Альманах клинической медицины. 2019; 47: 685-690
Хромогранин А и серотонин в оценке эффективности лечения нейроэндокринных опухолей
https://doi.org/10.18786/2072-0505-2019-47-054Аннотация
Актуальность. Целесообразность использования биохимических маркеров в контроле эффективности лечения больных нейроэндокринными опухолями (НЭО) не вызывает сомнений. Однако до сих пор отсутствуют четкие критерии оценки клинически значимых изменений уровней основных маркеров НЭО – хромогранина А (ХгА) и серотонина.
Цель – оценить значимость серийного определения ХгА и серотонина в сыворотке крови для мониторинга эффективности лечения больных НЭО.
Материал и методы. Определение ХгА и серотонина в сыворотке крови выполнено у 107 больных НЭО при первичном обследовании и в динамике через 3–4 недели после проведения курса лечения (химиотерапия, биотерапия), а также у 60 практически здоровых людей. Использовали иммуноферментный анализ на основе тест-систем Chromogranin A NEOLISA (Euro Diagnostica) и Serotonin ELISA (IBL International GmbH).
Результаты. Выявлена связь уровней ХгА с эффектом химиотерапии у больных НЭО. При прогрессировании заболевания медиана ХгА статистически значимо повышалась (с 412 до 2679 нг/мл, p=0,012), тогда как при частичном ответе наблюдали ее снижение (с 811 до 254 нг/мл, p=0,023). По данным ROC-анализа, порог значимого изменения ХгА для прогрессирования составил 33% при чувствительности 80,0% и специфичности 95,6%. Снижение (более 33% относительно уровня до лечения) или отсутствие значимых изменений ХгА было связано со стабилизацией заболевания или частичным ответом на терапию. Значимое снижение уровней ХгА отмечено в 75,0% случаев при частичном ответе и в 43,48% – при стабилизации, отсутствие значимых изменений – в 25 и 66,7% соответственно. Для серотонина зависимости от динамики аболевания на фоне лечения не установлено.
Заключение. ХгА может использоваться в качестве чувствительного маркера прогрессирования НЭО на фоне химиотерапевтического лечения.
Список литературы
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2. Vinik AI, Silva MP, Woltering EA, Go VL, Warner R, Caplin M. Biochemical testing for neuroendocrine tumors. Pancreas. 2009;38(8):876–89. doi: 10.1097/MPA.0b013e3181bc0e77.
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6. Ardill JE. Circulating markers for endocrine tumours of the gastroenteropancreatic tract. Ann Clin Biochem. 2008;45(Pt 6):539–59. doi: 10.1258/acb.2008.008039.
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13. Walter T, Chardon L, Chopin-laly X, Raverot V, Caffin AG, Chayvialle JA, Scoazec JY, Lombard-Bohas C. Is the combination of chromogranin A and pancreatic polypeptide serum determinations of interest in the diagnosis and follow-up of gastro-entero-pancreatic neuroendocrine tumours? Eur J Cancer. 2012;48(12): 1766–73. doi: 10.1016/j.ejca.2011.11.005.
14. Bajetta E, Procopio G, Catena L, Martinetti A, De Dosso S, Ricci S, Lecchi AS, Boscani PF, Iacobelli S, Carteni G, De Braud F, Loli P, Tartaglia A, Bajetta R, Ferrari L. Lanreotide autogel every 6 weeks compared with Lanreotide microparticles every 3 weeks in patients with well differentiated euroendocrine tumors: a Phase III Study. Cancer. 2006;107(10):2474–81. doi: 10.1002/cncr.22272.
15. Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P, Hoosen S, St Peter J, Haas T, Lebwohl D, Van Cutsem E, Kulke MH, Hobday TJ, O'Dorisio TM, Shah MH, Cadiot G, Luppi G, Posey JA, Wiedenmann B. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol. 2010;28(1):69–76. doi: 10.1200/JCO.2009.24.2669.
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17. Jensen EH, Kvols L, McLoughlin JM, Lewis JM, Alvarado MD, Yeatman T, Malafa M, Shibata D. Biomarkers predict outcomes following cytoreductive surgery for hepatic metastases from functional carcinoid tumors. Ann Surg Oncol. 2007;14(2):780–5. doi: 10.1245/s10434-006-9148-z.
18. Cheng Y, Sun Z, Bai C, Yan X, Qin R, Meng C, Ying H. Serum chromogranin A levels for the diagnosis and follow-up of well-differentiated non-functioning neuroendocrine tumors. Tumour Biol. 2016;37(3):2863–9. doi: 10.1007/s13277-015-4114-7.
19. Singh S, Law C. Chromogranin A: a sensitive biomarker for the detection and post-treatment monitoring of gastroenteropancreatic neuroendocrine tumors. Expert Rev Gastroenterol Hepatol. 2012;6(3):313–34. doi: 10.1586/egh.12.15.
20. Kim M, Lee S, Lee J, Park SH, Park JO, Park YS, Kang WK, Kim ST. The role of plasma chromogranin as assessment of treatment response in non-functioning gastroenteropancreatic neuroendocrine tumors. Cancer Res Treat. 2016;48(1):153–61. doi: 10.4143/crt.2014.183.
21. Han X, Zhang C, Tang M, Xu X, Liu L, Ji Y, Pan B, Lou W. The value of serum chromogranin A as a predictor of tumor burden, therapeutic response, and nomogram-based survival in well-moderate nonfunctional pancreatic neuroendocrine tumors with liver metastases. Eur J Gastroenterol Hepatol. 2015;27(5):527–35. doi: 10.1097/MEG.0000000000000332.
Almanac of Clinical Medicine. 2019; 47: 685-690
Chromogranin A and serotonin for evaluation of treatment efficacy of neuroendocrine tumors
https://doi.org/10.18786/2072-0505-2019-47-054Abstract
Background: The utility of biochemical markers in the monitoring of treatment efficacy in patients with neuroendocrine tumors (NETs) goes beyond any doubt. However, there are still no clear criteria for the assessment of clinically significant abnormalities of the main NET biomarkers chromogranin A (CgA) and serotonin.
Aim: To evaluate the value of serial measurement of serum CgA and serotonin in the monitoring of the treatment effect in NET patients.
Materials and methods: Serum CgA and serotonin levels were measured in 107 patients with NETs at baseline and at 3–4 weeks after the end of treatment (chemotherapy, biotherapy), as well as in 60 healthy controls. We used enzyme immunoassay based on Chromogranin A NEOLISA (Euro Diagnostica) and Serotonin ELISA (IBL International GmbH) test systems.
Results: There was an association between CgA levels and the efficacy of chemotherapy in NET patients. With progression of the disease, median CgA increased significantly from 412 to 2679 ng/mL (p = 0.012), whereas in the patients with partial response it decreased from 811 to 254 ng/mL (p = 0.023). The ROC analysis showed the 33% cut-off for significant CgA changes for progression, with sensitivity of 80.0% and specificity of 95.6%. A decrease (of more than 33% compared to baseline levels) or absence of significant CgA changes was associated with stabilization of the disease or with partial response to treatment. Significantly decreased CgA levels were found in 75.0% cases of partial response and 43.48% of stabilized patients, whereas the absence of any significant changes in 25 and 66.7%, respectively. There was no association between serotonin levels and the disease behavior under treatment.
Conclusion: CgA could be used as a sensitive marker of NET progression on chemotherapy.
References
1. Eriksson B, Oberg K, Stridsberg M. Tumor markers in neuroendocrine tumors. Digestion. 2000;62 Suppl 1:33–8. doi: 10.1159/000051853.
2. Vinik AI, Silva MP, Woltering EA, Go VL, Warner R, Caplin M. Biochemical testing for neuroendocrine tumors. Pancreas. 2009;38(8):876–89. doi: 10.1097/MPA.0b013e3181bc0e77.
3. Aluri V, Dillon JS. Biochemical testing in neuroendocrine tumors. Endocrinol Metab Clin North Am. 2017;46(3):669–77. doi: 10.1016/j.ecl.2017.04.004.
4. de Herder WW. Biochemistry of neuroendocrine tumours. Best Pract Res Clin Endocrinol Metab. 2007;21(1):33–41. doi: 10.1016/j.beem.2006.12.002.
5. Oberg K. Circulating biomarkers in gastroenteropancreatic neuroendocrine tumours. Endocr Relat Cancer. 2011;18 Suppl 1:S17–25. doi: 10.1530/ERC-10-0280.
6. Ardill JE. Circulating markers for endocrine tumours of the gastroenteropancreatic tract. Ann Clin Biochem. 2008;45(Pt 6):539–59. doi: 10.1258/acb.2008.008039.
7. Modlin IM, Gustafsson BI, Moss SF, Pavel M, Tsolakis AV, Kidd M. Chromogranin A – biological function and clinical utility in neuroendocrine tumor disease. Ann Surg Oncol. 2010;17(9):2427–43. doi: 10.1245/s10434-010-1006-3.
8. Lyubimova NV, Churikova TK, Kushlinskii NE. Khromogranin A – biokhimicheskii marker neiroendokrinnykh opukholei. Byulleten' eksperimental'noi biologii i meditsiny. 2015;16(11):657–60.
9. Ardill JE, Erikkson B. The importance of the measurement of circulating markers in patients with neuroendocrine tumours of the pancreas and gut. Endocr Relat Cancer. 2003;10(4):459–62.
10. Gkolfinopoulos S, Tsapakidis K, Papadimitriou K, Papamichael D, Kountourakis P. Chromogranin A as a valid marker in oncology: Clinical application or false hopes? World J Methodol. 2017;7(1):9–15. doi: 10.5662/wjm.v7.i1.9.
11. Rossi RE, Garcia-Hernandez J, Meyer T, Thirlwell C, Watkins J, Martin NG, Caplin ME, Toumpanakis C. Chromogranin A as a predictor of radiological disease progression in neuroendocrine tumours. Ann Transl Med. 2015;3(9): 118. doi: 10.3978/j.issn.2305-5839.2015.04.23.
12. Massironi S, Rossi RE, Casazza G, Conte D, Ciafardini C, Galeazzi M, Peracchi M. Chromogranin A in diagnosing and monitoring patients with gastroenteropancreatic neuroendocrine neoplasms: a large series from a single institution. Neuroendocrinology. 2014;100(2–3): 240–9. doi: 10.1159/000369818.
13. Walter T, Chardon L, Chopin-laly X, Raverot V, Caffin AG, Chayvialle JA, Scoazec JY, Lombard-Bohas C. Is the combination of chromogranin A and pancreatic polypeptide serum determinations of interest in the diagnosis and follow-up of gastro-entero-pancreatic neuroendocrine tumours? Eur J Cancer. 2012;48(12): 1766–73. doi: 10.1016/j.ejca.2011.11.005.
14. Bajetta E, Procopio G, Catena L, Martinetti A, De Dosso S, Ricci S, Lecchi AS, Boscani PF, Iacobelli S, Carteni G, De Braud F, Loli P, Tartaglia A, Bajetta R, Ferrari L. Lanreotide autogel every 6 weeks compared with Lanreotide microparticles every 3 weeks in patients with well differentiated euroendocrine tumors: a Phase III Study. Cancer. 2006;107(10):2474–81. doi: 10.1002/cncr.22272.
15. Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P, Hoosen S, St Peter J, Haas T, Lebwohl D, Van Cutsem E, Kulke MH, Hobday TJ, O'Dorisio TM, Shah MH, Cadiot G, Luppi G, Posey JA, Wiedenmann B. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol. 2010;28(1):69–76. doi: 10.1200/JCO.2009.24.2669.
16. Jensen KH, Hilsted L, Jensen C, Mynster T, Rehfeld JF, Knigge U. Chromogranin A is a sensitive marker of progression or regression in ileo-cecal neuroendocrine tumors. Scand J Gastroenterol. 2013;48(1):70–7. doi: 10.3109/00365521.2012.733953.
17. Jensen EH, Kvols L, McLoughlin JM, Lewis JM, Alvarado MD, Yeatman T, Malafa M, Shibata D. Biomarkers predict outcomes following cytoreductive surgery for hepatic metastases from functional carcinoid tumors. Ann Surg Oncol. 2007;14(2):780–5. doi: 10.1245/s10434-006-9148-z.
18. Cheng Y, Sun Z, Bai C, Yan X, Qin R, Meng C, Ying H. Serum chromogranin A levels for the diagnosis and follow-up of well-differentiated non-functioning neuroendocrine tumors. Tumour Biol. 2016;37(3):2863–9. doi: 10.1007/s13277-015-4114-7.
19. Singh S, Law C. Chromogranin A: a sensitive biomarker for the detection and post-treatment monitoring of gastroenteropancreatic neuroendocrine tumors. Expert Rev Gastroenterol Hepatol. 2012;6(3):313–34. doi: 10.1586/egh.12.15.
20. Kim M, Lee S, Lee J, Park SH, Park JO, Park YS, Kang WK, Kim ST. The role of plasma chromogranin as assessment of treatment response in non-functioning gastroenteropancreatic neuroendocrine tumors. Cancer Res Treat. 2016;48(1):153–61. doi: 10.4143/crt.2014.183.
21. Han X, Zhang C, Tang M, Xu X, Liu L, Ji Y, Pan B, Lou W. The value of serum chromogranin A as a predictor of tumor burden, therapeutic response, and nomogram-based survival in well-moderate nonfunctional pancreatic neuroendocrine tumors with liver metastases. Eur J Gastroenterol Hepatol. 2015;27(5):527–35. doi: 10.1097/MEG.0000000000000332.
