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Treatment of Intestinal NETs (Including Appendix)

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Neuroendocrine Neoplasia Management

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Abstract

Intestinal neuroendocrine tumors (NETs) consists of a heterogenous family of rare neoplasia, whose treatment may be difficult for physicians dealing with these patients. The prognosis of these diseases is affected by several factors, including tumor staging, grading, and expression of somatostatin receptors, which need to be assessed when planning a proper medical treatment. Surgery remains the sole therapeutic approach able to definitively cure these patients, unfortunately it is not always feasible with radical intent due to the presence of metastatic disease at time of initial diagnosis. In these patients, a medical therapeutic approach is required. The first-line therapy is usually represented by somatostatin analogs octreotide and lanreotide, which provide excellent symptoms control in functioning tumors and are able to inhibit tumor growth in the majority of slow-growing low-grade tumors. Peptide receptor radionuclide therapy with [177Lu]Lu-DOTA-TATE has showed to arrest disease progression in approximatively three-fourths of patients who progressed under therapy with the analogs, with a promising probability to induce objective tumor response which is reported in 30% of patients, and a significant positive impact on patients’ survival and quality of life. Given this favorable data, [177Lu]Lu-DOTA-TATE is approved worldwide for progressive gastro-entero-pancreatic NETs with grading G1 and G2 which express somatostatin receptors, usually administered as second-line treatment after failure of somatostatin analogs. In addition, the inhibitor of the mammalian target of rapamycin everolimus may be considered for the treatment of advanced, progressive disease. Its capability to induce tumor regression is low (5–10%); however, a significant prolong in progression-free survival has been reported by randomized controlled trials. Systemic chemotherapy has a negligible role for the treatment of intestinal NETs, unless a rare, aggressive poorly differentiated, rapidly growing tumor is present.

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References

  1. Magi L, Mazzuca F, Rinzivillo M, Arrivi G, Pilozzi E, Prosperi D, Iannicelli E, Mercantini P, Rossi M, Pizzichini P, Laghi A, Signore A, Marchetti P, Annibale B, Panzuto F. Multidisciplinary management of neuroendocrine neoplasia: a real-world experience from a referral center. J Clin Med. 2019;8(6).

    Google Scholar 

  2. WHO. Classification of tumours. In: Digestive system tumours, vol. 1. 5th ed. Lyon: IARC; 2019.

    Google Scholar 

  3. Modlin IM, Oberg K, Chung DC, Jensen RT, de Herder WW, Thakker RV, Caplin M, Delle Fave G, Kaltsas GA, Krenning EP, Moss SF, Nilsson O, Rindi G, Salazar R, Ruszniewski P, Sundin A. Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol. 2008;9(1):61–72.

    Article  CAS  Google Scholar 

  4. Panzuto F, Nasoni S, Falconi M, Corleto VD, Capurso G, Cassetta S, Di Fonzo M, Tornatore V, Milione M, Angeletti S, Cattaruzza MS, Ziparo V, Bordi C, Pederzoli P, Delle FG. Prognostic factors and survival in endocrine tumor patients: comparison between gastrointestinal and pancreatic localization. Endocr Relat Cancer. 2005;12(4):1083–92.

    Article  Google Scholar 

  5. Strosberg J, Gardner N, Kvols L. Survival and prognostic factor analysis of 146 metastatic neuroendocrine tumors of the mid-gut. Neuroendocrinology. 2009;89(4):471–6.

    Article  CAS  Google Scholar 

  6. Panzuto F, Campana D, Fazio N, Brizzi MP, Boninsegna L, Nori F, Di Meglio G, Capurso G, Scarpa A, Dogliotti L, De Braud F, Tomassetti P, Delle Fave G, Falconi M. Risk factors for disease progression in advanced jejunoileal neuroendocrine tumors. Neuroendocrinology. 2012;96(1):32–40.

    Article  CAS  Google Scholar 

  7. Arnold R, Rinke A, Klose KJ, et al. Octreotide versus octreotide plus interferon-alpha in endocrine gastroenteropancreatic tumors: a randomized trial. Clin Gastroenterol Hepatol. 2005;3:761–71.

    Article  CAS  Google Scholar 

  8. Yao JC, Guthrie KA, Moran C, 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. J Clin Oncol. 2017;35:1695–703.

    Article  CAS  Google Scholar 

  9. Faiss S, Pape UF, Böhmig M, Dörffel Y, Mansmann U, Golder W, Riecken EO, Wiedenmann B, International Lanreotide and Interferon Alfa Study Group. Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors—the International Lanreotide and Interferon Alfa Study Group. J Clin Oncol. 2003;21(14):2689–96.

    Article  CAS  Google Scholar 

  10. Kölby L, Persson G, Franzén S, Ahrén B. Randomized clinical trial of the effect of interferon alpha on survival in patients with disseminated midgut carcinoid tumours. Br J Surg. 2003;90(6):687–93.

    Article  Google Scholar 

  11. Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Bläker M, Harder J, Arnold C, Gress T, Arnold R, 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):4656–63.

    Article  CAS  Google Scholar 

  12. Caplin ME, Pavel M, Ćwikła JB, Phan AT, Raderer M, Sedláčková E, Cadiot G, Wolin EM, Capdevila J, Wall L, Rindi G, Langley A, Martinez S, Blumberg J. Ruszniewski P; CLARINET investigators. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014;371(3):224–33.

    Article  Google Scholar 

  13. Strosberg JR, Halfdanarson TR, Bellizzi AM, Chan JA, Dillon JS, Heaney AP, Kunz PL, O’Dorisio TM, Salem R, Segelov E, Howe JR, Pommier RF, Brendtro K, Bashir MA, Singh S, Soulen MC, Tang L, Zacks JS, Yao JC, Bergsland EK. The north American neuroendocrine tumor society consensus guidelines for surveillance and medical management of midgut neuroendocrine tumors. Pancreas. 2017;46(6):707–14.

    Article  Google Scholar 

  14. Niederle B, Pape UF, Costa F, Gross D, Kelestimur F, Knigge U, Öberg K, Pavel M, Perren A, Toumpanakis C, O’Connor J, O’Toole D, Krenning E, Reed N, Kianmanesh R, Vienna Consensus Conference Participants. ENETS consensus guidelines update for neuroendocrine neoplasms of the jejunum and ileum. Neuroendocrinology. 2016;103(2):125–38.

    Article  CAS  Google Scholar 

  15. Broder MS, Beenhouwer D, Strosberg JR, Neary MP, Cherepanov D. Gastrointestinal neuroendocrine tumors treated with high dose octreotide-LAR: a systematic literature review. World J Gastroenterol. 2015;21(6):1945–55.

    Article  CAS  Google Scholar 

  16. Lamberti G, Faggiano A, Brighi N, Tafuto S, Ibrahim T, Brizzi MP, Pusceddu S, Albertelli M, Massironi S, Panzuto F, Badalamenti G, Riccardi F, Butturini G, Gelsomino F, De Divitiis C, Modica R, Bongiovanni A, La Salvia A, Torchio M, Colao A, Ferone D, Campana D. Nonconventional doses of somatostatin analogs in patients with progressing well-differentiated neuroendocrine tumor. J Clin Endocrinol Metab. 2020;105(1):dgz035. https://doi.org/10.1210/clinem/dgz035.

    Article  PubMed  Google Scholar 

  17. Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, Mittra E, Kunz PL, Kulke MH, Jacene H, Bushnell D, O’Dorisio TM, Baum RP, Kulkarni HR, Caplin M, Lebtahi R, Hobday T, Delpassand E, Van Cutsem E, Benson A, Srirajaskanthan R, Pavel M, Mora J, Berlin J, Grande E, Reed N, Seregni E, Öberg K, Lopera Sierra M, Santoro P, Thevenet T, Erion JL, Ruszniewski P, Kwekkeboom D, Krenning E, NETTER-1 Trial Investigators. Phase 3 trial of 177Lu-Dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376(2):125–35.

    Article  CAS  Google Scholar 

  18. Brabander T, van der Zwan WA, Teunissen JJM, Kam BLR, Feelders RA, de Herder WW, van Eijck CHJ, Franssen GJH, Krenning EP, Kwekkeboom DJ. Long-term efficacy, survival, and safety of [177Lu-DOTA0,Tyr3] octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors. Clin Cancer Res. 2017;23(16):4617–24. https://doi.org/10.1158/1078-0432.CCR-16-2743.

    Article  CAS  PubMed  Google Scholar 

  19. Bodei L, Kidd M, Paganelli G, Grana CM, Drozdov I, Cremonesi M, Lepensky C, Kwekkeboom DJ, Baum RP, Krenning EP, Modlin IM. Long-term tolerability of PRRT in 807 patients with neuroendocrine tumours: the value and limitations of clinical factors. Eur J Nucl Med Mol Imaging. 2015;42(1):5–19.

    Article  CAS  Google Scholar 

  20. Bodei L, Modlin IM, Luster M, Forrer F, Cremonesi M, Hicks RJ, et al. Myeloid neoplasms after chemotherapy and PRRT: myth and reality. Endocr Relat Cancer. 2016;23:C1–7.

    Article  CAS  Google Scholar 

  21. Strosberg J, Kunz PL, Hendifar A, Yao J, Bushnell D, Kulke MH, Baum RP, Caplin M, Ruszniewski P, Delpassand E, Hobday T, Verslype C, Benson A, Srirajaskanthan R, Pavel M, Mora J, Berlin J, Grande E, Reed N, Seregni E, Paganelli G, Severi S, Morse M, Metz DC, Ansquer C, Courbon F, Al-Nahhas A, Baudin E, Giammarile F, Taïeb D, Mittra E, Wolin E, O'DorisioTM, Lebtahi R, Deroose CM, Grana CM, Bodei L, Öberg K, Polack BD, He B, Mariani MF, Gericke G, Santoro P, Erion JL, Ravasi L, Krenning E; NETTER-1 Study Group. Impact of liver tumour burden, alkaline phosphatase elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate: an analysis of the NETTER-1 study. Eur J Nucl Med Mol Imaging. 2020. https://doi.org/10.1007/s00259-020-04709-x.

  22. Strosberg J, Wolin E, Chasen B, Kulke M, Bushnell D, Caplin M, Baum RP, Kunz P, Hobday T, Hendifar A, Oberg K, Sierra ML, Thevenet T, Margalet I, Ruszniewski P, Krenning E, NETTER-1 Study Group. 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):2578–84.

    Article  CAS  Google Scholar 

  23. Sorbye H, Kong G, Grozinsky-Glasberg S. PRRT in high-grade gastroenteropancreatic neuroendocrine neoplasms (WHO G3). Endocr Relat Cancer. 2020;27(3):R67–77. https://doi.org/10.1530/ERC-19-0400.

    Article  CAS  PubMed  Google Scholar 

  24. Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, Winkler RE, Klimovsky J, Lebwohl D, Jehl V, Wolin EM, Öberg K, Van Cutsem E, Yao JC, RADIANT-2 Study Group. 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):2005–12. https://doi.org/10.1016/S0140-6736(11)61742-X.

    Article  CAS  PubMed  Google Scholar 

  25. Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, Tomasek J, Raderer M, Lahner H, Voi M, Pacaud LB, Rouyrre N, Sachs C, Valle JW, Fave GD, Van Cutsem E, Tesselaar M, Shimada Y, Oh DY, Strosberg J, Kulke MH, Pavel ME, RAD001 in Advanced Neuroendocrine Tumours, Fourth Trial (RADIANT-4) 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. https://doi.org/10.1016/S0140-6736(15)00817-X.

    Article  CAS  PubMed  Google Scholar 

  26. Dahan L, Bonnetain F, Rougier P, Raoul JL, Gamelin E, Etienne PL, Cadiot G, Mitry E, Smith D, Cvitkovic F, Coudert B, Ricard F, Bedenne L, Seitz JF, Fédération Francophone de Cancérologie Digestive (FFCD); Digestive Tumors Group of the Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC). Phase III trial of chemotherapy using 5-fluorouracil and streptozotocin compared with interferon alpha for advanced carcinoid tumors: FNCLCC-FFCD 9710. Endocr Relat Cancer. 2009;16(4):1351–61. https://doi.org/10.1677/ERC-09-0104.

    Article  CAS  PubMed  Google Scholar 

  27. Cives M, Pelle E, Quaresmini D, Mandriani B, Tucci M, Silvestris F. The role of cytotoxic chemotherapy in well-differentiated gastroenteropancreatic and lung neuroendocrine tumors. Curr Treat Options Oncol. 2019;20(9):72. Review. https://doi.org/10.1007/s11864-019-0669-7.

    Article  PubMed  Google Scholar 

  28. Lamarca A, Elliott E, Barriuso J, Backen A, McNamara MG, Hubner R, Valle JW. Chemotherapy for advanced non-pancreatic well-differentiated neuroendocrine tumours of the gastrointestinal tract, a systematic review and meta-analysis: a lost cause? Cancer Treat Rev. 2016;44:26–41. Epub 2016 Jan 25. Review. https://doi.org/10.1016/j.ctrv.2016.01.005.

    Article  PubMed  Google Scholar 

  29. Dermine S, Palmieri LJ, Lavolé J, Barré A, Dohan A, Abou Ali E, Cottereau AS, Gaujoux S, Brezault C, Chaussade S, Coriat R. Non-pharmacological therapeutic options for liver metastases in advanced neuroendocrine tumors. J Clin Med. 2019;8(11):E1907. https://doi.org/10.3390/jcm8111907.

    Article  CAS  PubMed  Google Scholar 

  30. Mohan H, Nicholson P, Winter DC, O’Shea D, O’Toole D, Geoghegan J, Maguire D, Hoti E, Traynor O, Cantwell CP. Radiofrequency ablation for neuroendocrine liver metastases: a systematic review. J Vasc Interv Radiol. 2015;26(7):935–942.e1. https://doi.org/10.1016/j.jvir.2014.12.009.

    Article  PubMed  Google Scholar 

  31. de Mestier L, Zappa M, Hentic O, Vilgrain V, Ruszniewski P. Liver transarterial embolizations in metastatic neuroendocrine tumors. Rev Endocr Metab Disord. 2017;18(4):459–71. https://doi.org/10.1007/s11154-017-9431-2.

    Article  PubMed  Google Scholar 

  32. Maire F, Lombard-Bohas C, O'Toole D, Vullierme MP, Rebours V, Couvelard A, Pelletier AL, Zappa M, Pilleul F, Hentic O, Hammel P, Ruszniewski P. Hepatic arterial embolization versus chemoembolization in the treatment of liver metastases from well-differentiated midgut endocrine tumors: a prospective randomized study. Neuroendocrinology. 2012;96(4):294–300. https://doi.org/10.1159/000336941.

    Article  CAS  PubMed  Google Scholar 

  33. Tchana-Sato V, Detry O, et al. Carcinoid tumor of the appendix: a consecutive series from 1237 appendectomies. World J Gastroenterol. 2006;12:6699–701.

    Article  Google Scholar 

  34. Pape UF, Niederle B, et al. ENETS consensus guidelines for neuroendocrine neoplasms of the appendix (excluding globet cell carcinomas). Neuroendocrinology. 2016;103:144–52.

    Article  CAS  Google Scholar 

  35. Brighi N, La Rosa S, Rossi G, Grillo F, Pusceddu S, Rinzivillo M, Spada F, Tafuto S, Massironi S, Faggiano A, Antonuzzo L, Santini D, Sessa F, Maragliano R, Gelsomino F, Albertelli M, Vernieri C, Panzuto F, Fazio N, De Divitiis C, Lamberti G, Colao A, Fave GD, Campana D, Brighi N, La Rosa S, Rossi G, Grillo F, Pusceddu S, Rinzivillo M, Spada F, Tafuto S, Massironi S, Faggiano A, Antonuzzo L, Santini D, Sessa F, Maragliano R, Gelsomino F, Albertelli M, Vernieri C, Panzuto F, Fazio N, De Divitiis C, Lamberti G, Colao A, Fave GD, Campana D. Morphological factors related to nodal metastases in neuroendocrine tumors of the appendix: a multicentric retrospective study. Ann Surg. 2020;271(3):527–33.

    Article  Google Scholar 

  36. Toumpanakis C, Fazio N, Tiensuu JE, Hörsch D, Pascher A, Reed N, O'Toole D, Nieveen van Dijkum E, Partelli S, Rinke A, Kos-Kudla B, Costa F, Pape U, Grozinsky-Glasberg S, Scoazec J, The ENETS 2016 Munich Advisory Board Participants. Unmet needs in appendiceal neuroendocrine neoplasms. Neuroendocrinology. 2019;108:37–44.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Digestive Disease Unit, Sant’Andrea University Hospital, ENETS Center of Excellence, Rome, Rome, Italy

    Francesco Panzuto & Maria Rinzivillo

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  1. Francesco Panzuto
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  2. Maria Rinzivillo
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Correspondence to Francesco Panzuto .

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Editors and Affiliations

  1. Oncology Unit, Humanitas Gavazzeni, Bergamo, Italy

    Giordano Beretta

  2. ASST-Spedali Civili, University of Brescia, BRESCIA, Brescia, Italy

    Alfredo Berruti

  3. Nuclear Medicine, Humanitas Gavazzeni, BERGAMO, Bergamo, Italy

    Emilio Bombardieri

  4. GIT Med Oncology & Neuroendocrine Tumors, European Institute of Oncology, Milan, Italy

    Nicola Fazio

  5. General Surgery Unit, Humanitas Gavazzeni, Bergamo, Italy

    Orlando Goletti

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Panzuto, F., Rinzivillo, M. (2021). Treatment of Intestinal NETs (Including Appendix). In: Beretta, G., Berruti, A., Bombardieri, E., Fazio, N., Goletti, O. (eds) Neuroendocrine Neoplasia Management. Springer, Cham. https://doi.org/10.1007/978-3-030-72830-4_15

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