Anemia in cancer
M. Dicato 0 1 2 3
L. Plawny 0 2 3
M. Diederich 1 2 3
1 Laboratory of the Foundation for Research in Cancer and Blood Disorders, Centre Hospitalier de Luxembourg , Luxembourg
2 Luxembourg , L-1210 Luxembourg
3 a The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology
Inflammatory cytokines such as tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6), among others, play a major role in the pathophysiology of anemia in the cancer patient not only through complex mechanisms of the purely inflammatory situation but also through genetic regulatory aspects of erythropoiesis via GATA-1 and GATA-2, and other factors. In terms of therapy, iron is used more and more; the late side effects of transfusions are not really understood and the recent controversy regarding erythropoietin usage has resulted in regulatory authorities and scientific societies providing several recommendations and guidelines. These various aspects are addressed herein.
These three mechanisms are often intricately linked, and the
origin of anemia in cancer patients is often multifactorial.
Anemia may be attributed to the underlying co-morbidities
such as coagulation disorders, hemolysis, hereditary diseases,
renal insufficiency, nutritional insufficiencies or underlying
inflammatory disease [
]. Cancer itself can directly cause or
exacerbate anemia either by suppressing hematopoiesis through
bone marrow infiltration or production of cytokines that
lead to iron sequestration, or by reduced red blood cell
production. In addition, treatment itself may be a major cause
of anemia [6. 7].
Cancer-induced anemia and anemia of chronic disease result
from multiple causes and the fine interplay of pro- and
antiapoptotic factors inducing a fine-tuned selective
differentiation of the trilineage committed hematopoietic stem
cell. A slight disruption of this equilibrium will present as one
of the many facets of blood count changes from anemia to
thrombocytosis, as commonly seen in cancer patients.
GATA-1 and GATA-2, tumor necrosis factor-a (TNF-a) and
other factors are players in this (dis)equilibrium.
TNF-a inhibits hemoglobin production in a proportional fashion
to the down-regulation of GATA-1 and also affects erythropoiesis
induced by erythropoietin (Epo). TNF-a induces a decrease in
the expression of FOG-1, a co-activator of GATA-1, as well as
a proteasome-dependent decrease of GATA-1. In addition TNF-a
suppresses the acetylated form of GATA-1, the post-translational
modification required for DNA binding.
Numerous in vitro studies have illustrated the central role of
TNF-a in the pathogenesis of anemia [
]. TNF-a might
indirectly inhibit the proliferation of erythroid progenitor cells
by triggering nuclear factor-jB (NF-jB) and GATA-2
pathways, thus suppressing erythropoietin production [
companion actor GATA-2 is part of these elements affecting
control of genetic expression in hematopoiesis. GATA
proteins are zinc-finger transcription factors involved in
erythropoiesis and megakaryopoiesis [
]. In hematopoietic
stem cells, GATA-2 is overexpressed and is believed to ensure
maintenance and proliferation, whereas GATA-1 is involved
in the survival of erythroid progenitors as well as in the
differentiation of erythroid cells. Overexpression of GATA-2
determines megakaryocytic differentiation whereas its
downregulation is required for erythroid differentiation. GATA-1
is key erythroid transcription factor. A cross-regulatory
mechanism between GATA-1 and GATA-2 seems to exist [
]. TNF-a might stimulate GATA-2, thus reducing erythroid
differentiation in cancer cells . The binding of TNF-a to its
ligand, TNF-R1, inhibits GATA-1 and suppresses the
expression of genes specific to erythroid differentiation such as
globin genes or Epo receptors (EPO-Rs). TNF-a reduces the
Epo-mediated hemoglobinization of erythroid progenitors.
Interaction of TNF-a with the EPO-R stimulates apoptosis via
the NF-jB pathway [
GATA-1 is a key erythroid transcription factor and a key
target for the inhibiting effect of TNF-a. TNF-a is probably the
major, but not the only player in anemia of chronic disease.
Other cytokines, such as interleukin-6 (IL-6), IL-1 and
interferon-c, have also been shown to inhibit erythroid
precursors in vitro [
], albeit to a lesser extent.
Interestingly, anemia in Crohn?s disease and in rheumatoid
arthritis improves after primary therapy of the disease with an
anti-TNF antibody. It can be shown in an in vitro model that
inhibition of erythropoiesis could be corrected by the addition
of an anti-TNF-a antibody. Hence improvement of anemia is
not only due to the improvement of the disease as such but in
fact is also due directly to the alleviation of the TNF-a-induced
In addition to the various cytokines discussed above, over the
past few years iron therapy has been increasingly addressed.
In inflammation, from whatever cause, IL-6 induces the liver
to produce hepcidin. Hepcidin decreases iron absorption from
the bowel and blocks iron utilization in the bone marrow. Iron
may be abundant in the bone marrow, but is not absorbed and
is not in the circulation, and so is not available for
erythropoiesis. Hepcidin blocks iron absorption in the gut as
well as iron in the bone marrow. Therefore, in inflammatory
anemia, iron deficiency should be defined by a low transferrin
saturation of <20%, ferritin levels of <100 ng/ml and a low
reticulocyte hemoglobin concentration of <32 pg.
In evaluating an anemia patient in whatever clinical
condition, other deficiencies such as folic acid, vitamin B12, etc.
should be excluded.
Some chemotherapeutic agents induce anemia by impairing
hematopoiesis (Table 1) [
]. In addition, nephrotoxic effects
of particular cytotoxic agents such as platinum salts can also
lead to the persistence of anemia through reduced Epo
production by the kidney [
anemia seems to be frequent in lung cancers and gynaecological
malignancy, partly due to the fact that their treatment may
require platinum-based regimens [
]. The myelosuppressive
effect of cytotoxic agents might accumulate over the course of
chemotherapy. This results in a steady increase of the incidence
of anemia with every new cycle of chemotherapy. The European
Cancer Anaemia Survey showed that anemia increased from
19.5% in the first cycle of chemotherapy to 46.7% after the fifth
]. Other risk factors for chemotherapy-related anemia
include low hemoglobin level, transfusions in the past 6
months, prior radiotherapy to>20% of the skeleton, a previous
myelosuppressive chemotherapy and co-morbidities such as
chronic inflammatory diseases [
Currently two options are at the disposal of the clinician for the
treatment of anemia in cancer patients: transfusion of packed
vii168 | Dicato et al.
Head and neck
Non-small cell lung
Head and neck
Small cell lung cancer
Small cell lung cancer
Small cell lung cancer
Head and neck
Non-small cell lung
Adapted from Groopman [
CHOP, cytoxan, hydroxyrubicin, oncovine and prednisone; 5-FU,
5-fluorouracil; VIP, Vp16, ifosfamide and csiplatin.
red blood cells and the use of erythropoiesis-stimulating agents
(ESAs). The goal of the treatment is to relieve the symptoms of
anemia such as fatigue and dyspnea.
Transfusion of packed red blood cells offers a rapid increase in
hemoglobin and hematocrit levels and is hence the ideal option
in patients requiring rapid correction of anemia. Transfusion
of 1 unit of packed red blood cells has been estimated to result
in an increase in the hemoglobin level of 1 g/dl in a
normalsized adult [
]. The results of a number of studies
evaluating the impact of transfusion on mortality in critically ill
patients are conflicting. One study of 56 esophageal cancer
patients receiving chemoradiation therapy showed that blood
transfusions increased overall survival [hazard ratio (HR) 0.26,
95% confidence interval (CI) 0.09?075, P = 0.01] .
Though transfusions bring obvious advantages, they are,
however, not devoid of risk, including transfusion-related
reactions, congestive heart failure, bacterial contamination,
viral infections and iron overload [5.18]. The introduction of
numerous safety interventions for infectious organisms has
dramatically decreased the incidence of transfusion-related
infections. Leukoreduction has been shown to reduce the
incidence of febrile non-hemolytic transfusion reactions [
recent study conducted in 60 US medical centers between 1995
and 2003 found an increased risk of venous and arterial
thromboembolism and mortality associated with packed red
blood cell transfusion [
]. Iron overload is a frequent
complication in patients with myelodysplastic syndrome
(MDS) requiring transfusion over a long period of time. This
condition is rarely seen however in patients with solid tumors
in which the transfusion period lasts less than a year [
Three types of ESA are currently available. Epoietin alfa
(EPREX ), epoetin beta (Neorecormon ) and darbepoetin alfa
(Aranesp ). A pegylated form of Epo (methoxy PEG Epoetin
beta, Mircera , CERA ) has been approved in some European
countries, and some biosimilars are readily available (Epoetin
zeta, Retacrit ).
Treatment with Epo has been shown to reduce transfusion
rates in cancer patients. The Littlewood study conducted in
2001 on breast cancer patients showed that patients receiving
epoietin beta had a decreased transfusion rate compared with
patients receiving placebo (24.7% versus 39.5%, P = 0.057).
Patients on Epo also achieved a higher rise in hemoglobin levels
than controls. (2.2 g/dl versus 0.5 g/dl, P = 0.01) [
results were obtained with darbepoetin alfa where a
doubleblind placebo-controlled randomized phase III trial in lung
cancer conducted by Vansteenkiste showed that patients
receiving darbepoietin required fewer transfusions than
patients receiving placebo (27% versus 52%, 95% CI 14% to
36%, P <0.001) [
]. A 2006 Cochrane review confirmed the
ability of ESA treatment to reduce the tranfusion rate [relative
risk (RR) 0.64, 95% CI 0.6?0.68). The same review indicated
that there was a trend towards an increase in quality of life in
patients receiving ESA treatment [
Over the last few years, however, many concerns regarding
the safety of ESA treatment in terms of mortality, venous
thromboembolism (VTE) and tumor progression have been
The BEST study and the PREPARE study, two double-blind
placebo-controlled phase III treatments investigating the effect
of ESA therapy in breast cancer patients receiving
chemotherapy, both indicated a higher mortality rate in
patients receiving ESA treatment [
]. In head and neck
cancer, the ENHANCE study and the DAHANCA-10 study
showed a reduction of time to locoregional progression in
patients receiving Epo [
]. A reduction of overall survival
in ESA patients was seen in the ENHANCE study [
]. In the
palliative setting, the AMGEN 103 anemia of cancer study, ESA
treatment was associated with a significantly shorter overall
survival and darbepoetin treatment was not able to achieve the
end point of transfusion reduction [
]. Three recent
metaanalyses performed by Bennett, Bohlius and Tonnelli confirmed
that patients receiving ESA treatment had a significantly
increased RR of mortality of 1.17, 1.15 and 1.1, respectively
]. Interestingly, in the Bennett meta-analysis, patients
treated for cancer-related anemia fared less well than patients
treated for chemotherapy-induced anemia (HR 1.29, 95% CI
1?1.67 versus HR 1.09, 95% CI 0.99?1.19) [
]. The three
above-mentioned meta-analyses contain patients included in
studies where Epo was used off-label with a target hemoglobin
>12 g/dl. More recently, a meta-analysis conducted by Glaspy
showed that when considering only the patients included in
studies where the target hemoglobin was <12 g/dl, the overall
mortality did not seem to vary between patients receiving ESA
therapy or patients receiving placebo [
Recent concerns regarding the risk of thromboembolism in
patients treated with ESA have been corroborated by the
metaanalyses conducted by Tonnelli and Bennett (RR 1.95, 95% CI
1.27?2.24, and RR 1.57, 95% CI 1.31?1.87) [
]. In breast
cancer patients, the BRAVE study conducted by Aapro
randomized breast cancer patients receiving chemotherapy to
either epoetin beta or best supportive care. Patients under ESA
experienced more thromboembolic events than controls (13%
versus 6%). There was however no difference in grade III?IV
VTE- or in thromboembolic event (TEE)-related deaths .
An analysis of six trials of darbepoetin alfa by Glaspy and
colleagues found an increased thromboembolic risk for patients
with a hemoglobin level >12 g/dl or with an increase in
hemoglobin of >1 g/dl in 14 days [
]. An ODAC review found
that the thromboembolic risk throughout studies varied with
the target hemoglobin level. When targeting 13 g/dl, the relative
risk for VTE is 0.7. It rises to 1.7 for a target hemoglobin
between 13 and 14 g/dl. In studies targeting levels >15 g/dl, it
rises to 1.92 [
]. The different meta-analyses which have been
assessing mortality and VTE may be biased by the fact that they
include studies where ESAs have been used off-label with
a target hemoglobin >12 g/dl [
]. In the meta-analysis
conducted by Bennett in 2008, the BEST study where the target
hemoglobin was >12 g/dl accounted for >20% [
] The 2006
meta-analysis and Cochrane review by Bohlius showed an RR
of VTE in ESA patients of 1.67 (95% CI 1.13?1.93). When
addressing only patients where the target hemoglobin lay under
12 g/dl, the RR was somewhat smaller [
Concerns about tumor progression under ESA treatment
have been raised in the last years; however, pre-clinical evidence
for the existence of EPO-Rs on tumor cells remains
]. In fact, immunohistochemical studies
might be biaised by the fact that anti-EPO-R antibodies, in
particular C20 (Santa Cruz, California), are not specific and
might in fact detect heat shock protein-70 (HSP-70), which is
expressed in cases of anoxia and is considered as a marker of
a poor prognosis [
] Moreover, in 2006, Elliott
demonstrated that an EPO-R knockout mouse model showed
the same uptake of anti-EPO-R antibodies as controls .
Some in vitro studies showed that cancer cell lines treated with
Epo at high concentration displayed increased phosphorylation
of ERK1/2 or STAT-5 AKT/ERK, which are signaling kinases
found downstream of the EPO-R. Phosphorylation of these
signals was, however, not correlated to proliferation [
Furthermore, the Epo concentrations used in these experiments
surpassed those currently encountered in patients treated with
ESA. In clinical studies, one author showed a substantially
lower progression-free survival in head and neck cancer
patients and identified a subgroup with a poor prognosis
expressing the EPO-R [
]. As the anti-Epo antibody used to
detect the EPO-R was non-specific, it is likely that the authors
have identified a subpopulation expressing HSP-70 [
Other side effects of Epo such as pure red cell aplasia or
hypertension have not yet been described in cancer patients. A
worrying publication in November 2009 showed a substantial
increase in strokes in diabetes patients [
]. This could be
a further argument cautioning against ESA therapy in general.
treatment of anemia
The treatment of chemotherapy-induced anemia depends on
the grade and on the symptoms of anemia. Transfusion remains
Titration for response
Adjust for the lowest dose sufficient to maintain
If increase >1 g/dl in 2 weeks reduce by 25?50%
Withhold dose if Hb >13 g/dl
Adapted from NCCN 2010 [
] and ESMO 2009 [
ESMO, European Society for Medical Oncology; Hb, hemoglobin; NCCN, National Comprehensive Cancer Network; U, units
an option for patients who need immediate correction of
anemia. In patients who do not require immediate correction,
treatment options include transfusion and ESA therapy. The
National Comprehensive Cancer Network (NCCN) and the
European Society for Medical Oncology (ESMO) caution
against ESA therapy in patients receiving chemotherapy with
curative intent [
In asymptomatic patients with risk factors for the
development of symptomatic anemia, ESA therapy might be
]. It must, however, be noted that ESA
treatment, when used within the guidelines, does not change
the course of the underlying malignancy. So, clinicians should
weigh the possible risks and benefits of ESA treatment and
discuss them with the patient [
The most common dosing schedules for epoetin alfa are 150
units/kg three times weekly and 40 000 units once weekly
]. Other dosages may be considered
including extended dosing of 80 000 units every 2 weeks and
120 000 units every 3 weeks [
]. Darbepoetin alfa is
initially administered at 2.25 lg/kg every week . Studies
using higher doses at longer intervals (500 lg every 3 weeks)
showed more efficacy than the standard doses [
Dosing schedules in the case of insufficient response are shown
in Table 2.
A functional iron deficiency is often seen in patients receiving
Epo. Iron supplementation should be given in patients to
maintain erythropoiesis [
]. Iron is available in oral or
intravenous forms. Studies in anemic patients receiving ESA
with oral iron supplementation, intravenous iron dextran or no
iron at all showed that patients receiving an intravenous bolus
experienced a higher rise in hemoglobin levels than patients
receiving oral iron or no iron supplementation at all [
Moreover, no statistically significant difference could be found
between patients receiving oral iron or no iron
alternatives to EPO and transfusions
Currently, relatively few alternatives to Epo or transfusions
exist: polymerized pegylated human hemoglobin (Polyheme )
has been used with success in cardiogenic shock when blood
was not available. It is, however, not readily available in
European countries or in the USA [
]. GATA-2 inhibitors
could be used in the future to raise endogenous Epo production
and stimulate erythroid differentiation [
]. Development of
these drugs is not proceeding at present.
Over the past few years, many aspects of the pathophysiology of
anemia in cancer are better understood. However, more needs
to be clarified, including the place of iron therapy and
transfusion-related side effects.
The various recent recommendations and guidelines have at
least partially indicated how best to use ESAs and probably
more will be learned about how best to treat patients and to
retain the cost?benefit balance of all the therapies.
The author has not declared any conflict of interest
1. Knight K , Wade S , Balducci L. Prevalence and outcomes of anaemia in cancer: a systematic review of the literature . Am J Med 2004 ; 116 Suppl 7A : 11S - 26S .
2. Tas F , Eralp Y , Basaran M et al. Anaemia in oncology practice: relation to diseases and their therapies . Am J Clin Oncol 2004 ; 2 Suppl 1 : 11 - 26 .
3. Stasi R , Abriani L , Beccaglia P et al. Cancer-related fatigue: evolving concepts in evaluation and treatmen . Cancer 2003 ; 98 : 1786 - 1801 .
4. Caro JJ , Salas M , Ward A et al. Anemia as an independant prognostic factor for survival in patients with cancer: a systematic, quantitative review . Cancer 2001 ; 91 : 2214 - 2221 .
5. NCCN clinical practice guidelines. Cancer- and chemotherapy-induced anemia . V2 . 2010 . Available at http://www.nccn.org/professionals/physician_gls/PDF/ anemia.pdf.
6. Adamson J. The anaemia of inflammation/malignancy: mechanism and management . Hematology Am Soc Haematol Educ Program 2008 : 159 - 165 .
7. Steensma DP . Is anaemia of cancer different from chemotherapy-induced anaemia ? J Clin Oncol 2008 ; 26 : 1022 - 1024 .
8. Buck I , Morceau F , Cristofanon S et al. Linking anemia to inflammation and cancer: the crucial role of TNFa . Biochem Pharmacol 2009 [epub ahead of print], doi: 10 .1016/j.bcp. 2008 . 12 .018.
9. Morceau F , Dicato M , Diederich M . Pro-inflammatory cytokine mediated anemia: regarding molecular mechanisms of erythropoiesis . Mediators Inflamm 2009 [epub ahead of print], doi: 10 .1155/ 2009 /405016.
10. Ohneda K , Yammamoto M. Roles of hematopoietic transcription factors GATA-1 and GATA-2 in the development of red blood cell lineage . Acta Haematol 2002 ; 108 : 237 - 245 .
11. Ikonomi P , Riviera C , Riordan G et al. Overexpression of GATA-2 inhibits erythroid and promotes megakaryocyte differentiation . Exp Haematol 2000 ; 28 : 1423 - 1431 .
12. Wilson J , Yao G , Rafferty J et al. A systematic review and economic evaluation of epoetin alpha epoetin beta and darbepoetin alpha in anaemia associated with cancer, especially that attributable to cancer treatment . Health Technol Assess 2007 ; 11 : 1 - 202 , III-IV.
13. Groopman J , Itri L . Chemotherapy-induced anemia in adults: incidence and treatment . J Natl Cancer Inst 1999 ; 91 : 1616 - 1634 .
14. Ludwig H , Belle S , Barrett-Lee P et al. The European Cancer Anaemia Survey (ECAS): a large multinational, prospective survey defining prevalence, incidence and treatment of anaemia in cancer patients . Eur J Cancer 2004 ; 40 : 2293 - 2306 .
15. Cable R , Carlson B , Chambers L et al. Practice Guidelines for Blood Transfusion: A Compilation from Recent Peer-reviewed Literature . American Red Cross Publication 2002 ; 52 .
16. Wiesen AR , Hospenthal DR , Byrd JC et al. Equilibrationof haemoglobin concentration after transfusion in medical inpatients not actively bleeding . Ann Intern Med 1994 ; 121 : 218 - 230 .
17. Kader A , Lim J , Berthelet E et al. Prognostic significance of blood transfusions in patients with esophageal cancer treated with combined chemoradiotherapy . Am J Clin Oncol 2007 ; 30 : 492 - 497 .
18. Fatalities reported to the FDA following blood collection and transfusion http:// www.fda.gov/downloads/biologicsbloodvaccines/safetyavailability/bloodsafety/ ucm113904. pdf annual summary for fiscal year 2008 .
19. King K , Shirey R , Thoman S et al. Universal leukoreduction decreases the incidence of febrile nonhemolytic transfusion reactions to RBCs . Transfusion 2004 ; 44 : 25 - 29 .
20. Khorana A , Francis C , Blumberg N et al. Blood transfusions, thrombosis and mortality in hospitalized patients with cancer . Arch Intern Med 2008 ; 168 : 2377 - 2381 .
21. Jabbour E , Kantarjan H , Koller C et al. Red blood cell transfusion and iron overload in the treatment of patients with myelodysplastic syndromes . Cancer 2008 ; 112 : 1089 - 1095 .
22. Littlewood TJ , Baretta E , Nortier JW et al. Effects of erythropoietin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomised, double-blind, placebo controlled trial . J Clin Oncol 2001 ; 19 : 2865 - 2874 .
23. Vansteenkiste J , Pirker R , Massuti B et al. Double-blind, placebo controlled, randomised phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy . J Natl Cancer Inst 2001 ; 94 : 1211 - 1220 .
24. 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 - 714 .
25. Leyland-Jones B , Semiglazov V , Pawlicki M et al. Maintaining normal haemoglobin levels with epoetin alfa in mainly non-anemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study J Clin Oncol 2005 ; 23 : 5960 - 5972 .
26. FDA press release: FDA receives new data on risks of anemia drugs consistent with previous data on tumor growth and death . http://www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/2008/ucm116830.htm.
27. Henke M , Laszig R , Rube C et al. Erythropoietin to treat head and neck cancer patients with anemia undergoing radiotherapy: randomised double-blind, placebo-controlled trial . Lancet 2003 ; 362 : 1255 - 1260 .
28. Overgard J , Hoff C , San 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. Eur J Cancer Suppl 2007 ; 5 .
29. Goldberg P. Study finds more deaths on Aranesp arm in cancer anemia study, no benefit seen . Cancer Lett 2007 ; 33 : 1 .
30. Bennett CL , Silver SM , Djulbegovic B et al. Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoietin administration for the treatment of cancer-associated aemia . JAMA 2008 ; 299 : 914 - 924 .
31. Bohlius J , Schmidlin K , Brillant C et al. Recombinant human erythropoietinstimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials . Lancet 2009 ; 373 : 1532 - 1542 .
32. Tonelli M , Hemmelgarn B , Reiman T et al. Benefits and harms of erythropoiesisstimulating agents for anemia related to cancer: a meta analysis . CMAJ 2009 ; 180 : E62 - E71 .
33. Glaspy J , Crawford J , Vansteenkiste J et al. Erythropoiesis-stimulating agents in oncology: a study-level meta-analysis of survival and other safety outcomes . Br J Cancer 2010 ; 102 : 01 - 35 .
34. Aapro M , Leonard RC , Barnadas A et al. Effect of once-weekly epoetin beta on survival in patients with metastatic breast cancer receiving anthracycline- and/or taxane-based chemotherapy: results of the Breast Cancer-Anemia and the Value of Erythropoietin (BRAVE) study . J Clin Oncol 2008 ; 26 : 592 - 598 .
35. Glaspy J , Osterborg A , Ludwig H et al. Evaluation of the association between (Hb) events and safety outcomes in cancer patients with chemotherapy induced anemia: an integrated analysis of patient-level data from 6 randomized, placebocontrolled trials of darbepoetin . Eur J Cancer Suppl 2007 ; 5 .
36. 2007 Oncologic Drug Advisory Committee (ODAC) Meeting Information Package . Darbepoetin alfa (BLA # 103951) and Epoetin alfa ( BLA # 103234) . 53 . 54. Available at http://www.scribd.com/doc/1117102/ US-Food- and -DrugAdministration- 20074301b20101Amgen.
37. Osterborg A , Aapro M , Cornes P . Preclinical studies of erythropoietin receptor expression in tumour cells: impact on clinical use of erythropoietic proteins to correct cancer-related anaemia . Eur J Cancer 2007 ; 43 : 510 - 519 .
38. Fandrey J , Dicato M. Examining the involvement of erythropoiesis-stimulating agents in tumor proliferation (erythropoietin receptors, receptor binding, signal transduction), angiogenesis, and venous thromboembolic events . Oncologist 2009 ; 14 ( suppl ): 34 - 42 .
39. Elliott S , Busse L , Bass MB et al. Anti-Epo receptor antibodies do not predict Epo receptor expression . Blood 2006 ; 107 : 1892 - 1895 .
40. Della Ragione F , Cucciolla V , Borriello A et al. erythropoietin recetors on cancer cells: a still open question . J Clin Oncol 2007 ; 25 : 1812 - 1813 .
41. Ciocca DR , Calderwood SK . Heatshock proteins in cancer: diagnostic, prognostic, predictive and treatment implications . Cell Stress Chaperones 2005 ; 10 : 86 - 103 .
42. Jeong JY , Feldman L , Solar P et al. Characterization of erythropoietin receptor and erythropoietin expression and function in human ovarian cancer cells . Int J Cancer 2008 ; 122 : 274 - 280 .
43. Dunlop EA , Percy MJ , Boland MP et al. Induction of signalling in non erythroid cells by pharmacological levels of erythropoietin . Neurodegener Dis 2006 ; 3 : 94 - 100 .
44. Pfeffer M , Burdmann E , Chen C et al. A trial of darbepoetin alpha in type 2 diabetes and chronic kidney disease . N Engl J Med 2009 ; 361 : 2019 - 2032 .
45. Schrijvers D , Roila F. Erythropoiesis-stimulating agents in cancer patients: ESMO recommendations for use . Ann Oncol 2009 ; 20 ( suppl 4 ): iv159 - iv161 .
46. Henry D , Gordan L , Charu V et al. Randomized open-label comparison of epoetin alfa extended dosing (80000 U Q2W) vs weekly dosing in patients with chemotherapy-induced anaemia . Curr Med Res Opin 2006 ; 22 : 1403 - 1413 .
47. Steensma D , Molina R , Sloan J et al. Phase III study of two different dosing schedules of erythropoietin in anemic patients with cancer . J Clin Oncol 2006 ; 24 : 1079 - 1089 .
48. Hedenus M , Adriansson M , San Miguel J et al. Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: a randomized, double-blind, placebo-controlled study . Br J Haematol 2003 ; 362 : 1255 - 1260 .
49. Canon J , Vansteenkiste J , Bodoky G et al. Randomized double-blind, activecontrolled trial of every 3-week darbepoetin alfa for the treatment of chemotherapy-induced anaemia . J Natl Cancer Inst 2006 ; 98 : 273 - 284 .
50. Henry D , Dahl N , 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 - 242 .
51. Hedenus M , Birgegard G , Nasman P et al. Addition of intravenous iron to epoetin beta increases hemoglobin response and decreases epoetin dose requirements in anemic patients with lymphoproliferative malignancies. A randomised multicenter study . Leukemia 2007 ; 21 : 627 - 632 .
52. Bastit L , Vandebroek A , Altintas S et al. Randomized multicenter controlled trial comparing the efficacy and safety of darbepoetin alfa administered every 3 weeks with or without intravenous iron in patients with chemotherapyinduced anemia . J Clin Oncol 2008 ; 26 : 1611 - 1618 .
53. Moore E , Moore F , Fabian T . Human polymerised haemoglobin for the treatment of hemorrhagic shock when blood is unavailable: the USA multicenter trial . J Am Coll Surg 2009 ; 208 : 1 - 13 .
54. Jelkmann W. Control of erythropoietin gene expression and its use in medicine . Methods Enzymol 2007 ; 435 : 179 - 197 .