Eritropoetiny v onkologii:pokazaniya k primeneniyu i problemy


Cite item

Full Text

Abstract

Анемия – одно из наиболее частых симптомов, сопровождающих развитие злокачественных опухолевых процессов. При онкологических заболеваниях анемия является независимым фактором неблагоприятного прогноза выживаемости больных.Анемия присутствует у 40% больных немиелоидными злокачественными опухолями: легкая степень – в 30%, умеренная – в 9% и тяжелая – в 1% случаев. Общая частота анемии во время противоопухолевого лечения (химиотерапии или лучевой терапии) составляет 54% (легкая форма – 39%, умеренная – 14%, тяжелая – 1%). Частота ее выше у больных раком легкого (71%) или злокачественными опухолями женской репродуктивной системы (65%) и возрастает с увеличением количества курсов химиотерапии.Причины развития анемии при злокачественных опухолях могут быть разными и связаны как с состоянием здоровья больного (гемоглобинопатии, талассемия, нарушение питания с дефицитом необходимых элементов, метаболические нарушения, болезнь почек), так и с самим опухолевым процессом (кровотечение, опухолевая инфильтрация костного мозга, гиперспленизм, анемия хронического заболевания) или противоопухолевым лечением (обширное облучение, гематологическая или почечная токсичность цитостатиков, индуцированный лекарственными препаратами гемолиз).Согласно рекомендациям ESMO анемия определяется как снижение концентрации гемоглобина (Hb), количества эритроцитов или гематокрита ниже нормального уровня. В зависимости от концентрации Hb выделяют анемию легкой (уровень Hb 10–11,9 г/дл), умеренной (8,0–9,9 г/дл) и тяжелой степени (менее 8,0 г/дл).Степень тяжести анемии, являющейся следствием противоопухолевого лечения, определяется согласно основной шкале токсичности Национального института рака – CTCAEv3:степень 0 – Hb в пределах нормы;степень I – Hb ниже нижней границы нормы, но не ниже 10 г/дл;степень II – Hb выше 8 г/дл, но ниже 10 г/дл;степень III – Hb выше 6,5 г/дл, но ниже 8 г/дл;степень IV – Hb ниже 6,5 г/дл.Химиотерапия является одной из наиболее частых причин развития или усугубления анемии у онкологических больных. Анализ частоты гемотрансфузий у 2719 пациентов, проведенный в Великобритании, показал, что на фоне химиотерапии в 38% случаев наблюдалось падение концентрации Hb ниже 11 г/дл и в 33% потребовалась по крайней мере однократная гемотрансфузия.В настоящее время для коррекции анемии в онкологии широкое распространение получили стимуляторы эритропоэза или непосредственно в переводе с английского языка (erythropoiesis-stimulating agents – ESAS) эритропоэзстимулирующие агенты (ЭСА), клиническая эффективность которых доказана в многочисленных клинических исследованиях. Известно, что при анемии у онкологических больных наблюдается абсолютное или относительное снижение продукции эндогенного эритропоэтина, дефицит которого может быть компенсирован путем введения экзогенных стимулятов эритропоэза: эпоэтина-α, эпоэтина-β, дарбэпоэтина-α.

About the authors

N S Besova

РОНЦ им. Н.Н.Блохина РАМН, Москва

Отделение химиотерапии

References

  1. Albain K, Crowley J, Le Blanc M. Survival determinants in extensivestage non - small - cell lung cancer: the Southwest Oncology Group experience. J Clin Oncol 1991; 9: 1618–26.
  2. Wagner W, Hermann R, Hartlapp J. Prognostic value of hemoglobin concentrations in patients with advanced head and neck cancer treated with combined radio - chemotherapy and surgery. Strahlenthaer Onkol 2000; 176: 73–80.
  3. Ludwig H, Van Belle S, Barrett-Lee 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: 2293–306.
  4. Scrijvers D, Roila F and on behalf of the ESMO Guidelines Working Group. Erythropoiesis - stimulating agents in cancer patients: ESMO Recommendations for use. Ann Oncol 2009; 20(Suppl 4): iv159–iv161; doi: 10.1093/annonc/mdp161.
  5. Henry D, Abels R. Recombinant human erythropoietin in the treatment of cancer and chemotherapy - induced anemia: results of double - blind and open - label follow - up studies. Semin Oncol. 1994; 21(suppl 3): 21–8.
  6. Demetri G, Kris M, Wade J et al. Quality - of life benefit in chemotherapy patients treated with epoetin alfa is independent of disease response or tumor type: Results from a prospective community oncology study — Procrit Study Group. J Clin Oncol 1998; 16: 3412–25.
  7. Glaspy J. The impact of epoetin alfa on quality of life during cancer chemotherapy: A fresh look at an old problem. Semin Hematol 1997; 34: 20–6.
  8. Gabrilove J, Cleeland C, Livingston R et al. Clinical evaluation of onceweekly dosing of epoetin alfa in chemotherapy patients: Improvements in hemoglobin and quality of life are similar to threetimesweekly dosing. J Clin Oncol 2001; 19: 2875–82.
  9. Littlewood T, Bajetta E, Nortier J 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, placebocontrolled trial. J Clin Oncol 2001; 19: 2865–74.
  10. Vansteenkiste J, Pirker R, Massuti B et al: Double - blind, placebo - controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy. J Natl Cancer Inst 94:1211- 1220, 2002
  11. Osterborg A, Brandberg Y, Molostova V et al. Randomized, double - blind, placebo - controlled trial of recombinant human erythropoietin, epoetin beta, in hematologic malignancies. J Clin Oncol 2002; 20: 2486–94.
  12. Taylor K, Ganly P, Charu V et al. Randomized, double - blind, placebo - controlled study of darbepoetin alfa every 3 weeks for the treatment of chemotherapy - induced anemia. Blood 2005; 106: abstr 3556.
  13. Grote T, Yeilding A, Castillo R et al. Efficacy and safety analysis of epoetin alfa in patients with small - cell lung cancer: A randomized, double - blind, placebo - controlled trial. J Clin Oncol 2005; 23: 9377–86.
  14. Witzig T, Silberstein P, Loprinzi C et al. Phase III, randomized, double - blind study of epoetin alfa compared with placebo in anemic patients receiving chemotherapy. J Clin Oncol 2005; 23: 2606–617.
  15. Kotasek D, Steger G, Faught W et al. Darbepoetin alfa administered every 3 weeks alleviates anaemia in patients with solid tumours receiving chemotherapy: Results of a double - blind, placebocontrolled, randomised study. Eur J Cancer 2003; 39: 2026–34.
  16. Moebus V, Lueck H, Thomssen C et al. The impact of epoetin - alpha on anemia, red blood cell RBC) transfusions, and survival in breast cancer patients (pts) treated with dose - dense sequential chemotherapy: Mature results of an AGO phase III study (ETC trial). J Clin Oncol 2007; 25 (suppl); abstr 569.
  17. Pirker R, Ramlau R, Schuette W et al. A phase 3 randomized, double blind, placebocontrolled study of patients with previously untreated extensive - stage small cell lung cancer (SCLC) treated with platinum plus etoposide chemotherapy with or without darbepoetin alfa. J Thorac Oncol 2007; 2: abstr PD6-3-6.
  18. Bohlius J, Wilson J, Seidenfeld J et al. Recombinant human erythropoietins and cancer patients: Updated meta - analysis of 57 studies including 9353 patients. J Natl Cancer Inst 2006; 98: 708–14.
  19. Seidenfeld J, Pipe M, J et al. Comparative effectiveness of epoetin and darbepoetin for managing anemia in patients undergoing cancer treatment: Comparative Effectiveness Review no. 3. Prepared by Blue Cross and Blue Shield Association Evaluation Center Evidence - based Practice Center under contract no. 290- 02-0026. Rockville M.D., Agency for Healthcare Research and Quality, 2006. www.effectivehealthcare.arhq.gov/reports/final.cfm
  20. Ross S, Allen I, Henry D et al. Clinical benefits and risks associated with epoetin and darbepoetin in patients with chemotherapy - induced anemia: A systematic review of the literature. Clin Ther 2006; 28: 801–31.
  21. Aapro M, Coiffier B, Dunst J et al. Effect of treatment with epoetin beta on short - term tumour progression and survival in anaemic patients with cancer: A meta - analysis. Br J Cancer 2006; 95: 1467–73.
  22. Smith R.J.r, Aapro M, Ludwig H et al. Darbepoetin alpha for the treatment of anemia in patients with active cancer not receiving chemotherapy or radiotherapy: Results of a phase III, multicenter, randomized, double - blind, placebocontrolled study. J Clin Oncol 2008; 26: 1040–50.
  23. Henke M, Laszig R, Rube C et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: Randomised, double - blind, placebo - controlled trial. Lancet 2003; 362: 1255–60.
  24. Leyland-Jones B, Semiglazov V, Pawlicki M et al. Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first - line chemotherapy: A survival study. J Clin Oncol 2005; 23: 5960–72.
  25. Wright J, Ung Y, Julian J et al. Randomized, double - blind, placebo - controlled trial of erythropoietin in non - small - cell lung cancer with disease - related anemia. J Clin Oncol 2007; 25: 1027–32.
  26. Overgaard J, Hoff C, Sand Hansen H et al. Randomized study of the importance of novel erythropoiesis stimulating protein (Aranesp®) for the effect of radiotherapy in patients with primary squamous cell carcinoma of the head and neck (HNSCC): The Danish Head and Neck Cancer Group (DAHANCA 10) randomized trial. Presented at 14th European Cancer Conference, Barcelona, Spain, September 23–27, 2007: abstr 6LB.
  27. Hedenus M, Adriansson M, San Miguel J et al: Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: randomized, double - blind, placebo - controlled study. Br J Haematol 2003; 122: 394–03.
  28. Amgen: Update to Hedenus et al. (2003), Safety of Erythropoiesis - Stimulating Agents (ESAs) in Oncology: Background Information for Oncologic Drugs Advisory Committee. http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4301b2-01-01-Amgen.pdf
  29. Thomas G, Ali S, Hoebers F.J., et al. Phase trial to evaluate the efficacy of maintaining hemoglobin levels above 12.0 g/dL with erythropoietin above 10.0 g/dL without erythropoietin in anemic patients receiving concurrent radiation and cisplatin for cervical cancer. Gynecol Oncol 2008; 108: 317–25.
  30. Amgen: Amgen announces interim results Aranesp “PREPARE” study in breast cancer patients [Amgen press release]: November 30, 2007. Http:// wwwext.amgen.com/ media / media_pr_detail. jsp? year_2007 & release ID_ 1083091
  31. Azria D, Zouhair A, Serre A et al. Anemia head and neck cancers. Bull Cancer 2005; 92: 445–51.
  32. Bennett C, Silver S, Djulbegovic B et al. Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancerassociated anemia. JAMA 2008; 299: 914–24.
  33. Henke M, Mattern D, Pepe M et al. Do Erythropoietin Receptors on Cancer Cells Explain Unexpected Clinical Findings? J Clin Oncol 2006; 24: 4708–13.
  34. Bohlius J, Schmidlin K, Brillant C et al. Recombinant human erythropoiesisstimulating agents and mortality in patients with cancer: a meta - analysis of randomized trials. Lancet 2009; 373: 1532–42.
  35. Tonelli M, Reiman T, Reaume M et al. Benefits and harms of erythropoiesis - stimulating agents for anemia related to cancer: a meta - analysis. CMAJ 2009; 180(11).
  36. Gascon P. Safety Update on Erythropoiesis-Stimulating Agents:Trials Within and Outside the Accepted Indications. Oncologist 2008; 13(suppl 3): 4–10.
  37. Nowrousian M, Dunst J, Vaupel P. Erythropoiesis-Stimulating Agents: Favorable Safety Profile When Used as Indicated. Strahlenther Onkol 2008; 184: 121–36.
  38. Melosky B. Erythropoiesis - stimulating agents: benefits and risks in supportive care of cancer. Curr Oncol 2008; 15(Suppl 1): S10–5.
  39. Ludwig H, Crawford J, Cterborg F et al. Pooled Analysis of Individual Patient - Level Data From All Randomized, Double-Blind, Placebo - Controlled Trials of Darbepoetin Alfa in the Treatment of Patients With Chemotherapy-Induced Anemia. J Clin Oncol 2009; 27: s1–10.
  40. Heit J, Silverstein M, Mohr D et al: Risk factors for deep vein thrombosis and pulmonary embolism: A population - based case - control study. Arch Intern Med 2000; 160: 809–15.
  41. Blom J, Doggen C, Osanto S et al: Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 2005; 293: 715–22.
  42. Lyman G, Glaspy J. Are there clinical benefits with early erythropoietic intervention for chemotherapy - induced anemia? A systematic review. Cancer 2006; 106: 223–3.

Copyright (c) 2009 Consilium Medicum

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
 


This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies