Recombinant Human Erythropoietin (rhEPO) in Clinical Oncology: Scientific and Clinical Aspects of Anemia in Cancer, 2nd Edition

867 Pages·2002·4.75 MB·English

by  Mohammad Resa Nowrousian

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SpringerWienNewYork
Prof. Dr. med. M. R. Nowrousian
Department of Internal Medicine (Cancer Research),West German Cancer
Center,University Hospital of Essen,Essen,Germany
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Preface
Since the introduction of rhEPO in clinical oncology in 1993, considerable
insight has been gained into the pathogenesis, prevalence and incidence of
anemia in cancer and its impact on the life of cancer patients and the course
of their disease.Anemia is not only a frequent complication of cancer and its
treatment but also a major factor deteriorating patients’ physical well-being
and quality of life (QOL).In addition,it may be involved in the development
of tumor resistance against radiotherapy and chemotherapy. A number of
studies indicates a close relationship between anemia and tumor hypoxia,and
shows that the latter negatively and significantly determines the outcome of
radiotherapy. Also, there is evidence suggesting that hypoxia stimulates
angiogenesis and contributes to the selection of a more malignant phenotype
of tumor cells with a reduced sensitivity to irradiation and chemotherapeu-
tic agents.These findings and the impact of anemia on metabolic and organ
function, as well as QOL, identify anemia as a much more serious problem
for cancer patients than previously recognized.
Over many decades,treatment of anemia in cancer patients has consisted
of red blood cell (RBC) transfusions.However,these are of limited value in
achieving a sustained and sufficient increase in Hb level. Furthermore, fluc-
tuating Hb levels resulting from repeated RBC transfusions may produce
intermittent hypoxia,which is considered an important factor for tumor pro-
gression.Acute, cyclic hypoxia has been shown to be even more deleterious
than chronic hypoxia in selecting aggressive, apoptosis-resistant tumor cells
and promoting metastasis. RBC transfusions are also associated with a
number of side effects and risks,such as febrile and allergic reactions,alloim-
munization, transmission of infection, iron overload and suppression of cel-
lular immunity, which may be of particular concern in cancer patients.
Furthermore,RBC transfusions,because of their risks and limitations as well
as shortness of supply,are usually given at Hb levels below 8g/dl.Numerous
studies, including large prospective randomized and nonrandomized trials
and meta-analyses of data from these trials have shown that patients with
cancer are already seriously affected by the impact of anemia on metabolic
and organ functions, exercise capacity and QOL long before such low levels
of Hb are present. In addition, they have indicated that by using erythro-
poiesis-stimulating agents (ESAs),it is possible to achieve sustained physio-
logical and much more effective Hb levels than with RBC transfusions.
Furthermore, they have shown that such an increase in Hb level not only
reduces or eliminates the need for RBC transfusions,but it is also associated
vi Preface
with significant improvement in exercise capacity, physical well-being and
QOL of patients. The majority of these studies was carried out in anemic
patients receiving chemotherapy or chemoradiotherapy and the results have
identified ESAs not only as significantly effective but also comparatively safe
drugs. However, some studies have reported on a slight but significantly
increased risk of thromboembolic events associated with the use of ESAs.
This has to be considered in patients with a history of such events and patients
who are receiving thrombogenic treatments. Some other studies have raised
the question on the safety of ESAs with regard to the outcome of anticancer
treatment.These studies,however,were performed in settings other than cur-
rently approved for the use of ESAs in cancer patients and the results have
been critically reviewed because of a number of methodological problems,
which have been present in these studies, e.g. high initial and/or target Hb
levels used and imbalances in the distribution of patients and disease-related
factors determining survival between patients receiving ESAs and control
patients (Chapters 17–19, 31). Another issue of concern exclusively arising
from in vitro studies has been a possible stimulatory effect of ESAs on tumor
cells expressing EPO receptors (EPO-R).The results of these studies are in
part controversial and have become a subject of critical reviews because of
methodological problems associated with the determination of EPO-R and
their functionality. In many of these studies, the stimulatory effects of ESAs
on tumor cells were marginal and typically achieved with extremely high con-
centrations of ESAs, which do not occur in the treatment of cancer patients
receiving ESAs.In some studies,in-vitro concentrations used were at several
magnitudes higher than the peak concentrations observed in serum of
patients treated with ESAs (Chapters 3, 4, 17, 18, Addendum 1). Further-
more, numerous animal experiments have failed to show tumor growth pro-
motion by ESAs,even when the tumor cells were expressing EPO-R.In many
of these studies,ESA treatment of anemic animals significantly improved the
results of radiotherapy or chemotherapy. Nevertheless, further preclinical
and clinical studies are required to better understand the benefits and risks
of treatment with ESAs and to use these drugs with the highest possible
benefit and safety for our patients.
Like its first edition, the second edition of this book aims to be a com-
prehensive source of information on clinical and scientific aspects of anemia
in cancer and its treatment with ESAs.All chapters were updated and some
new chapters were added to achieve a greater spectrum of topics and to
include future developments of ESAs in other fields of clinical medicine,such
as neurology and cardiology.Under certain circumstances,e.g.in preventing
adverse effects of radiotherapy and chemotherapy,neuroprotective and car-
dioprotective effects of ESAs may be of value for patients with malignant
diseases.
It was again a great pleasure and honor for me, and highly appreciated,
that outstanding authors, all experts on their topics, agreed to contribute to
Preface vii
this edition and to comprehensively present the state of knowledge in their
fields. My sincere gratitude is also extended to Mrs. Ch. Wartchow for her
help in proof-reading and Mrs. I. Demirer and Mrs. U. Senkel-Nicklaus for
their excellent organizational assistance in preparing the book.
Prof. Dr. M. R. Nowrousian
Contents
Contributors xiii
1. Physiology of erythropoiesis 1
U.Testa
2. Biology of EPO and EPO-receptor 67
C. Lacombe, and P. Mayeux
3. The role of erythropoietin receptor expression on tumor cells 81
J. Fandrey
4. Problems associated with erythropoietin receptor
determination on tumor cells 103
A. Österborg
5. Definition, classification and characterization of anemia
in cancer 117
M. R. Nowrousian
6. Pathophysiology of anemia in cancer 149
M. R. Nowrousian
7. Prevalence and incidence of anemia and risk factors for
anemia in patients with cancer 189
H. Ludwig
8. Significance of anemia in cancer chemotherapy 207
M. R. Nowrousian
9. Incidence and impact of anemia in radiation oncology 249
J. Dunst and M. Molls
10. Relationship between hemoglobin levels and tumor
oxygenation 265
P.Vaupel,A. Mayer and M. Höckel
x Contents
11. Tumor hypoxia and therapeutic resistance 283
P.Vaupel and M. Höckel
12. Symptoms of anemia 307
R. Pirker
13. Impact of anemia and red blood cell transfusion on
organ function 317
M. R. Nowrousian
14. Relationship of hemoglobin, fatigue, and quality of life in
anemic cancer patients 369
Z. Butt and D. Cella
15. When to use red blood cell transfusions in cancer patients
with solid tumours? 393
J. K. Jacob and P. J. Barrett-Lee
16. Pharmacology, pharmacokinetics and safety of recombinant
human erythropoietin preparations 407
W. Jelkmann
17. Epoetin treatment of anemia associated with multiple myeloma
and non-Hodgkin’s lymphoma 433
A. Österborg
18. rhEPO in anemic patients with solid tumors and
chemotherapy – efficacy and safety 449
M. R. Nowrousian
19. Early intervention with recombinant human erythropoietin
for chemotherapy-induced anemia 509
G. H. Lyman and J. Glaspy
20. Recombinant human erythropoietin (rhEPO) therapy
in myelodysplasia 531
E. Hellström-Lindberg
21. Prediction of response to rhEPO in the anemia of cancer 541
Y. Beguin and G.Van Straelen
22. rhEPO in hematopoietic stem cell transplantation 583
G.Van Straelen and Y. Beguin
Contents xi
23. Treatment of anemia with rhEPO in radiation oncology 615
J. Dunst
24. Recombinant human erythropoietin in pediatric oncology 635
C. Hastings and J. Feusner
25. rhEPO in surgical oncology 663
M. J. Fontaine and L.T. Goodnough
26. Erythropoiesis, iron metabolism and iron supplementation
during erythropoietin therapy 679
L.T. Goodnough
27. Are there risks for use of iron in cancer patients? 703
P. Gascón
28. Metabolic and physiologic effects of rhEPO in anemic
cancer patients 713
K. Lundholm and P. Daneryd
29. Effects of rhEPO on quality of life in anemic cancer patients 729
S. Chowdhury, J. F. Spicer, and P. G. Harper
30. Thrombosis during therapy with erythropoiesis stimulating
agents in cancer 745
J. Glaspy
31. The effect of rhEPO on survival in anemic cancer patients 759
T. J. Littlewood
32. From bench to bedside: Neuroprotective effects of
erythropoietin 771
H. Ehrenreich and C. Bartels
33. rhEPO in patients with anemia and congestive heart failure 793
D. S. Silverberg, D.Wexler,A. Iaina, S. Steinbruch,
Y.Wollman, and D. Schwartz
34. Cost-effectiveness of treating cancer anaemia 813
P. Cornes
Addendum 851
Index 853