tumorsMalignant tumoursMalignant tumours2224-50572587-6813Rosoncoweb10.18027/2224-5057-2019-9-4-49-58tumors-685Research ArticleОБЗОРЫ И АНАЛИТИКАREVIEWS AND ANALYSISПрименение таргетной терапии в лечении пациентов с нейроэндокринными опухолями желудочнокишечного тракта и поджелудочной железыTargeted therapy for gastrointestinal and pancreatic neuroendocrine tumorsИсянгуловаА. З.IsyangulovaA.  Z.

Алина З. Исянгулова, врач-онколог

Казань

Alina Z. Isyangulova, oncologist

Kazan

a.isyangulova@rambler.ruХасановР. Ш.KhasanovR.  Sh.

Рустем Ш. Хасанов, д. м. н., член-корр. РАН, профессор, директор

директор 

Казань

Rustem Sh. Khasanov, MD, PhD, DSc, Corresponding Member of the RAS, Prof., Director 

Director 

Kazan

ЕникеевР. Ф.EnikeevR.  F.

Рафаэль Ф. Еникеев, к. м. н., врач-онколог

Казань

Rafael F. Enikeev, MD, PhD, oncologist

Kazan

ГАУЗ «Республиканский клинический онкологический диспансер» МЗ Республики Татарстан; Казанская государственная медицинская академия — филиал ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Минздрава РоссииРоссияRepublican Clinical Cancer Center; Kazan State Medical Academy — Branch Campus of the Russian Medical Academy of Continuous Professional EducationRussian FederationКазанская государственная медицинская академия — филиал ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Минздрава России; Приволжский филиал ФГБУ «НМИЦ онкологии им. Н.Н. Блохина» Минздрава РоссииРоссияKazan State Medical Academy — Branch Campus of the Russian Medical Academy of Continuous Professional Education; Volga branch «N. N. Blokhin National Medical Research Center of Oncology»Russian FederationГАУЗ «Республиканский клинический онкологический диспансер» МЗ Республики ТатарстанРоссияRepublican Clinical Cancer CenterRussian Federation201903032020944958Copyright © Исянгулова А.З., Хасанов Р.Ш., Еникеев Р.Ф., 20202020Исянгулова А.З., Хасанов Р.Ш., Еникеев Р.Ф.Isyangulova A.Z., Khasanov R.S., Enikeev R.F.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.malignanttumors.org/jour/article/view/685

Проблема нейроэндокринных опухолей (НЭО) стала углубленно изучаться только в последние годы. Возросшее внимание к ней обусловлено увеличением частоты обнаружения НЭО в связи с совершенствованием методов диагностики.

Ограниченная эффективность химиотерапии у высокодифференцированных распространенных метастатических НЭО желудочно-кишечного тракта (ЖКТ) и поджелудочной железы (ПЖ) подчеркивает необходимость поиска новых и более эффективных вариантов лекарственного лечения.

Недавние исследования специфических биологических особенностей НЭО привели к разработке новых целевых методов лечения, которые учитывают высокую васкуляризацию и гиперэкспрессию специфических факторов роста и родственных рецепторов тирозинкиназы. Таким образом, с изучением сигнальных путей mTOR TSC2, PTEN и PIK3CA открываются новые возможности в лечении пациентов с НЭО ЖКТ и ПЖ, особенно неоперабельных и метастатических форм. Таргетная терапия, которая специфически ингибирует рецепторы факторов роста и связанные с ними сигнальные пути, является многообещающим подходом лекарственного лечения НЭО ЖКТ и ПЖ.

В этом обзоре кратко изложено состояние и перспективы использования таргетной терапии, описаны клинические исследования в лечении НЭО ЖКТ и ПЖ.

Extensive investigation of neuroendocrine tumors (NETs) has only started in recent years. The increased attention to this issue is due to the more frequent detection of NETs as a result of diagnostic methods improvement.

The limited effectiveness of chemotherapy for well-differentiated advanced metastatic NETs of gastrointestinal tract (GIT) and pancreas demonstrates the need for development of the new and more effective treatment options.

Recent studies on specific biological features of NETs have led to the development of the new targeted therapies which take into account high vascularization and overexpression of specific growth factors and related tyrosine kinase receptors. Thus, studying the mTOR TSC2, PTEN and PIK3CA signaling pathways opens up the new opportunities in the treatment of gastrointestinal or pancreatic NETs, especially in case of inoperable or metastatic tumors. Targeted therapy, which specifically inhibits growth factor receptors and related signaling pathways, is a promising approach to drug therapy for patients with gastrointestinal or pancreatic NETs.

This review summarizes the state of the art and prospects for using targeted therapy, and describes clinical studies in the treatment of gastrointestinal and pancreatic NETs.

нейроэндокринная опухольтаргетная терапиякарциноидрак поджелудочной железырак желудочно-кишечного трактаneuroendocrine tumortargeted therapycarcinoidpancreatic cancergastrointestinal cancerReferencesDiagnosis and management of gastrointestinal neuroendocrine tumors: an evidence-based Canadian consensus / Singh S, Asa SL, Dey C, Kennecke H, Laidley D, Law C. et al. // Cancer Treat. 2016. V. 47. P. 32 – 45.Diagnosis and management of gastrointestinal neuroendocrine tumors: an evidence-based Canadian consensus / Singh S, Asa SL, Dey C, Kennecke H, Laidley D, Law C. et al. // Cancer Treat. 2016. V. 47. P. 32 – 45.One hundred years after «carcinoid»: epidemiology of and prognostiс factors for neuroendocrine tumors in 35,825 cases in the United States / Yao J., Hassan M., Phan A., Dagohoy C., Leary C., Mares JE. et al. // Clin. Oncol. 2008. V. 26. N18. P. 3063 – 3072.One hundred years after «carcinoid»: epidemiology of and prognostiс factors for neuroendocrine tumors in 35,825 cases in the United States / Yao J., Hassan M., Phan A., Dagohoy C., Leary C., Mares JE. et al. // Clin. Oncol. 2008. V. 26. N18. P. 3063 – 3072.Горбунова В. А. Нейроэндокринные опухоли. Общие принципы диагностики и лечения. М.: Кодекс, 2015. 456 с.Gorbunova V. A. Neuroendocrine tumors. General principles of diagnostics and treatment. M.: Kodeks; 2015. 456 р. (In Russian).UKNETwork for neuroendocrine tumours. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours / Ramage J., Davies A., Ardill J. et al. // Gut. 2005. V. 54. N4. P. 1 – 16.UKNETwork for neuroendocrine tumours. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours / Ramage J., Davies A., Ardill J. et al. // Gut. 2005. V. 54. N4. P. 1 – 16.Pancreatic neuroendocrine tumors (PNETs): incidence, prognosis and recent trend toward improved survival / Halfdanarson T., Rabe K., Rubin J. et al. // Annals of Oncology. 2008. V. 19. N10. P. 1727 – 1733.Pancreatic neuroendocrine tumors (PNETs): incidence, prognosis and recent trend toward improved survival / Halfdanarson T., Rabe K., Rubin J. et al. // Annals of Oncology. 2008. V. 19. N10. P. 1727 – 1733.Modlin I. M., Lye K. D., Kidd M. A. 5‑decade analysis of 13,715 carcinoid tumors // Cancer. 2003. V. 97. P. 934 – 959.Modlin I. M., Lye K. D., Kidd M. A. 5‑decade analysis of 13,715 carcinoid tumors // Cancer. 2003. V. 97. P. 934 – 959.Lepage C, Rachet B, Coleman MP. Survival from malignant digestive endocrine tumors in England and Wales: a population-based study // Gastroenterology. 2007. V. 132. P. 899 – 904.Lepage C, Rachet B, Coleman MP. Survival from malignant digestive endocrine tumors in England and Wales: a population-based study // Gastroenterology. 2007. V. 132. P. 899 – 904.Population-based study of islet cell carcinoma / Yao J., Eisner M., Leary C. et al. // Ann Surg Oncol. 2007. V. 14. P. 492 – 500.Population-based study of islet cell carcinoma / Yao J., Eisner M., Leary C. et al. // Ann Surg Oncol. 2007. V. 14. P. 492 – 500.Moertel C., Kvols L., O’Connell M., Rubin J. Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Evidence of major therapeutic activity in the anaplastic variants of these neoplasms // Cancer. 1991. V. 68. P. 227 – 232.Moertel C., Kvols L., O’Connell M., Rubin J. Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Evidence of major therapeutic activity in the anaplastic variants of these neoplasms // Cancer. 1991. V. 68. P. 227 – 232.Moertel C., Hanley J. Combination chemotherapy trials in metastatic carcinoid tumor and the malignant carcinoid syndrome // Cancer clinical trials. 1979. V. 2. P. 327 – 334.Moertel C., Hanley J. Combination chemotherapy trials in metastatic carcinoid tumor and the malignant carcinoid syndrome // Cancer clinical trials. 1979. V. 2. P. 327 – 334.Практические рекомендации Российского общества клинической онкологии. Лекарственное лечение злокачественных опухолей. Поддерживающая терапия в онкологии / под ред. В. М. Моисеенко. // Злокачественные опухоли. Спецвыпуск. 2019. 776 с.Practical recommendations of the Russian Society of Clinical Oncology. Drug treatment of malignant tumors. Supportive care in oncology / ed. V. M. Moiseenko. // Malignant tumors. Special issue. 2019.776 p. (In Russian).O’Toole D., Kiaуmanesh R., Caplin M. ENETS 2016 Consensus Guidelines for the Management of Patients with Digestive Neuroendocrine Tumors: An Update // Neuroendocrinology. 2016. V. 103. P. 117 – 118.O’Toole D., Kiaуmanesh R., Caplin M. ENETS 2016 Consensus Guidelines for the Management of Patients with Digestive Neuroendocrine Tumors: An Update // Neuroendocrinology. 2016. V. 103. P. 117 – 118.Susini C, Buscail L. Rationale for the use of somatostatin analogs as antitumor agents // Annals Oncology. 2006. V. 17. N12. P. 1733 – 1742.Susini C, Buscail L. Rationale for the use of somatostatin analogs as antitumor agents // Annals Oncology. 2006. V. 17. N12. P. 1733 – 1742.Wimmel A., Wiedenmann B., Rosewicz S. Autocrine growth inhibition by transforming growth factor beta-1 (TGFbeta-1) in human neuroendocrine tumour cells // Gut. 2003. V. 52. P. 1308 – 1316.Wimmel A., Wiedenmann B., Rosewicz S. Autocrine growth inhibition by transforming growth factor beta-1 (TGFbeta-1) in human neuroendocrine tumour cells // Gut. 2003. V. 52. P. 1308 – 1316.Effects of interferon alpha on vascular endothelial growth factor gene transcription and tumor angiogenesis / von Marschall Z., Scholz A., Cramer T., Schafer G., Schirner M., Oberg K, et al. // Natl Cancer Inst. 2003. V. 95. P. 437 – 448.Effects of interferon alpha on vascular endothelial growth factor gene transcription and tumor angiogenesis / von Marschall Z., Scholz A., Cramer T., Schafer G., Schirner M., Oberg K, et al. // Natl Cancer Inst. 2003. V. 95. P. 437 – 448.Chaudhry A., Papanicolaou V., Oberg K., Heldin C., Funa K. Expression of platelet-derived growth factor and its receptors in neuroendocrine tumors of the digestive system // Cancer Res. 1992. V. 52. P. 1006 – 1012.Chaudhry A., Papanicolaou V., Oberg K., Heldin C., Funa K. Expression of platelet-derived growth factor and its receptors in neuroendocrine tumors of the digestive system // Cancer Res. 1992. V. 52. P. 1006 – 1012.Wulbrand U., Remmert G., Zofel P., Wied M., Arnold R., Fehmann H. mRNA expression patterns of insulin-like growth factor system components in human neuroendocrine tumours // Eur J Clin Invest. 2000. V. 30. P. 729 – 739.Wulbrand U., Remmert G., Zofel P., Wied M., Arnold R., Fehmann H. mRNA expression patterns of insulin-like growth factor system components in human neuroendocrine tumours // Eur J Clin Invest. 2000. V. 30. P. 729 – 739.Insulin-like growth factor-I is an autocrine regulator of chromogranin A secretion and growth in human neuroendocrine tumor cells / von Wichert G., Jehle P., Hoeflich A., Koschnick S., Dralle H, Wolf E. et al. // Cancer Res. 2000. V. 60. P. 4573 – 4581.Insulin-like growth factor-I is an autocrine regulator of chromogranin A secretion and growth in human neuroendocrine tumor cells / von Wichert G., Jehle P., Hoeflich A., Koschnick S., Dralle H, Wolf E. et al. // Cancer Res. 2000. V. 60. P. 4573 – 4581.Nilsson O., Wangberg B., Theodorsson E., Skottner A., Ahlman H. Presence of IGF-I in human midgut carcinoid tumours--an autocrine regulator of carcinoid tumour growth? // Int J Cancer. 1992. V. 51. P. 195 – 203.Nilsson O., Wangberg B., Theodorsson E., Skottner A., Ahlman H. Presence of IGF-I in human midgut carcinoid tumours--an autocrine regulator of carcinoid tumour growth? // Int J Cancer. 1992. V. 51. P. 195 – 203.Zhang H., Yee D. The therapeutic potential of agents targeting the type I insulin-like growth factor receptor // Expert Opin Investig Drugs. 2004. V. 13. P. 1569 – 1577.Zhang H., Yee D. The therapeutic potential of agents targeting the type I insulin-like growth factor receptor // Expert Opin Investig Drugs. 2004. V. 13. P. 1569 – 1577.Gastrointestinal Neuroendocrine Tumors: Pancreatic Endocrine Tumors / Metz, David C. et al. // Gastroenterology. 2008. V. 135. N5. P. 1469 – 1492.Gastrointestinal Neuroendocrine Tumors: Pancreatic Endocrine Tumors / Metz, David C. et al. // Gastroenterology. 2008. V. 135. N5. P. 1469 – 1492.Wiedmann M., Caca K. Molecularly targeted therapy for gastrointestinal cancer // Curr Cancer Drug Targets. 2005. V. 5. P. 171 – 193.Wiedmann M., Caca K. Molecularly targeted therapy for gastrointestinal cancer // Curr Cancer Drug Targets. 2005. V. 5. P. 171 – 193.Smolewski P. Recent developments in targeting the mammalian target of rapamycin (mTOR) kinase pathway // Anticancer Drugs. 2006. V. 17. P. 487 – 494.Smolewski P. Recent developments in targeting the mammalian target of rapamycin (mTOR) kinase pathway // Anticancer Drugs. 2006. V. 17. P. 487 – 494.Dancey J. Therapeutic targets: MTOR and related pathways // Cancer Biol Ther. 2006. V. 5. P. 1065 – 1073.Dancey J. Therapeutic targets: MTOR and related pathways // Cancer Biol Ther. 2006. V. 5. P. 1065 – 1073.EGFR targeting of solid tumors / Rocha-Lima C., Soares H., Raez L. et al. // Cancer Control. 2007. V. 14. P. 295 – 304.EGFR targeting of solid tumors / Rocha-Lima C., Soares H., Raez L. et al. // Cancer Control. 2007. V. 14. P. 295 – 304.Harari P. Epidermal growth factor receptor inhibition strategies in oncology // Endocr Relat Cancer. 2004. V. 11. P. 689 – 708.Harari P. Epidermal growth factor receptor inhibition strategies in oncology // Endocr Relat Cancer. 2004. V. 11. P. 689 – 708.Bjornsti M., Houghton P. The TOR pathway: a target for cancer therapy // Nat Rev Cancer. 2004. V. 4. P. 335 – 348.Bjornsti M., Houghton P. The TOR pathway: a target for cancer therapy // Nat Rev Cancer. 2004. V. 4. P. 335 – 348.BAY 43 – 9006 exhibits broad spectrum oral antitumor activity and targets the RAF / MEK / ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis / Wilhelm S., Carter C., Tang L., Wilkie D., McNabola A., Rong H. et al.// Cancer Res. 2004. V. 64. P. 7099 – 7109.BAY 43 – 9006 exhibits broad spectrum oral antitumor activity and targets the RAF / MEK / ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis / Wilhelm S., Carter C., Tang L., Wilkie D., McNabola A., Rong H. et al.// Cancer Res. 2004. V. 64. P. 7099 – 7109.Interaction between the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF) pathways: a rational approach for multi-target anticancer therapy / Ciardiello F., Troiani T., Bianco R., Orditura M., Morgillo F., Martinelli E. et al. // Annals of Oncology. 2006. V. 17. N 7. P. 109 – 114.Interaction between the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF) pathways: a rational approach for multi-target anticancer therapy / Ciardiello F., Troiani T., Bianco R., Orditura M., Morgillo F., Martinelli E. et al. // Annals of Oncology. 2006. V. 17. N 7. P. 109 – 114.Maione P., Gridelli C., Troiani T., Ciardiello F. Combining targeted therapies and drugs with multiple targets in the treatment of NSCLC// Oncologist. 2006. V. 11. P. 274 – 284.Maione P., Gridelli C., Troiani T., Ciardiello F. Combining targeted therapies and drugs with multiple targets in the treatment of NSCLC// Oncologist. 2006. V. 11. P. 274 – 284.Burgaud JL, Baserga R. Intracellular transactivation of the insulin-like growth factor I receptor by an epidermal growth factor receptor // Exp Cell Res. 1996. V. 223. P. 412 – 419.Burgaud JL, Baserga R. Intracellular transactivation of the insulin-like growth factor I receptor by an epidermal growth factor receptor // Exp Cell Res. 1996. V. 223. P. 412 – 419.Activation of BAD by therapeutic inhibition of epidermal growth factor receptor and transactivation by insulin-like growth factor receptor / Gilmore A., Valentijn A., Wang P., Ranger A., Bundred N., O’Hare M. et al.//J Biol Chem. 2002. V. 277. P. 27643 – 27650.Activation of BAD by therapeutic inhibition of epidermal growth factor receptor and transactivation by insulin-like growth factor receptor / Gilmore A., Valentijn A., Wang P., Ranger A., Bundred N., O’Hare M. et al.//J Biol Chem. 2002. V. 277. P. 27643 – 27650.Jain R., Duda D., Clark J., Loeffler J. Lessons from phase III clinical trials on anti-VEGF therapy for cancer // Nat Clin Pract Oncol. 2006. V. 3. P. 24 – 40.Jain R., Duda D., Clark J., Loeffler J. Lessons from phase III clinical trials on anti-VEGF therapy for cancer // Nat Clin Pract Oncol. 2006. V. 3. P. 24 – 40.Morabito A., De Maio E., Di Maio M., Normanno N., Perrone F. Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials: current status and future directions // Oncologist. 2006. V. 11. P. 753 – 764.Morabito A., De Maio E., Di Maio M., Normanno N., Perrone F. Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials: current status and future directions // Oncologist. 2006. V. 11. P. 753 – 764.Hopfner M., Sutter A., Gerst B., Zeitz M., Scherubl H. A novel approach in the treatment of neuroendocrine gastrointestinal tumours. Targeting the epidermal growth factor receptor by gefitinib (ZD1839) // Br J Cancer. 2003. V. 89. P. 1766 – 1775.Hopfner M., Sutter A., Gerst B., Zeitz M., Scherubl H. A novel approach in the treatment of neuroendocrine gastrointestinal tumours. Targeting the epidermal growth factor receptor by gefitinib (ZD1839) // Br J Cancer. 2003. V. 89. P. 1766 – 1775.Hopfner M., Baradari V., Huether A., Schofl C., Scherubl H. The insulin-like growth factor receptor 1 is a promising target for novel treatment approaches in neuroendocrine gastrointestinal tumours // Endocr Relat Cancer. 2006. V. 13. P. 135 – 149.Hopfner M., Baradari V., Huether A., Schofl C., Scherubl H. The insulin-like growth factor receptor 1 is a promising target for novel treatment approaches in neuroendocrine gastrointestinal tumours // Endocr Relat Cancer. 2006. V. 13. P. 135 – 149.Elevated expression of vascular endothelial growth factor correlates with increased angiogenesis and decreased progression-free survival among patients with low-grade neuroendocrine tumors / Zhang J., Jia Z., Li Q., Wang L., Rashid A, Zhu Z. et al. // Cancer. 2007. V. 109. P. 1478 – 1486.Elevated expression of vascular endothelial growth factor correlates with increased angiogenesis and decreased progression-free survival among patients with low-grade neuroendocrine tumors / Zhang J., Jia Z., Li Q., Wang L., Rashid A, Zhu Z. et al. // Cancer. 2007. V. 109. P. 1478 – 1486.Pavel M., Hassler G., Baum U., Hahn E., Lohmann T., Schuppan D. Circulating levels of angiogenic cytokines can predict tumour progression and prognosis in neuroendocrine carcinomas // Clin Endocrinol (Oxf). 2005. V. 62. P. 434 – 443.Pavel M., Hassler G., Baum U., Hahn E., Lohmann T., Schuppan D. Circulating levels of angiogenic cytokines can predict tumour progression and prognosis in neuroendocrine carcinomas // Clin Endocrinol (Oxf). 2005. V. 62. P. 434 – 443.Carmeliet P., Jain R. Molecular mechanisms and clinical applications of angiogenesis // Nature 473. 2011. P. 298 – 307.Carmeliet P., Jain R. Molecular mechanisms and clinical applications of angiogenesis // Nature 473. 2011. P. 298 – 307.Anti-vascular endothelial growth factor antibody single therapy for pancreatic neuroendocrine carcinoma exhibits a marked tumor growth-inhibitory effect / Kasuya K., Nagakawa Y., Suzuki M., Tanaka H., Ohta H., Itoi T. et al.. // Exp Ther Med 2. 2011. P. 1047 – 1052.Anti-vascular endothelial growth factor antibody single therapy for pancreatic neuroendocrine carcinoma exhibits a marked tumor growth-inhibitory effect / Kasuya K., Nagakawa Y., Suzuki M., Tanaka H., Ohta H., Itoi T. et al.. // Exp Ther Med 2. 2011. P. 1047 – 1052.Prospective study of bevacizumab plus temozolomide in patients with advanced neuroendocrine tumors / Chan J., Stuart K., Earle C., Clark J., Bhargava P., Miksad R. et al. // J Clin Oncol. 2012. V. 30. P. 2963 – 2968.Prospective study of bevacizumab plus temozolomide in patients with advanced neuroendocrine tumors / Chan J., Stuart K., Earle C., Clark J., Bhargava P., Miksad R. et al. // J Clin Oncol. 2012. V. 30. P. 2963 – 2968.Reinacher-Schick, ASCO-update 2015 — highlights of the 51 meeting of the american society of clinical oncology // Lorenzen S., Arnold D., Fottner C., Leichsenring J., Moehler M., Seufferlein T., et al. //ASCO 2015, Z Gastroenterol. 2016. V. 54. N 02. P. 167 – 172.Reinacher-Schick, ASCO-update 2015 — highlights of the 51 meeting of the american society of clinical oncology // Lorenzen S., Arnold D., Fottner C., Leichsenring J., Moehler M., Seufferlein T., et al. //ASCO 2015, Z Gastroenterol. 2016. V. 54. N 02. P. 167 – 172.(2015b) Randomized phase II study of everolimus (E) versus everolimus plus bevacizumab (E+B) in patients (Pts) with locally advanced or metastatic pancreatic neuroendocrine tumors (pNET), CALGB 80701 (Alliance) / Kulke M., Niedzwiecki D., Foster N., Fruth B., Kunz P., Kennecke H. et al.// J Clin Oncol. 2015. V. 33. N 15. P. 4005.(2015b) Randomized phase II study of everolimus (E) versus everolimus plus bevacizumab (E+B) in patients (Pts) with locally advanced or metastatic pancreatic neuroendocrine tumors (pNET), CALGB 80701 (Alliance) / Kulke M., Niedzwiecki D., Foster N., Fruth B., Kunz P., Kennecke H. et al.// J Clin Oncol. 2015. V. 33. N 15. P. 4005.Randomized phase II study of everolimus (E) versus everolimus plus bevacizumab (E+B) in patients (Pts) with locally advanced or metastatic pancreatic neuroendocrine tumors (pNET), CALGB 80701 (Alliance) / Matthew H. Kulke, Donna Niedzwiecki, Nathan R. Foster, Briant Fruth, Pamela L. Kunz, Hagen F. Kennecke et al. // J Clin Oncol. 2015. V. 33. N 15. P. 4005.Randomized phase II study of everolimus (E) versus everolimus plus bevacizumab (E+B) in patients (Pts) with locally advanced or metastatic pancreatic neuroendocrine tumors (pNET), CALGB 80701 (Alliance) / Matthew H. Kulke, Donna Niedzwiecki, Nathan R. Foster, Briant Fruth, Pamela L. Kunz, Hagen F. Kennecke et al. // J Clin Oncol. 2015. V. 33. N 15. P. 4005.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 / Yao J., Guthrie K., Moran C. et al. // J Clin Oncol. 2017. doi: 10.1200 / JCO. 2016. V. 70. P. 4072Phase 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 / Yao J., Guthrie K., Moran C. et al. // J Clin Oncol. 2017. doi: 10.1200 / JCO. 2016. V. 70. P. 4072Перспективы использования бевацизумаба при НЭО. Клинический случай / Г. С. Емельянова, Н. Ф. Орел, В. А. Горбунова, А. А. Коломейцева, А. А. Кузнецова, А. Е. Кузьминов и др. // Сибирский онкологический журнал. 2017. Т. 16. № 6. C. 100 – 104.Perspectives on use of bevacizumab in patients with neuroendocrine tumors. Case report / G. S. Emelianova, N. F. Orel, V. A. Gorbunova, A. A. Kolomeytseva, A. A. Kuznetsova, A. E. Kuzminov et al. // Siberian Journal of Oncology. 2017. V. 16. N 6. P. 100 – 104 (In Russian).Bevacizumab plus octreotide and metronomic capecitabine in patients with metastatic well-to-moderately differentiated neuroendocrine tumors: the xelbevoct study / Berruti A., Fazio N., Ferrero A., Brizzi M., Volante M., Nobili E. et al. // BMC Cancer. 2014. V. 14. P. 184.Bevacizumab plus octreotide and metronomic capecitabine in patients with metastatic well-to-moderately differentiated neuroendocrine tumors: the xelbevoct study / Berruti A., Fazio N., Ferrero A., Brizzi M., Volante M., Nobili E. et al. // BMC Cancer. 2014. V. 14. P. 184.Bevacizumab plus capecitabine in patients with progressive advanced well-differentiated neuroendocrine tumors of the gastro-intestinal (GI-NETs) tract (BETTER trial) — a phase II non-randomised trial / Mitry E., Walter T., Baudin E., Kurtz J. E., Ruszniewski P., Dominguez-Tinajero S. et al. // Eur J Cancer. 2014. V. 50. N 18. P. 3107 – 3115.Bevacizumab plus capecitabine in patients with progressive advanced well-differentiated neuroendocrine tumors of the gastro-intestinal (GI-NETs) tract (BETTER trial) — a phase II non-randomised trial / Mitry E., Walter T., Baudin E., Kurtz J. E., Ruszniewski P., Dominguez-Tinajero S. et al. // Eur J Cancer. 2014. V. 50. N 18. P. 3107 – 3115.Resistance to antiangiogenic therapy is directed by vascular phenotype, vessel stabilization, and maturation in malignant melanoma / Helfrich I., Scheffrahn I., Bartling S., Weis J., von Felbert V., Middleton M. et al. // J Exp Med 207. 2010. P. 491 – 503.Resistance to antiangiogenic therapy is directed by vascular phenotype, vessel stabilization, and maturation in malignant melanoma / Helfrich I., Scheffrahn I., Bartling S., Weis J., von Felbert V., Middleton M. et al. // J Exp Med 207. 2010. P. 491 – 503.Sitohy B., Nagy J., Dvorak H. Anti-VEGF / VEGFR therapy for cancer: Reassessing the target // Cancer Res 72. 2012. P. 1909 – 1914.Sitohy B., Nagy J., Dvorak H. Anti-VEGF / VEGFR therapy for cancer: Reassessing the target // Cancer Res 72. 2012. P. 1909 – 1914.Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericytemediated endothelial cell survival mechanisms / Erber R., Thurnher A., Katsen A., Groth G., Kerger H., Hammes H. et al. // FASEB J 18. 2004. P. 338 – 340.Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericytemediated endothelial cell survival mechanisms / Erber R., Thurnher A., Katsen A., Groth G., Kerger H., Hammes H. et al. // FASEB J 18. 2004. P. 338 – 340.Wilhelm S., Chien D. BAY 43 – 9006: preclinical data // Curr Pharm Des. 2002. V. 8. P. 2255 – 2257.Wilhelm S., Chien D. BAY 43 – 9006: preclinical data // Curr Pharm Des. 2002. V. 8. P. 2255 – 2257.Role of Raf kinase in cancer: therapeutic potential of targeting the Raf / MEK / ERK signal transduction pathway / Gollob J., Wilhelm S., Carter C., Kelley S. //Semin Oncol. 2006. V. 33. P. 392 – 406.Role of Raf kinase in cancer: therapeutic potential of targeting the Raf / MEK / ERK signal transduction pathway / Gollob J., Wilhelm S., Carter C., Kelley S. //Semin Oncol. 2006. V. 33. P. 392 – 406.Sorafenib blocks the RAF / MEK / ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC / PRF / 5 / Liu L., Cao Y., Chen C., Zhang X., McNabola A., Wilkie D. et al. // Cancer Res. 2006. V. 66. P. 11851 – 11858.Sorafenib blocks the RAF / MEK / ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC / PRF / 5 / Liu L., Cao Y., Chen C., Zhang X., McNabola A., Wilkie D. et al. // Cancer Res. 2006. V. 66. P. 11851 – 11858.Hobday TJ, Rubin J, Holen K. MC044h, a phase II trial of sorafenib in patients with metastatic neuroendocrine tumors (NET): A Phase II Consortium (P2C) study // Clin Oncol. 2007, ASCO Annual Meeting Proceedings Part 1. 2007. V. 25. N 18. P. 4504.Hobday TJ, Rubin J, Holen K. MC044h, a phase II trial of sorafenib in patients with metastatic neuroendocrine tumors (NET): A Phase II Consortium (P2C) study // Clin Oncol. 2007, ASCO Annual Meeting Proceedings Part 1. 2007. V. 25. N 18. P. 4504.Activity of Sunitinib in Patients With Advanced Neuroendocrine Tumors / Matthew H. Kulke, Heinz-Josef Lenz, Neal J. Meropol et al. // Clin Oncol. 2008. V. 20. P. 3404 – 3410.Activity of Sunitinib in Patients With Advanced Neuroendocrine Tumors / Matthew H. Kulke, Heinz-Josef Lenz, Neal J. Meropol et al. // Clin Oncol. 2008. V. 20. P. 3404 – 3410.Sunitinib malate for the treatment of pancreatic neuroendocrine tumors Raymond E., Dahan L., Raoul J. et al. // N Engl J Med. 2011. V. 364. Р. 501 – 513.Sunitinib malate for the treatment of pancreatic neuroendocrine tumors Raymond E., Dahan L., Raoul J. et al. // N Engl J Med. 2011. V. 364. Р. 501 – 513.Motzer R., Bukowski R.. Targeted therapy for metastatic renal cell carcinoma // Clin Oncol. 2006. V. 24. P. 5601 – 5608.Motzer R., Bukowski R.. Targeted therapy for metastatic renal cell carcinoma // Clin Oncol. 2006. V. 24. P. 5601 – 5608.Kulke M., Bergsland E., Ryan D. A Phase II study to evaluate the safety and efficacy of SU11248 in patients with unresectable neuroendocrine tumors // Proc Am Soc Clin Oncol. 2003. V. 22. P. 958.Kulke M., Bergsland E., Ryan D. A Phase II study to evaluate the safety and efficacy of SU11248 in patients with unresectable neuroendocrine tumors // Proc Am Soc Clin Oncol. 2003. V. 22. P. 958.A phase two study to evaluate the efficacy and safety of SU11248 in patients (pts) with unresectable neuroendocrine tumors (NET) // Kulke M., Lenz H., Meropol N., Posey J., Ryan D., Picus J. et al. // J Clin Oncol. 2005. V. 23. P. 4008.A phase two study to evaluate the efficacy and safety of SU11248 in patients (pts) with unresectable neuroendocrine tumors (NET) // Kulke M., Lenz H., Meropol N., Posey J., Ryan D., Picus J. et al. // J Clin Oncol. 2005. V. 23. P. 4008.Updated results of the phase III trial of sunitinib (SU) versus placebo (PBO) for treatment of advanced pancreatic neuroendocrine tumors (NET) / Raymond E., Niccoli-Sire P., Bang Y. et al. // ASCO Gastrointestinal Cancers Symposium. Book of abstracts. 2010. Abstract 127.Updated results of the phase III trial of sunitinib (SU) versus placebo (PBO) for treatment of advanced pancreatic neuroendocrine tumors (NET) / Raymond E., Niccoli-Sire P., Bang Y. et al. // ASCO Gastrointestinal Cancers Symposium. Book of abstracts. 2010. Abstract 127.Pietras K., Hanahan D. A multitargeted, metronomic, and maximum-tolerated dose «chemo-switch» regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cance // Clin Oncol. 2005. V. 23. P. 939 – 952.Pietras K., Hanahan D. A multitargeted, metronomic, and maximum-tolerated dose «chemo-switch» regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cance // Clin Oncol. 2005. V. 23. P. 939 – 952.Combined anti-VEGFR and anti-PDGFR actions of sunitinib on blood vessels in preclinical tumor models / Yao V., Sennino B., Davis R. et al.// Eur J Cancer. 2006. V. 4. P. 27 – 28.Combined anti-VEGFR and anti-PDGFR actions of sunitinib on blood vessels in preclinical tumor models / Yao V., Sennino B., Davis R. et al.// Eur J Cancer. 2006. V. 4. P. 27 – 28.Activity of sunitinib in patients with advanced neuroendocrine tumors / Kulke M., Lenz H., Meropol N. et al. // Clin Oncol. 2008. V. 26. P. 3403 – 3410.Activity of sunitinib in patients with advanced neuroendocrine tumors / Kulke M., Lenz H., Meropol N. et al. // Clin Oncol. 2008. V. 26. P. 3403 – 3410.Phase 11 study of sunitinib (SU) in Japanese patients with unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumors (NET) / Okusaka T., Ito T., Nishida T. et al. // Clin Oncol. 2012. V. 30. P. 381.Phase 11 study of sunitinib (SU) in Japanese patients with unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumors (NET) / Okusaka T., Ito T., Nishida T. et al. // Clin Oncol. 2012. V. 30. P. 381.Chan J., Kulke M. Targeting the mTOR signaling pathway in neuroendocrine tumors// Curr Treat Options Oncol. 2014. V. 15. N3. P. 365 – 379. doi:10.1007 / s11864‑014‑0294‑4.Chan J., Kulke M. Targeting the mTOR signaling pathway in neuroendocrine tumors// Curr Treat Options Oncol. 2014. V. 15. N3. P. 365 – 379. doi:10.1007 / s11864‑014‑0294‑4.Симоненко В. Б., Дулин П. А., Маканин М. А. Возможности таргетной терапии нейроэндокринных опухолей // Клиническая медицина. 2014. Т. 92. № 8. С. 5 – 14.Simonenko V. B., Dulin P. A., Makanin M. A. Possibilities for targeted therapy of neuroendocrine tumours // Klinicheskaya meditsina. 2014. V. 92. N 8. P. 5 – 14. (In Russian).mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates / O’Reilly K., Rojo F., She Q., Solit D., Mills G., Smith D. et al. // Akt. Cancer Research 66. 2006. P. 1500 – 1508.mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates / O’Reilly K., Rojo F., She Q., Solit D., Mills G., Smith D. et al. // Akt. Cancer Research 66. 2006. P. 1500 – 1508.A randomized, double-blind, placebo-controlled, multicenter phase III trial of everolimus + octreotide LAR vs placebo + octreotide lar in patients with advanced neuroendocrine tumors (NET) (RADIANT-2) / Pavel M., Hainsworth J., Baudin E. et al. // 35th ESMO Congress. Book of abstracts. 2010. Abstract LBA8.A randomized, double-blind, placebo-controlled, multicenter phase III trial of everolimus + octreotide LAR vs placebo + octreotide lar in patients with advanced neuroendocrine tumors (NET) (RADIANT-2) / Pavel M., Hainsworth J., Baudin E. et al. // 35th ESMO Congress. Book of abstracts. 2010. Abstract LBA8.Everolimus treatment for neuroendocrine tumors: latest results and clinical potential / Pusceddu S., Verzoni E., Prinzi N. et al. // Therapeutic Advances in Medical Oncology. 2017. V. 9. N 3. P. 183 – 188. doi:10.1177 / 1758834016683905.Everolimus treatment for neuroendocrine tumors: latest results and clinical potential / Pusceddu S., Verzoni E., Prinzi N. et al. // Therapeutic Advances in Medical Oncology. 2017. V. 9. N 3. P. 183 – 188. doi:10.1177 / 1758834016683905.Everolimus for advanced pancreatic neuroendocrine tumors / Yao J., Shah M., Ito T. et al. // N Engl J Med. 2011. V. 364. P. 514 – 523.Everolimus for advanced pancreatic neuroendocrine tumors / Yao J., Shah M., Ito T. et al. // N Engl J Med. 2011. V. 364. P. 514 – 523.Кузьминов А. Е., Полозкова С. А., Орел Н. Ф., Горбунова В. А. Нейроэндокринные опухоли // Эффективная фармакотерапия. Онкология, гематология и радиология. 2012. N1. С. 44 – 48.Kuzminov A. E., Polozkova S. A., Orel N. F., Gorbunova V. A. Neuroendocrine tumors // Effective pharmacotherapy. Oncology, hematology and radiology. 2012. N 1. P. 44 – 48. (In Russian).A randomized, double-blind, placebo-controlled, multicenter phase III trial of everolimus in patients with advanced pancreatic neuroendocrine tumors (PNET) (RADIANT-3) / Yao J., Shah M., Ito T. et al. // 35th ESMO Congress. Book of abstracts. 2010. Abstract LBA9.A randomized, double-blind, placebo-controlled, multicenter phase III trial of everolimus in patients with advanced pancreatic neuroendocrine tumors (PNET) (RADIANT-3) / Yao J., Shah M., Ito T. et al. // 35th ESMO Congress. Book of abstracts. 2010. Abstract LBA9.Jensen R., Delle Fave G. Promising advances in the treatment of malignant pancreatic endocrine tumors // N Engl J Med. 2011. V. 364. P. 564 – 565.Jensen R., Delle Fave G. Promising advances in the treatment of malignant pancreatic endocrine tumors // N Engl J Med. 2011. V. 364. P. 564 – 565.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 / Yao C., Fazio N., Singh S., Buzzoni R., Carnaghi C., Wolin E. et al. // The Lancet. 5 – 11 March 2016. V. 387. N10022. P. 968 – 977.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 / Yao C., Fazio N., Singh S., Buzzoni R., Carnaghi C., Wolin E. et al. // The Lancet. 5 – 11 March 2016. V. 387. N10022. P. 968 – 977.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, placebocontrolled, phase 3 trial / Pavel M., Singh S., Strosberg J., Bubuteishvili-Pacaud L., Degtyarev E., Neary M. et al. // The Lancet. October 2017. V. 18, N10, P. 1411 – 1422.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, placebocontrolled, phase 3 trial / Pavel M., Singh S., Strosberg J., Bubuteishvili-Pacaud L., Degtyarev E., Neary M. et al. // The Lancet. October 2017. V. 18, N10, P. 1411 – 1422.Chan J., Kulke M. Progressing in the treatment of neuroendocrine tumors // Curr. Oncol. Rep. 2009. V. 11. P. 193 – 199.Chan J., Kulke M. Progressing in the treatment of neuroendocrine tumors // Curr. Oncol. Rep. 2009. V. 11. P. 193 – 199.Targeted Systemic Treatment of Neuroendocrine Tumors: Current Options and Future Perspectives / Herrera-Martínez, Aura D et al.// Drugs. 2019. V. 79. N1. P. 21 – 42.Targeted Systemic Treatment of Neuroendocrine Tumors: Current Options and Future Perspectives / Herrera-Martínez, Aura D et al.// Drugs. 2019. V. 79. N1. P. 21 – 42.

The authors declare that there are no conflicts of interest present.