ERITROPOETIN AND

ANEMIA IN ONCOLOGY
Dairion Gatot, Savita Handayani,
Soegiarto Gani

Divisi Hematologi & Onkologi Medik

Departemen Ilmu Penyakit Dalam
FK-USU/RSUP H.Adam Malik
Medan 2012

Anaemia in Cancer Represents

a Substantial Burden
Anaemia is highly prevalent
affects up to 90% of patients with cancer,
depending on malignancy and chemotherapy type 1,2

Anaemia is associated with

poor clinical outcome (increased mortality risk,
impaired tumour control)36
reduced quality of life (QoL)

Fatigue = one of the main symptoms of

1. Groopman & Itri. JNCI 1999; 91: 161634
anaemia affecting
patient
QoL
2. Knight et al. Am
J Med 2004;116
(Suppl 7A): 11S26S
3. Moullet et al. Ann Oncol 1998; 9: 110915
4. Lutterbach & Guttenberger. Int J Radiat Oncol Biol Phys 2000; 48: 134550
5. Caro et al. Cancer 2001; 91: 221421
6. Van Belle & Cocquyt. Crit Rev Oncol Hematol 2003; 47: 111

Incidence of Anaemia is High in

Patients with Cancer
31%

In remission
Newly diagnosed

35%

Persistent/
recurrent disease

48%
39%

Overall
0

10

20
30
40
50
Patients with anaemia (%)

60

Anaemia: Hb <12 g/dl at enrolment

European Cancer Anaemia Survey (ECAS), Ludwig et al. Ann Oncol 2002; 13 (Suppl 5): 169 [A623PD]

Anaemia Worsens with

Chemotherapy
Radiotherapy

28%

Chemo-radiotherapy

45%

Chemotherapy

50%
32%

No treatment
0

10

20
30
40
50
Patients with anaemia (%)

60

Anaemia: Hb <12 g/dl at enrolment

European Cancer Anaemia Survey (ECAS), Ludwig et al. Ann Oncol 2002; 13 (Suppl 5): 169 [A623PD]

Cause of Anaemia is Multifactorial in

Patients with Cancer
Myelosuppression by
chemotherapy and/or
radiotherapy

Haemolysis

Malignancy
itself

Anaemia

Abnormal iron
metabolism

Bone marrow
infiltration

Blood loss

Renal
impairment
Nutritional deficiency
(iron/vitamin B12/folic acid)
Beguin. Leuk Lymphoma 1995; 18: 41321
Ludwig & Fritz. Semin Oncol 1998; 25 (Suppl 7): 26
Ludwig et al. Hematol J 2002; 3: 12130
Wood & Hrushesky. J Clin Invest 1995; 95: 16509
Mercadente et al. Cancer Treat Rev 2000; 26: 30311

Anaemia Adversely Impacts Organ

Function in Patients with Cancer
Central nervous system
Reduced cognitive
function
Depressed mood
Cardiovascular system
Tachycardia
Weakness
Cardiopulmonary
system
Exertional dyspnoea
Dyspnoea
Cardiac
decompensation

Skin
Reduced

perfusion

Pale
Cold

Kidney function
Reduced perfusion
Fluid retention
Reproductive function
Menstrual disturbances
Loss of libido
Impotence
Immune system
Immune deficiency

Adapted from Ludwig & Strasser. Semin Oncol 2001; 28 (Suppl 8): 714

Decreases
Quality of Life
Fatigue

Reduced
ability to
work

Impaired social
function

Depression

Anaemia

Sexual
dysfunction

Reduced
exercise
capacity

Poor
concentration

Anaemia Reduces Survival in

Patients with Cancer
Mean increase in mortality
risk (%)

150
125
100
75
50

67%

65%

47%

25
0

75%

19%
Lung

Prostate

Lymphoma

Systematic review of 60 studies

Head &
Neck

Overall

Caro et al. Cancer 2001; 91: 221421

Pathophysiology of
Malignancy-Induced Anaemia
AIS

Erythrocytes
= shortened survival

Tumour cells

Activated
immune system

Erythrophagocytosis,
dyserythropoiesis

Macrophages

TNF

Cytokines (TNF, IL-1/, IFN-)

Anaemia

Reduced
erythropoietin
production

Impaired
iron
utilisation

Suppressed
BFU-E
CFU-E

AIS, Anaemia-Inducing Substance; BFU-E, Burst-Forming Unit-Erythroid; CFU-E, ColonyForming Unit-Erythroid; TNF, Tumour Necrosis Factor; IL, Interleukin; IFN, Interferon
Nowrousian. Med Oncol 1998; 15 (Suppl 1): S1928

Poor Prognosis in Patients with

Cancer
Anaemia
Tumour hypoxia
Chemo- and
radio-resistance

Genetic
instability

Selection pressure
Apoptotic deficiency

Angiogenesis

Accelerated progression
Increased rate of distant metastases

Poor prognosis

Management Options
for Anaemia in Patients
with Cancer

Options for Anaemia Management

in Patients with Cancer
Transfusion
(15%)
Iron alone
(7%)
No treatment
(60%)
Epoetin
(18%)

European Cancer Anaemia Survey (ECAS), Ludwig et al. Ann Oncol 2002; 13 (Suppl 5): 169 [A623PD]

Options for Anaemia Management

in Patients with Cancer
Red blood cell transfusions
transient and unsustainable Hb increase3
potential for serious side effects (e.g. iron overload, Haemolysis, Viral
transmission)4,5
transfused red blood cells are functionally defective
dwindling blood supplies6
Erythropoietic agents (EPOs)
produce significant and sustained Hb increases1
stimulate formation of red blood cells that function normally 2
are generally well tolerated
are more convenient than transfusions
Erythropoietic agents (EPOs)
Iron and/or vitamin supplements
Iron and/or vitamin supplements

1. Ludwig et al. N Engl J Med 1990; 322: 16939

2. Ludwig et al. Hematol J 2002; 3: 12130
3. sterborg. Med Oncol 1998;
15 (Suppl 1): S479

4. Williamson et al. BMJ 1999; 319: 169

5. Jensen et al. Blood 2003; 101: 916
6. Brittenham et al. Hematology
(Am Soc Hematol Educ Program) 2001: 42232

Drawbacks of Transfusion
Emergency treatment for acute, severe
anaemia
Usually not given until symptomatic severe
anaemia (Hb 89 g/dl)
Effects are immediate, but transient and
unsustainable1
Associated with serious side effects2, 3
(iron overload, immunosuppression,
haemolysis, infections) 1. sterborg. Med Oncol 1998; 15 (Suppl 1): S479
2. Williamson et al. BMJ 1999; 319: 1619
3. Jensen et al. Blood 2003; 101: 916

Drawbacks of Transfusion
Transfused red blood cells are functionally
defective with shorter survival time
Blood supply becoming less available
owing to decreasing donor pool1 and
requirement for more stringent processing 2
Inconvenient for both the patient and
healthcare professional
1. Brittenham et al. Hematology (Am Soc Hematol Educ Program) 2001: 42232
2. Goodnough. Curr Opin Hematol 2001; 8: 40510

Transfusion - Transmitted
Infections
Indonesian Red Cross (Position on Screening):
All blood supply screened
Major blood-borne diseases screened (HIV, HCV,
HBV, Syphylis ).
Historical data in Indonesia: Incidence of HIV and
hepatitis C from blood donor have been documented
(Syaifullah Noer, 1994)
Up to 60% haemodialysis patients infected Hepatitis c
( Haemodialysis center Indonesian multi center study2005, PIT Pernefri july2005 )
Several Private Hospitals re-screen blood supply to
avoid blood-borne diseases (additional cost to patients)

Adverse Events Associated with

Blood Transfusions
Transfusion-transmitted infections
3%

Post-transfusion purpura
6%

Acute lung injury

Graft vs host 2%
disease

Delayed
transfusion
reaction

8%
52%

Incorrect
blood/component
transfused

14%

15%
Acute transfusion
reaction
Williamson et al. BMJ 1999; 319: 1619

Advantages of Epoetin over

Transfusion
Epoetins
can be used for treatment of mild-to-moderate
anaemia1, 2
produce smooth and sustained increase in Hb3
improve Quality of Life by maintaining higher
Hb targets
are well tolerated
are more convenient than transfusions
Induce red blood cells that function normally 1
1. Ludwig et al. Hematol J 2002; 3: 12130
2. Rizzo et al. J Clin Oncol 2002; 20: 4083107
3. Ludwig et al. N Engl J Med 1990; 322: 16939

Epoetin Produces a Smooth and

Sustained Hb Increase Compared
with Transfusions
14
Epoetin

Hb (g/dl)

12
Transfusions

10
8
6
4
0

30

60

90

120

150

180

210

Days of treatment
= transfusion given

sterborg. Med Oncol 1998; 15 (Suppl 1): S479

Ludwig et al. N Engl J Med 1990; 322: 16939

Management Options for Anaemia

in Patients with Cancer: Summary
Red blood cell transfusion has many
disadvantages

Eritropoetin treatment produces

smooth and sustained Hb increases
and is an alternative treatment option
to transfusion
No treatment is not an appropriate option

Erythropoietin and
Erythropoiesis

Erythropoietin
Glycoprotein of 34 kDa
Produced in kidney and liver; trace amounts in brain
Not involved in commitment of cells to the erythroid
lineage
Stimulates proliferation, differentiation, and survival of
erythroid progenitors

Lacombe (1998, 1999) Krantz (1991) Bernaudin (2000)

Erythropoietin: Properties
Glycoprotein regulating erythropoiesis
Produced primarily by renal peritubular
fibroblasts and transported via bloodstream
to bone marrow
Production is upregulated under anaemic
or hypoxic conditions
Binds to specific receptor on erythroid
progenitor cells
Fisher. Exp Biol Med 2003; 228: 114

Normal
Erythropoiesis

Erythropoietin:
Mechanism of Action
Erythropoietin
Erythropoietin
Reticulocyte

BFU-E

CFU-E

Erythroblasts
without
erythropoietin

Apoptosis
BFU-E: Burst-Forming Unit-Erythroid
CFU-E: Colony-Forming Unit-Erythroid

Red blood cells

Fisher. Exp Biol Med 2003; 228: 114

Erythropoietic agents produce a

smooth and sustained Hb increase
14

Erythropoietic agents

Hb (g/dL)

12
Transfusions

10
8
6
4
0

30

60

90

120

150

180

210

Days of treatment
transfusion given

sterborg. Med Oncol 1998;15(Suppl 1):S479

Ludwig et al. N Engl J Med 1990;322:16939

Advantages of Epoetin over

Transfusion
Epoetin
can be used for treatment of mild-to-moderate
anaemia1, 2
produces smooth and sustained increase in
Hb3
improves Quality of Life by maintaining higher
Hb targets
is well tolerated
is more convenient than transfusions
induces red blood cells that function normally 1
1. Ludwig et al. Hematol J 2002; 3: 12130
2. Rizzo et al. J Clin Oncol 2002; 20: 4083107
3. Ludwig et al. N Engl J Med 1990; 322: 16939

EORTC Guideline
Recommendations
Goals of EPO therapy
improve QoL
prevent transfusions

Treatment guidelines
initiate EPO therapy at Hb 911 g/dl
continue EPO treatment as long as patients show
symptomatic improvement
target Hb concentration should be 1213 g/dl

Bokemeyer et al. Eur J Cancer 2006, doi:10.1016/j.ejca.2006.10.014

EORTC Guideline
Recommendations

Increase in QoL score

(LASA, mm)

Maximum QoL benefit seen at 12 g/dl

(range
1113 g/dl)
3.5
Epoetin 30 000 IU/week in
patients with non-myeloid
malignancies undergoing
chemotherapy

3.0
2.5
2.0
1.5
1.0
0.5
0
8

LASA: Linear Analog Scale Assessment

10

11
Hb level (g/dl)

12

13

Crawford et al. Cancer 2002; 95: 88895

EORTC Guidelines Recommend

Once Weekly or TIW EPO
Administration
Supportive evidence for once weekly
administration with different EPOs
Epoetin alfa 40 000 IU
Epoetin beta 30 000 IU
Darbepoetin alfa 2.25 mcg/kg

Current evidence to support the use of

EPOs in Q2W, Q3W or Q4W dosing
intervals is limited
Q2W: once every 2 weeks; Q3W: once every 3 weeks; Q4W: once every 4 weeks
Bokemeyer et al. Eur J Cancer 2006, doi:10.1016/j.ejca.2006.10.014