Anemia of Chronic Disease: Key Mechanisms of Pathogenesis in Patients with Malignancies and Feasible Classification Approaches

VT Sakhin1, ER Madzhanova1, EV Kryukov3, AV Sotnikov2, AV Gordienko2, OA Rukavitsyn3

1 1586 Military Clinical Hospital, 4 Mashtakova str., Moscow Region, Podolsk, Russian Federation, 142110

2 SM Kirov Military Medical Academy, 6 Akademika Lebedeva str., Saint Petersburg, Russian Federation, 194044

3 NN Burdenko Central Military Clinical Hospital, 3 Gospital’naya sq., Moscow, Russian Federation, 105229

For correspondence: Valerii Timofeevich Sakhin, MD, PhD, 4 Mashtakova str., Moscow Region, Podolsk, Russian Federation, 142110; Tel.: +7(916)314-31-11; e-mail: SahinVT@yandex.ru

For citation: Sakhin VT, Madzhanova ER, Kryukov EV, et al. Anemia of Chronic Disease: Key Mechanisms of Pathogenesis in Patients with Malignancies and Feasible Classification Approaches. Clinical oncohematology. 2019;12(3):344–9 (In Russ).

doi: 10.21320/2500-2139-2019-12-3-344-349


ABSTRACT

Aim. To study the effect of hepcidin, soluble transferrin receptor (sTfR), and cytokines on iron metabolism and occurrence of anemia in patients with malignancies and to propose, on this basis, a draft classification of anemia of chronic disease (ACD) based on the major pathogenic factor.

Materials & Methods. The trial included 63 patients with malignancies of stage II/IV: 41 patients with anemia (34 men, 7 women, mean age 67.1 ± 9.9 years), 22 patients without anemia (17 men, 5 women, mean age 60.2 ± 14.9 years). Comparative analysis was based on the values of iron metabolism, C-reactive protein (CRP), hepcidin, sTfR, as well as pro-inflammatory (interleukin-6 [IL-6], tumour necrosis factor α [TNF-α]) and anti-inflammatory (IL-10) cytokines in solid malignancy patients with and without anemia. The correlation analysis between IL-6, IL-10, TNF-α, hepcidin, sTfR, and blood count was performed.

Results. Compared with the control group patients with anemia show lower levels of iron concentration, total iron-binding capacity (TIBC), and percent transferrin saturation (TSAT), as well as higher level of CRP, hepcidin, sTfR, IL-6, IL-10, and TNF-α (< 0.05). IL-6 (r = –0.58), TNF-α (r = –0.32), and hepcidin (r = –0.57) proved to negatively affect erythrocyte level. A negative correlation was established between hemoglobin concentration and IL-6 (r = –0.57), IL-10 (r = –0.64), TNF-α (r = –0.65), hepcidin (r = –0.3), and sTfR (r = –0.57). A correlation was identified between concentrations of hepcidin and IL-6 (r = 0.58), IL-10 (r = 0.33), TNF-α (r = –0.4), as well as between concentrations of sTfR and IL-10 (r = 0.58), TNF-α (r = –0.53). A relationship was identified between IL-6 concentration and iron status (r = –0.38), TIBC (r = –0.56), TSAT (r = –0.31), ferritin (r = 0.56), transferrin (r = –0.72), CRP (r = 0.86) as well as between concentrations of IL-10 and iron (r = –0.63), TSAT (r = –0.67), transferrin (r = –0.7), ferritin (r = 0.55), CRP (r = 0.65), TIBC (r = –0.71). A correlation between the levels of TNF-α and TIBC (r = –0.36), transferrin (r = –0.5) was confirmed.

Conclusion. The paper deals with multi-factorial pathogenesis of anemia in patients with malignancies. Most important factors are iron deficiency and erythropoietic disorder. A draft ACD classification based on the major pathogenic factor of anemia (ACD with dominating iron deficiency, ACD with impaired regulatory mechanism of erythropoiesis, and ACD with insufficient erythropoietin production) is proposed.

Keywords: cancer, anemia, iron metabolism, interleukin-6, interleukin-10, tumor necrosis factor alpha, hepcidin, soluble transferrin receptor.

Received: January 21, 2019

Accepted: June 18, 2019

Read in PDF 


REFERENCES

  1. Weiss G. Pathogenesis and treatment of anaemia of chronic disease. Blood Rev. 2002;16(2):87–96. doi: 10.1054/blre.2002.0193.

  2. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005;352(10):1011–23. doi: 10.1056/nejmra041809.

  3. Means RT. Recent developments in the anemia of chronic disease. Curr Hematol Rep. 2003;2(2):116–21.

  4. Poggiali E, De Amicis MM, Motta I, et al. Anemia of chronic disease: a unique defect of iron recycling for many different chronic diseases. Eur J Int Med. 2014;25(1):12–17. doi: 10.1016/j.ejim.2013.07.011.

  5. Weiss G. Iron metabolism in the anemia of chronic disease. Biochim Biophys Acta. 2009;1790(7):682–93. doi: 10.1016/j.bbagen.2008.08.006.

  6. Ganz T, Nemeth E. Hepcidin and iron homeostasis. Biochim Biophys Acta. 2012;1823(9):1434–43. doi: 10.1016/j.bbamcr.2012.01.014.

  7. McCranor BJ, Kim MJ, Cruz NM, et al. Interleukin-6 directly impairs the erythroid development of human TF-1 erythroleukemic cells. Blood Cells Mol Dis. 2014;52(2–3):126–33. doi: 10.1016/j.bcmd.2013.09.004.

  8. Анемии. Под ред. О.А. Рукавицына. 2-е изд., перераб. и доп. М.: ГЭОТАР-Медиа, 2016. 256 c.

    [Rukavitsyn OA, ed. (Anemias.) 2nd revised edition. Moscow: GEOTAR-Media Publ.; 2016. 256 p. (In Russ)]

  9. Сахин В.Т., Маджанова Е.Р., Крюков Е.В. и др. Анемия хронических заболеваний: особенности патогенеза и возможности терапевтической коррекции (обзор литературы и результаты собственных исследований). Онкогематология. 2018;13(1):45–53. doi: 10.17650/1818-8346-2018-13-1-45-53.

    [Sakhin VТ, Madzhanova ЕR, Kryukov EV, et al. Anemia of chronic disease: features of pathogenesis and possible therapeutic correction (literature review and results of own research). Oncohematology. 2018;13(1):45–53. doi: 10.17650/1818-8346-2018-13-1-45-53. (In Russ)]

  10. Steinmetz T, Totzke U, Schweigert M, et al. A prospective observational study of anaemia management in cancer patients–results from the German Cancer Anaemia Registry. Eur J Cancer Care. 2011;20(4):493–502. doi: 10.1111/j.1365-2354.2010.01230.x.

  11. Waters JS, O’Brien MER, Ashley S. Management of anemia in patients receiving chemotherapy. J Clin Oncol. 2002;20(2):601–3. doi: 10.1200/JCO.2002.20.2.601.

  12. Grotto HZ. Anaemia of cancer: an overview of mechanisms involved in its pathogenesis. Med Oncol. 2008;25(1):12–21. doi: 1007/s12032-007-9000-8.

  13. Гематология: национальное руководство. Под ред. О.А. Рукавицына. М.: ГЭОТАР-Медиа, 2015. С. 143–9.

    [Rukavitsyn OA, ed. Gematologiya: natsional’noe rukovodstvo. (Hematology: national guidelines.) Moscow: GEOTAR-Media Publ.; 2015. pp. 143–9. (In Russ)]

  14. Steinmetz HT, Tsamaloukas A, Schmitz S, et al. A new concept for the differential diagnosis and therapy of anaemia in cancer patients. Support Care Cancer. 2010;19(2):261–9. doi: 10.1007/s00520-010-0812-2.

  15. Maccio A, Madeddu C, Massa D, et al. Hemoglobin levels correlate with interleukin-6 levels in patients with advanced untreated epithelial ovarian cancer: role of inflammation in cancer-related anemia. 2005;106(1):362–7. doi: 10.1182/blood-2005-01-0160.

  16. Сахин В.Т., Маджанова Е.Р., Крюков Е.В. и др. Патогенетические особенности анемии у больных с солидными опухолями. Клиническая онкогематология. 2017;10(4):514–8. doi: 10.21320/2500-2139-2017-10-4-514-518.

    [Sakhin VT, Madzhanova ER, Kryukov EV, et al. Pathogenetic Characteristics of Anemia in Patients with Solid Tumors. Clinical oncohematology. 2017;10(4):514–8. doi: 10.21320/2500-2139-2017-10-4-514-518. (In Russ)]

  17. Park S, Jung CW, Kim K, et al. Iron deficient erythropoiesis might play key role in development of anemia in cancer patients. Oncotarget. 2015;6(40):42803–12. doi: 10.18632/oncotarget.5658.

  18. Speeckaert MM, Speeckaert R, Delanghe JR. Biological and clinical aspects of soluble transferrin receptor. Crit Rev Clin Lab Sci. 2010;47(5–6):213–28. doi: 10.3109/10408363.2010.550461.

  19. Moldawer LL, Marano MA, Wei H, et al. Cachectin/tumor necrosis factor-alpha alters red blood cell kinetics and induces anemia in vivo. FASEB J. 1989;3(5):1637–43.

  20. Raj DSC. Role of interleukin-6 in the anemia of chronic disease. Sem Arthritis Rheum. 2009;38(5):382–8. doi: 10.1016/j.semarthrit.2008.01.006.

  21. Wrighting DM, Andrews NC. Interleukin-6 induces hepcidin expression through STAT3. Blood. 2006;108(9):3204–9. doi: 10.1182/blood-2006-06-027631.

  22. Huang P, Wang J, Lin X, et al. Effects of IL-10 on iron metabolism in LPS-induced inflammatory mice via modulating hepcidin expression. Eur Rev MedPharmacol Sci. 2017;21(15):3469–75.

  23. Shanmugam NKN, Ellenbogen S, Trebicka E, et al. Tumor necrosis factor α inhibits expression of the iron regulating hormone hepcidin in murine models of innate colitis. PLoS One. 2012;7(5):e38136. doi: 10.1371/journal.pone.0038136.

  24. De Lurdes Cabrita AA, Pinho A, Malho A, et al. Risk factors for high erythropoiesis stimulating agent resistance index in pre-dialysis chronic kidney disease patients, stages 4 and 5. Int Urol Nephrol. 2011;43(3):835–40. doi: 10.1007/s11255-010-9805-9.

  25. Nazemian F, Karimi G, Moatamedi M, et al. Effect of silymarin administration on TNFalpha serum concentration in peritoneal dialysis patients. Phytother Res. 2010;24(11):1654–7. doi: 10.1002/ptr.3175.

Correction of Anemia and Evaluation of Efficacy of Red Blood Cell Transfusion in Patients with Oncohematological Diseases

NA Romanenko1, AV Chechetkin1, LYu Zhiguleva1, GV Grishina1, SV Bondarchuk2, SS Bessmel’tsev1

1 Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024

2 SM Kirov Military Medical Academy, 6 Akademika Lebedeva str., Saint Petersburg, Russian Federation, 194044

For correspondence: Nikolai Aleksandrovich Romanenko, MD, PhD, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024; Tel.: 8(812)717-58-57; Fax: 8(812)717-67-80; е-mail: rom-nik@yandex.ru

For citation: Romanenko NA, Chechetkin AV, Zhiguleva LYu, et al. Correction of Anemia and Evaluation of Efficacy of Red Blood Cell Transfusion in Patients with Oncohematological Diseases. Clinical oncohematology. 2018;11(3):265–72.

DOI: 10.21320/2500-2139-2018-11-3-265-272


ABSTRACT

Aim. To study the quality of life (QL) of patients with oncohematological diseases and anemia with respect to hemoglobin level and to evaluate the efficacy of red blood cell transfusion (RBCT).

Materials & Methods. QL of patients (n = 326) was studied using FACT-An questionnaire. RBCT efficacy was evaluated in two groups. The first group included patients (n = 28; 13 men and 15 women) with oncohematological diseases and chronic anemia aged 23–80 (median 65) years, the second (control) group included patients (n = 12; 11 men and 1 woman) after severe blood loss after injury (acute anemia) aged 25–43 (median 36) years. The baseline levels of hemoglobin (Hb) and hematocrit (Ht) were < 80 g/L and < 25 % in all patients, respectively. The target levels of Hb and Ht were > 80 g/L and > 25 %, respectively.

Results. The association between the severity of anemia and QL was shown. The lowest QL was observed in patients with grade III–IV anemia (Hb < 80 g/L). Each patient in both groups received 1–8 units of blood cells (median 2) during the hospital stay. After RBCT the levels of Hb and Ht increased from 64.1 ± 2.7 g/L to 90.2 ± 1.7 g/L and from 20.1 ± 0.8 % to 28.9 ± 0.7 %, respectively. The levels of Hb and Ht in the second (control) group increased from 65.9 ± 3.0 g/L to 88.3 ± 3.2 g/L and from 19.6 ± 0.9 % to 26.7 ± 1.4 %, respectively. Venous blood oxygen saturation (SvO2) increased in the first group from 42.0 ± 3.3 % to 57.6 ± 4.1 %, and in the second group from 51.3 ± 1.9 % to 69.0 ± 1.3 %. However, after RBCT the SvO2 level reached > 60 % only in 67.9 % of patients in the first group and in all the patients (100 %) in the second group. In 32.1 % of patients with various forms of hematologic cancer and chronic anemia tissue hypoxia was still observed after RBCT despite increased Hb > 80 g/L and Ht > 25 %. Therefore, it was proposed to raise the target Hb and Ht threshold levels for patients with low SvO2.

Conclusion. The effect of the severity of anemia on QL was demonstrated. The patients with Hb < 80 g/L were shown to have low quality of life. SvO2 determination in anemia patients proved to be of great importance for RBCT efficacy evaluation. In patients with low SvO2 (< 60 %) RBCT should be continued until the target levels of Hb 100 g/L and Ht 33 % are reached.

Keywords: anemia, chronic anemia, red blood cell transfusions, hemoglobin concentration, hematocrit, venous blood oxygen saturation, quality of life, FACT-An questionnaire.

Received: March 10, 2018

Accepted: May 30, 2018

Read in PDF 

REFERENCES

  1. Сахин В.Т., Маджанова Е.Р., Крюков Е.В. и др. Патогенетические особенности анемии у больных с солидными опухолями. Клиническая онкогематология. 2017;10(4):514–8. doi: 10.21320/2500-2139-2017-10-4-514-518.[Sakhin VT, Madzhanova ER, Kryukov EV, et al. Pathogenetic Characteristics of Anemia in Patients with Solid Tumors. Clinical oncohematology. 2017;10(4):514–8. doi: 10.21320/2500-2139-2017-10-4-514-518. (In Russ)]
  2. Santos FPS, Alvarado Y, Kantarjian H, et al. Long-term prognostic impact of the use of erythropoietic-stimulating agents in patients with chronic myeloid leukemia in chronic phase treated with imatinib. Cancer. 2011;117(5):982–91. doi: 10.1002/cncr.25533.
  3. Steurer M, Wagner H, Gastel G. Prevalence and management of anaemia in haematologic cancer patients receiving cyclic nonplatinum chemotherapy: results of a prospective national chart survey. Wien Klin Wochenschr. 2004;116(11–12):367–72. doi: 1007/bf03040915.
  4. Романенко Н.А. Патогенез и терапия анемии препаратами рекомбинантного эритропоэтина у онкогематологических больных (обзор современной литературы). Онкогематология. 2012;7(3):22–9. doi: 10.17650/1818-8346-2012-7-3-22-29.[Romanenko NA. Pathogenesis and therapy of anemia in oncohematology patients with recombinant erythropoietin agent (literature review). Onkogematologiya. 2012;7(3):22–9. doi: 10.17650/1818-8346-2012-7-3-22-29. (In Russ)]
  5. Truong PT, Parhar T, Hart J, et al. Population-based analysis of the frequency of anemia and its management before and during chemotherapy in patients with malignant lymphoma. Am J Clin. Oncol. 2010;33(5):465–8. doi: 10.1097/COC.0b013e3181b4b147.
  6. Leitch HA, Vickars LM. Supportive care and chelation therapy in MDS: are we saving lives or just lowering iron? Hematology. 2009;2009(1):664–72. doi: 10.1182/asheducation-2009.1.664.
  7. Passamonti F, Rumi E, Arcaini L, et al. Blast phase of essential thrombocythemia: A single center study. Am J Hematol. 2009;84(10):641–4. doi: 10.1002/ajh.21496.
  8. Tefferi A, Lasho TL, Jimma T, et al. One thousand patients with primary myelofibrosis: the Mayo clinic experience. Mayo Clin Proc. 2012;87(1):25–33. doi: 10.1016/j.mayocp.2011.11.001.
  9. Quintas-Cardama A, De Souza Santos FP, Kantarjian H, et al. Dynamics and management of cytopenias associated with dasatinib therapy in patients with chronic myeloid leukemia in chronic phase after imatinib failure. Cancer. 2009;115(17):3935–43. doi: 10.1002/cncr.24432.
  10. Romanenko N, Abdulkadyrov K, Gritsaev S, Bessmeltsev S. Study of effectiveness recombinant human erythropoietin in chronic myeloid leukemia patients with anemia induced imatinib therapy. Haematologica. 2011;96(Suppl. 2):S
  11. Бессмельцев С.С., Романенко Н.А., Потихонова Н.А. и др. Злокачественные лимфопролиферативные заболевания с анемией: изменение качества жизни пациентов на фоне переливаний донорских эритроцитов и применения препаратов рекомбинантного эритропоэтина. Клиническая онкогематология. 2015;8(4):368–78. doi: 10.21320/2500-2139-2015-8-4-368-378.[Bessmel’tsev SS, Romanenko NA, Potikhonova NA, et al. Malignant Lymphoproliferative Disorders with Anemia: Changes of Quality of Life in Patients Treated with Donor Red Blood Cell Transfusions and Recombinant Erythropoietin. Clinical oncohematology. 2015;8(4):368–78. doi: 10.21320/2500-2139-2015-8-4-368-378. (In Russ)]
  12. Samuelsson J. Long-standing resolution of anemia in symptomatic low-grade non-Hodgkin’s lymphoma patients treated with recombinant human erythropoietin as sole therapy. Med Oncol. 2002;19(1):69–72. doi: 1385/MO:19:1:69.
  13. Романенко Н.А., Бессмельцев С.С., Потихонова Н.А. и др. Качество жизни больных лимфопролиферативными заболеваниями с анемией на фоне трансфузий эритроцитов и эритропоэзстимулирующих препаратов. Биомедицинский журнал Medline.ru. 2014;15(56):703–17.[Romanenko NA, Bessmel’tsev SS, Potikhonova NA, et al. Quality of life of anemia patients with lymphoproliferative disorders treated with red blood cell transfusions and erythropoiesis stimulating drugs. Biomeditsinskii zhurnal Medline.ru. 2014;15(56):703–17. (In Russ)]
  14. Romanenko N, Bessmeltsev S, Romanenko A, et al. Quality of life in anemic patients with hematological malignancies. Haematologica. 2017;102(Suppl 1):843.
  15. Бессмельцев С.С., Абдулкадыров К.М. Множественная миелома: руководство для врачей. М.: МК, 2016. 504 с.[Bessmel’tsev SS, Abdulkadyrov KM. Mnozhestvennaya mieloma: rukovodstvo dlya vrachei. (Multiple myeloma: guidelines for doctors.) Moscow: MK Publ.; 2016. 504 p. (In Russ)]
  16. Романенко Н.А., Бессмельцев С.С., Чечеткин А.В. Коррекция иммунного статуса пациентов иммуноглобулином человека для внутривенного введения. Казанский медицинский журнал. 2017;98(5):775–83.[Romanenko NA, Bessmel’tsev SS, Chechetkin AV. Correction of patients’ immune status with human intravenous immunoglobulin. Kazanskii meditsinskii zhurnal. 2017;98(5):775–83. (In Russ)]
  17. Романенко Н.А., Головченко Р.А., Бессмельцев С.С. и др. Эффективность трансфузий донорских эритроцитов у больных гемобластозами с анемией. Трансфузиология. 2015;16(2):29–42.[Romanenko NA, Golovchenko RA, Bessmel’tsev SS, et al. Efficacy of donor red blood cell transfusions in patients with blood cancer and anemia. Transfuziologiya. 2015;16(2):29–42. (In Russ)]
  18. Romanenko N, Potikhonova N, Tiranova S, et al. Dynamics of Quality of Life in anemic patients with lymphoproliferative disorders treated with red blood cell transfusions and erythropoiesis-stimulating agents. 2016;101(Suppl 1):S40.
  19. Приказ МЗ РФ № 363 от 25.11.2002 г. «Об утверждении Инструкции по применению компонентов крови»). М., 2002.[Decree No. 363 of RF MH dated November 25, 2002. Approval of the Instruction on use of blood components. Mоscow; 2002. (In Russ)]
  20. Provan D, Baglin T, Dokal I, de Vos J. Oxford Handbook of Clinical Haematology, 4th edition. Oxford University Press; 2015. 805 p. doi: 10.1093/med/9780199683307.001.0001.
  21. Бессмельцев С.С., Романенко Н.А. Анемия при опухолевых заболеваниях системы крови: руководство для врачей. М.: СИМК, 2017. 228 с.[Bessmel’tsev SS, Romanenko NA. Anemiya pri opukholevykh zabolevaniyakh sistemy krovi: rukovodstvo dlya vrachei. (Anemia in patients with blood cancer: guidelines for doctors.) Moscow: SIMK Publ.; 2017. 228 p. (In Russ)]
  22. Трансфузиология: Клиническое руководство. Под ред. М.Ф. Заривчацкого. Пермь: ГБОУ ВПО ПГМА им. акад. Е.А. Вагнера Минздрава России, 2014. 900 с.[Zarivchatskii MF, ed. Transfuziologiya: Klinicheskoe rukovodstvo. (Transfusiology: clinical guidelines.) Perm: E.A. Vagner Medical University Publ.; 2014. 900 p. (In Russ)]
  23. Приказ МЗ РФ № 183н от 2.04.2013 г. «Об утверждении правил клинического использования донорской крови и (или) ее компонентов». М., 2013.[Decree No. 183н of RF MH dated April 2, 2013. Approval of the Instruction on clinical use of donated blood and/or its components. Mоscow; 2013. (In Russ)]
  24. Чечеткин А.В., Данильченко В.В., Шайдаков Е.В. и др. Трансфузионная терапия послеоперационной анемии у больных при плановых хирургических вмешательствах в военных лечебных учреждениях. Методические рекомендации. СПб., 2006. 28 c.[Chechetkin AV, Danil’chenko VV, Shaidakov EV, et al. Transfuzionnaya terapiya posleoperatsionnoi anemii u bol’nykh pri planovykh khirurgicheskikh vmeshatel’stvakh v voennykh lechebnykh uchrezhdeniyakh. Metodicheskie rekomendatsii. (Transfusion therapy of post-surgery anemia in scheduled surgeries in military medical institutions. Guidelines.) Saint Petersburg; 2006. 28 p. (In Russ)]
  25. Романенко Н.А., Грицаев С.В., Бессмельцев С.С., Абдулкадыров К.М. Эффективность эритропоэзстимулирующих препаратов при анемии у больных миелодиспластическим синдромом. Гематология и трансфузиология. 2013;58(4):18–21.[Romanenko NA, Gritsaev SV, Bessmel’tsev SS, Abdulkadyrov KM. Efficacy of erythropoiesis stimulating drugs in anemia patients with myelodysplastic syndrome. Gematologiya i transfuziologiya. 2013;58(4):18–21. (In Russ)]

Pathogenetic Characteristics of Anemia in Patients with Solid Tumors

VT Sakhin1, ER Madzhanova1, EV Kryukov3, AV Sotnikov2, AV Gordienko2, OA Rukavitsyn3

11586 Military Clinical Hospital, 4 Mashtakova str., Podolsk, Russian Federation, 142110

2SM Kirov Military Medical Academy, 6 Akademika Lebedeva str., Saint Petersburg, Russian Federation, 194044

3NN Burdenko Main Military Clinical Hospital, 3 Gospitalnaya sq., Moscow, Russian Federation, 105229

For correspondence: Valery Timofeevich Sakhin, PhD, 4 Mashtakova str., Podolsk, Russia, 142110; Tel.: +7(916)314-31-11; e-mail: SahinVT@yandex.ru

For citation: Sakhin VT, Madzhanova ER, Kryukov EV, et al. Pathogenetic Characteristics of Anemia in Patients with Solid Tumors. Clinical oncohematology. 2017;10(4):514–8 (In Russ).

DOI: 10.21320/2500-2139-2017-10-4-514-518


ABSTRACT

Aim. To study the impact iron metabolism disturbances and cytokine levels on the development of anemia in patients with solid tumors.

Materials & Methods. The research included 42 patients with malignant neoplasms, including 24 patients with anemia (19 men and 5 women, median age 67.7 ± 10 years) and 18 patients without anemia (15 men, 3 women, median age 65.7 ± 14 years). Anemia was diagnosed according to the WHO criteria (in men: erythrocytes < 4.0 × 1012/L, hemoglobin < 130 g/L, hematocrit < 39 %; in women: erythrocytes < 3.8 × 1012/L, hemoglobin < 120 g/L, hematocrit < 36 %).

Results. A comparative analysis of iron metabolism in patients with and without anemia was performed. The lower values of serum iron and transferrin saturation in patients with anemia were shown (< 0.05). The total iron-binding capacity, the levels of ferritin, transferrin, C-reactive protein, indirect bilirubin were similar between groups (> 0,05). Higher levels of interleukins 6 and 10 (IL-6 and IL-10) were observed in patients with anemia (< 0.05). For IL-6, correlations were observed with levels of erythrocytes (r = –0,58), hemoglobin (r = –0,57), hematocrit (r = –0,52), and leukocytes (r = 0,42). The levels of IL-10 slightly correlated with the levels of erythrocytes, leukocytes, platelets, MCV, and MCH (r < 0.3). For IL-10, correlations were established with levels of MCHC (r = –0,71), hemoglobin (r = –0,64) and hematocrit (r = –0,32). Correlations between the levels IL-6, IL-6 and hemoglobin, erythrocytes and several color indices may indicate their influence on the development of anemia in patients with malignant neoplasms.

Conclusion. A functional iron deficiency in patients with anemia was found. Several causes of anemia development and significant role of interleukins in anemia pathogenesis were also discovered.

Keywords: cancer, anemia, iron metabolism, interleukin-6, interleukin-10.

Received: March 21, 2017

Accepted: June 22, 2017

Read in PDF

REFERENCES

  1. Maccio A, Madeddu C, Gramignano G, et al. The role of inflammation, iron, and nutritional status in cancer-related anemia: results of a large, prospective, observational study. Haematologica. 2015;100(1):124–32. doi: 10.3324/haematol.2014.112813.
  2. Ludwig H, Van Belle S, Barrett-Lee P, et al. The European Cancer Anaemia Survey (ECAS): A large, multinational, prospective survey defining the prevalence, incidence, and treatment of anaemia in cancer patients. Eur J Cancer. 2004;40(15):2293–306. doi: 10.1016/j.ejca.2004.06.019.
  3. Steinmetz T, Totzke U, Schweigert M, et al. A prospective observational study of anaemia management in cancer patients–results from the German Cancer Anaemia Registry. Eur J Cancer Care. 2011;20(4):493–502. doi: 10.1111/j.1365-2354.2010.01230.x.
  4. Waters JS, O’Brien MER, Ashley S. Management of anemia in patients receiving chemotherapy. J Clin Oncol. 2002;20(2):601–3. doi: 10.1200/JCO.2002.20.2.601.
  5. Grotto HZ. Anaemia of cancer: an overview of mechanisms involved in its pathogenesis. Med Oncol. 2008;25(1):12–21. doi: 10.1007/s12032-007-9000-8.
  6. Гематология: национальное руководство. Под ред. О.А. Рукавицына. М.: ГЭОТАР-Медиа, 2015. С. 143–9.[Rukavitsyn OA, ed. Gematologiya: natsional’noe rukovodstvo. (Hematology: national guidelines.) Moscow: GEOTAR-Media Publ.; 2015. pp. 143–9 (In Russ)]
  7. Ludwig H, Muldur E, Endler G, et al. Prevalence of iron deficiency across different tumors and its association with poor performance status, disease status and anemia. Ann Oncol. 2013;24(7):1886–92. doi: 10.1093/annonc/mdt118.
  8. de Castro J, Gascоn P, Casas A, et al. Iron deficiency in patients with solid tumours: prevalence and management in clinical practice. Clin Transl Oncol. 2014;16(9):823–8. doi: 10.1007/s12094-013-1155-5.
  9. Beguin Y. Prediction of response and other improvements on the limitations of recombinant human erythropoietin therapy in anemic cancer patients. Haematologica. 2002;87(11):1209–21.
  10. Steinmetz HT, Tsamaloukas A, Schmitz S, et al. A new concept for the differential diagnosis and therapy of anaemia in cancer patients. Support Care Cancer. 2010;19(2):261–9. doi: 10.1007/s00520-010-0812-2.
  11. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005;352(10):1011–23. doi: 10.1056/nejmra041809.
  12. Maccio A, Madeddu C, Massa D, et al. Hemoglobin levels correlate with interleukin-6 levels in patients with advanced untreated epithelial ovarian cancer: role of inflammation in cancer-related anemia. Blood. 2005;106(1):362–7. doi: 10.1182/blood-2005-01-0160.
  13. Falkensammer CE, Thurnher M, Leonhartsberger N, Ramoner R. C-reactive protein is a strong predictor for anaemia in renal cell carcinoma: role of IL-6 in overall survival. BJU Int. 2011;107(12):1893–8. doi: 10.1111/j.1464-410x.2010.09817.x.

Anemias and iron deficiency in cancer patients

V.V. Ptushkin

Federal Scientific and Clinical Centre of Pediatric Hematology, Oncology and Immunology named after Dmitriy Rogachev, Moscow, Russian Federation


ABSTRACT

Anemia is frequent in cancer patients and its incidence increases with chemotherapy. Anemia negatively impacts survival and accentuates fatigue in cancer patients. Cancer promotes inflammatory cytokine production, which suppresses erythropoiesis and erythropoietin production. Erythropoiesis-stimulating agents improve erythropoiesis and reduce transfusion needs in anemic cancer patients receiving chemotherapy. However, meta-analyses have shown an increased risk of thromboembolic events with еrythropoiesis-stimulating agents use during chemotherapy, but not increased on-study mortality or reduced overall survival. Inflammatory cytokine production in patients with cancer, reduce the availability of iron for effective erythropoiesis. This review summarises clinical consequences of iron deficiency and anaemia in cancer patients, mechanisms how impaired iron homeostasis affects diagnosis and treatment of iron deficiency, and data from clinical trials evaluating i.v. iron with or without concomitant erythropoiesis-stimulating agents.


Keywords: Anemia, cancer, erythropoietin, iron propagates, ferric carboxymaltose, ferritin, transferrin

Read in PDF (RUS)pdficon


REFERENCES

  1. Ludwig H., Van B.S., Barrett-Lee P. et al. The European Cancer AnaemiaSurvey (ECAS): a large, multinational, prospective survey defining the prevalence, incidence, and treatment of anaemia in cancer patients. Eur. J. Cancer 2004; 40: 2293–306.
  2. Groopman J.E., Itri L.M. Chemotherapy-induced anemia in adults: incidence and treatment. J. Natl. Cancer Inst. 1999; 91: 1616–34.
  3. Beale A.L., Penney M.D., Allison M.C. The prevalence of iron deficiency among patients presenting with colorectal cancer. Colorectal. Dis. 2005; 7: 398–402.
  4. Kuvibidila S.R., Gauthier T., Rayford W. Serum ferritin levels and transferrin saturation in men with prostate cancer. J. Natl. Med. Assoc. 2004; 96: 641–9.
  5. Steinmetz H.T., Tsamaloukas A., Schmitz S. et al. A new concept for the differential diagnosis and therapy of anaemia in cancer patients. Support Care Cancer 2010; 19: 261–9.
  6. Beguin Y., Lybaert W., Bosly A. A prospective observational study exploring the impact of iron status on response to darbepoetin alfa in patients with chemotherapy induced anemia. Blood 2009; 114 (Abstr 2007).
  7. Ludwig H., Muldur E., Endler G. et al. High prevalence of iron deficiency across different tumors correlates with anemia, increases during cancer treatment and is associated with poor performance status. Haematologica 2011; 96 (Abstr 982).
  8. Anker S.D., Comin C.J., Filippatos G. et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N. Engl. J. Med. 2009; 361: 2436–48.
  9. Crawford J., Cella D., Cleeland C.S. et al. Relationship between changes in hemoglobin level and quality of life during chemotherapy in anemic cancer patients receiving epoetin alfa therapy. Cancer 2002; 95: 888–95.
  10. Auerbach M., Ballard H., Trout J.R. et al. Intravenous iron optimizes the response to recombinant human erythropoietin in cancer patients with chemotherapy-related anemia: a multicenter, open-label, randomized trial. J. Clin. Oncol. 2004; 22: 1301–7.
  11. Rizzo J.D., Brouwers M., Hurley P. et al. American Society of Hematology/ American Society of Clinical Oncology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. Blood 2010; 116: 4045–59.
  12. Auerbach M., Silberstein P.T., Webb R.T. et al. Darbepoetin alfa 300 or 500 mg once every 3 weeks with or without intravenous iron in patients with chemotherapyinduced anemia. Am. J. Hematol. 2010; 85: 655–63.
  13. Henry D.H., Dahl N.V., Auerbach M. et al. Intravenous ferric gluconate significantly improves response to epoetin alfa versus oral iron or no iron in anemic patients with cancer receiving chemotherapy. Oncologist 2007; 12: 231–42.
  14. Pedrazzoli P., Farris A., Del P.S. et al. Randomized trial of intravenous iron supplementation in patients with chemotherapy-related anemia without iron deficiency treated with darbepoetin alpha. J. Clin. Oncol. 2008; 26: 1619–25.
  15. Beguin Y. Prediction of response and other improvements on the limitations of recombinant human erythropoietin therapy in anemic cancer patients. Haematologica 2002; 87: 1209–21.
  16. Wish J.B. Assessing iron status: beyond serum ferritin and transferrin saturation. Clin. J. Am. Soc. Nephrol. 2006; 1(Suppl. 1): S4–S8.
  17. Hedenus M., Birgegard G., Nasman P et al. Addition of intravenous iron to epoetin beta increases hemoglobin response and decreases epoetin dose requirement in anemic patients with lymphoproliferative malignancies: a randomized multicenter study. Leukemia 2007; 21: 627–32.
  18. Ludwig H., Endler G., Hubl W. et al. High prevalence of iron deficiency in patients with various hematological and malignant diseases: a single center study in 1989 sequential patients. Haematologica 2010; 95 (Abstr 1819).
  19. Ludwig H., Aapro M., Bokemeyer C. et al. Treatment patterns and outcomes in the management of anaemia in cancer patients in Europe: findings from the Anaemia Cancer Treatment (ACT) study. Eur. J. Cancer 2009; 45: 1603–15.
  20. Aapro M.S., Link H. September 2007 update on EORTC guidelines and anemia management with erythropoiesis-stimulating agents. Oncologist 2008; 13(Suppl. 3): 33–6.
  21. Vamvakas E.C., Blajchman M.A. Transfusion-related mortality: the ongoing risks of allogeneic blood transfusion and the available strategies for their prevention. Blood 2009; 113: 3406–17.
  22. Marik P.E., Corwin H.L. Efficacy of red blood cell transfusion in the critically ill: a systematic review of the literature. Crit. Care Med. 2008; 36: 2667–74.
  23. Thomson A., Farmer S., Hofmann A. et al. Patient blood management—a new paradigm for transfusion medicine? ISBT Sci. Series 2009; 4: 423–35.
  24. Amato A.C., Pescatori M. Effect of perioperative blood transfusions on recurrence of colorectal cancer: meta-analysis stratified on risk factors. Dis. Colon Rectum 1998; 41: 570–85.
  25. Bohlius J., Schmidlin K., Brillant C. et al. Erythropoietin or darbepoetin for patients with cancer—meta-analysis based on individual patient data. Cochrane Database Syst. Rev. 2009; CD007303.
  26. Gabrilove J.L., Cleeland C.S., Livingston R.B. et al. Clinical evaluation of once-weekly dosing of epoetin alfa in chemotherapy patients: improvements in hemoglobin and quality of life are similar to three-times-weekly dosing. J. Clin. Oncol. 2001; 19: 2875–82.
  27. Littlewood T.J., Bajetta E., Nortier J.W. et al. Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomized, double-blind, placebo-controlled trial. J. Clin. Oncol. 2001; 19: 2865–74.
  28. US Food and Drug Administration. Epoetin Alfa (Marketed as Epoetin, Procrit) Label. http://www.accessdata.fda.gov/drugsatfda_docs/ label/2010/103234s5199lbl.pdf (5 September 2011, date last accessed).
  29. US Food and Drug Administration. Darbepoetin Alfa (Marketed as Aransep) Label. http://www.accessdata.fda.gov/drugsatfda_docs/ label/2010/103951s5197lbl.pdf (5 September 2011, date last accessed).
  30. Macdougall I.C. Strategies for iron supplementation: oral versus intravenous. Kidney Int. Suppl. 1999; 69: S61–S66.
  31. Bastit L., Vandebroek A., Altintas S. et al. Randomized, multicenter, controlled trial comparing the efficacy and safety of darbepoetin alpha administered every 3 weeks with or without intravenous iron in patients with chemotherapyinduced anemia. J. Clin. Oncol. 2008; 26: 1611–8.
  32. Steensma D.P., Sloan J.A., Dakhil S.R. et al. Phase III, randomized study of the effects of parenteral iron, oral iron, or no iron supplementation on the erythropoietic response to darbepoetin alfa for patients with chemotherapy associated anemia. J. Clin. Oncol. 2011; 29: 97–105.
  33. Gafter-Gvili A., Rozen-Zvi B., Vidal L. et al. Intravenous iron supplementation for the treatment of cancer-related anemia—systematic review and metaanalysis. Blood 2010; 116 (Abstr 4249).
  34. Petrelli F., Borgonovo K., Cabiddu M. et al. Addition of iron to erythropoiesis-stimulating agents in cancer patients: a meta-analysis of randomized trials. J. Cancer Res. Clin. Oncol. 2012; 138: 179–87.
  35. Dangsuwan P., Manchana T. Blood transfusion reduction with intravenous iron in gynecologic cancer patients receiving chemotherapy. Gynecol. Oncol. 2010; 116: 522–5.
  36. Steinmetz T., Tschechne B., Virgin G. et al. Ferric carboxymaltose for the correction of cancer- and chemotherapy-associated anemia in clinical practice. Haematologica 2011; 96 (Abstr 983).
  37. Evstatiev R., Marteau P., Iqbal T. et al. FERGIcor, a randomized controlled trial on ferric carboxymaltose for iron deficiency anemia in inflammatory bowel disease. Gastroenterology 2011; 141: 846–53.
  38. Kulnigg S., Stoinov S., Simanenkov V. et al. A novel intravenous iron formulation for treatment of anemia in inflammatory bowel disease: the ferric carboxymaltose (FERINJECT) randomized controlled trial. Am. J. Gastroenterol. 2008; 103: 1182–92.
  39. Aapro M., Beguin Y., Birgegard G. et al. Too-low iron doses and too many dropouts in negative iron trial? J. Clin. Oncol. 2011; 29: e525–e526.
  40. Bailie G.R., Horl W.H., Verhof J.J. Differences in spontaneously reported hypersensitivity and serious adverse events for intravenous iron preparations: comparison of Europe and North America. Drug Res. 2011; 61: 267–75.
  41. Bailie G.R., Clark J.A., Lane C.E. et al. Hypersensitivity reactions and deaths associated with intravenous iron preparations. Nephrol. Dial. Transplant. 2005; 20: 1443–9.
  42. Chertow G.M., Mason P.D., Vaage-Nilsen O. et al. Update on adverse drug events associated with parenteral iron. Nephrol. Dial. Transplant. 2006; 21: 378–82.
  43. Zhang F., Wang W., Tsuji Y. et al. Post-transcriptional modulation of iron homeostasis during p53-dependent growth arrest. J. Biol. Chem. 2008; 283: 33911–8.
  44. Baliga R., Zhang Z., Baliga M. et al. In vitro and in vivo evidence suggesting a role for iron in cisplatin-induced nephrotoxicity. Kidney Int. 1998; 53: 394–401.
  45. Toyokuni S. Role of iron in carcinogenesis: cancer as a ferrotoxic disease. Cancer Sci. 2009; 100: 9–16.
  46. Bergeron R.J., Streiff R.R., Elliott G.T. Influence of iron on in vivo proliferation and lethality of L1210 cells. J. Nutr. 1985; 115: 369–74.
  47. Carthew P., Nolan B.M., Smith A.G. et al. Iron promotes DEN initiated GST-P foci in rat liver. Carcinogenesis 1997; 18: 599–603.
  48. Auerbach M., Glaspy J. What is the right balance between iron and erythropoiesis stimulating agents in chemotherapy induced anemia? Eur. J. Clin. Med. Oncol. 2009; 1: 7–12.
  49. Beguin Y., Maertens J., De Prijck B. et al. Darbepoetin-alfa and i.v. iron administration after autologous hematopoietic stem cell transplantation: a prospective randomized multicenter trial. Blood 2008; 112 (Abstr 54).