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. 2021 Nov 25;11(11):CD013700.
doi: 10.1002/14651858.CD013700.pub2.

Treatment for gastrointestinal and pancreatic neuroendocrine tumours: a network meta-analysis

Martin A Walter #  1 , Cédric Nesti #  2 , Marko Spanjol  1 , Attila Kollár  3 , Lukas Bütikofer  4 , Viktoria L Gloy  5 , Rebecca A Dumont  1 , Christian A Seiler  2 , Emanuel R Christ  6 , Piotr Radojewski  1 , Matthias Briel  5 , Reto M Kaderli  2
Affiliations

Treatment for gastrointestinal and pancreatic neuroendocrine tumours: a network meta-analysis

Martin A Walter et al. Cochrane Database Syst Rev. .

Abstract

Background: Several available therapies for neuroendocrine tumours (NETs) have demonstrated efficacy in randomised controlled trials. However, translation of these results into improved care faces several challenges, as a direct comparison of the most pertinent therapies is incomplete.

Objectives: To evaluate the safety and efficacy of therapies for NETs, to guide clinical decision-making, and to provide estimates of relative efficiency of the different treatment options (including placebo) and rank the treatments according to their efficiency based on a network meta-analysis.

Search methods: We identified studies through systematic searches of the following bibliographic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library; MEDLINE (Ovid); and Embase from January 1947 to December 2020. In addition, we checked trial registries for ongoing or unpublished eligible trials and manually searched for abstracts from scientific and clinical meetings.

Selection criteria: We evaluated randomised controlled trials (RCTs) comparing two or more therapies in people with NETs (primarily gastrointestinal and pancreatic).

Data collection and analysis: Two review authors independently selected studies and extracted data to a pre-designed data extraction form. Multi-arm studies were included in the network meta-analysis using the R-package netmeta. We separately analysed two different outcomes (disease control and progression-free survival) and two types of NET (gastrointestinal and pancreatic NET) in four network meta-analyses. A frequentist approach was used to compare the efficacy of therapies.

Main results: We identified 55 studies in 90 records in the qualitative analysis, reporting 39 primary RCTs and 16 subgroup analyses. We included 22 RCTs, with 4299 participants, that reported disease control and/or progression-free survival in the network meta-analysis. Precision-of-treatment estimates and estimated heterogeneity were limited, although the risk of bias was predominantly low. The network meta-analysis of progression-free survival found nine therapies for pancreatic NETs: everolimus (hazard ratio [HR], 0.36 [95% CI, 0.28 to 0.46]), interferon plus somatostatin analogue (HR, 0.34 [95% CI, 0.14 to 0.80]), everolimus plus somatostatin analogue (HR, 0.38 [95% CI, 0.26 to 0.57]), bevacizumab plus somatostatin analogue (HR, 0.36 [95% CI, 0.15 to 0.89]), interferon (HR, 0.41 [95% CI, 0.18 to 0.94]), sunitinib (HR, 0.42 [95% CI, 0.26 to 0.67]), everolimus plus bevacizumab plus somatostatin analogue (HR, 0.48 [95% CI, 0.28 to 0.83]), surufatinib (HR, 0.49 [95% CI, 0.32 to 0.76]), and somatostatin analogue (HR, 0.51 [95% CI, 0.34 to 0.77]); and six therapies for gastrointestinal NETs: 177-Lu-DOTATATE plus somatostatin analogue (HR, 0.07 [95% CI, 0.02 to 0.26]), everolimus plus somatostatin analogue (HR, 0.12 [95%CI, 0.03 to 0.54]), bevacizumab plus somatostatin analogue (HR, 0.18 [95% CI, 0.04 to 0.94]), interferon plus somatostatin analogue (HR, 0.23 [95% CI, 0.06 to 0.93]), surufatinib (HR, 0.33 [95%CI, 0.12 to 0.88]), and somatostatin analogue (HR, 0.34 [95% CI, 0.16 to 0.76]), with higher efficacy than placebo. Besides everolimus for pancreatic NETs, the results suggested an overall superiority of combination therapies, including somatostatin analogues. The results indicate that NET therapies have a broad range of risk for adverse events and effects on quality of life, but these were reported inconsistently. Evidence from this network meta-analysis (and underlying RCTs) does not support any particular therapy (or combinations of therapies) with respect to patient-centred outcomes (e.g. overall survival and quality of life).

Authors' conclusions: The findings from this study suggest that a range of efficient therapies with different safety profiles is available for people with NETs.

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Conflict of interest statement

Martin Alexander Walter: None known. Marko Spanjol: None known. Cédric Nesti: Meeting honoraria from IPSEN. Attila Kollár: Advisory board and meeting honoraria from IPSEN. Lukas Bütikofer: Affiliation with CTU Bern, University of Bern, which has a staff policy of not accepting honoraria or consultancy fees. However, CTU Bern is involved in design, conduct, or analysis of clinical studies funded by not‐for‐profit and for‐profit organizations. In particular, pharmaceutical and medical device companies provide direct funding to some of these studies. For an up‐to‐date list of CTU Bern’s conflicts of interest see http://www.ctu.unibe.ch/research/declaration_of_interest/index_eng.html. Viktoria L Gloy: None known. Rebecca Anne Dumont: None known. Christian A Seiler: None known. Emanuel R Christ: Advisory board honoraria from IPSEN, Novartis and Pfizer. Piotr Radojewski: None known. Matthias Briel: None known. Reto Martin Kaderli: Meeting honoraria from IPSEN.

Figures

1
1
Study flow diagram.
2
2
3
3
4
4
Treatment efficacy in pNET. Network plot (A) and Forest plot (B) for disease control in pNET. The thickness of the edges in the network plots is proportional to the inverse standard errors of the pairwise comparisons, and the numbers indicate the number of studies. One three‐arm study is marked by shading. Each section in the Forest plots refers to one treatment (in bold) compared to all others. An odds ratio larger than one indicates increased disease control of the bold treatment. A hazard ratio smaller than one indicates a reduced risk for progression for the bold treatment. All therapies are listed in order of their P‐scores, with the most effective therapy on top. Heterogeneity was assessed by the between‐study variance tau2, Cochran's Q with a P value, and I2. N refers to the total number of patients, and n to the number of patients with disease control. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to rate the quality of evidence of estimates from pairwise and network meta‐analysis. The final network meta‐analysis GRADE evidence quality corresponds to *very low, **low, ***moderate, and ****high. SSA refers to somatostatin analogues.
5
5
Treatment efficacy in pNET. Network plot (A) and Forest plot (B) for progression‐free survival in pNET. The thickness of the edges in the network plots is proportional to the inverse standard errors of the pairwise comparisons, and the numbers indicate the number of studies. One three‐arm study is marked by shading. Each section in the Forest plots refers to one treatment (in bold) compared to all others. An odds ratio larger than one indicates increased disease control of the bold treatment. A hazard ratio smaller than one indicates a reduced risk for progression for the bold treatment. All therapies are listed in order of their P‐scores, with the most effective therapy on top. Heterogeneity was assessed by the between study variance tau2, Cochran's Q with a P value, and I2. N refers to the total number of patients, and n to the number of patients with disease control. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to rate the quality of evidence of estimates from pairwise and network meta‐analysis. The final network meta‐analysis GRADE evidence quality corresponds to *very low, **low, ***moderate, and ****high. SSA refers to somatostatin analogues.
6
6
Treatment efficacy in GI‐NET. Network plot (A) and Forest plot (B) for disease control in GI‐NET. The thickness of the edges in the network plots is proportional to the inverse standard errors of the pairwise comparisons, and the numbers indicate the number of studies. One three‐arm study is marked by shading. Each section in the Forest plots refers to one treatment (in bold) compared to all others. An odds ratio larger than one indicates increased disease control of the bold treatment. A hazard ratio smaller than one indicates a reduced risk for progression for the bold treatment. All therapies are listed in order of their P‐scores, with the most effective therapy on top. Heterogeneity was assessed by the between study variance tau2, Cochran's Q with a P value, and I2. N refers to the total number of patients, and n to the number of patients with disease control. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to rate the quality of evidence of estimates from pairwise and network meta‐analysis. The final network meta‐analysis GRADE evidence quality corresponds to *very low, **low, ***moderate, and ****high. SSA refers to somatostatin analogues.
7
7
Treatment efficacy in GI‐NET. Network plot (A) and Forest plot (B) for progression‐free survival in GI‐NET. The thickness of the edges in the network plots is proportional to the inverse standard errors of the pairwise comparisons, and the numbers indicate the number of studies. One three‐arm study is marked by shading. Each section in the Forest plots refers to one treatment (in bold) compared to all others. An odds ratio larger than one indicates increased disease control of the bold treatment. A hazard ratio smaller than one indicates a reduced risk for progression for the bold treatment. All therapies are listed in order of their P‐scores, with the most effective therapy on top. Heterogeneity was assessed by the between study variance tau2, Cochran's Q with a P value, and I2. N refers to the total number of patients, and n to the number of patients with disease control. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to rate the quality of evidence of estimates from pairwise and network meta‐analysis. The final network meta‐analysis GRADE evidence quality corresponds to *very low, **low, ***moderate, and ****high. SSA refers to somatostatin analogues.
8
8
Ranking of treatment efficacies for disease control and progression‐free survival. Plot of treatment efficacies in pancreatic neuroendocrine tumors (pNET, A) and gastrointestinal neuroendocrine tumors (GI‐NET, B). Data are expressed as P‐scores, measuring the extent of certainty that one therapy is better than another, averaged over all competing therapies. Black nodes are combination therapies with somatostatin analogues (SSA). Due to a lack of P‐scores for disease control and progression‐free survival, everolimus plus bevacizumab plus somatostatin analogue in pNET and streptozocin plus 5‐FU in GI‐NET are not depicted.
See this image and copyright information in PMC

Update of

  • doi: 10.1002/14651858.CD013700

References

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    1. Caplin ME, Pavel M, Cwikla JB, Phan AT, Raderer M, Sedlackova E, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. New England Journal of Medicine 2014;371(3):224-33. - PubMed
    1. Phan AT, Caplin ME, Pavel ME, Cwikla JB, Raderer M, Sedláčková E, et al. Effects of lanreotide autogel/depot (LAN) in pancreatic neuroendocrine tumors (pNETs): a subgroup analysis from the CLARINET study. Journal of Clinical Oncology 2015;33:233.
Pusceddu 2018 {published data only}
    1. Caplin ME, Pavel M, Cwikla JB, Phan AT, Raderer M, Sedlackova E, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. New England Journal of Medicine 2014;371(3):224-33. - PubMed
    1. Pusceddu S, Vernieri C, Di Maio M, Prinzi N, Torchio M, Buzzoni R, et al. Post-hoc analysis of CLARINET phase III study to investigate the influence of diabetic status on progression-free survival (PFS) of patients with neuroendocrine tumours (NETs) treated with lanreotide(LAN) or placebo (PBO). Annals of Oncology 2018;29:viii472. [DOI: ]
Raymond 2011 (1) {published data only}
    1. Faivre S, Niccoli P, Castellano D, Valle JW, Hammel P, Raoul JL, et al. Sunitinib in pancreatic neuroendocrine tumors: updated progression-free survival and final overall survival from a phase III randomized study. Annals of Oncology 2017;28(2):339-43. - PubMed
    1. Raoul JL, Niccoli P, Bang YJ, Borbath I, Lombard-Bohas C, Metrakos P, et al. Sunitinib (SU) vs placebo for treatment of progressive, well-differentiated pancreatic islet cell tumours: results of a phase III, randomised, double-blind trial. European Journal of Cancer, supplement 2009;7:361. [EMBASE: 70210640]
    1. Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. New England Journal of Medicine 2011;364(6):501-13. - PubMed
    1. Raymond E, Niccoli P, Castellano D, Valle J, Hammel P, Raoul JL, et al. Sunitinib (SU) in patients with advanced, progressive pancreatic neuroendocrine tumors (PNET): final overall survival (OS) results from a phase III randomized study including adjustment for crossover. Neuroendocrinology 2016;103:84. [EMBASE: 613188549]
    1. Raymond E, Niccoli P, Raoul J, Bang Y, Borbath I, Lombard-Bohas C, et al. Updated overall survival (OS) and progression-free survival (PFS) by blinded independent central review (BICR) of sunitinib (SU) versus placebo (PBO) for patients (Pts) with advance unresectable pancreatic neuroendocrine tumors (NET). Journal of Clinical Oncology 2011;29(15 SUPPL. 1):4008. [EMBASE: 70709834]
Raymond 2011 (2) {published data only}
    1. Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. New England Journal of Medicine 2011;364(6):501-13. - PubMed
    1. Raymond E, Harmon C, Niccoli P, Metrakos P, Borbath I, Bang YJ, et al. Impact of baseline Ki-67 index and other baseline characteristics on outcome in a study of sunitinib (SU) for the treatment of advanced, progressive pancreatic neuroendocrine tumor (NET). Neuroendocrinology 2011;94:41. [EMBASE: 70610285]
Rinke 2009 {published data only}
    1. Rinke A, Muller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. Journal of Clinical Oncology 2009;27(28):4656-63. - PubMed
    1. Rinke A, Neary MP, Eriksson J, Hunger M, Doan T, Karli D, et al. Health-related quality of life for long-acting octreotide versus placebo in patients with metastatic midgut neuroendocrine tumors in the phase 3 PROMID Trial. Neuroendocrinology 2019;109(2):141-51. - PubMed
    1. Rinke A, Wittenberg M, Schade-Brittinger C, Aminossadati B, Ronicke E, Gress TM, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors (PROMID): Results of long-term survival. Neuroendocrinology 2017;104(1):26-32. - PubMed
Sakata 2006 {published data only}
    1. Sakata H, Iwakiri R, Ootani A, Tsunada S, Ogata S, Ootani H, et al. A pilot randomized control study to evaluate endoscopic resection using a ligation device for rectal carcinoid tumors. World Journal of Gastroenterology 2006;12(25):4026-8. - PMC - PubMed
Salazar 2018 {published data only}
    1. Salazar R, Garcia‐Carbonero R, Libutti SK, Hendifar AE, Custodio A, Guimbaud R, et al. Phase II study of BEZ235 versus everolimus in patients with mammalian target of rapamycin inhibitor‐naïve advanced pancreatic neuroendocrine tumors. Oncologist 2018;23(7):766‐71. - PMC - PubMed
Saslow 1998 {published data only}
    1. Saslow SB, Scolapio JS, Camilleri M, Forstrom LA, Thomforde GM, Burton DD, et al. Medium-term effects of a new 5HT3 antagonist, alosetron, in patients with carcinoid diarrhoea. Gut 1998;42(5):628-34. - PMC - PubMed
Singh 2018 (1) {published data only}
    1. Singh S, Carnaghi C, Buzzoni R, Pommier RF, Raderer M, Tomasek J, et al. Everolimus in neuroendocrine tumors of the gastrointestinal tract and unknown primary. Neuroendocrinology 2018;106(3):211-20. - PubMed
    1. Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, et al, Rad001 in Advanced Neuroendocrine Tumours, Fourth Trial Study Group. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet 2016;387(10022):968-77. - PMC - PubMed
Soulen 2020 {published data only}
    1. Soulen M, Avritscher R, El-Haddad G, Fidelman N, Garcia-Monaco R, White S, et al. Randomized embolization trial for neuroendocrine tumors (RETNET): first safety report. Pancreas 2020;49:488. [EMBASE: 631301779]
Strosberg 2011 {published data only}
    1. Strosberg J, Anthony L, Sideris L, Lebrec J, Tsuchihashi Z, Winkler R, et al. Prognostic value of chromogranin a and neuron-specific enolase in patients with advanced pancreatic neuroendocrine tumors (pNET): phase III RADIANT-3 study results 2011 ACG presidential poster. American Journal of Gastroenterology 2011;106:S58.
    1. Yao JC, Shah MH, Ito T, Lombard-Bohas C, Wolin EM, Van Cutsem E, et al, Rad001 in Advanced Neuroendocrine Tumors, Third Trial Study Group. Everolimus for advanced pancreatic neuroendocrine tumors. New England Journal of Medicine 2011;364(6):514-23. - PMC - PubMed
Strosberg 2017 {published data only}
    1. Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, et al. Phase 3 trial of (177)Lu-Dotatate for midgut neuroendocrine tumors. New England Journal of Medicine 2017;376(2):125-35. - PMC - PubMed
    1. Strosberg J, Wolin E, Chasen B, Kulke M, Bushnell D, Caplin M, et al. QOL improvements in netter-1 phase III trial in patients with progressive midgut neuroendocrine tumors. Pancreas 2018;47:355. [DOI: 10.1097/MPA.0000000000000997] - DOI - PMC - PubMed
    1. Strosberg J, Wolin E, Chasen B, Kulke MH, Bushnell D, Caplin M, et al. NETTER-1 phase III trial: Recent findings on quality of life in patients with midgut neuroendocrine tumors. Neuroendocrinology 2017;105:257. [DOI: 10.1159/000484263] - DOI
Strosberg 2020 {published data only}
    1. Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, et al. Phase 3 trial of (177)Lu-Dotatate for midgut neuroendocrine tumors. New England Journal of Medicine 2017;376(2):125-35. - PMC - PubMed
    1. Strosberg J, Kunz P, Hendifar A, Yao J, Bushnell D, Kulke M, et al. Impact of baseline liver tumor burden, alkaline phosphatase (ALP) elevation, and target size lesion on therapeutic effect of 177LU-DOTATATE treatment: Analysis of progression free survival, and safety in NETTER-1 study. Pancreas 2020;49:489. [DOI: 10.1097/MPA.0000000000001516] - DOI - PubMed
Van Der Zwan 2018 {published data only}
    1. Van Der Zwan W, Wyld D, Brabander T, Teunissen J, Kam B, MacFarlane D, et al. A randomized controlled study comparing treatment of gastro-entero-pancreatic neuroendocrine tumors (GEPNET) with 177Lu-Dotatate alone and in combination with capecitabine. Neuroendocrinology 2018;106:261. [DOI: 10.1159/000487699] - DOI
Vinik 2016 {published data only}
    1. Duchateau L, Lescrauwaet B, Blot K, Liyanage N, Ray D, Lowenthal SP, et al. An exploratory patientcentricanalysis of the elect trial: A phase 3 study of efficacy and safety of lanreotide autogel/depot (LAN) treatment for patients with carcinoid syndrome (CS). Pancreas 2018;Conference: 10th Annual Meeting of the North American Neuroendocrine Tumor Society. United States. 47:338. [EMBASE: 621394428]
    1. Vinik AI, Wolin EM, Liyanage N, Gomez-Panzani E, Fisher GA, Elect Study Group. Evaluation of lanreotide depot/autogel efficacy and safety as a carcinoid syndrome treatment (elect): A randomized, double-blind, placebo-controlled trial. Endocrine Practice 2016;22(9):1068-80. - PubMed
    1. Wolin EM, Lowenthal SP, Fisher GA, Liyanage N, Mirakhur B, Pommier RF, et al. Change in patient-reported symptom control in patients with neuroendocrine tumors treated with lanreotide depot. Pancreas 2018;47:358. [DOI: 10.1097/MPA.0000000000000997] - DOI - PMC - PubMed
Wolin 2015 {published data only}
    1. Wolin EM, Jarzab B, Eriksson B, Walter T, Toumpanakis C, Morse MA, et al. Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues. Drug Design, Development and Therapy 2015;9:5075-86. - PMC - PubMed
Wolin 2016 {published data only}
    1. Caplin ME, Pavel M, Cwikla JB, Phan AT, Raderer M, Sedlackova E, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. New England Journal of Medicine 2014;371(3):224-33. - PubMed
    1. Wolin EM, Caplin ME, Pavel ME, Cwikla JB, Phan AT, Raderer M, et al. Lanreotide depot/autogel (LAN) in intestinal and pancreatic neuroendocrine tumors (NETs) according to body mass index (BMI): Subgroup analyses from the CLARINET study. Journal of Clinical Oncology 2015;33(15_suppl):e15182. [EMBASE: 72012396]
    1. Wolin EM, Caplin ME, Pavel ME, Cwikla JB, Phan AT, Raderer M, et al. Lanreotide depot/autogel (LAN) in intestinal and pancreatic neuroendocrine tumors (NETs) according to body mass index (BMI): Subgroup analyses from the CLARINET study. Pancreas 2016;33(15_suppl):e15182.
Xu 2020 (ep) {published data only}
    1. Xu J, Shen L, Bai C, Wang W, Li J, Yu X, et al. Surufatinib in advanced extrapancreatic neuroendocrine tumours (SANET-ep): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncology 2020;21(11):1500-12. - PubMed
    1. Xu J, Shen L, Zhou Z, Li J, Bai C, Chi Y, et al. Efficacy and safety of surufatinib in patients with well-differentiated advanced extrapancreatic neuroendocrine tumors (NETs): results from the randomized phase III study (SANET-ep). Annals of Oncology 2019;30:v911. [EMBASE: 630606088]
Xu 2020 (p) {published data only}
    1. Xu J, Shen L, Bai C, Li J, Zhou Z, Yu X, et al. Surufatinib (S) for patients (Pts) with advanced pancreatic neuroendocrine tumours (SANET-p): a randomized, double-blind, placebo (P)-controlled phase III trial (NCT02589821). Annals of Oncology 2020;31:S770. [EMBASE: 2007890722]
    1. Xu J, Shen L, Bai C, Wang W, Li J, Yu X, et al. Surufatinib in advanced pancreatic neuroendocrine tumours (SANET-p): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncology 2020;21(11):1489-99. - PubMed
Yao 2008 (1) {published data only}
    1. Yao JC, Phan A, Hoff PM, Chen HX, Charnsangavej C, Yeung SC, et al. Targeting vascular endothelial growth factor in advanced carcinoid tumor: a random assignment phase II study of depot octreotide with bevacizumab and pegylated interferon alpha-2b. Journal of Clinical Oncology 2008;26(8):1316-23. - PubMed
Yao 2011 {published data only}
    1. De Vries E, Anthony LB, Sideris L, Chen L, Lebrec J, Tsuchihashi Z, et al. Effect of everolimus treatment on chromogranin A, neuron-specific enolase, gastrin, and glucagon levels in patients with advanced pancreatic neuroendocrine tumors (pNET): phase III RADIANT-3 study results. Journal of Clinical Oncology 2011;29(15_suppl):10624. [EMBASE: 70712574]
    1. Yao JC, Pavel M, Lombard-Bohas C, Van Cutsem E, Voi M, Brandt U, et al. Everolimus for the treatment of advanced pancreatic neuroendocrine tumors: Overall survival and circulating biomarkers from the randomized, phase III RADIANT-3 study. Journal of Clinical Oncology 2016;34(32):3906-13. - PMC - PubMed
    1. Yao JC, Shah MH, Ito T, Lombard-Bohas C, Wolin EM, Van Cutsem E, et al. Everolimus for advanced pancreatic neuroendocrine tumors. New England Journal of Medicine 2011;364(6):514-23. - PMC - PubMed
Yao 2016 {published data only}
    1. Pavel ME, Singh S, Strosberg JR, Bubuteishvili-Pacaud L, Degtyarev E, Neary MP, et al. Health-related quality of life for everolimus versus placebo in patients with advanced, non-functional, well-differentiated gastrointestinal or lung neuroendocrine tumours (RADIANT-4): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncology 2017;18(10):1411-22. - PubMed
    1. Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet 2016;387(10022):968-77. - PMC - PubMed
Yao 2017 {published data only}
    1. Yao JC, Guthrie KA, Moran C, Strosberg JR, Kulke MH, Chan JA, et al. Phase III prospective randomized comparison trial of depot octreotide plus interferon alfa-2b versus depot octreotide plus bevacizumab in patients with advanced carcinoid tumors: SWOG S0518. Journal of Clinical Oncology 2017;35(15):1695-703. - PMC - PubMed
Yao 2019 {published data only}
    1. Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet 2016;387(10022):968-77. - PMC - PubMed
    1. Yao JC, Oh DY, Qian J, Park YS, Herbst F, Ridolfi A, et al. Everolimus for the treatment of advanced gastrointestinal or lung nonfunctional neuroendocrine tumors in east asian patients: A subgroup analysis of the RADIANT-4 study. OncoTargets and Therapy 2019;12:1717-28. - PMC - PubMed
Zhang 2020 {published data only}
    1. Zhang P, Li J, Li J, Zhang X, Zhou J, Wang X, et al. Etoposide and cisplatin versus irinotecan and cisplatin as the first-line therapy for patients with advanced, poorly differentiated gastroenteropancreatic neuroendocrine carcinoma: A randomized phase 2 study. Cancer 2020;126 Suppl 9(Suppl 9):2086-92. - PMC - PubMed

References to studies excluded from this review

Caplin 2014 {published data only}
    1. Caplin ME, Ruszniewski PB, Pavel ME, Cwikla JB, Phan AT, Raderer M, et al. Progression-free survival (PFS) with lanreotide autogel/depot (LAN) in enteropancreatic NETs patients: The CLARINET extension study. Journal of Clinical Oncology 2014;32:4107.
Chan 2018 {published data only}
    1. Chan DL, Yao JC, Carnaghi C, Buzzoni R, Herbst F, Ridolfi A, et al. Systemic markers of inflammation in neuroendocrine tumors (NETs) and outcomes with everolimus: A pooled analysis from the randomized, phase 3 RADIANT-3 and RADIANT-4 trials. Neuroendocrinology 2018;Conference: 15th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease. Spain. 106:151.
Cwikla 2017 {published data only}
    1. Cwikla JB, Wolin EM, Pavel M, Phan AT, Raderer M, Sedláčková E, et al. Final analysis of time to subsequent disease progression/death in patients with metastatic enteropancreatic neuroendocrine tumours progressing under placebo and switched to lanreotide autogel/depot 120mg in the CLARINET open-label extension. Annals of Oncology 2017;28:v150.
Fazio 2018 {published data only}
    1. Fazio N, Carnaghi C, Buzzoni R, Valle J, Herbst F, Ridolfi A, et al. Relationship between metabolic toxicity and efficacy of everolimus in patients with neuroendocrine tumors (NETs): A pooled analysis from the randomized, phase 3 RADIANT-3 and RADIANT-4 trials. Neuroendocrinology 2018;Conference: 15th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease. Spain. 106:211.
Herrera Cabezón 2019 {published data only}
    1. Herrera Cabezón J, Sánchez Acedo P, Tarifa Castilla A, Zazpe Ripa C. Delayed gastric emptying following pancreatoduodenectomy: a Roux-en-Y gastrojejunostomy vs Billroth II gastrojejunostomy randomized study. Revista espanola de enfermedades digestivas 2019;111(1):34-9. - PubMed
Hörsch 2018 {published data only}
    1. Hörsch D, Kulke MH, Caplin ME, Anthony LB, Bergsland E, Oberg K, et al. Efficacy and safety of telotristat ethyl in patients with carcinoid syndrome inadequately controlled by somatostatin analogs: Analysis of the completed telestar extension period. Pancreas 2018;47:341-2.
Ito 2011 {published data only}
    1. Ito T, Okusaka T, Ikeda M, Tajima T, Kasuga A, Fujita Y, et al. Everolimus versus placebo in Japanese patients with advanced pancreatic neuroendocrine tumors (pNET): japanese subgroup analysis of RADIANT-3. Journal of Clinical Oncology 2011;29:289. - PMC - PubMed
Kulke 2019 {published data only}
    1. Kulke MH, Ruszniewski P, Van Cutsem E, Lombard-Bohas C, Valle JW, De Herder WW, et al. Erratum: a randomized, open-label, phase 2 study of everolimus in combination with pasireotide LAR or everolimus alone in advanced, well-differentiated, progressive pancreatic neuroendocrine tumors: COOPERATE-2 trial. Annals of Oncology 2019;30(11):1846. - PMC - PubMed
Lapuerta 2018 {published data only}
    1. Lapuerta P, Kulke MH, Pavel M, Biran T, Fleming R, Zacks JS, et al. Integrated safety analysis of telotristat ethyl in patients with carcinoid heart disease. Pancreas 2018;47:345.
Meyer 2016 {published data only}
    1. Meyer T, Qian W, Valle JW, Talbot D, Cunningham D, Reed N, et al. Capecitabine and streptozocin ± cisplatin for gastroenteropancreatic neuroendocrine tumours: predictors of long-term survival in the NET01 trial. Annals of Oncology 2016;27:vi136–48.
Miller 2020 {published data only}
    1. Miller C, Virgolini I, Kjaer A, Gronbaek H, Terve P, Shamsi K, et al. A novel read methodology to evaluate the optimal dose of 68Ga-satoreotide trizoxetan as a PET imaging agent in patients with GEP-NETs in a phase II clinical trial. Journal of Nuclear Medicine 2020;61(supplement 1):60. - PubMed
Okusaka 2012 {published data only}
    1. Okusaka T, Ito T, Ikeda M, Igarashi H, Morizane C, Nakachi K, et al. Phase III trial of everolimus in advanced pancreatic neuroendocrine tumors (RADIANT-3): overall population and Japanese subgroup analysis. Annals of Oncology 2012;23:xi15. - PMC - PubMed
Pavel 2015 {published data only}
    1. Pavel ME, Lombard‐Bohas C, Van Cutsem E, Lam DH, Kunz T, Brandt U, et al. Everolimus in patients with advanced, progressive pancreatic neuroendocrine tumors: overall survival results from the phase III RADIANT-3 study after adjusting for crossover bias. Journal of Clinical Oncology 2015;33(15 SUPPL. 1):4091.
Pavel 2018 (2) {published data only}
    1. Pavel M, Denecke T, Lahner H, Hörsch D, Rinke A, Koch A, et al. Disease control in progressive pancreatic and intestinal neuroendocrine tumours with combined treatment with lanreotide Autogel and temozolomide: The SONNET study. Oncology Research and Treatment 2018;41:263.
Pavel 2018 (3) {published data only}
    1. Pavel M, Denecke T, Lahner H, Hörsch D, Rinke A, Koch A, et al. Disease control in progressive pancreatic and intestinal neuroendocrine tumors by combined treatment with lanreotide autogel and temozolomide: The sonnet study. Neuroendocrinology 2018;106:202. - PMC - PubMed
Phan 2017 {published data only}
    1. Phan AT, Pavel M, Caplin M, Wolin EM, Mirakhur B, Massien C, et al. Long-term efficacy and safety with lanreotide autogel/depot (LAN) from CLARINET and Open-Label Extension (OLE) studies. Neuroendocrinology 2017;105:207.
Raderer 2015 {published data only}
    1. Raderer M, Caplin M, Pavel M, C'wikla JB, Phan A, Sedlackova E, et al. Update on antitumor acitivity of lanreotide autogel (LAN) treatment for enteropancreatic neuroendocrine tumours (NET): the CLARINET open-label extension (OLE) study. Austrian journal of clinical endocrinology and metabolism 2015;8(SONDERHEFT 1):9.
Salazar 2015 {published data only}
    1. Salazar R, Verslype C, Baudin E, Libutti SK, Yao JC, Buzzoni R, et al. Phase II studies of BEZ235 in patients with advanced pancreatic neuroendocrine tumors (pNET). Journal of Clinical Oncology 2015;33(15 SUPPL. 1):4102.
Singh 2018 (2) {published data only}
    1. Singh AN, Pal S, Mangla V, Kilambi R, George J, Dash NR, et al. Pancreaticojejunostomy: Does the technique matter? A randomized trial. Journal of Surgical Oncology 2018;117(3):389-96. - PubMed
Wolin 2013 {published data only}
    1. Wolin EM, Hainsworth JD, Hörsch D, Luppi G, Jehl V, Peeters M. Effect of open-label everolimus in patients with advanced neuroendocrine tumors after disease progression on somatostatin analog: A RADIANT-2 analysis. Pancreas 2013;42(2):385.
Wolin 2018 {published data only}
    1. Wolin EM, Pavel ME, Cwikla JB, Phan AT, Raderer M, Sedlackova E, et al. Final progression-free survival analyses for lanreotide autogel/depot 120 mg in metastatic enteropancreatic neuroendocrine tumors: the CLARINET extension study. Pancreas 2018;47(3):358‐9.
Yao 2015 {published data only}
    1. Yao JC, Oh DY, Qian J, Park YS, Herbst F, Ridolfi A, et al. Everolimus for the treatment of advanced gastrointestinal or lung nonfunctional neuroendocrine tumors in east asian patients: A subgroup analysis of the RADIANT-4 study. OncoTargets and Therapy 2015;12:1717-28. - PMC - PubMed

References to ongoing studies

NCT01744249 {published data only}
    1. NCT01744249. Sandostatin LAR and axitinib versus placebo in patients with advanced well-differentiated non-pancreatic neuroendocrine carcinomas [A phase II/III randomized double-blind study of sandostatin LAR in combination with axitinib versus sandostatin LAR with placebo in patients with advanced G1-G2 neuroendocrine tumours (WHO 2010) of non-pancreatic origin]. clinicaltrials.gov/show/NCT01744249 (first posted 6 December 2012).
NCT02246127 {published data only}
    1. NCT02246127. Efficacy and safety of everolimus and (streptozotocin- fluorouracil) given one upfront the other upon progression in advanced pancreatic neuroendocrine tumour [Randomized open label study to compare the efficacy and safety of everolimus followed by chemotherapy with streptozotocin- fluorouracil upon progression or the reverse sequence, in advanced progressive pancreatic neuroendocrine tumours]. clinicaltrials.gov/show/NCT02246127 (first posted 22 September 2014).
NCT03049189 {published data only}
    1. NCT03049189. Efficacy and safety of 177Lu-edotreotide PRRT in GEP-NET patients [A prospective, randomised, controlled, open-label, multicentre phase III study to evaluate efficacy and safety of peptide receptor radionuclide therapy (PRRT) with 177Lu-edotreotide compared to targeted molecular therapy with everolimus in patients with inoperable, progressive, somatostatin receptor-positive (SSTR+), neuroendocrine tumours of gastroenteric or pancreatic origin (GEP-NET)]. clinicaltrials.gov/show/NCT03049189 (first posted 9 February 2017).

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DePalo 2019
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Imaoka 2017
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