scholarly journals Somatostatin Analogues in the Treatment of Neuroendocrine Tumors: Past, Present and Future

2019 ◽  
Vol 20 (12) ◽  
pp. 3049 ◽  
Author(s):  
Anna Kathrin Stueven ◽  
Antonin Kayser ◽  
Christoph Wetz ◽  
Holger Amthauer ◽  
Alexander Wree ◽  
...  

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.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS4660-TPS4660
Author(s):  
Aman Chauhan ◽  
Charles Kunos ◽  
Riham El Khouli ◽  
Jill Kolesar ◽  
Heidi Weiss ◽  
...  

TPS4660 Background: Radiolabeled somatostatin analogues provide a means of delivering targeted radiation with a high therapeutic index to NETs that express somatostatin receptors (SSTRs). Radiolabeled somatostatin analogue Lutetium Lu 177 Dotatate (Lutathera) is a beta-emitting radionuclide, recently FDA approved for use in SSTR positive gastroenteropancreatic neuroendocrine tumors (GEPNETS) in the US based on the NETTER-1 Phase III trial. Despite favorable PFS and safety profile, the drug has limited cytoreductive capability with a 17% ORR. We hypothesize that addition of an effective radiation sensitizer could help improve antitumor activity of Lutathera. Ribonucleotide reductase (RNR) is the only enzyme responsible for conversion of ribonucleoside diphosphate to deoxyribonucleotide diphosphate (dNDP), the key building blocks for DNA synthesis. Radiation is a potent inducer of DNA double-strand breaks (DSBs), and RNR is the rate-limiting enzyme in the repair of DNA in this setting. Triapine is an inhibitor of RNR. This study will test the hypothesis that radiation sensitizer triapine can be safely combined with peptide receptor radionuclide therapy and ultimately may improve antitumor activity of Lutetium Lu 177 Dotatate. Methods: This study is an investigator initiated, NCI sponsored, multicenter phase 1 trial of triapine and Lutetium Lu 177 Dotatate in well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumor (GEP-NETs) after the failure of at least one line of prior systemic cancer treatment. A total of 29 patients will be enrolled in the dose escalation with help of Bayesian optimal interval design (BOIN) and dose expansion cohorts. The study will be open through the NCI ETCTN (National Cancer Institute Experimental Therapeutics Clinical Trials Network) program. Patients will be treated with 177 lutetium dotatate in combination with triapine. Triapine will be administered orally (100 mg once a day starting dose) from D1-14 with each dose of PRRT [200 mCi]. Primary endpoint is to evaluate recommended phase II dose (RP2D). Secondary endpoints are to evaluate safety, pharmacokinetics, and clinical activity (ORR and PFS). We are also evaluating NETEST, a novel blood based test that evaluates levels of 51 neuroendocrine tumor gene transcripts. In addition, the study will correlate clinical outcome with baseline somatostatin receptor density, somatic tumor mutations and germline mutations. Clinical trial information: 04234568 .


2021 ◽  
Vol 10 (6) ◽  
pp. 1267
Author(s):  
Baptiste Camus ◽  
Anne-Ségolène Cottereau ◽  
Lola-Jade Palmieri ◽  
Solène Dermine ◽  
Florence Tenenbaum ◽  
...  

Radionuclide therapy for neuroendocrine tumors is a form of systemic radiotherapy that allows the administration of targeted radionuclides into tumor cells that express a large quantity of somatostatin receptors. The two most commonly used radio-peptides for radionuclide therapy in neuroendocrine tumors are 90Y-DOTATOC and 177Lu-DOTATATE. Radio-peptides have been used for several years in the treatment of advanced neuroendocrine tumors. Recently, the randomized Phase III study NETTER-1 compared177Lu-DOTATATE versus high-dose (double-dose) octreotide LAR in patients with metastatic midgut neuroendocrine tumors, and demonstrated its efficacy in this setting. Strong signals in favor of efficiency seem to exist for other tumors, in particular for pancreatic and pulmonary neuroendocrine tumors. This focus on radionuclide therapy in gastroenteropancreatic and pulmonary neuroendocrine tumors addresses the treatment modalities, the validated and potential indications, and the safety of the therapy.


2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 11-11 ◽  
Author(s):  
Yung-Jue Bang

11 Background: The use of trastuzumab has been established as the standard first-line treatment of HER2 positive (+) AGC. However, the role of anti-HER2 agents in the second-line treatment of HER2+ AGC has not been clearly established yet. TyTAN is the first randomized study to compare the efficacy and safety of adding lapatinib (L) to paclitaxel (P) vs P alone in the second-line treatment of HER2+ AGC. Methods: Eligibility required patients (pts) with AGC, amplification of HER2 by fluorescence in situ hybridization (FISH), and one prior regimen containing fluoropyrimidines and/or cisplatin. Pts were randomized 1:1 to L (1500mg QD) and P (80mg/m2, Day 1, 8, 15 q4w) or P alone. The treatments were given until disease progression or unacceptable toxicity. Stratification variables were prior trastuzumab treatment and gastrectomy status. Primary endpoint was overall survival (OS). Results: From March 2008 to June 2011, 1923 pts were screened and 430 pts were HER2+ AGC. 261 out of 430 pts were enrolled. All pts were from Asian countries: Japan (100), China (95), Korea (46), and Taiwan (20). Median OS was 11.0 months for L+P and 8.9 months for P alone in the intent-to-treat (ITT) population (HR 0.84; p=0.2088). In a pre-planned subgroup analysis, median OS in HER2 immunohistochemistry (IHC) 3+ subgroup was 14.0 months for L+P and 7.6 months for P alone (HR 0.59; p=0.0176). The endpoints in efficacy and AEs of special interest for L+P are summarized below (Table). Conclusions: Although OS was prolonged in L+P arm by 2 months, the difference was not statistically significant. HER2 IHC 3+ subgroup demonstrated statistically significant prolongation of OS by adding L. Clinical trial information: NCT00486954. [Table: see text]


2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 194-194 ◽  
Author(s):  
Jonathan R. Strosberg ◽  
Edward M. Wolin ◽  
Beth Chasen ◽  
Matthew H. Kulke ◽  
David L Bushnell ◽  
...  

194 Background: Currently, there are limited therapeutic options for patients with advanced midgut neuroendocrine tumors progressing on first-line somatostatin analog therapy. Methods: NETTER-1 is the first Phase III multicentric, randomized, controlled trial evaluating 177Lu-DOTA0-Tyr3-Octreotate (Lutathera) in patients with inoperable, progressive, somatostatin receptor positive midgut NETs. 230 patients with Grade 1-2 metastatic midgut NETs were randomized to receive Lutathera 7.4 GBq every 8 weeks (x4 administrations) versus Octreotide LAR 60 mg every 4-weeks. The primary endpoint was PFS per RECIST 1.1 criteria, with objective tumor assessment performed by an independent reading center every 12 weeks. Secondary objectives included objective response rate, overall survival, toxicity, and health-related quality of life. Results: Enrolment was completed in February 2015, with a target of 230 patients randomized (1:1) in 36 European and 15 sites in the United States. At the time of statistical analysis, the number of centrally confirmed disease progressions or deaths was 23 in the Lutathera group and 67 in the Octreotide LAR 60 mg group. The median PFS was not reached for Lutathera and was 8.4 months with 60 mg Octreotide LAR [95% CI: 5.8-11.0 months], p < 0.0001, with a hazard ratio of 0.21 [95% CI: 0.13-0.34]. Within the current evaluable patient dataset for tumor responses (n = 201), the number of CR+PR was 19 (18.8%) in the Lutathera group and 3 (3.0%) in the Octreotide LAR 60 mg group (p < 0.0004). Although the OS data were not mature enough for a definitive analysis, the number of deaths was 13 in the Lutathera group and 22 in the Octreotide LAR 60 mg group (p < 0.019 at interim analysis) which suggests an improvement in overall survival. Conclusions: The Phase III NETTER-1 trial provides evidence for a clinically meaningful and statistically significant increase in PFS and ORR, and also suggests a survival benefit in patients with advanced midgut NETs treated with Lutathera. Clinical trial information: NCT01578239.


2015 ◽  
Vol 100 (4) ◽  
pp. 1699-1708 ◽  
Author(s):  
Shlomo Melmed ◽  
Vera Popovic ◽  
Martin Bidlingmaier ◽  
Moises Mercado ◽  
Aart Jan van der Lely ◽  
...  

Background: A novel oral octreotide formulation was tested for efficacy and safety in a phase III, multicenter, open-label, dose-titration, baseline-controlled study in patients with acromegaly. Methods: We enrolled 155 complete or partially controlled patients (IGF-1 &lt;1.3 × upper limit of normal [ULN], and 2-h integrated GH &lt;2.5 ng/mL) receiving injectable somatostatin receptor ligand (SRL) for ≥3 months. Subjects were switched to 40 mg/d oral octreotide capsules (OOCs), and the dose escalated to 60 and then up to 80 mg/d to control IGF-1. Subsequent fixed doses were maintained for a 7-month core treatment, followed by a voluntary 6-month extension. Results: Of 151 evaluable subjects initiating OOCs, 65% maintained response and achieved the primary endpoint of IGF-1 &lt;1.3 × ULN and mean integrated GH &lt;2.5 ng/mL at the end of the core treatment period and 62% at the end of treatment (up to 13 mo). The effect was durable, and 85 % of subjects initially controlled on OOCs maintained this response up to 13 months. When controlled on OOCs, GH levels were reduced compared to baseline, and acromegaly-related symptoms improved. Of 102 subjects completing the core treatment, 86% elected to enroll in the 6-month extension. Twenty-six subjects who were considered treatment failures (IGF-1 ≥1.3 × ULN) terminated early, and 23 withdrew for adverse events, consistent with those known for octreotide or disease related. Conclusions: OOC, an oral therapeutic peptide, achieves efficacy in controlling IGF-1 and GH after switching from injectable SRLs for up to 13 months, with a safety profile consistent with approved SRLs. OOC appears to be effective and safe as an acromegaly monotherapy.


2015 ◽  
Vol 102 (1-2) ◽  
pp. 18-25 ◽  
Author(s):  
Lowell B. Anthony ◽  
Marianne E. Pavel ◽  
John D. Hainsworth ◽  
Larry K. Kvols ◽  
Scott Segal ◽  
...  

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7014-7014 ◽  
Author(s):  
M. P. Mehta ◽  
R. Gervais ◽  
P. Chabot ◽  
W. R. Shapiro ◽  
R. A. Patchell ◽  
...  

7014 Background: In a previous randomized study, RT plus MGd prolonged time to neurologic progression (TNP) in NSCLC patients (pts) with brain metastases (BM) (p=0.048). Methods: This Phase 3 trial randomized pts with BM from NSCLC and KPS ≥70 to RT (30 Gy) or RT+MGd, 5 mg/kg qd x 10. A sample size of 550 was based on α=0.001, β=0.8, hazard ratio (HR)=0.65, with a primary endpoint of TNP determined by a blinded events review committee. Results: 554 pts received RT (N=275) or RT+MGd (N=279), 348 in North America (NA), 206 in Europe and Australia (EA). Treatment arms were balanced for factors of known prognostic importance. Most pts had multiple BM (81%), extracranial metastases (51%) and presented with neurologic deficits (84%). Treatment with MGd was well tolerated, with >92% of intended doses administered. Most common MGd-related grade 3+ adverse events were hypertension (4%), ALT increase (3%), and fatigue (3%). TNP improved from 10 months (mo) for RT to 15.4 mo for RT+MGd, p=0.12, HR=0.78. Time to neurocognitive progression was also improved, p=0.089, HR=0.79. More RT pts required salvage brain surgery or radiosurgery than RT+MGd pts (41 RT, 19 RT+MGd). In NA pts, statistically significant prolongation of both TNP, from 8.8 mo for RT to 24.2 mo for RT+MGd, p=0.004, HR=0.53, and time to neurocognitive progression, p=0.04, HR=0.69, were observed. In NA, RT was started sooner after the diagnosis of BM than in EA (median/mean 1.6/2.2 weeks NA vs. 3.0/6.5 weeks EA). There was a significant interaction between earlier RT and MGd benefit, p=0.017. When RT was initiated within 3 weeks of BM diagnosis, regardless of region, TNP was significantly prolonged by addition of MGd (N=378, p=0.006, HR=0.59). When initiation of RT was delayed beyond 3 weeks after BM diagnosis (N=176, 21% of NA pts, 50% of EA pts), MGd benefit was lost. A major reason for RT delay was use of chemotherapy as initial treatment for BM in 41 pts, 17% NA, 83% EA. Conclusions: MGd significantly prolonged TNP in NSCLC patients with BM receiving prompt RT in this randomized Phase 3 trial. The majority of patients in NA received prompt RT (79%), leading to a statistically and clinically significant benefit when combined with MGd. [Table: see text]


2021 ◽  
pp. jrheum.201088
Author(s):  
Peter C. Taylor ◽  
Désirée van der Heijde ◽  
Robert Landewé ◽  
Shannon McCue ◽  
Sue Cheng ◽  
...  

Objective To evaluate the efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with active ankylosing spondylitis (AS). Methods This phase III, multicenter, double-blind, placebo-controlled study (NCT01583374) randomized patients with active AS (1:1:1) to placebo, apremilast 20 mg twice daily, or apremilast 30 mg twice daily for 24 weeks, followed by a long-term extension phase (up to 5 years). The primary endpoint was assessment of the SpondyloArthritis International Society 20 (ASAS 20) response at Week 16. The impact of treatment on radiographic outcomes after 104 weeks was assessed using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Results In total, 490 patients with active AS were randomized in the study (placebo: n=164; apremilast 20 mg twice daily: n=163; apremilast 30 mg twice daily: n=163). The primary endpoint of ASAS 20 response at Week 16 was not met (placebo: 37%; apremilast 20 mg twice daily: 35%; apremilast 30 mg twice daily: 33%; p=0.44 vs placebo). At Week 104, mean (SD) changes from baseline in mSASSS were 0.83 (3.6), 0.98 (2.2), and 0.57 (1.9) in patients initially randomized to placebo, apremilast 20 mg twice daily, and apremilast 30 mg twice daily, respectively. The most frequently reported adverse events through Week 104 were diarrhea, nasopharyngitis, upper respiratory infection, and nausea. Conclusion No clinical benefit was observed with apremilast treatment in patients with active AS. The safety and tolerability of apremilast were consistent with its known profile.


2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Mohamed Elsayed Afandy ◽  
Motaz M. A. Abusabaa ◽  
Hashem Adel Lotfy ◽  
Radwa Fathy Mansour

Abstract Background Multiple methods exist for the management of pain during normal labor. Epidural analgesia has been reported to be an effective method in that perspective. The current study was conducted to evaluate the efficacy of dexmedetomidine as an adjuvant to local anesthetics in epidural analgesia for pregnant females presented for normal delivery. Sixty pregnant females were included in this prospective randomized study, and they were divided into two equal groups: control group which received bupivacaine alone and dexmedetomidine group that received bupivacaine with dexmedetomidine. The primary outcome was the onset of analgesia, while the secondary outcomes included the duration of analgesia, hemodynamic changes, labor progress, neonatal outcomes, and maternal complications. Results Dexmedetomidine group was associated with earlier onset of analgesia (P ˂ 0.001), prolonged duration (P ˂ 0.001), and lower need for top-up doses (P ˂ 0.001) compared to control group. Also, sedation and maternal satisfaction were significantly better in the same group (P = 0.001, 0.025; respectively). Labor progress parameters and neonatal outcomes were comparable between the two groups. Dexmedetomidine group has lower heart rate and mean arterial blood pressure compared to the control group. Despite of dexmedetomidine group had higher incidence of hypotension and bradycardia, it was statistically insignificant when compared to control group. Conclusions Dexmedetomidine is a reliable and an effective adjuvant to the local anesthetics in epidural analgesia during normal delivery as it resulted in earlier onset and significant prolongation of the analgesic time with decrease in the top-up doses intake. Trial registration Pan African Clinical Trial Registry (PACTR201710002664704). Register on 3 October 2017.


2015 ◽  
Vol 143 (1-2) ◽  
pp. 108-115 ◽  
Author(s):  
Mila Todorovic-Tirnanic ◽  
Vera Artiko ◽  
Smiljana Pavlovic ◽  
Dragana Sobic-Saranovic ◽  
Vladimir Obradovic

The new positron emission tomography (PET/CT) methods for neuroendocrine tumors detection are presented and compared with classic, conventional methods. Conventional methods use a gamma scintillation camera for patients with neuroendocrine tumor imaging, after intravenous injection of one of the following radiopharmaceuticals: 1) somatostatin analogues labeled with indium-111 (111In-pentetreotide) or technetium-99m (99mTc-EDDA/HYNIC-TOC); 2) noradrenaline analogue labeled with iodine-131 or -123 (131I/123I-MIBG); or 3) 99mTc(V)-DMSA. Contemporary methods use PET/CT equipment for patients with neuroendocrine tumor imaging, after intravenous injection of pharmaceuticals labeled with positron emitters [fluorine-18 (18F), galium-68 (68Ga), or carbon-11 (11C)]: 1) glucose analogue (18FDG); 2) somatostatin analogue (68Ga-DOTATOC/68Ga-DOTATATE/68Ga-DOTANOC); 3) aminoacid precursors of bioamines: [a) dopamine precursor 18F-DOPA (6-18F-dihydroxyphenylalanine), b) serotonin precursor 11C-5HTP (11C-5-hydroxytryptophan)]; or 4) dopamine analogue 18F-DA (6-18F-fluorodopamine). Conventional and contemporary (PET/ CT) somatostatin receptor detection showed identical high specificity (92%), but conventional had very low sensitivity (52%) compared to PET/CT (97%). It means that almost every second neuroendocrine tumor detected by contemporary method cannot be discovered using conventional (classic) method. In metastatic pheochromocytoma detection contemporary (PET/ CT) methods (18F-DOPA and 18F-DA) have higher sensitivity than conventional (131I/123I-MIBG). In medullary thyroid carcinoma diagnostics contemporary method (18F-DOPA) is more sensitive than conventional 99mTc(V)-DMSA method, and is similar to 18FDG, computed tomography and magnetic resonance. In carcinoid detection contemporary method (18F-DOPA) shows similar results with contemporary somatostatin receptor detection, while for gastroenteropancreatic neuroendocrine tumors it is worse. To conclude, contemporary (PET/CT) methods for somatostatin receptor detection (68Ga-DOTATOC/-NOC/-TATE) in neuroendocrine tumors are much more sensitive (almost twice) and more accurate than conventional. Therefore the classical methods should be urgently replaced by contemporary methods.


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