Systematic Reviews
Copyright ©The Author(s) 2020.
World J Gastroenterol. Jul 7, 2020; 26(25): 3686-3711
Published online Jul 7, 2020. doi: 10.3748/wjg.v26.i25.3686
Table 1 Extracted literature
Ref.InterventionComparator(s)Study design, “Open” Label / “Blinded” / “Double blinded”Total sample sizePatient sub-groupPt sub-group sample sizeSex (% female)Average age (yr)Mean/medianTotal GI-NET, %P-NET, %Functioning /Non-functioning, “function”Additional information about disease1: “Stage (TNM)” “progressive” “stable”, (“advanced” “metastatic/metastases” “spread”) (“grow” “grade” “differentiated”)
Zandee et al[58], 2019177Lu-DOTATATENARetrospective study34NANA5059MeanNA100Functioning (100%)Grade 1 or 2 tumours with metastases (stage IV). Metastatic disease sites: Liver (97%), bone (21%), lung (6%)
Ramage et al[54], 2019EverolimusNAPhase IV, open48All Patients463064.3MedianNR100NRAdvanced and/or metastatic, well-differentiated, grade 1 and 2
Continuing treatment at month 630NRNRNRNRNR
Ballal et al[8], 2019225Ac-DOTATATENAProspective study, open21NANA5754Median3857NRMetastatic GEP-NETs with stable disease after completing 177Lu-PRRT (57%) or progressive disease on 177Lu-PRRT (43%). Grades 1 (n = 9), 2 (n = 11), and 3 (n = 1). Metastatic disease sites: Liver (86%), lymph node (71%), bone (33%)
Marinova et al[61], 2019177Lu-DOTATATENARetrospective study70NANA44.364.2Mean100NRFunctioning (83%), non-functioning (17%)Metastatic. Grade 1 (50%), grade 2 (35.7%), unknown (14.3%). Morphological or clinical progression prior to 1st cycle PRRT (78.6%)
Rinke et al[16], 2019Long-acting octreotidePlacebo (sodium chloride)Clinical trial (RCT), Phase IIIb trial, double blind, placebo controlled85Long-acting octreotide4249.462.4MeanNRNRFunctioning (39%), non-functioning (61%)Metastatic, liver metastases (86%)
Martini et al[59], 2018DOTATATE or 90Y-DOTATOCGeneral population normsRetrospective study61Small intestine NET patients3740.562.8Mean1000NRNo brain metastases; otherwise not defined
P-NET patients2437.561.0Mean0100
Lewis et al[3], 2018Not definedPatients with CS vs patients without CSProspective study50Without CS (CS)2548.062.0Median60.040.0NRAdvanced, well-differentiated, with liver metastases
With CS (CS)2536.067.0Median96.04.0NR
Strosberg et al[17], 2018177Lu-DOTATATEHigh-dose octreotideClinical trial (RCT), phase III, open231177Lu-DOTATATE117NRNRNR100NRNRAdvanced, progressive, low- or intermediate-grade
octreotide LAR114NRNRNR100NR
Karppinen et al[46], 2018NAControl populationCross-sectional134Impaired excretion875566.8Mean100NRFlushing (31%), diarrhoea (63%)Locally advanced or metastatic disease (91%), grade 1 (54.1%), grade 2 (45.9%)
Cella et al[44], 2018Telotristat ethylPlaceboClinical trial (RCT), phase III trial, double blind135NA13548.163.6MeanNRNRNRWell-differentiated, metastatic NETs and CS inadequately controlled by somatostatin analogues (for ≥ 3 mo)
Durable responders (DR)4852.163.4MeanNRNR
Non-durable responders (DR)874663.6MeanNRNR
Meng et al[28], 2017Somatostatin analogue lanreotidePlaceboClinical trial (RCT), phase III trial, double blind204Lanreotide1014862.1MeanNRNRNon-functioningAdvanced, well-differentiated or moderately differentiated, somatostatin receptor-positive NETs of grade 1 or 2
Vinik et al[35], 2016Sunitinib plus best supportive carePlacebo plus best supportive careClinical trial (RCT), phase III trial, double blind171NANANRNRNRNA100NRAdvanced and/or metastatic, pathologically confirmed, well-differentiated P-NETs with disease progression as assessed by RECIST
Haugland et al[9], 2016NoneNoneCross-sectional196NoneNA50.565.0Mean100.00.0NRNR
Pavel et al[56], 2016EverolimusNAClinical trial, Phase IIIb, open, expanded access study246P-NET1264661MedianNR100Functioning (n = 38), non-functioning (n = 88)Metastatic, well differentiated (n = 81), moderately differentiated (n = 26), poorly differentiated (n = 1), unknown (n = 16), missing (n = 2)
Non P-NET12050.866MedianNR0Functioning (n = 66), non-functioning (n = 55)Metastatic, well differentiated (n = 65), moderately differentiated (n = 34), poorly differentiated (n = 2), unknown (n = 19)
Delpassand et al[66], 2014177Lu-DOTATATENAClinical trial, phase II, open37Patients with available data participated in quality of life questionnaire2756.863.4Mean43.237.8NRGrade 1 and grade 2, disseminated, progressive, somatostatin receptor-positive. Multiple metastases in the liver: grade 2 (n = 4), grade 3 (n = 26), grade 4 (n = 7). Metastatic disease sites: Liver (n = 34), lymph nodes (n = 16), bone (n = 11), pancreas (n = 8), lung (n = 3)
Ducreux et al[41], 2014Bevacizumab combined with 5-FU/ streptozocin (Mitry et al[40] 2014)Capecitabine plus bevacizumabClinical trial, phase II, open34NANA3555MedianNR100Functioning (n = 7): CS (n = 3), Zollinger–Ellison syndrome (n = 1), other (n = 3)Progressive, metastatic disease. Metastatic disease sites: Liver (n = 33), lymph node (n = 14), peritoneum (n = 2), lung (n = 3), bone (n = 2), other (n = 2)
Mitry et al[40], 2014Bevacizumab combined with 5-FU/ streptozocin (reported in a companion paper focusing on P-NET patients (Ducreux et al[41], 2014)Capecitabine plus bevacizumabClinical trial, phase II, open49NANA4760Median100NANRProgressive, metastatic well-differentiated. Metastatic disease sites: Liver (n = 46), lymph node (n = 24), peritoneum (n = 23), lung (n = 7), bone (n = 7), other (n = 5)
Meyer et al[42], 2014Capecitabine and streptozocin plus cisplatin (stratified)Capecitabine and streptozocin (stratified)Clinical trial (RCT), Phase II86Capecitabine and streptozocin443957Median2146.0Functioning (n = 31; 36%)Advanced and/or metastatic. Metastatic disease sites: Local/regional (n = 2), distant (n = 42), liver (included in distant; n = 41)
Capecitabine and streptozocin plus cisplatin424559Median1950.0
Yadegarfar et al[33], 2013Somatostatin analogues or interferon therapy (88 patients)Peptide-receptor radiotherapy (102 patients), chemotherapy (23 patients), surgery (20 patients) or ablative/ other therapies (20 patients)Phase IV, open253P-NET70NRNRNRNRNRFunctioning: Secreting 5-hydroxy-indoloacetic acid (n = 111), gastrin (n = 4), glucagon (n = 3), insulin (n = 5), vasoactive intestinal peptide (n = 1). Non-functioning (secreting only chromogranin-A; n = 124)Any gut-primary with metastases, lung-primary with liver/abdominal metastases and pancreas with/without metastases
Casciano et al[36], 2012Everolimus (Afinitor)Sunitinib (Sutent)Economic analysis of phase III studiesNANANANANANANANANRAdvanced, progressive
Kvols et al[29], 2012PasireotideOctreotideProspective study, phase II, open44Pasireotide responders12 (Baseline), 12 (Month 1), 10 (Month 2), 11 (Month 3)4461MeanNRNRNRAdvanced, metastatic (symptoms refractory or resistant to octreotide LAR therapy). Metastatic disease sites: Liver (87%), lymph node (n = 16), peritoneum (n = 8), lung (n = 5), bone (n = 3), abdomen (n = 3), pleura (n = 3), retroperitoneal (n = 2), pancreas (n = 2), kidney (n = 1)
Pasireotide non responders13 (Baseline), 13 (Month 1), 13 (Month 2), 13 (Month 3)NRNR
Patients who discontinued treatment before 3 mo19 (Baseline), 15 (Month 1), 8 (Month 2)NRNR
Raymond et al[34], 2011Sunitinib plus Best Supportive CarePlacebo plus Best Supportive CareClinical trial (RCT), phase III, double blind171sunitinib865156MedianNR100Sunitinib Arm: Functioning: Gastrinoma (n = 9), glucagonoma (n = 3), insulinoma (n = 2), somatostatinoma (n = 1), other, multisecretory, or unknown (n = 10). Non-functioning (n = 42)Advanced and/or metastatic, progressive, well-differentiated
Placebo855357MedianNR100Placebo Arm: Functioning: Gastrinoma (n = 10), glucagonoma (n = 2), insulinoma (n = 2), vasoactive intestinal peptide–secreting tumour (n = 2), other, multisecretory, or unknown (n = 5). Non-functioning (n = 44)
Pezzilli et al[49], 2009NANAProspective study51NANA58.861MeanNR100NRAdvanced disease (lymph node involvement/liver metastases) (n = 22)
Rinke et al[27], 2009Octreotide LARPlaceboClinical trial (RCT), phase IIIb, double blind85Octreotide LAR4252.463.5Median100NROctreotide LAR arm: Functioning: CS (n = 17) 40.5%Well-differentiated, metastatic. Metastatic disease sites: Liver (n = 73), regional lymph node involvement (n = 6)
Placebo4346.561Median100NRPlacebo arm: Functioning: CS (n = 16) 37.2%
Korse et al[30], 2009Long-acting sandostatin LARShort-acting SandostatinClinical trial, phase II39NANA51.361Mean51.3NRFunctioning: CS (n = 39)Metastatic: Liver metastases (n = 35)
van der Horst-Schrivers et al[67] , 2009NANAProspective study43NANA37.260.6MeanNRNRNRMetastatic midgut carcinoid tumours: Liver metastases (n = 37)
Haugland et al[47], 2009NANACross-sectional5341NET patients1895065Mean100NRNRGI-NET patients (excluded radical surgery that may have been curative), otherwise undefined
General population515248.8NRNRNANA
Larsson and Janson[50], 2008ErythropoietinNonePilot study18NoneNA50.063.0Mean100NRNRNR
Kulke et al[55], 2008SunitinibNAClinical trial, phase II, open107NANA40.2Carcinoid tumour = 58, P-NET= 56Median37.361.7P-NET: Functioning: Gastrinoma n = 5 (7.6%), insulinoma n = 3 (4.5%), VIPoma n = 2 (3.0%), glucagonoma n = 4 (6.1%), other n = 5 (7.6%). Non-functioning n = 46 (69.7%)Advanced carcinoid or P-NET
Fröjd et al[37] , 2007Various includedNoneLongitudinal, prospective, comparative study59T1-T4 successful3647.060.0MeanNRNRNRMetastatic (70% metastatic at start; 78% metastatic at end)
Davies et al[68], 2006NANACross-sectional, open50Patients3542.960MeanNRNRNRMetastatic
Healthcare workers15NRNRNRNANA
Frilling et al[48], 200690Y-DOTATOC then 177Lu-DOTATOCNAProspective study20Excluding pt (no 3) with Paraganglioma-neck193053.8MedianNRNRNRAdvanced, progressive, and metastatic
Arnold et al[31], 2005Octreotide plus interferon alphaOctreotide monotherapyClinical trial (RCT), open114Octreotide monotherapy5147.158MedianNRNROctreotide: Functioning (n = 23), non-functioning (n = 28). Octreotide plus Interferon-alpha: functioning (n = 24), non-functioning (n = 30)Metastatic or locally advanced disease without curative therapeutic option
Octreotide plus interferon alpha5444.457MedianNRNR
Teunissen et al[62], 2004177Lu-DOTATOCNoneClinical trial50NoneNA56.058.3MeanNR26.0NRMetastatic
Pasieka et al[43], 2004I-MIBGNAClinical trial, open19I-MIBG104059Mean9010NRProgressive
Kwekkeboom et al[60], 2003Somatostatin analogue 177Lu-DOTATOCNAClinical trial, open35NoneNA6054MeanNRNRNRMetastatic
Larsson et al[25], 2001Interferon, somatostatin analogue, interferon, and a somatostatinNoneProspective study24NoneNA42.062.0Median100NRNRNR
O'Toole et al[32], 2000Octreotide followed by lanreotideLanreotide followed by octreotideClinical trial (RTC), double blind33Patients received octreotide followed by Lanreotide165063NR62.50
Patients received lanreotide followed by octreotide175364NR765.9NRNR
Wymenga et al[57], 1999Lanreotide prolonged releaseNAClinical trial, phase II, open55NANA49.159.7MeanNR5.5NRAdvanced (Stage IV), metastatic. Metastatic disease sites: Lymph nodes (n = 39), distant organs (n = 44)
Larsson et al[26], 1999Ongoing treatment: interferon and octreotide, otherNACross-sectional119Patients with carcinoid tumours6443.764Median53.8NANRNR
Patients with EPT5537.554MedianNR46.20
Larsson et al[38] , 1999Interferon and/or a somatostatin analogueNAClinical trial99NANA39.459MeanNRNRNRStage = not terminal, no other status provided.
HADS Anxiety (cases)19NRNRNRNRNR
HADS Depression (cases)13NRNRNRNRNR
Larsson et al[69], 1998Interferon and/or a somatostatin analogueNACross-sectional17NANA4758MeanNRNRNRNR
Table 2 Literature reporting scores for health-related quality of life average global health score for gastroenteropancreatic neuroendocrine tumours patients using European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30
Ref.Intervention/comparatorTime pointGlobal health scoreStatistical analysis and P values, as presented in the literature
Arnold et al[31], 2005Octreotide plus interferon alphaBaseline57.90.04 (between treatment arms at 3 mo)
3 mo51.2
Octreotide monotherapyBaseline63
3 mo74.4
Cella et al[44], 2018Telotristat ethyl-Overall: 55.4; Durable responders: 40; Non-durable responders: 66NR (NS)
Fröjd et al[37], 2007Various (i.e. interferon, octreotide, chemotherapy and other)Timepoint 158NR
Timepoint 261NR
Timepoint 358NR
Timepoint 458NR
van der Horst-Schrivers et al[67], 2009NA-61.8NR
Korse et al[30], 2009Long-acting sandostatin LARBaseline700.275 (repeated measurement analysis using mixed linear models)
3 mo71
6 mo67
9 mo68
12 mo64
Larsson et al[50], 2008ErythropoietinBaseline56NR (NS)
4 mo55
8 mo66
2 yr70
Larsson et al[25], 2001Interferon, somatostatin analogue, interferon, and a somatostatin.Baseline68NR (NS)
3 mo59
6 mo58
9 mo50
12 mo63
Larsson et al[26], 1999Interferon and/or a somatostatin analogue for at least 4 weeks - Five patients were treated with interferon, three with a somatostatin analogue, and nine with a combination-64.71NR
Larsson et al[38], 1999Interferon and/or a somatostatin analogue-Overall: 66.7; HADS Anxiety (cases): 46; HADS Anxiety (non-cases): 71.6; HADS Depression (cases): 43; HADS Depression (non-cases): 70.2< 0.001 between HADS anxiety “cases” (n = 19) and “non-cases” (n = 80) and 0.001 between HADS depression “cases” (n = 13) and “non-cases” (n = 86)
Larsson et al[69], 1998Interferon and/or a somatostatin analogue and/or a combination-64.71NR
Lewis et al[3], 2018NA-Without CS: 63.0; With CS: 61.70.04 (between subpopulations)
Marinova et al[61], 2019177Lu-DOTATATEBaseline62.6
3 mo66.7< 0.05 (compared to baseline using mixed longitudinal model)
6 mo69.6< 0.01 (compared to baseline using mixed longitudinal model)
9 mo69.4< 0.01 (compared to baseline using mixed longitudinal model)
Meyer et al[42], 2014Capecitabine and streptozocin plus cisplatin.Baseline69.3
≤ 9 wk - after 3 × 3 weekly cycles52.20.052 (compared to baseline)
6 mo560.68 (compared to baseline)
Capecitabine and streptozocinBaseline67
≤ 9 wk - after 3 × 3 weekly cycles62.20.5 (compared to baseline)
6 mo68.90.75 (compared to baseline)
Mitry et al[40], 2014Bevacizumab plus capecitabineBaseline67
6 mo63NR (NS)
12 mo71NR (NS)
Pavel et al[56], 2016EverolimusEnd of treatment (compared to baseline)P-NET: -3.9; non P-NET: -13NR
Ramage et al[54], 2019Everolimus1 moFAS Population (paired scores baseline and 1 m): 58NR (NS)
Continuing tx at 6m (paired scores baseline and 1 m): 56.9NR (NS)
2 moFAS Population (paired scores baseline and 2 m): 57.6NR (NS)
Continuing tx at 6m (paired scores baseline and 2 m): 56.9NR (NS)
3 moFAS Population (paired scores baseline and 3 m): 56.7NR (NS)
Continuing tx at 6m (paired scores baseline and 3 m): 56.3NR (NS)
4 moFAS Population (paired scores baseline and 4 m): 56NR (NS)
Continuing tx at 6 m (paired scores baseline and 4 m): 56.8NR (NS)
5 moFAS Population (paired scores baseline and 5 m): 56.6NR (NS)
Continuing tx at 6 m (paired scores baseline and 5 m): 58.6NR (NS)
6 moFAS Population (paired scores baseline and 6 m): 56.9NR (NS)
Continuing tx at 6 m (paired scores baseline and 6 m): 56.9NR (NS)
Raymond et al[34], 2011SunitinibBaseline67
Rinke et al[16], 2019Long-acting octreotideBaseline64
12 wk+4.13 (difference in global health score compared to placebo)NR
24 wk+5.05 (difference in global health score compared to placebo)NR
36 wk+1.85 (difference in global health score compared to placebo)NR
Strosberg et al[17], 2018177Lu-DOTATATEBaseline67NR
High-dose octreotideBaseline64NR
Teunissen et al[62], 2004177Lu-DOTATOCBaseline69
6 wk78.2< 0.01 (Analysis of variance (two-sided) compared to baseline)
Vinik et al[35], 2016SunitinibBaseline67NR (NS difference between arms)
Up to cycle 10 (about 9 mo)60.4
PlaceboBaseline64NR (NS difference between arms)
Up to cycle 10 (about 9 mo)61.3
Wymenga et al[57], 1999Lanreotide prolonged releaseBaseline60.4
1 mo69.70.001 (compared to baseline using t tests or Wilcoxon signed rank)
End of treatment65.5NR (NS)
Yadegarfar et al[33], 2013Somatostatin analogues or interferon therapyBaseline61
3 mo67NR
6 mo67NR
Zandee et al[58], 2019177Lu-DOTATATEBaseline61.7
3 mo (after final PRRT cycle)79.50.002 (compared to baseline using paired t test)
Table 3 The specific domain scores reported in the literature for gastroenteropancreatic neuroendocrine tumours patients using QLQ-GI.NET21
Ref.Intervention/ comparatorTime pointEndocrine SymptomsGastrointestinal SymptomsSocial functionDisease related worriesMuscle/bone pain symptomWeight gainInformation/Communication functionBody ImageSexual functionTreatment related symptoms scale
Ramage et al[54], 2019EverolimusBaseline (paired scores with 3 mo)14.824.444.151.135.2NR1.925.937NA
3 mo12.320.242.644.835.2NR4.624.142.622
Baseline (paired scores with 6 mo)14.425.844.850.933.3NR1.12035.6NA
6 mo12.621.834.443.730NR1.121.137.814.1
Lewis et al[3], 2018NASingle timepoint (patients without CS)16.718.960.056.941.318.710.715.360.817.5
Single timepoint (patients with CS)28.424.068.438.746.713.316.013.368.410.1
Yadegarfar et al[33], 2013VariousBaseline (P-NETs)22263956251110253218
3 mo (P-NETs)161833443194213122
6 mo (P-NETs)18223050321310193123
Ballal et al[8], 2019225Ac-DOTATATE TATBaseline21.440.264.361.238.825NR28.8406.53
End of assessment3.5722.872.984.226.827.8NR15.64526.24
Strosberg et al[17], 2018177Lu-DOTATATEBaselineNR22.833.443.729NR5.42030.611.6
High-dose octreotideBaselineNR23.837.143.834.6NR12.320.328.211.9
Cella et al[44], 2018Telotristat ethylBaseline (Durable responders)37.833.846.741.135NR529.147.218.1
Baseline (Nondurable responders)29.528.538.537.630.3NR726.932.612.8
Difference in change from baseline between subpopulations-1.9-9.6-2.81.9-4.5NR3.91-1.6-3.4