Management Options for Advanced Low or Intermediate Grade Gastroenteropancreatic Neuroendocrine Tumors: Review of Recent Literature.

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Term Occurence Count Dictionary
carcinoid 10 endocrinologydiseases
hyperglycemia 4 endocrinologydiseases
multiple endocrine neoplasia 1 endocrinologydiseases
neuroendocrine tumor 4 endocrinologydiseases
sorafenib 2 endocrinologydiseasesdrugs
Octreotide 2 endocrinologydiseasesdrugs
everolimus 17 endocrinologydiseasesdrugs
hypertriglyceridemia 1 endocrinologydiseases
sunitinib 12 endocrinologydiseasesdrugs

Graph of close proximity drug and disease terms (within 200 characters).

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Select Drug Character Offset Drug Term Instance
Octreotide 48780 study) RECIST Everolimus207 11.0 Placebo203 4.6 Small bowel NETs Rinke et al. [[65]] (PROMID study) WHO Octreotide LAR422 14.3 Placebo432 6.0 Pavel et al. [[73]] (RADIANT-2 study) RECIST Everolimus
Octreotide 49779 studies NETTER-1 study 177Lu-DOTATATE116 Not achieved RECIST [[83]] Octreotide LAR113 8.4Phase I and II studies 177Lu-DOTATATE3102933RECIST[[80]] 177Lu-DOTATATE2638 RECIST[[84]] 177Lu-DOTATATE1217 RECIST[[85]] 177Lu-DOTATATE423236RECIST[[86]] 90Y-DOTATOC582317RECIST[[87]] 90Y-DOTATOC532329RECIST[[88]] 90Y-DOTATOC90416RECIST[[89]] 90Y-DOTATOC58929RECIST[[90]] 90Y-DOTATOC2129 RECIST[[91]]ORR,
everolimus 937 revolutionized by the development of new treatment strategies such as molecular targeting therapies with everolimus and sunitinib, somatostatin analogs, tryptophan hydroxylase inhibitors, and peptide receptor radionuclide
everolimus 33927 with advanced NETs (Table 2).Everolimus is a well-studied oral mTOR inhibitor. A phase II trial of everolimus in combination with long-acting octreotide in patients with advanced low to intermediate grade NETs
everolimus 34310 patients with metastatic pancreatic NETs (who experienced progression on or after chemotherapy) to everolimus or everolimus in combination with long-acting octreotide, showed a significantly longer median PFS in
everolimus 34324 metastatic pancreatic NETs (who experienced progression on or after chemotherapy) to everolimus or everolimus in combination with long-acting octreotide, showed a significantly longer median PFS in patients receiving
everolimus 34477 octreotide, showed a significantly longer median PFS in patients receiving combination therapy as compared to everolimus alone (16.7 months versus 9.7 months) [[104]]. More recently, a multicenter double-blind placebo-controlled
everolimus 34634 More recently, a multicenter double-blind placebo-controlled phase III trial (RADIANT-3) comparing everolimus to placebo in 410 patients with progressive, advanced low or intermediate grade NETs showed that median
everolimus 34771 with progressive, advanced low or intermediate grade NETs showed that median PFS was improved with everolimus therapy (11.0 months versus 4.6 months) [[72]]. The most common adverse events in the everolimus group
everolimus 34868 with everolimus therapy (11.0 months versus 4.6 months) [[72]]. The most common adverse events in the everolimus group versus placebo group were stomatitis (64% versus 17%), rash (49% versus 10%), diarrhea (34% versus
everolimus 35105 versus 14%), and infections (23% versus 6%). The results of these studies have led to the approval of everolimus by the European Medicines Agency in the European Union and by the Food and Drug Administration in the
everolimus 35535 302 patients with advanced, progressive, well-differentiated, nonfunctional NETs were randomized to everolimus 10 mg per day orally or placebo, both with supportive care [[74]]. The primary endpoint was PSF, and
everolimus 35758 quality of life were secondary endpoints. Median PFS of 11.0 months was significantly improved in the everolimus group compared to 3.9 months in the placebo group (p < 0.00001). Although not statistically significant,
everolimus 35945 not statistically significant, the results of the first preplanned interim OS analysis indicated that everolimus might be associated with a reduction in the risk of death [[74]].6.2. Sunitinib: Targeting Key Drivers
everolimus 38030 progressive, unresectable, locally advanced or metastatic pancreatic NETs.None of the clinical trials with everolimus and sunitinib for treatment of patients with advanced NETs assessed whether response to therapy was
everolimus 38343 phase II clinical trial for treatment of low or intermediate grade advanced, progressive NETs with everolimus or sunitinib based on the genetic alterations present in the tumor (NCT02315625) is now underway [[51]].6.3.
everolimus 38580 Therapeutics Investigated for Treatment of Advanced NETsIn addition to the approval of sunitinib and everolimus , a number of other agents targeting different RTKs, growth factors, and mTOR signaling pathway have
everolimus 42485 NETs treated with routinely used first-line therapeutic agents including octreotide, lanreotide, and everolimus or sunitinib, the overall tumor response rates with these agents have been less than satisfactory (Table
everolimus 44341 development of new systemic and biological treatment strategies such as molecular targeted therapies with everolimus and sunitinib, PRRT, as well as revealing the antiproliferative properties of SA. The growing list of
sorafenib 39201 events of all grades included fatigue (78%), hyperglycemia (69%), and rash (64%) [[106]].The activity of sorafenib , an orally active multityrosine kinase inhibitor targeting VEGFR-2, VEGFR-3, PDGFR-β, FLT3, c-KIT,
sorafenib 40800 and rash (3%).While the above clinical trials showed moderate clinical activity of monotherapies with sorafenib , pazopanib, gefitinib, and temsirolimus, combination therapy with somatostatin analogs and/or selective
sunitinib 952 the development of new treatment strategies such as molecular targeting therapies with everolimus and sunitinib , somatostatin analogs, tryptophan hydroxylase inhibitors, and peptide receptor radionuclide therapy
sunitinib 37078 FMS-like tyrosine kinase-3 (FLT3) [[105]]. A phase II trial in patients with advanced NETs who received sunitinib demonstrated a median time to tumor progression of 7.7 and 10.2 months in patients with pancreatic NETs
sunitinib 37350 randomized, double-blind phase III trial comparing the response of 86 randomly selected patients given sunitinib with that of 85 patients on placebo demonstrated significant improvement in median PFS of patients on
sunitinib 37462 with that of 85 patients on placebo demonstrated significant improvement in median PFS of patients on sunitinib (11.4 months versus 5.5 months) [[71]]. Moreover, patients treated with sunitinib showed early signs
sunitinib 37544 PFS of patients on sunitinib (11.4 months versus 5.5 months) [[71]]. Moreover, patients treated with sunitinib showed early signs of an increase in overall survival. The most common adverse events associated with
sunitinib 37656 showed early signs of an increase in overall survival. The most common adverse events associated with sunitinib treatment were diarrhea, nausea, asthenia, vomiting, and fatigue; each occurred in 30% or more of patients
sunitinib 37806 asthenia, vomiting, and fatigue; each occurred in 30% or more of patients [[71]]. Based on these findings, sunitinib was approved by the European Medicines Agency and by the Food and Drug Administration for the treatment
sunitinib 38045 unresectable, locally advanced or metastatic pancreatic NETs.None of the clinical trials with everolimus and sunitinib for treatment of patients with advanced NETs assessed whether response to therapy was related to the
sunitinib 38357 clinical trial for treatment of low or intermediate grade advanced, progressive NETs with everolimus or sunitinib based on the genetic alterations present in the tumor (NCT02315625) is now underway [[51]].6.3. Other
sunitinib 38566 Other Molecular Therapeutics Investigated for Treatment of Advanced NETsIn addition to the approval of sunitinib and everolimus, a number of other agents targeting different RTKs, growth factors, and mTOR signaling
sunitinib 42499 with routinely used first-line therapeutic agents including octreotide, lanreotide, and everolimus or sunitinib , the overall tumor response rates with these agents have been less than satisfactory (Table 2) and for
sunitinib 44356 systemic and biological treatment strategies such as molecular targeted therapies with everolimus and sunitinib , PRRT, as well as revealing the antiproliferative properties of SA. The growing list of effective therapeutics
Select Disease Character Offset Disease Term Instance
carcinoid 2082 develop from the dispersed neuroendocrine cells of the gastrointestinal tract (GI) mucosa (also called “ carcinoid s”) and the pancreatic islet cells. Approximately 85% of NETs are sporadic and the remainder occur
carcinoid 2832 hormones can result in significant morbidity and mortality. Up to 20% of patients with NETs may develop carcinoid syndrome: flushing, abdominal pain, diarrhea, bronchoconstriction, and carcinoid heart disease [[6]].Treatment
carcinoid 2913 with NETs may develop carcinoid syndrome: flushing, abdominal pain, diarrhea, bronchoconstriction, and carcinoid heart disease [[6]].Treatment of NETs is largely dependent on the functional status and the stage. Advanced
carcinoid 25611 embolization have been successfully used for control of symptoms in patients with advanced NETs who develop carcinoid syndrome. Yet, a significant proportion of these patients remain refractory to treatment with SA and
carcinoid 26845 conduct of a placebo-controlled, double-blind, phase III clinical trial (TELESTAR) of 211 patients with carcinoid syndrome randomly assigned to placebo (n = 71) or TE 250 mg (n = 70) or TE 500 mg (n = 70), each
carcinoid 28384 serotonin levels and become a valuable alternative for the treatment of patients with advanced NETs and carcinoid syndrome refractory to treatment with SA.5.3. Peptide Receptor Radiotherapy (PRRT)The potential therapeutic
carcinoid 34042 combination with long-acting octreotide in patients with advanced low to intermediate grade NETs (30 carcinoid and 30 islet cell tumors) demonstrated a partial response rate of 20% and median PFS of 15 months [[103],
carcinoid 37196 demonstrated a median time to tumor progression of 7.7 and 10.2 months in patients with pancreatic NETs and carcinoid tumors, respectively [[96]]. A follow-up randomized, double-blind phase III trial comparing the response
carcinoid 47281 grade 1Neuroendocrine carcinoma, grade 1 Intermediate grade (grade 2)2–203–20Carcinoid, atypical carcinoid c, islet cell, PNETNeuroendocrine tumor, grade 2Neuroendocrine carcinoma, grade 2Poorly differentiated High
carcinoid 48198 taken from American Joint Committee on Cancer staging system (seventh edition); cThe term atypical carcinoid only applies to intermediate grade neuroendocrine tumor of the lung.Table 2Phase III trials of somatostatin
hyperglycemia 24947 severity drug-related adverse events were nausea (27%), abdominal pain (20%), weight loss (20%), and hyperglycemia (16%). Another phase II clinical trial evaluating the antiproliferative activity of pasireotide in treatment-naive
hyperglycemia 25352 and high expression of SR type 5 in tumor cells [[70]]. The most common adverse effect observed was hyperglycemia in 79% of patients [[70]].5.2. Tryptophan Hydroxylase InhibitorsSomatostatin analogs alone or in combination
hyperglycemia 39141 71.5%, was observed. The most frequent drug-related adverse events of all grades included fatigue (78%), hyperglycemia (69%), and rash (64%) [[106]].The activity of sorafenib, an orally active multityrosine kinase inhibitor
hyperglycemia 41411 adverse events attributed to therapy were hypertension (21%), fatigue (16%), lymphopenia (14%), and hyperglycemia (14%) [[110]].A prospective, multi-institutional phase II study of pazopanib and depot octreotide in
hypertriglyceridemia 41853 hypertension (n = 6), neutropenia (n = 3), fatigue (n = 3), diarrhea (n = 3), transaminitis (n = 3), hypertriglyceridemia (n = 2), anemia (n = 1), nausea (n = 1), pain (n = 1), rash (n = 1), syncope (n = 1), and confusion
multiple endocrine neoplasia 2239 Approximately 85% of NETs are sporadic and the remainder occur as part of familial cancer syndromes including multiple endocrine neoplasia -type 1 (MEN1), von Hippel-Lindau disease (VHL), von Recklinghausen's disease (neurofibromatosis 1, NF1),
neuroendocrine tumor 551 /2017Publication date (epub): 5/2017AbstractOur understanding of the biology, genetics, and natural history of neuroendocrine tumor s (NETs) of the gastrointestinal tract and pancreas has improved considerably in the last several decades
neuroendocrine tumor 46911 advanced NETs and, ultimately, help patients and their families.Table 1Nomenclature and classification of neuroendocrine tumor s.Differentiation and gradeMitotic count (/10 HPF)aKi-67 index (%)bTraditional classificationENETS/WHO
neuroendocrine tumor 47757 3, large cellHPF, high-power field; ENETS, European Neuroendocrine Tumor Society; PNET, pancreatic neuroendocrine tumor ; aHPF = 2 mm2; at least 40 fields (at ×40 magnification) were evaluated in areas of highest mitotic
neuroendocrine tumor 48243 Cancer staging system (seventh edition); cThe term atypical carcinoid only applies to intermediate grade neuroendocrine tumor of the lung.Table 2Phase III trials of somatostatin analogs and molecular targeting therapy in advanced

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