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Anemia in Cancer: Some Pathophysiological Aspects

Haematology-Oncology, Luxembourg Medical Center, Luxembourg

Correspondence: Mario Dicato, M.D., Haematology-Oncology, Luxembourg Medical Center, L-1210 Luxembourg. Telephone: 352-4411-2084; Fax: 352-44-12-15; e-mail: dicato.mario{at}chl.lu

	LEARNING OBJECTIVES

Top Learning Objectives Abstract Introduction Anemia and Erythropoietin Anemia of Cancer Treatment of Anemia References

 
After completing this course, the reader will be able to:

1. Recognize the causes of anemia in cancer patients.
   
2. Describe ways in which the action of erythropoietin is regulated.
   
3. Explain the methods for treating anemia and indications for treatment.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction Anemia and Erythropoietin Anemia of Cancer Treatment of Anemia References

 
More than 30% of cancer patients experience anemia and its side effect, fatigue. Its causes can be numerous, but anemia is usually secondary to an imbalance of cytokines. Among these, tumor necrosis factor-alpha seems to be the major culprit, creating anemia by blunting the physiological effect of erythropoietin. Pharmacologically increasing the erythropoietin level corrects the anemia in about half the treated patients. Several studies have shown that quality of life is substantially improved through such therapy.

Key Words. Erythropoietin • TNF-alpha • Quality of life • Neoplasms

	INTRODUCTION

Top Learning Objectives Abstract Introduction Anemia and Erythropoietin Anemia of Cancer Treatment of Anemia References

 
Anemia, commonly defined as a hemoglobin level of <12 g/dL, occurs in over 30% of cancer patients at any point in time, and its incidence increases with treatment and progressive disease [1]. This anemia can have many causes:

• related to the patient (hemoglobinopathies, thalassemia, gastrointestinal problems, etc.);
  
• related to the disease (bone marrow infiltration, bowel resection, hypersplenism, diminished nutritional state, etc.);
  
• related to therapy (hypoplasia of bone marrow-bearing areas such as the pelvis secondary to radiotherapy; bone marrow and renal toxicity secondary to chemotherapy; and, occasionally, drug-induced hemolysis, etc.).
  

	ANEMIA AND ERYTHROPOIETIN

Top Learning Objectives Abstract Introduction Anemia and Erythropoietin Anemia of Cancer Treatment of Anemia References

 
Bone marrow stem cells are self-renewing and able to support a normal hemoglobin level over a lifetime. Red blood cells derive from committed stem cells that differentiate and multiply through the different erythroblastic stages. There is, as in all human cells, an inverse relationship between proliferation potential and differentiation. Both events are finely regulated by cytokines, of which erythropoietin is the most important once the erythroid pathway is entered. Hypoxia is sensed by the nephron, and the kidney responds with erythropoietin production. The erythropoietin binds to a specific receptor on the red blood cell progenitors, and its signaling induces proliferation and differentiation and has an antiapoptotic effect. Another general antiapoptotic pathway, NF-B production—which occurs as a response to inflammatory events—has recently been linked by possible cross-talking to the erythropoietin antiapoptosis mechanism in the central nervous system [2].

Interestingly, erythropoietin receptors have been described in multiple organs and are essential for normal development. In erythropoietin receptor knockout mice, an interruption of fetal liver erythropoiesis, defective cardiac development, and increased apoptosis in brain and heart are described. Death occurs at about embryonic day 13. These events can be prevented by transfection of the erythropoietin receptor gene; normal development into adulthood is then observed. Thus, the erythropoietin effect is crucial in embryonic life. Interestingly, in the same knockout mice, the human erythropoietin receptor transgene also assures a normal development [3].

	ANEMIA OF CANCER

Top Learning Objectives Abstract Introduction Anemia and Erythropoietin Anemia of Cancer Treatment of Anemia References

 
In anemia of cancer, as in anemia of chronic disease, multiple mechanisms can interfere with normal erythrocyte production. The cytokines tumor necrosis factor-alpha (TNF-), transforming growth factor-beta, interleukin (IL)-1, IL-6, and interferon-gamma are likely most prevalent as inhibitory mechanisms. This network of cytokines probably modulates iron metabolism, and the erythropoietin effect may be blunted by TNF- among others. An anti-TNF- antibody may abrogate this effect, as has been demonstrated in rheumatoid arthritis [4].

Anemia impairs virtually every organ and tissue of the body and causes multiple function disturbances, decreasing mental and physical performance capacity. One of the major symptoms of organ disturbance is fatigue. In oncology, this symptom ranks first among patient complaints [5], and parallels the hemoglobin level [6]. On average, over one third of patients become anemic after three cycles of chemotherapy [7].

	TREATMENT OF ANEMIA

Top Learning Objectives Abstract Introduction Anemia and Erythropoietin Anemia of Cancer Treatment of Anemia References

 
Several studies have shown that improving the hemoglobin level will increase quality of life, as measured with visual analogue scales [7]. The most marked increment in the rate of improvement of quality of life takes place when hemoglobin levels are increased to between 11 and 12 g/dL.

Anemia can be corrected by blood transfusion, which has the advantage of effecting a direct improvement if required. Long-term improvement, including a progressive and stable hemoglobin level, can be achieved in about half of patients by giving recombinant erythropoietin on a regular schedule. About 70% of patients respond to erythropoietin treatment (Hb increase of at least 2 g/dL), but it would still be useful to know who will respond and who may not. Although a number of predictive algorithms have been put forward, some showing statistical relationships between baseline lab tests and response [8], most are not accurate enough to be useful in clinical practice. In any case, because inflammatory cytokines blunt the erythropoietin response, inflammation should be treated when possible.

Anemia may also be treated with iron supplementation. Iron deficiency hampers the erythropoietin effect. If it is not clear whether a patient is iron deficient, iron should be given. Often an initial response to erythropoietin levels off at an unsatisfactory level. This can be a sign of iron deficiency and indicates that iron supplementation is worthwhile.

A frequently asked question is: at what threshold should treatment be started? The situation is different in different specialties. In surgery, transfusion attitudes are very conservative, and most studies show that there is no advantage to raising the hemoglobin level in an otherwise stable patient unless it has dropped to <8 g/dL. The same is true in clinical cardiology for elderly patients being admitted with an acute coronary event and anemia [9]. In oncology, chronic anemic patients are the rule, and improving quality of life can be a desirable end point. Effects on other end points are less substantiated. Subgroups of anemic breast cancer patients (Hb < 10.5) treated with chemotherapy have shown a trend, though statistically not significant, for improvement of survival [6]. Further randomized controlled studies with survival as an end point are needed to prove or disprove these observations. Favorable results have been shown in various radiotherapy studies where, in comparable patients, clinical results and survival data are in favor of correcting the cancer-related anemia starting at an Hb of around 10 g/dL [10]. Hypoxia favors cancer cells and gives them a net survival and proliferation advantage, probably through induction of vascular endothelial growth factor. This hypothesis is the basis for studies aimed at improving hypoxia by raising hemoglobin levels as well as using antiangiogenic drugs.

Overall, in cancer, anemia is frequent, depending on the clinical situation and treatment, and treatment of anemia seems to be quite worthwhile. More studies are needed to assess effects of improving hemoglobin levels and quality of life in addition to treating the symptoms of anemia, the most important of which, in the patient’s view, is fatigue.

	REFERENCES

Top Learning Objectives Abstract Introduction Anemia and Erythropoietin Anemia of Cancer Treatment of Anemia References

 

1. Mercadante S, Gebbia V, Marrazzo A et al. Anemia in cancer: pathophysiology and treatment. Cancer Treat Rev 2000;26:303–311.[CrossRef][Medline]
2. Digicaylioglu M, Lipton SA. Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kappaB signalling cascades. Nature 2001;412:641–647.[CrossRef][Medline]
3. Yu X, Lin CS, Costantini F et al. The human erythropoietin receptor gene rescues erythropoiesis and developmental defects in the erythropoietin receptor null mouse. Blood 2001;98:475–477.[Abstract/Free Full Text]
4. Papadaki HA, Kritikos HD, Valatas V et al. Anemia of chronic disease in rheumatoid arthritis is associated with increased apoptosis of bone marrow erythroid cells: improvement following anti-tumor necrosis factor-alpha antibody therapy. Blood 2002;100:474–482.[Abstract/Free Full Text]
5. Curt GA, Breitbart W, Cella D et al. Impact of cancer-related fatigue on the lives of patients: new findings from the Fatigue Coalition. The Oncologist 2000;5:353–360.[Abstract/Free Full Text]
6. Littlewood TJ, Bajetta E, Nortier JW 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;19:2865–2874.[Abstract/Free Full Text]
7. Glaspy J, Degos L, Dicato M et al. Comparable efficacy of epoetin alfa for anemic cancer patients receiving platinum- and nonplatinum-based chemotherapy: a retrospective subanalysis of two large, community-based trials. The Oncologist 2002;7:126–135.[Abstract/Free Full Text]
8. Adamson JW, Ludwig H. Predicting the hematopoietic response to recombinant human erythropoietin (Epoietin alfa) in the treatment of the anemia of cancer. Oncology 1999;56:46–53.[CrossRef][Medline]
9. Wu WC, Rathore SS, Wang Y et al. Blood transfusion in elderly patients with acute myocardial infarction. N Engl J Med 2001;345:1230–1236.[Abstract/Free Full Text]
10. Lavey RS. Clinical trial experience using erythropoietin during radiation therapy. In: Vaupel P, Kelleher D, eds. Tumor Hypoxia. Stuttgart, Germany: WVG Publishers, 1999:99–105.

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This Article Abstract Full Text (PDF) CME: Take the course for this article: Anemia in Cancer: Some Pathophysiological Aspects eLetters: Submit a response to this article Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dicato, M. Search for Related Content PubMed PubMed Citation Articles by Dicato, M.