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Anemia in Cancer: Some Pathophysiological Aspects

Article  in  The Oncologist · February 2003

DOI: 10.1634/theoncologist.8-suppl_1-19 · Source: PubMed

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 Anemia in Cancer: Some Pathophysiological Aspects
Mario Dicato

The Oncologist 2003, 8:19-21.

doi: 10.1634/theoncologist.8-suppl_1-19

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 The
Oncologist ®

Anemia in Cancer: Some Pathophysiological Aspects

MARIO DICATO
Haematology-Oncology, Luxembourg Medical Center, Luxembourg

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

L EARNING O BJECTIVES
After completing this course, the reader will be able to:

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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.

CME Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com

A BSTRACT
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 physiologi-
cal effect of erythropoietin. Pharmacologically increasing
the erythropoietin level corrects the anemia in about half
the treated patients. Several studies have shown that qual-
ity of life is substantially improved through such therapy.
The Oncologist 2003;8(suppl 1):19-21

INTRODUCTION ANEMIA AND ERYTHROPOIETIN

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.).
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 differenti-
ate 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 erythro-
poietin 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-κB production—which occurs as a response to
inflammatory events—has recently been linked by possible

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@chl.lu Received January 24, 2003; accepted for publication
January 24, 2003. ©AlphaMed Press 1083-7159/2003/$5.00/0

The Oncologist 2003;8(suppl 1):19-21 www.TheOncologist.com

20
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 pre-
vented by transfection of the erythropoietin receptor gene; nor-
mal 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
In anemia of cancer, as in anemia of chronic disease, mul-
tiple mechanisms can interfere with normal erythrocyte pro-
duction. The cytokines tumor necrosis factor-alpha (TNF-α),
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-α among others. An anti-TNF-α antibody may abro-
gate 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 oncol-
ogy, 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
Several studies have shown that improving the hemo-
globin 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
R EFERENCES
1 Mercadante S, Gebbia V, Marrazzo A et al. Anemia in can-
cer: pathophysiology and treatment. Cancer Treat Rev
2000;26:303-311.
Anemia in Cancer
regular schedule. About 70% of patients respond to erythro-
poietin 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.
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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 conser-
vative, 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 sub-
stantiated. 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 prolif-
eration 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.
2 Digicaylioglu M, Lipton SA. Erythropoietin-mediated neuro-
protection involves cross-talk between Jak2 and NF-kappaB
signalling cascades. Nature 2001;412:641-647.
Dicato
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.
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: improve-
ment following anti-tumor necrosis factor-alpha antibody
therapy. Blood 2002;100:474-482.
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.
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
21
randomized, double-blind, placebo-controlled trial. J Clin
Oncol 2001;19:2865-2874.
7 Glaspy J, Degos L, Dicato M et al. Comparable efficacy of epo-
etin alfa for anemic cancer patients receiving platinum- and non-
platinum-based chemotherapy: a retrospective subanalysis of two
large, community-based trials. The Oncologist 2002;7:126-135.
8 Adamson JW, Ludwig H. Predicting the hematopoietic response
to recombinant human erythropoietin (Epoietin alfa) in the treat-
ment of the anemia of cancer. Oncology 1999;56:46-53.
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.
10 Lavey RS. Clinical trial experience using erythropoietin dur-
ing radiation therapy. In: Vaupel P, Kelleher D, eds. Tumor
Hypoxia. Stuttgart, Germany: WVG Publishers, 1999:99-105.
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