Table Of Content.~.
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M. R. Nowrousian (Ed.)
Recombinant Human Erythropoietin (rhEPO)
in Clinical Oncology
Scientific and Clinical Aspects
of Anemia in Cancer
Prof. Dr. med. M. R. Nowrousian
Innere Klinik und Poliklinik (Tumorforschung), Westdeutsches Thmorzentrum
Essen, Universitatsklinikum, Essen, Deutschland
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© 2002 Springer-VerlaglWien
Softcover reprint of the hardcover 1s t edition 2002
Typesetting: SNP Best-set Typesetter Ltd., Hong Kong
Printed on acid-free and chlorine-free bleached paper
SPIN: 10797756
With 66 (partly coloured) Figures
ISBN-13: 978-3-7091-7660-3 e-ISBN-13: 978-3-7091-7658-0
DOl: 10.1007/978-3-7091-7658-0
Preface
During the last decade, considerable insight has been gained into the
pathogenic mechanisms of anemia in cancer and cancer treatment and its
important role in the life of cancer patients and the course of their disease.
Anemia is a frequent complication that not only presents a negative prog
nostic factor for the outcome of treatment in a variety of malignant diseases,
but is also associated with enormous impacts on physical well-being and
quality of life (QoL) of patients. Anemia may also be involved in the develop
ment of tumor resistance against radiotherapy and chemotherapy. Recent
studies indicate a close relationship between anemia and tumor hypoxia,
and show that the latter is a factor that significantly determines the outcome
of radiotherapy. Furthermore, there is evidence suggesting that hypoxia
stimulates angiogenesis within the tumor and contributes to a selection of a
more malignant phenotype of tumor cells and a reduced sensitivity of these
cells to irradiation and chemotherapy. These findings and the consequences
that arise from anemia for metabolic and organ functions as well as QoL
identify anemia as a much more serious problem for cancer patients than
previously considered.
Treatment of anemia has been traditionally red blood cell (RBC)
transfusion, which, however, only transiently increases the hemoglobin level
and is of minimal effect on QoL. It is also associated with a number of side
effects and risks, such as febrile and allergic reactions, alloimmunization,
transmission of infections, iron overload and suppression of cellular im
munity that could be particularly harmful for cancer patients. In these
patients, in addition, symptoms of anemia are frequently attributed, to the
malignant disease or its treatment, and many patients remain untreated until
severe clinical symptoms occur or the hemoglobin level decreases below
8-10 g/dl.
The introduction of recombinant human erythropoietin (rhEPO) has
dramatically improved the treatment of anemia in patients with end-stage
renal disease and is also a major advantage for the treatment of anemia in
patients with malignant diseases. Using rhEPO, it is possible to achieve sus
tained physiological, and much more effective, levels of hemoglobin than
with RBC transfusion. The use of rhEPO, in addition, has considerably
vi Preface
physical well-being and to ameliorate tumor oxygenation with the aim of
improving the outcome of cancer treatment.
This book aims to present a comprehensive and up-to-date review of
scientific and clinical aspects of anemia in cancer patients and its treatment
with rhEPO. It was a great pleasure for me, and highly appreciated, that out
standing authors, all experts on their topics, agreed to contribute to this book
and to present the state of knowledge on anemia in cancer and the current
as well as future potential of the use of rhEPO in clinical oncology, both in
patients with solid tumors and patients with hematological malignancies. My
sincere gratitude is also extended to Mrs. Ch. Wartchow for her help in proof
reading and Mrs. I. Demirer for her excellent organizational assistance in
preparing this book.
Essen, March 2002 M. R. Nowrousian
Contents
I. Biology of erythropoietin 1
C. Lacombe, P. Mayeux
II. Classification and characterization of anemia in cancer 23
M. R. Nowrousian
III. Pathophysiology of cancer-related anemia 39
M. R. Nowrousian
IV. Prevalence, pathophysiology, predictive factors, and
prognostic significance of anemia in cancer chemotherapy 63
M. R. Nowrousian
V. Incidence and impact of anemia in radiation oncology 101
1 Dunst, M. Molls
VI. Relationship between anemia and tumor hypoxia 117
1 Dunst, M. Molls
VII. Tumor hypoxia and therapeutic resistance 127
P. Vaupel, M. Hackel
VIII. Impact of anemia on organ functions ·147
M. R. Nowrousian
IX. Relationship between anemia, fatigue, and quality of life in
cancer patients 173
Y. Brandberg
X. Red blood cell transfusion, risks and limitations 185
F. Mercuriali, G. Inghilleri
viii Contents
XII. Recombinant human erythropoietin (rhEPO) in anemia
associated with multiple myeloma and non-Hodgkin
lymphoma 223
A. Osterborg
XIII. Use of recombinant human erythropoietin in the treatment
of myelodysplastic syndromes 235
M. Cazzola
XIV. rhEPO in anemia associated with solid tumors and
chemotherapy 241
M. R. Nowrousian
XV. Predictive factors for response of anemia to recombinant
human erythropoietin 263
Y. Beguin
XVI. rhEPO in hematopoietic stem cell mobilization,
transplantation, and in-vitro expansion 287
S. Klaesson
XVII. Clinical trials using rhEPO in radiation oncology 301
M. Henke
XVIII. rhEPO in pediatric oncology 313
C. Cappelli, G. Ragni, A. Clerico
XIX. rHuEPO in surgical oncology 325
F. Mercuriali, G. Inghilleri
XX. Erythropoiesis, iron metabolism and iron supplementation
during erythropoietin therapy 347
L. T. Goodnough
XXI. Optimal level of hemoglobin in cancer patients 369
M. R. Nowrousian
XXII. Protection of metabolic and exercise capacity following
treatment with recombinant erythropoietin 391
K. Lundholm, P. Daneryd
Contents ix
XXIV. Effect of rhEPO on survival in anaemic cancer patients
receiving chemotherapy 425
T. J Littlewood
xxv. Cost-effectiveness of rHuEPO in oncology 435
P.-¥. Cremieux, Ellison Dial, M. Gustafson, B. Sarokhan,
M. B. Slavin
XXVI. Current status and future developments of rhEPO in
clinical oncology 447
M. R. Nowrousian
Subject Index 493
Chapter I
Biology of erythropoietin
C. Lacombe1,2 and P. Mayeux!
lInstitut National de la Sante et de la Recherche Medicale, ICGM,
Universite Rene Descartes,
2 Service d'Hematologie, AP-Hp, Hopital Cochin, Paris, France
Introduction
Patients undergoing chemotherapy for cancer are at risk of developing
anemia, and recombinant human erythropoietin (Epo) is an alternative to
replace transfusions of allogenic red blood cells in this setting. This article
will review the regulation of the Epo gene, the structure of the Epo receptor
(EpoR) and the Epo-induced intracellular signaling events. Finally, we will
describe other compounds and mechanisms which mimic Epo action, thereby
also leading to intracellular signalling albeit with a decreased efficiency when
compared to Epo.
The role of Epo, a 34 kDa glycoprotein hormone is to control red blood
cell production through the promotion of survival and proliferation of the
erythroid progenitors in the bone marrow. Epo is the hematopoietic growth
factor which is acting specifically on the late erythroid progenitors, so-called
CFU-E (colony forming unit-erythroid). These cells correspond to the last
amplification compartment of the erythroid lineage and give rise to the ery
throblasts in the bone marrow. Because the main function of red cells is to
transport oxygen from the lungs to the peripheral tissues, the regulation of
Epo production is an important feature of the control of tissue oxygenation.
Accordingly, Epo is the only hematopoietic growth factor whose production
is regulated by hypoxia.
Epo acts through a specific receptor, EpoR, belonging to the family of
the hematopoietic growth factor receptors. Activation of the EpoR by its
ligand leads to the tyrosine phosphorylation of numerous proteins into the
target cell; among these proteins, some migrate to the nucleus, where they
stimulate the transcription of specific target genes.
2 C. Lacombe and P. Mayeux
1 Role of Epo in erythropoiesis
Cultures of hematopoietic progenitors in semi-solid media have shown that
the main targets of Epo are the late erythroid progenitors CFU-E (Gregory
and Eaves 1978). Epo and EpoR gene disruptions in mice confirmed that
Epo stimulation was absolutely necessary for survival and proliferation of
CFU-E (Lin et al. 1996; Wu et al. 1995). Moreover, these experiments showed
that Epo stimulation was not required for the commitment of the progeni
tors in the erythroid lineage. Indeed, both BFU-E and CFU-E were produced
to normal levels in Epo or EpoR null mice (Lin et al. 1996; Wu et al. 1995),
demonstrating that Epo is not involved in the determination of the erythroid
lineage.
Epo is able to sustain the proliferation of several hematopoietic cell lines
either naturally expressing the EpoR, such as HCD57 (Spivak et al. 1991)
or UT7 (Komatsu et al. 1991) or after ectopic expression of the EpoR
(D'Andrea et al. 1991; Quelle and Wojchowski 1991). These cells as well as
primary erythroid cells undergo apoptosis after Epo deprivation. HCD-57
cells infected with a retroviral vector encoding either Bel-2 or Bel-XL remain
viable in the absence of Epo. However, Epo is still required for proliferation
(Silva et al. 1996). These results demonstrate that the overall action of Epo
is to protect from apoptosis and to induce the proliferation of the CFU-E
progenitors.
2 Tissue-specific Epo gene expression
The elonage of the Epo gene (Jacobs et al. 1985; Lin et al. 1985) allowed to
gain insights into the molecular biology of Epo. In the fetal stage, the liver is
the major site of Epo synthesis (Zanjani et al. 1981), however, the Epo gene
appears to be also strongly expressed in the mammalian mesonephric kidney
early in gestation. In adult mammals, the renal synthesis of Epo was first
demonstrated by Jacobson et al. (1957). Studies on mice have shOWN that Epo
gene transcription was stimulated by hypoxia or cobalt treatment (Beru
et al. 1986), and there was a clear correlation between induction of anemia
and increase of Epo mRNA content in the kidney (Bondurant and Koury
1986). It was further shown, by in situ hybridization experiments, that Epo
mRNA was produced by interstitial cells of the kidney cortex (Koury et al.
1988; Lacombe et al. 1988). This specialized population of interstitial cells
was shown to be labelled by immunohistochemical staining with antibodies
to 5' ectonucleotidase (Bachmann et al. 1993) and thereby to belong to a
fibroblast-like cell population of the renal interstitium.
Similar results were obtained in transgenic mice containing the SV40
large tumor antigen (SV40T-antigen) placed behind the Epo gene regulatory
sequences; immunohistochemical detection of T-antigen was found in the
