Cancer Related
Anemia
Dr. Shad Salim Akhtar
MBBS, MD, MRCP(UK), FRCP (Edin), FACP (USA)
Member AUICC Fellows
Consultant Medical Oncologist & Medical Director
Prince Faisal Oncology Center
King Fahd Specialist Hospital
Buraidah Al-Qassim, KSA
Anemia - Definition
 Decrease
in Hb value or HCT from an
individual’s baseline
 We do not always know the baseline?
 Available sex & race specific reference
ranges are used
 How much below reference range?
Tefferi A. Mayo Clin Proceedings 2003:78:1274
Comparison of Hb Scales
Anemia grade
Hb level
NCI
12-16 ♀
14-18 ♂
WHO
>11
EORTC
>11
Mild anemia
10-12 ♀
10-14 ♂
9.5-11
9.5-11
Moderate anemia
8.0-10
8.0-9.5 7.5-9.5
Severe anemia
6.5-8.0
6.5-8.0 5-7.5
No anemia
Very severe anemia <6.5
<6.5
-
Ferrario E et al: Cancer Treat Reviews 2004; 30:563-75
Knight K etal: Am J Med 2004;116:11s-26s
Anemia Prevalence in
Cancer Patients ECAS data
 Total
no of pts
 Cancer centers screened
 Countries included
 Time period
 Prevalence
• Hematological malignancies
• Solid tumors
 Hb
level considered
15367
748
24
6 months
72%
66%
<12g/dl
Ludwig H et al: Blood 2002; 234-235(a)
Anemia Prevalence in
Cancer Patients
 Depends
upon the level of Hb one
considers as anemia
 Variable according to malignancy type
• Prostate cancer
• Multiple myeloma
 Average
5%
90%
30-86%
Knight K et al. Am J Med 2004;116:11s
Why do these pateints
get anemia?
 Normal
erythropoeitic mechanisms
 Abnormalities in cancer patients
Survival, proliferation and
differentiation
What is needed for this process?
BM microenvironment
Essential nutrients
Haematopoietic regulatory
growth factors
C kit ligand
Erythropoietin
Peritubular renal cells
Liver (small amount)
Liver minor
amount
EPO receptor
CFU-E +++
BFU-E ++
Absent on retics
STAT 5
Hb Increased
Is anemia in cancer
patients a single entity?
Hb
Hct
MCV
MCHC Retic
9.7
28.6
88.3
34
PBF Ab
8
26
70
23
Mc/Hy
6
20
102
30
16%
Anemia in cancerCauses
Disease
related
Therapy related
Concomitant factors
Disease related causesCytokine Mediated
Tumor
cells
Activated immune & inflammatory system
Cytokines
TNF IFN-γ IL1
Hepcidin levels ?
Down regulation of EPO-R
Reduced
Reduced erythropoietin
erythropoietin
production
production
Other
effects
Suppression of
BFU-E/ CFU-E
Impaired iron
utilization
Anemia
Mercandante S et al: Cancer Treat Rev 2000;26:303-11
Disease related causes others
Hemolysis
Hemophagocytosis
Hypersplenism
MAHA
Marrow infiltration
Shortened
RBC survival
Tumor
cells
hematopoeitic cell
clonal disorder
Disrupted
homeostatic
mechanisms
Deficiencies
Intercurrent infections
Consumption
Blood loss
Anemia
Reduced
Reduced
erythropoietin
erythropoietin
production
production
Mercandante S et al: Cancer Treat Rev 2000;26:303-11
Anemia of chronic
disease
 Neoplastic
progression is frequently
associated with ACD
 ACD (anemia of chronic disease)
• Erythroid bone marrow hypoplasia
• Decreased (slightly) RBC survival
• Low reticulocytes
• Hypoferremia
• Low EPO levels
Anemia causesTreatment related
Radiotherapy
induced
Chemotherapy induced
Effect of other drugs being used
Transient or sustained
Treatment related
causes-mechanism
 Stem
cell death
 Growth factor blockade
 Oxidant damage to mature cells
 Myelodysplasia
 Immune mediated destruction
 Plasma volume expansion
 Nephrotoxicity causing reduced EPO
production
Concomitant factors
 Nutritional
deficiency
• Surgical resection
• Poor appetite
• Gut involvement
 Ageing
• Decreased pluripotent stem cell reserve
• Decreased production of growth factors
• Decreased sensitivity to growth factors
• Bone marrow microenvironment changes
Anemia-effect on the
patient?
Physiological
response
Cancer related fatigue
Increased mortality
Effect on treatment efficacy
Ferrario E et al: Cancer Treat Rev 2004; 30:563-75
Anemia-effect on the
patient?
Physiological
response
Cancer related fatigue
• A common symptom (58-90% pts)
• Associated with anemia?
Increased
mortality
Effect on treatment efficacy
Cancer related fatigue &
QOL
 Which
of the following most adversely
effects the quality of life in this patient
group?
• Pain
• Oncologists’ belief
61% vs 37%
• Patients’ belief
61% vs 19%
• Fatigue
Vogelzang NJ et al: Semin Hematol 1997; 34(s):4-12
Fatigue and anemia
relationship
MFI-20
subscales
with
with no Controls 1 vs 3 2 vs 3
anemia anemia
effect effect
(1)
(2)
(3)
size
size
General fatigue
13.2±4.8
11.9±6.1
7.8±4.2
1.29
0.98
Physical fatigue 13.3±4.7
11.1±5.3
7.8±3.7
1.49
0.89
ed activity
13.4±4.6
10.2±5.8
7.4±4.2
1.43
0.67
ed Motivation
9.7±4.6
9.2±4.9
6.4±2.8
1.18
1.00
Mental fatigue
9.5±4.1
11.1±4.7
7.8±4.6
0.37
0.72
60 pts of cancer receiving 3 CT cycles
Anemia 10-12 g/dl
Higher values indicate more fatigue Range (4-20)
P<0.05
P<0.01
P<0.001
Holzner B et al: Ann Oncol 2002; 13:965-73
Ovarian
Lung
Colorectal
All
Level of hemoglobin
*
Holzner B et al: Ann Oncol 2002;13:965-73
Anemia and mortality
 Multiple
studies reveal ed survival
related to anemia
 Different types of malignancies
• Hematological
• Solid tumors
• Mixed
 Anemia
? Indicates advanced disease
 Significance of this finding?
Knight K etal: Am J Med 2004;116:11s-26s
Anemia and effect on
treatment efficacy
 Anemia
causes tissue hypoxia
• Resistance to ionizing radiation
• Resistance to some chemotherapy
agents
• More aggressive disease
• Changes in proteom and genome
• Clonal selection
Vaupal P etal: Semin Oncol 2001;28(s):29-35
Denko NC etal: Oncogene 2003; 22:5907-14
Anemia in a cancer patienthow
to
investigate?

Multifactorial
 Rule out a correctable cause
 Laboratory evaluation
• CBC
• Retic count
• PBF
• Chemistry
• Nutritional evaluation/Iron stores
• Hemolysis
 Bone
marrow examination
 EPO estimation ?? value
Mercandante S et al: Cancer Treat Rev 2000;26:303-11
Anemia in cancer-how
to treat?
 No
single paradigm
 Varies according to cause and presentation
 Cause
• AIHA
• Nutritional deficiency
steroids
supplements
 Severity
• Hemorrhage
• Severe symptoms
transfusion
transfusion
Red cell transfusionhazards









Incidence 3-10% (20% in some instances)
Incompatibility / Febrile reactions /Infections
Overload / Thrombophlebitis
Massive transfusion hazards
Hypothermia
Metabolic citrate intoxication
Clotting factor dilution
Microaggregates
Oxygen dissociation curve shift
Jones JA: Br J Anaesth 1995; 74: 697-703
Cancer related anemiatreatment breakthrough
 PROCRIT®
EPREX (Epoetin alfa), a 165 amino acid
glycoprotein manufactured by recombinant DNA
technology, has the same biological effects as
endogenous erythropoietin. It has a molecular weight of
30,400 daltons and is produced by mammalian cells
into which the human erythropoietin gene has
been introduced. The product contains the identical amino
acid sequence of isolated natural
erythropoietin……..
Manufacturers data sheet
EPO types
Recormon
(erythropoietin)
EPO beta-NeoRecormon
EPO alpha-Eprex
Goodnough LT et al: N Engl J Med 1997; 336:933-38
Does it work??
 Cumulative
metaanalysis
 19 Randomized clinical trials included
 Design
• EPO vs no therapy or vs placebo
 Total
no of patients
• All patients 1896
• Post 1995 1240
 The
number of patients requiring
transfusion
Clark O et al: BMC cancer 2002; 2:23 EPO Uncertainty Principle & CMA
Does it work?
What do you
think?
EPO use does
reduce the
number of
patients requiring
transfusion
Clark O et al: BMC cancer 2002; 2:23 EPO
Uncertainty Principle & CMA
EPO rise in Hb in
various trials
Major trials 7000 patients response to EPO alpha therapy
Ferrario E et al: Cancer Treat Rev 2004; 30:563-75
EPO- effect on fatigue
 Improves
fatigue
 Improves over all quality of life
 Increases energy levels
 Improves overall HRQOL
 Effect related to increased Hb levels
Cella D etal:Ann Oncol 2003; 14:511-9
RCT 375 pts; non myeloid
malignancy; EPO alfa150300u/kg TIW
Cella D etal: Ann Oncol 2004; 15:979-986
EPO efficacy
 Response
definition
• Increase in Hb >=2g/dl
• Hb level >=12g/dl no transfusion in 30 days
 Response
rate
~70% (40-85%)
 Among responders a >=1 g/dl increase
seen within first week of therapy in 46%
 Response may take 4-6 wks
Dosage schedules
 Epoetin
beta
 Epoetin
alpha
• 450 IU/kg/week/s/c single or divided doses
• 10,000 u s/c thrice a week
• 40,000 u s/c once weekly
 Inconvenient
dosage schedule
 Unpredictable dose response relation
Henry DH. The Oncologist 2004;9:97-107
European approval launches more convenient and
cost-effective delivery of once weekly NeoRecormon
for patients with lymphoid cancers
March 2004: New presentation offers same high efficacy with even more
convenience and cost effectiveness Roche announced today that
European marketing approval has been granted for a new
NeoRecormon (epoetin beta) 30,000 IU pre-filled syringe for
patients with lymphoid malignancies who are suffering from
anaemia. This new presentation launched today provides equivalent efficacy to 3
times weekly administration and allows for even more convenient and cost effective
a once weekly
regimen of NeoRecormon will help improve patients’ lives
by decreasing the number of injections per cancer
treatment cycle and reducing their number of clinic visits.
once weekly delivery of NeoRecormon. Most importantly,
Why some do not
respond to EPO?
 Approximately
1/3rd don’t respond
 Predictors of no response
• Pretreatment Hb level
• EPO level/ O/P ratio (observed /predicted log ratio)
• Retics count
• Ferritin level
• Transferrin saturation
 Doubtful
clinical benefit in a recent review
 Functional iron deficiency may be a cause
Littlewood TJ etal: The Oncologist 2003;8:99-107
What can be done to
improve response rate?
 Since
functional iron deficiency may be a
cause
 Can iron supplementation help?
 I/V iron supplementation may be
necessary in some cases
 Trials on going in this regard
Henry DH. The Oncologist 1998; 3:275-78
Iron therapy and Hb
response
175 pts RCT
Auerbach M etal: J Clin Oncol 2004;22:1301-1307
Change in QOL score in
relation to iron therapy
Auerbach M etal: J Clin Oncol 2004;22:1301-1307
EPO during
chemotherapy
 Cisplatin
induced anemia
• Renal toxicity
 Useful
particularly if given early
 Use when Hb is >10g/dl ?
Henry DH. The Oncologist 2004;1:97-102
EPO -other good effects?
 EPO-R
expressed
• Gastric mucosa
• Vascular smooth muscle
• Brain neurones
• Testis oviduct cells
 Less
cognitive decline
 Neuroprotective effect in stroke pts
EPO contraindications
and side effects
 Uncontrolled
hypertension
 Known hypersensitivity
 Thrombotic events
 Seizures
 Allergic reactions
 Red cell aplasia
Novel erythropoiesis stimulating
protein-Darbepoetin
 Increased
carbohydrate and sialic acid
content
 Serum half life 3 times longer
 EPO-R affinity ? Less
 Effective at longer intervals
 Loading dose followed by maintenance
doses at longer intervals
 Efficacy related to rHUEPO ? higher
Siena S etal: Critical Rev Onco Hematol 2003; 48S:39-47
Is this true?
 939
pts or MBC, 139 sites, 20 countries
 Epoetin alfa
 Target Hb >12g/dl and <14g/dl
 Terminated at 19 months
 41 deaths in Eprex group vs 16 in placebo
 Causes of death
• Disease progression (6% vs 3%)
• Higher incidence of thrombotic events (1% vs 0.2%)
Leyland-Jones B and BEST group: Lancet Oncology 2003:4:459-60
Yet other one??
Henke M etal: Lancet 2003; 362: 1255–60
All H & Neck ca pts treated
with radiotherapy +/-surgery
Henke M etal: Lancet 2003; 362: 1255–60
Patients treated with RT
after incomplete resection
Time (months)
Henke M etal: Lancet 2003; 362: 1255–60
The use of epoetin is recommended
as a treatment option for patients
with chemotherapy-associated
anemia and a hemoglobin
concentration that has declined to a
level 10 g/dL. RBC transfusion is
also an option depending upon the
severity of anemia or clinical
circumstances.
Rizzo DJ etal: J Clin Oncol 2010;28:4999
dose is 150 U/kg thrice weekly for a
minimum of 4 weeks, alternative weekly
dosing regimen (40,000 U/wk), based on
common clinical practice, can be
considered dose escalation to 300 U/kg
thrice weekly for an additional 4 to 8
weeks in those who do not respond…
Continuing epoetin treatment beyond 6 to 8
weeks…. does not appear to be beneficial.
Rizzo DJ etal: J Clin Oncol 2010;28:4999