High serum levels of TNF-α and IL-6 predict the clinical outcome of treatment with human recombinant erythropoietin in anaemic cancer patients.

BACKGROUND A number of anaemic cancer patients are not responsive to treatment with recombinant human erythropoietin (rHuEPO). The aim of the present study is to investigate whether serum levels of tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-6 and additional laboratory parameters, together with clinical variables, can predict the clinical outcome of treatment with rHuEPO in anaemic cancer patients. PATIENTS AND METHODS Thirty-five cancer patients and 25 healthy controls were enrolled in this study. Patients were treated with epoetin alfa at the dose of 150 IU/kg s.c. three times a week for 12 weeks. If the haemoglobin (Hb) level failed to improve at least 2 g/dl above baseline by week 6 of treatment, dose was increased to 300 IU/kg s.c. for the remainder of the treatment period. All patients filled out the Brief Fatigue Inventory (BFI), a questionnaire for the self-evaluation of cancer-related fatigue. Serum samples from patients and control groups were frozen at -80 degrees C and TNF-alpha, IL-1beta and IL-6 were later examined by enzyme-linked immunosorbent assay. RESULTS Fatigued cancer patients had significant higher levels of circulating TNF-alpha, IL-1beta and IL-6 than healthy controls. Responders (Rs) to erythropoietin had significant lower medium levels of TNF-alpha and IL-6 than nonresponders (NRs). Fatigued patients with a general BFI score > or =6 presented higher medium level of cytokines than nonfatigued patients (general BFI score <6), but each group responded similarly to treatment with rHuEPO. CONCLUSIONS High serum levels of TNF-alpha and IL-6 at the baseline are significantly correlated with a negative response to administration with rHuEPO. Thus, pretreatment evaluation of TNF-alpha and IL-6 serum levels can help to select those patients who are most likely to benefit from treatment with rHuEPO. On the contrary, Hb level, red blood cell count, lactate dehydrogenase and BFI score do not predict the outcome of treatment with rHuEPO.

[1]  D. Dorr,et al.  Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. , 2008, JAMA.

[2]  C. Trautwein,et al.  Mechanisms of Disease: the role of hepcidin in iron homeostasis—implications for hemochromatosis and other disorders , 2004, Nature Clinical Practice Gastroenterology &Hepatology.

[3]  Elizabeta Nemeth,et al.  IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. , 2004, The Journal of clinical investigation.

[4]  L. Harrison,et al.  Once‐weekly dosing of epoetin‐α increases hemoglobin and improves quality of life in anemic cancer patients receiving radiation therapy either concomitantly or sequentially with chemotherapy , 2003, Cancer.

[5]  V. Mock,et al.  Assessment and management of cancer-related fatigue in adults , 2003, The Lancet.

[6]  R. Dantzer,et al.  Are the symptoms of cancer and cancer treatment due to a shared biologic mechanism? , 2003, Cancer.

[7]  D. Cella,et al.  Control of cancer-related anemia with erythropoietic agents: a review of evidence for improved quality of life and clinical outcomes. , 2003, Annals of oncology : official journal of the European Society for Medical Oncology.

[8]  D. Patrick,et al.  Assessing the clinical significance of health-related quality of life (HrQOL) improvements in anaemic cancer patients receiving epoetin alfa. , 2003, European journal of cancer.

[9]  D. Cella,et al.  Epoetin alfa treatment results in clinically significant improvements in quality of life in anemic cancer patients when referenced to the general population. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[10]  L. Fallowfield,et al.  Multivariate regression analyses of data from a randomised, double-blind, placebo-controlled study confirm quality of life benefit of epoetin alfa in patients receiving non-platinum chemotherapy , 2002, British Journal of Cancer.

[11]  C. Jung,et al.  Erythropoietin Response Is Inadequate in Cancer Patients Receiving Chemotherapy , 2001, International journal of hematology.

[12]  M. McKenzie,et al.  Epoetin alfa therapy increases hemoglobin levels and improves quality of life in patients with cancer-related anemia who are not receiving chemotherapy and patients with anemia who are receiving chemotherapy. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  R. Kurzrock.  The role of cytokines in cancer‐related fatigue , 2001, Cancer.

[14]  C. Cleeland,et al.  The rapid assessment of fatigue severity in cancer patients , 1999, Cancer.

[15]  R. Stasi,et al.  Serum levels of tumour necrosis factor-alpha predict response to recombinant human erythropoietin in patients with myelodysplastic syndrome. , 1997, Clinical and laboratory haematology.

[16]  R. Stasi,et al.  Serum levels of tumour necrosis factor‐α predict response to recombinant human erythropoietin in patients with myelodysplastic syndrome , 1997 .

[17]  C. Lacombe.  Resistance to erythropoietin. , 1996, The New England journal of medicine.

[18]  H. Samonigg,et al.  Prediction of response to erythropoietin treatment in chronic anemia of cancer [see comments] , 1994 .

[19]  S. Marsters,et al.  Inhibition of murine erythroid colony formation in vitro by interferon gamma and correction by interferon receptor immunoadhesin. , 1994, Blood.

[20]  S. Krantz,et al.  Inhibition of human erythroid colony-forming units by tumor necrosis factor requires beta interferon. , 1993, The Journal of clinical investigation.

[21]  S. Krantz,et al.  Progress in understanding the pathogenesis of the anemia of chronic disease. , 1992, Blood.

[22]  M. Goldberg,et al.  EFFECT OF INFLAMMATORY CYTOKINES ON HYPOXIA-INDUCED ERYTHROPOIETIN PRODUCTION , 1992 .

[23]  S. Krantz,et al.  Inhibition of human erythroid colony-forming units by gamma interferon can be corrected by recombinant human erythropoietin. , 1991, Blood.

[24]  P. Furmanski,et al.  Negative regulators of in vivo erythropoiesis: interaction of IL-1 alpha and TNF-alpha and the lack of a strict requirement for T or NK cells for their activity. , 1991, Experimental Hematology.

[25]  E. Dessypris,et al.  Inhibition of human colony-forming-unit erythroid by tumor necrosis factor requires accessory cells. , 1990, The Journal of clinical investigation.

[26]  D. Williams,et al.  The suppressive influences of human tumor necrosis factors on bone marrow hematopoietic progenitor cells from normal donors and patients with leukemia: synergism of tumor necrosis factor and interferon-gamma. , 1986, Journal of immunology.

[27]  M. Somerfield,et al.  Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update. , 2008, Blood.

[28]  M. Somerfield,et al.  Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[29]  M. Elder.  The Role of Cytokines , 1997 .

[30]  H. Samonigg,et al.  Prediction of response to erythropoietin treatment in chronic anemia of cancer. , 1994, Blood.

[31]  P. Musto,et al.  Low serum levels of tumor necrosis factor and interleukin-1 beta in myelodysplastic syndromes responsive to recombinant erythropoietin. , 1994, Haematologica.