten dogs with hypoglycemia due to insulinomas were studied to assess the expression of somatostatin receptors (SSTRs) in canine insulinomas and its potential diagnostic value.
METHODS
The response of circulating glucose and insulin concentrations to the subcutaneous administration of a somatostatin analog, octreotide, was measured. SSTRs were visualized in vitro by autoradiography. [Iodine-125-Tyr3]-octreotide and [125I-Tyr11]-somatostatin-14 (SRIF-14) were used as radioligands. SPECT was performed 6 hr after the injection of [111In-DTPA-D-Phe1]-octreotide.
RESULTS
After subcutaneous injection of 50 micrograms octreotide, plasma glucose concentration rose from 2.3 +/- 0.2 mmol/liter to 3.2 +/- 0.3 mmol/liter at 3.5 hr (p < 0.05) and plasma insulin concentration decreased from 451 +/- 135 pmol/liter to a nadir of 249 +/- 115 pmol/liter at 30 min (p < 0.05). In vitro autoradiography revealed that all primary insulinomas and their metastases had specific SSTRs for both [125I-Tyr3]-octreotide and [126I-Tyr11]-SRIF-14. Scatchard analysis of SSTR binding in the tumor tissue of one dog revealed high-affinity binding sites for [125I-Tyr3]-octreotide (dissociation constant (Kd) 1.7 nM, maximum binding capacity (Bmax) 499 fmol/mg membrane protein). The primary tumor and/or metastases in five of six dogs could be visualized and localized by SPECT with [111In-DTPA-D-Phe1]-octreotide. In the remaining dog, multiple metastases (< 3 mm) were found in the liver at necropsy, apparently too small to be visualized by SPECT.
CONCLUSION
The in vitro autoradiography and ligand binding studies indicate that canine insulinomas express one type of SSTR. This is in contrast with findings in humans where, on the basis of ligand binding studies, different subtypes of SSTRs have been identified. The uniformity of SSTRs, their high frequency of expression and the high incidence of metastatic disease make canine insulinomas very suitable for investigation of the value of SRIF analogs in the diagnosis and treatment of metastasized endocrine pancreatic tumors.
Topics: Animals; Autoradiography; Blood Glucose; Dogs; Female; Indium Radioisotopes; Insulin; Insulinoma; Iodine Radioisotopes; Liver Neoplasms; Male; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Radiopharmaceuticals; Receptors, Somatostatin; Somatostatin
PubMed: 9225787
DOI: No ID Found -
BMJ (Clinical Research Ed.) Feb 1992
Topics: Graves Disease; Humans; Octreotide
PubMed: 1547436
DOI: 10.1136/bmj.304.6825.507-a -
Zhongguo Yi Xue Ke Xue Yuan Xue Bao.... Dec 2022Most of the neuroendocrine tumors(NETs) overexpress the somatostatin receptor(SSTR),which provides a reliable target for SSTR-targeted peptide receptor radionuclide...
Most of the neuroendocrine tumors(NETs) overexpress the somatostatin receptor(SSTR),which provides a reliable target for SSTR-targeted peptide receptor radionuclide therapy(PRRT).Compared with drug therapy,PRRT has high objective response rate and significantly prolongs patients' survival.Moreover,the patients have good tolerance to this therapy.Considering that PRRT is in clinical trial phase in China,this article elaborates on the selection and preparation of patients,pre-treatment medications,administration methods,treatment cycles,side effects,follow-up plan,and the combination of PRRT with other drugs based on the published international guidelines in this field and our experience from clinical practice.Hoping that relevant professionals can well understand the principle of PRRT and apply it in clinical practice,we write this article to provide a basis for serving real-world patients and carrying out clinical trials.
Topics: Humans; Neuroendocrine Tumors; Octreotide; Organometallic Compounds; China
PubMed: 36373637
DOI: 10.3881/j.issn.1000-503X.14463 -
Journal of Nuclear Medicine : Official... Oct 2000This article reviews the results of somatostatin receptor imaging (SRI) in patients with somatostatin receptor-positive neuroendocrine tumors, such as pituitary tumors,... (Review)
Review
This article reviews the results of somatostatin receptor imaging (SRI) in patients with somatostatin receptor-positive neuroendocrine tumors, such as pituitary tumors, endocrine pancreatic tumors, carcinoids, gastrinomas, and paragangliomas, or other diseases in which somatostatin receptors may also be expressed, like sarcoidosis and autoimmune diseases. [(111)In-DTPA0]octreotide is a radiopharmaceutical that has great potential for helping visualize whether somatostatin receptor-positive tumors have recurred. The overall sensitivity of SRI to localize neuroendocrine tumors is high. In several neuroendocrine tumor types, inclusion of SRI in the localization or staging procedure may be very rewarding in terms of cost effectiveness, patient management, or quality of life. The value of SRI in patients with other tumors, such as breast cancer or malignant lymphomas, or in patients with granulomatous diseases has to be established. The application of radiolabeled peptides may be clinically useful in another way: after the injection of [(111)In-DTPA0]octreotide, surgeons can detect tumor localizations by a probe that is used during the operation. This may be of particular value if small tumors with a high receptor density are present (e.g., gastrinomas). As the success of peptide receptor scintigraphy for tumor visualization became clear, the next logical step was to try to label these peptides with radionuclides emitting alpha or beta particles, or Auger or conversion electrons, and to perform radiotherapy with these radiolabeled peptides. The results of the described studies with 90Y- and (111)In-labeled octreotide show that peptide receptor radionuclide therapy using radionuclides with appropriate particle ranges may become a new treatment modality. One might consider the use of radiolabeled somatostatin analogs first in an adjuvant setting after surgery of somatostatin receptor-positive tumors to eradicate occult metastases and second for cancer treatment at a later stage.
Topics: Humans; Indium Radioisotopes; Neoplasms; Neuroendocrine Tumors; Octreotide; Oligopeptides; Pentetic Acid; Radiopharmaceuticals; Receptors, Somatostatin; Tomography, Emission-Computed, Single-Photon; Yttrium Radioisotopes
PubMed: 11038002
DOI: No ID Found -
AAPS PharmSciTech Dec 2011The study reports on the drug release behavior of a potent synthetic somatostatin analogue, octreotide acetate, from biocompatible and biodegradable microspheres...
The study reports on the drug release behavior of a potent synthetic somatostatin analogue, octreotide acetate, from biocompatible and biodegradable microspheres composed of poly-lactic-co-glycolic acid (PLGA) following a single intramuscular depot injection. The serum octreotide levels of three Oakwood Laboratories formulations and one Sandostatin LAR(®) formulation were compared. Three formulations of octreotide acetate-loaded PLGA microspheres were prepared by a solvent extraction and evaporation procedure using PLGA polymers with different molecular weights. The in vivo drug release study was conducted in male Sprague-Dawley rats. Blood samples were taken at predetermined time points for up to 70 days. Drug serum concentrations were quantified using a radioimmunoassay procedure consisting of radiolabeled octreotide. The three octreotide PLGA microsphere formulations and Sandostatin LAR(®) all showed a two-phase drug release profile (i.e., bimodal). The peak serum drug concentration of octreotide was reached in 30 min for all formulations followed by a decline after 6 h. Following this initial burst and decline, a second-release phase occurred after 3 days. This second-release phase exhibited sustained-release behavior, as the drug serum levels were discernible between days 7 and 42. Using pharmacokinetic computer simulations, it was estimated that the steady-state octreotide serum drug levels would be predicted to fall in the range of 40-130 pg/10 μL and 20-100 pg/10 μL following repeat dosing of the Oakwood formulations and Sandostatin LAR(®) every 28 days and every 42 days at a dose of 3 mg/rat, respectively.
Topics: Animals; Chemistry, Pharmaceutical; Computer Simulation; Drug Carriers; Drug Compounding; Drug Implants; Injections, Intramuscular; Lactic Acid; Male; Microspheres; Models, Biological; Octreotide; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Solubility; Technology, Pharmaceutical
PubMed: 21948321
DOI: 10.1208/s12249-011-9693-z -
International Journal of Molecular... Apr 2023Neuroendocrine tumors (NEN) are a group of neoplasms that arise from hormonal and neural cells. Despite a common origin, their clinical symptoms and outcomes are varied....
Neuroendocrine tumors (NEN) are a group of neoplasms that arise from hormonal and neural cells. Despite a common origin, their clinical symptoms and outcomes are varied. They are most commonly localized in the gastrointestinal tract. Targeted radioligand therapy (RLT) is a treatment option which has proven to be successful in recent studies. However, the possible outcomes and true safety profile of the treatment need to be fully determined, especially by new, more sensitive methods. Our study aimed to present an extended analysis of acute and chronic renal complications during and after radioligand therapy using, for the first time in the literature, innovative and complex renal parameters. Forty patients with neuroendocrine tumors underwent four courses of radioligand therapy with [Lu]Lu-DOTATATE or [Lu]Lu/[Y]Y-DOTATATE. Radioisotopes were administrated in intervals of 8-12 weeks, with concurrent intravenous nephroprotection. New detailed and sensitive renal parameters were used to determine the renal safety profile during and after radioisotope therapy for standard treatment of NEN. During the first and fourth courses of RLT, no change in the glomerular filtration rate (GFR) was observed. However, long-term observations one year after the treatment showed a 10% reduction in the GFR. During the first course of treatment, the fractional urea and calcium excretions increased, while the fractional potassium concentration decreased. The fractional calcium excretion remained highly increased in long-term observations. Decreases in urine IL-18, KIM-1 and albumin concentrations were observed during RLT. The concentrations of IL-18 and KIM-1 remained low even a year after therapy. The ultrasound parameters of renal perfusion changed during treatment, before partially returning to the baseline one year after therapy, and were correlated with the biochemical parameters of renal function. A permanent increase in diastolic blood pressure was correlated with the decrease in the GFR observed during the study. In this innovative and complex renal assessment during and after RLT, we found a permanent 10% per year decrease in the GFR and noticeable disturbances in renal tubule function. The diastolic blood pressure also increased.
Topics: Humans; Interleukin-18; Neuroendocrine Tumors; Calcium; Kidney; Radioisotopes; Octreotide
PubMed: 37108668
DOI: 10.3390/ijms24087508 -
Chemical & Pharmaceutical Bulletin 2014The purpose of this study was to predict the stability of octreotide in a mixed infusion containing sodium bisulfite (SBS). In aqueous solution the hydrolysis of...
The purpose of this study was to predict the stability of octreotide in a mixed infusion containing sodium bisulfite (SBS). In aqueous solution the hydrolysis of octreotide was found to be accelerated by pH, and by increasing concentrations of SBS. Equations for the degradation rate constants (kobs) of pH and SBS were derived. The fractional rate constants were estimated by the nonlinear least-squares method (quasi-Newton method using the solver in Microsoft Excel) at 25°C. The activation energy (Ea) and frequency factor (A) were calculated using the Arrhenius equation. The pH of the mixed infusion was estimated using the pH characteristic (PHC) curve. From these results, an equation was derived giving the residual ratio (%) of octreotide at any time after mixing an infusion containing SBS at any temperature in the pH range 4.0-7.0. A high correlation was shown to exist between the estimated and determined residual ratios (%).
Topics: Drug Stability; Hydrogen-Ion Concentration; Hydrolysis; Octreotide; Sulfites; Temperature
PubMed: 24695340
DOI: 10.1248/cpb.c13-00681 -
Annals of Oncology : Official Journal... 2001Neuroendocrine tumors are rare, occurring in less than 1% of the population. They are divided clinically into functionally active or non-active tumors. Functionally... (Review)
Review
Neuroendocrine tumors are rare, occurring in less than 1% of the population. They are divided clinically into functionally active or non-active tumors. Functionally active tumors produce a variety of substances (mainly peptides or serotonin) that are responsible for symptoms and sometimes can lead to the death of the patient independently from tumor proliferation. The most important compounds that can control symptoms in these patients are somatostatin analogs. Native somatostatin is not suitable for long-term clinical application due to its short half-life. Therefore, synthetic drugs were developed with improved pharmacokinetic characteristics. The best-characterized analog, octreotide, has been successfully applied to patients with functioning tumors. Octreotide can ameliorate symptoms in 30%-70% of the patients, mainly through a direct inhibitory effect on hormone production from the tumors. There is little or no effect on tumor growth during octreotide therapy; clinical responses were recorded in only 10%-30% of the patients. Recently, significant improvement in the management of the disease has been demonstrated with long-acting repeatable (LAR) octreotide. This new formulation requires only one monthly intramuscolar injection, and shows better acceptability and patient compliance to therapy. Data available to date show superimposable results of both standard octreotide and LAR octreotide in controlling symptoms, lowering hormone and tumor marker levels, and in reducing tumor growth. The availability of long-acting molecules have permitted the exploration of high-dose therapy in increasing tumor shrinkage and prolonging survival. Although there is a clear dose-response trend, the published data are not conclusive and further investigations are needed. The possible lack of cross-resistance between LAR octreotide and a different analog, Lanreotide, is a very stimulating finding and this might lead to the development of new therapeutical strategies in the management of neuroendocrine tumors.
Topics: Antineoplastic Agents; Antineoplastic Agents, Hormonal; Clinical Trials as Topic; Delayed-Action Preparations; Dose-Response Relationship, Drug; Humans; Injections, Subcutaneous; Neuroendocrine Tumors; Octreotide; Peptides, Cyclic; Somatostatin; Survival Analysis
PubMed: 11762334
DOI: 10.1093/annonc/12.suppl_2.s105 -
Annals of Surgery Sep 2000To evaluate the endpoints of complications (specifically pancreatic fistula and total complications) and death in patients undergoing pancreaticoduodenectomy. (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Does prophylactic octreotide decrease the rates of pancreatic fistula and other complications after pancreaticoduodenectomy? Results of a prospective randomized placebo-controlled trial.
OBJECTIVE
To evaluate the endpoints of complications (specifically pancreatic fistula and total complications) and death in patients undergoing pancreaticoduodenectomy.
SUMMARY BACKGROUND DATA
Four randomized, placebo-controlled, multicenter trials from Europe have evaluated prophylactic octreotide (the long-acting synthetic analog of native somatostatin) in patients undergoing pancreatic resection. Each trial reported significant decreases in overall complication rates, and two of the four reported significantly lowered rates of pancreatic fistula in patients receiving prophylactic octreotide. However, none of these four trials studied only pancreaticoduodenal resections, and all trials had high pancreatic fistula rates (>19%) in the placebo group. A fifth randomized trial from the United States evaluated the use of prophylactic octreotide in patients undergoing pancreaticoduodenectomy and found no benefit to the use of octreotide. Prophylactic use of octreotide adds more than $75 to the daily hospital charge in the United States. In calendar year 1996, 288 patients received octreotide on the surgical service at the authors' institution, for total billed charges of $74,652.
METHODS
Between February 1998 and February 2000, 383 patients were recruited into this study on the basis of preoperative anticipation of pancreaticoduodenal resection. Patients who gave consent were randomized to saline control versus octreotide 250 microg subcutaneously every 8 hours for 7 days, to start 1 to 2 hours before surgery. The primary postoperative endpoints were pancreatic fistula, total complications, death, and length of hospital stay.
RESULTS
Two hundred eleven patients underwent pancreaticoduodenectomy with pancreatic-enteric anastomosis, received appropriate saline/octreotide doses, and were available for endpoint analysis. The two groups were comparable with respect to demographics (54% male, median age 66 years), type of pancreaticoduodenal resection (60% pylorus-preserving), type of pancreatic-enteric anastomosis (87% end-to-side pancreaticojejunostomy), and pathologic diagnosis. The pancreatic fistula rates were 9% in the control group and 11% in the octreotide group. The overall complication rates were 34% in the control group and 40% in the octreotide group; the in-hospital death rates were 0% versus 1%, respectively. The median postoperative length of hospital stay was 9 days in both groups.
CONCLUSIONS
These data demonstrate that the prophylactic use of perioperative octreotide does not reduce the incidence of pancreatic fistula or total complications after pancreaticoduodenectomy. Prophylactic octreotide use in this setting should be eliminated, at a considerable cost savings.
Topics: Aged; Double-Blind Method; Female; Humans; Male; Middle Aged; Octreotide; Pancreatic Fistula; Pancreaticoduodenectomy; Postoperative Complications; Prospective Studies; Survival Rate; Treatment Outcome
PubMed: 10973392
DOI: 10.1097/00000658-200009000-00014