Navigating the treatment landscape in gastroenteropancreatic neuroendocrine neoplasms Review article
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Published:
Feb 23, 2019
Keywords:
gastroenteropancreatic neuroendocrine tumors, treatment options, neuroendocrine tumors
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Abstract
Gastroenteropancreatic neuroendocrine neoplasms are a large and very diverse group of neoplasms. They are becoming a burning clinical problem because of increasing frequency and diagnosis in the advanced state. The treatment landscape has been changed over the last years. Treatment choice depends on many factors such as the tumor’s type, location, aggressiveness, and hormone-producing capabilities. The main goals of treatment are long-term symptomatic control, antitumor effect, and improvement of the quality of life. The results of the PROMID and CLARINET trials have augmented fundamental position of somatostatin analogs. Our understanding of the biology, genetics of the neoplasms has improved considerably in the last several decades and the spectrum of available therapeutic options is rapidly expanded. The current evidence-based treatment options include everolimus, sunitinib, peptide receptor radionuclide therapy, and chemotherapy. Treatment practice changed as a result of high-quality phase 3 clinical trials which shaped current guidelines; multiple retrospective studies which raised new questions and attempted to fill some of the data gaps. Here we review the treatment options for gastroenteropancreatic neuroendocrine neoplasms, discussing important diagnosis and biomarker-related factors, safety of therapy with special insight into cardiac safety, as well we looked at promising investigative therapies.
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1.
Rogowski W, Wachuła E, Sulżyc-Bielicka V. Navigating the treatment landscape in gastroenteropancreatic neuroendocrine neoplasms. OncoReview [Internet]. 2019Feb.23 [cited 2024May5];9(1(33):31-9. Available from: https://www.journalsmededu.pl/index.php/OncoReview/article/view/411
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ENDOCRINOLOGY IN ONCOLOGY
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Copyright: © Medical Education sp. z o.o. This is an Open Access article distributed under the terms of the Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). License (https://creativecommons.org/licenses/by-nc/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.
Address reprint requests to: Medical Education, Marcin Kuźma (marcin.kuzma@mededu.pl)
References
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26. Caplin ME, Pavel M, Ćwikła JB, et al. Anti-tumour effects of lanreotide for pancreatic and intestinal neuroendocrine tumours: the CLARINET open-label extension study. Endocr Relat Cancer 2016; 23(3): 191-199.
27. Strosberg J, El-Haddad G, Wolin E et al. Phase 3 trial of 177Lu-Dotatate for midgut neuroendocrine tumors. N Engl J Med 2017; 376(2): 125-135.
28. Boerman OC, Oyen WJG, Corstens FHM. Between the Scylla and Charybdis of peptide radionuclide therapy: hitting the tumor and saving the kidney. Eur J Nucl Med 2001; 28: 1447-1449.
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35. Lutathera. Summary of product characteristics. [online: www.ema.org] (Accessed on 17.01.2019).
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37. Claringbold PG, Price RA, Turner JH. Phase I-II study of radiopeptide 177Lu-octreotate in combination with capecitabine and temozolomide in advanced low-grade neuroendocrine tumors. Cancer Biother Radiopharm 2012; 27(9): 561-569.
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49. Pavel ME, Hainsworth JD, Baudin E et al. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet 2011; 378(9808): 2005-2012.
50. Yao JC, Shah MH, Ito T et al. Everolimus for Advanced Pancreatic Neuroendocrine Tumors. N Engl J Med. 2011; 364(6): 514-523.
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2. Lloyd RV, Osamura RY, Klöppel G. (ed). WHO Classification of Tumours of Endocrine Organs. 4th ed. International Agency for Research on Cancer, Lyon 2017; 6: 210-239.
3. Milione M, Maisonneuve P, Spada F et al. The Clinicopathologic Heterogeneity of Grade 3 Gastroenteropancreatic Neuroendocrine Neoplasms: Morphological Differentiation and Proliferation Identify Different Prognostic Categories. Neuroendocrinology 2017; 104: 85-93.
4. Kos-Kudła B, Blicharz- Dolniak B, Strzelczyk J et al. Diagnostic and therapeutic guidelines for gastro-entero pancreatic neuroendocrine neoplasms (recommended by the Polish Network of Neuroendocrine Tumours). Endokrynol Pol 2017; 68(2): 79-110.
5. Basturk O, Yang Z, Tang LH et al. The high-grade (WHO G3) pancreatic neuroendocrine tumor category is morphologically and biologically heterogeneous and includes both well differentiated and poorly differentiated neoplasms. Am J Surg Pathol. 2015; 39(5): 683-90.
6. Lipiński M, Rydzewska G, Foltyn W et al. Gastroduodenal neuroendocrine neoplasms, including gastrinoma – management guidelines (recommended by the Polish Network of Neuroendocrine Tumours). Endokrynol Pol 2017; 68(2): 138-153.
7. Delle Fave G, O’Toole D, Sundin A et al. ENETS Consensus Guidelines Update for Gastroduodenal Neuroendocrine Neoplasms. Neuroendocrinology 2016; 103(2): 119-24.
8. Marotta V, Nuzzo V, Ferrara T et al. Limitations of chromogranin A in clinical practice. Biomarkers 2012; 17(2): 186-191.
9. Massironi S, Rossi RE, Casazza G et al. Chromogranin A in diagnosing and monitoring patients with gastroenteropancreatic neuroendocrine neoplasms: a large series from a single institution. Neuroendocrinology 2014; 100(2-3): 240-249.
10. Shanahan MA, Salem A, Fisher A et al. Chromogranin A predicts survival for resected pancreatic neuroendocrine tumors. J Surg Res 2016; 201(1): 38-43.
11. Welin S, Strisberg M, Cunningham J et al. Elevated plasma chromogranin A is the first indication of recurrence in radically operated midgut carcinoid tumors. Neuroendocrinology 2009; 89(3): 302-307.
12. Rogowski W, Wachuła E, Lewczuk A et al. Baseline chromogranin A and its dynamics are prognostic markers in gastroenteropancreatic neuroendocrine tumors. Future Oncol 2017; 13(12): 1069-1079.
13. Kidd M, Bodei L, Modlin IM. Chromogranin A: any relevance in neuroendocrine tumors? Curr Opin Endocrinol Diabetes Obes 2016; 23(1): 28-37.
14. Modlin IM, Gustafsson BI, Moss SF et al. Chromogranin A – biological function and clinical utility in neuro endocrine tumor disease. Ann Surg Oncol 2010; 17(9): 2427-2443.
15. Oberg K. Chemotherapy and biotherapy in neuroendocrine tumors. Curr Opin Oncol 1993; 5(1): 110-120.
16. Oberg K, Kvols L, Caplin M et el. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol 2004; 15(6): 966-973.
17. Oberg K, Norheim I, Theodorsson E et al. The effects of octreotide on basal and stimulated hormone levels in patients with carcinoid syndrome. Clin Endocrinol Metab 1989; 68(4): 796-800.
18. Wymenga AN, Eriksson B, Salmela PI et al. Efficacy and safety of prolonged-release lanreotide in patients with gastrointestinal neuroendocrine tumors and hormone-related symptoms. J Clin Oncol 1999; 17(4): 1111.
19. Phan AT. Metastatic pancreatic neuroendocrine tumors (pNET): placing current findings into perspective. Cancer Treat Rev 2013; 39(1): 3-9.
20. O’Toole D, Ducreux M, Bommelaer G et al. Treatment of carcinoid syndrome: a prospective crossover evaluation of lanreotide versus octreotide in terms of efficacy, patient acceptability, and tolerance. Cancer 2000; 15; 88(4): 770-776.
21. Orlewska E, Kos-Kudła B, Kamiński G et al. LanroNET – A Non-Interventional Prospective Study to Assess the Resource Utilisation and Cost of Lanreotide Autogel 120 mg in the Population of Polish Patients with Symptomatic Neuroendocrine Tumours. Endokrynol Pol 2018; 69(5): 567-573.
22. Xu Y, Shih YCT, Leary CC et al. Dosing patterns of octreotide LAR among elderly patients with neuroendocrine tumors: Analysis of the SEER-Medicare database. J Clin Oncol 2012; 30: e14550a.
23. Riechelmann RP, Pereira AA, Rego JF et al. Refractory carcinoid syndrome: a review of treatment options. Ther Adv Med Oncol 2017; 9(2): 127-137.
24. Chalabi M, Duluc C, Caron P et al. Somatostatin analogs: does pharmacology impact antitumor efficacy? Trends in endocrinology and metabolism: Trends Endocrinol Metab 2014; 25(3): 115-127.
25. Rinke A, Müller HH, Schade-Brittinger C et al. PROMID Study Group. 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. J Clin Oncol 2009; 27(28): 4656-4663.
26. Caplin ME, Pavel M, Ćwikła JB, et al. Anti-tumour effects of lanreotide for pancreatic and intestinal neuroendocrine tumours: the CLARINET open-label extension study. Endocr Relat Cancer 2016; 23(3): 191-199.
27. Strosberg J, El-Haddad G, Wolin E et al. Phase 3 trial of 177Lu-Dotatate for midgut neuroendocrine tumors. N Engl J Med 2017; 376(2): 125-135.
28. Boerman OC, Oyen WJG, Corstens FHM. Between the Scylla and Charybdis of peptide radionuclide therapy: hitting the tumor and saving the kidney. Eur J Nucl Med 2001; 28: 1447-1449.
29. Strosberg J, Wolin E, Chasen B et al. Health-Related Quality of Life in Patients With Progressive Midgut Neuroendocrine Tumors Treated With 177Lu-Dotatate in the Phase III NETTER-1 Trial. J Clin Oncol 2018; 36(25): 2578-2584.
30. Kolasińska-Ćwikła A, Łowczak A, Maciejkiewicz KM et al. Peptide receptor radionuclide therapy for advanced gastroenteropancreatic neuroendocrine tumors – from oncology perspective. Nucl Med Rev Cent East Eur 2018; 21(2).
31. Rogowski W, Wachuła E, Lewczuk A et al. Long-term efficacy of (90)Y-DOTATATE in patients with nonresectable pancreatic and small bowel neuroendocrine neoplasms. Future Oncol 2016; 12: 1877-1885.
32. Bodei L, Kidd MS, Singh A et al. PRRT genomic signature in blood for prediction of 177Lu-octreotate efficacy. Eur J Nucl Med Mol Imaging 2018; 45(7): 1155-1169.
33. Panzuto F, Rinzivillo M, Fazio N et al. Real-world study of everolimus in advanced progressive neuroendocrine tumors. Oncologist 2014; 19(9): 966-974.
34. Pavel M, O’Toole D, Costa F et al. ENETS Consensus Guidelines Update for the Management of Distant Metastatic Disease of Intestinal, Pancreatic, Bronchial Neuroendocrine Neoplasms (NEN) and NEN of Unknown Primary Site. Neuroendocrinology 2016; 103(2): 172-185.
35. Lutathera. Summary of product characteristics. [online: www.ema.org] (Accessed on 17.01.2019).
36. Yordanova A, Wicharz MM, Mayer K et al. The Role of Adding Somatostatin Analogues to Peptide Receptor Radionuclide Therapy as a Combination and Maintenance Therapy. Clin Cancer Res 2018; 24(19): 4672-4679.
37. Claringbold PG, Price RA, Turner JH. Phase I-II study of radiopeptide 177Lu-octreotate in combination with capecitabine and temozolomide in advanced low-grade neuroendocrine tumors. Cancer Biother Radiopharm 2012; 27(9): 561-569.
38. Claringbold PG, Turner JH. Pancreatic Neuroendocrine Tumor Control: Durable Objective Response to Combination 177Lu-Octreotate-Capecitabine-Temozolomide Radiopeptide Chemotherapy. Neuroendocrinology 2016; 103(5): 432-439.
39. Claringbold PG, Turner JH. NeuroEndocrine Tumor Therapy with Lutetium-177-octreotate and Everolimus (NETTLE): A Phase I Study. Cancer Biother Radiopharm 2015; 30(6): 261-269.
40. Cives M, Ghayouri M, Morse B et al. Analysis of potential response predictors to capecitabine/temozolomide in metastatic pancreatic neuroendocrine tumors. Endocr Relat Cancer 2016; 23(9): 759-767.
41. Crespo G, Jiménez-Fonseca P, Custodio A et al. Capecitabine and temozolomide in grade ½ neuroendocrine tumors: a Spanish multicenter experience. Future Oncol 2017; 13(7): 615-624.
42. Strosberg JR, Fine RL, Choi J et al. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer 2011; 117(2): 268-275.
43. Peixoto RD, Noonan K, Kennecke HF et al. Outcomes of patients treated with capecitabine and temozolamide for advanced pancreatic neuroendocrine tumors (pNETs) and non-pNETs. J Gastrointest Oncol 2014; 5(4): 247-252.
44. Chauhan A, Farooqui Z, Murray LA et al. Capecitabine and Temozolomide in Neuroendocrine Tumor of Unknown Primary. J Oncol 2018; 2018: 3519247.
45. Owen DH, Alexander AJ, Konda B et al. Combination therapy with capecitabine and temozolomide in patients with low and high grade neuroendocrine tumors, with an exploratory analysis of O(6)-methylguanine DNA methyltransferase as a biomarker for response. Oncotarget 2017; 8(61): 104046-104056.
46. Ramirez RA, Beyer DT, Chauhan A et al. The Role of Capecitabine/Temozolomide in Metastatic Neuroendocrine Tumors. Oncologist 2016; 21(6): 671-675.
47. Lu Y, Zhao Z, Wang J et al. Safety and efficacy of combining capecitabine and temozolomide (CAPTEM) to treat advanced neuroendocrine neoplasms: A meta-analysis. Medicine (Baltimore) 2018; 97(41): e12784.
48. Pamela LK, Paul JC, Halla N et al. A randomized study of temozolomide or temozolomide and capecitabine in patients with advanced pancreatic neuroendocrine tumors: A trial of the ECOG-ACRIN Cancer Research Group (E2211). J Clin Oncol 2018; 36(15): 4004-4004.
49. Pavel ME, Hainsworth JD, Baudin E et al. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet 2011; 378(9808): 2005-2012.
50. Yao JC, Shah MH, Ito T et al. Everolimus for Advanced Pancreatic Neuroendocrine Tumors. N Engl J Med. 2011; 364(6): 514-523.
51. U.S. National Library of Medicine. NCT02246127. Efficacy and Safety of Everolimus and (STZ-5FU) Given One Upfront the Other Upon Progression in Advanced pNET (SEQTOR). Available from: Clinicaltrials.gov. (Accessed on 17.01.2019).
52. Yao JC, Pavel M, Lombard-Bohas C et al. Everolimus for the Treatment of Advanced Pancreatic Neuroendocrine Tumors: Overall Survival and Circulating Biomarkers From the Randomized, Phase III RADIANT-3 Study. J Clin Oncol 2016; 34(32): 3906-3913.
53. Pavel ME, Singh S, Strosberg JR 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 Oncol 2017; 18(10): 1411-1422.
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