Anemia is common in cancer patients, occurring in 30-86% of cases depending on malignancy type and Hb level definition of anemia. Anemia can be caused by the disease itself through cytokine-mediated effects on erythropoiesis or nutritional deficiencies, or be treatment-related due to chemotherapy, radiotherapy or other drugs. Erythropoietin treatment is effective at reducing transfusion needs and improving quality of life by increasing Hb levels and reducing fatigue in the majority of anemic cancer patients. However, some patients do not respond due iron deficiency or other factors. Iron supplementation can help improve response rates to EPO treatment.

1. 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

2. 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

3. Comparison of Hb Scales
Anemia grade Hb level
NCI WHO EORTC
No anemia 12-16 ♀
14-18 ♂
>11 >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
Very severe anemia <6.5 <6.5 -
Ferrario E et al: Cancer Treat Reviews 2004; 30:563-75

4. Knight K etal: Am J Med 2004;116:11s-26s

5. Anemia Prevalence in
Cancer Patients ECAS data
 Total no of pts 15367
 Cancer centers screened 748
 Countries included 24
 Time period 6 months
 Prevalence
• Hematological malignancies 72%
• Solid tumors 66%
 Hb level considered <12g/dl
Ludwig H et al: Blood 2002; 234-235(a)

6. Anemia Prevalence in
Cancer Patients
 Depends upon the level of Hb one
considers as anemia
 Variable according to malignancy type
• Prostate cancer 5%
• Multiple myeloma 90%
 Average 30-86%
Knight K et al. Am J Med 2004;116:11s

7. Why do these pateints
get anemia?
Normal erythropoeitic mechanisms
Abnormalities in cancer patients

8. 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)

9. Liver minor
amount
EPO receptor
CFU-E +++
BFU-E ++
Absent on retics
STAT 5
Hb Increased

10. 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%

11. Anemia in cancer-
Causes
Disease related
Therapy related
Concomitant factors

12. Disease related causes-
Cytokine Mediated
TumorTumor
cellscells
Activated immune & inflammatory system
CytokinesCytokines
Hepcidin levels ?
Other
effects
Reduced erythropoietin
production
Reduced erythropoietin
production
Impaired iron
utilization
TNF IFN-γ IL1
Down regulation of EPO-R
Suppression of
BFU-E/ CFU-E
AnemiaAnemia
Mercandante S et al: Cancer Treat Rev 2000;26:303-11

13. Shortened
RBC survival
AnemiaAnemia
Blood loss
Disease related causes -
others
Disrupted
homeostatic
mechanisms
TumorTumor
cellscells
Reduced
erythropoietin
production
Reduced
erythropoietin
production
hematopoeitic cell
clonal disorder
Hemolysis
Hemophagocytosis
Hypersplenism
MAHA
Marrow infiltration
Consumption
Deficiencies
Intercurrent infections
Mercandante S et al: Cancer Treat Rev 2000;26:303-11

14. 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

15. Anemia causes-
Treatment related
Radiotherapy induced
Chemotherapy induced
Effect of other drugs being used
Transient or sustained

16. 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

17. 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

18. Anemia-effect on the
patient?
Physiological response
Cancer related fatigue
Increased mortality
Effect on treatment efficacy

19. Ferrario E et al: Cancer Treat Rev 2004; 30:563-75

20. 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

21. 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%
• Fatigue
• Patients’ belief 61% vs 19%
Vogelzang NJ et al: Semin Hematol 1997; 34(s):4-12

22. Fatigue and anemia
relationship
MFI-20
subscales
with
anemia
(1)
with no
anemia
(2)
Controls
(3)
1 vs 3
effect
size
2 vs 3
effect
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
Holzner B et al: Ann Oncol 2002; 13:965-73
P<0.05
P<0.01
P<0.001Higher values indicate more fatigue Range (4-20)
Anemia 10-12 g/dl
60 pts of cancer receiving 3 CT cycles

23. Level of hemoglobin
Holzner B et al: Ann Oncol 2002;13:965-73
Ovarian
Lung
Colorectal
All
*

24. 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

25. 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

26. Anemia in a cancer patient-
how 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

27. Anemia in cancer-how
to treat?
 No single paradigm
 Varies according to cause and presentation
 Cause
• AIHA steroids
• Nutritional deficiency supplements
 Severity
• Hemorrhage transfusion
• Severe symptoms transfusion

28. Red cell transfusion-
hazards
 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

29. Cancer related anemia-
treatment 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

30. EPO types
Recormon (erythropoietin)
EPO beta-NeoRecormon
EPO alpha-Eprex

31. Goodnough LT et al: N Engl J Med 1997; 336:933-38

32. 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 requiringThe number of patients requiring
transfusiontransfusion
Clark O et al: BMC cancer 2002; 2:23 EPO Uncertainty Principle & CMA

33. Does it work?Does it work?
Clark O et al: BMC cancer 2002; 2:23 EPO
Uncertainty Principle & CMA
EPO use doesEPO use does
reduce thereduce the
number ofnumber of
patients requiringpatients requiring
transfusiontransfusion
What doWhat do youyou
think?think?

34. 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

35. EPO- effect on fatigue
 Improves fatigue
 Improves over all quality of life
 Increases energy levels
 Improves overall HRQOL
 Effect related to increased Hb levels

36. Cella D etal:Ann Oncol 2003; 14:511-9
RCT 375 pts; non myeloid
malignancy; EPO alfa150-
300u/kg TIW

37. Cella D etal: Ann Oncol 2004; 15:979-986

38. 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

39. Dosage schedules
 Epoetin beta
• 450 IU/kg/week/s/c single or divided doses
 Epoetin alpha
• 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

40. 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
once weekly delivery of NeoRecormon. Most importantly, 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.

41. 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

42. 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

43. Iron therapy and Hb
response
Auerbach M etal: J Clin Oncol 2004;22:1301-1307
175 pts RCT

44. Change in QOL score in
relation to iron therapy
Auerbach M etal: J Clin Oncol 2004;22:1301-1307

45. 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

46. 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

47. EPO contraindications
and side effects
 Uncontrolled hypertension
 Known hypersensitivity
 Thrombotic events
 Seizures
 Allergic reactions
 Red cell aplasia

48. 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

49. 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

50. Yet other one??
Henke M etal: Lancet 2003; 362: 1255–60

51. All H & Neck ca pts treated
with radiotherapy +/-surgery
Henke M etal: Lancet 2003; 362: 1255–60

52. Time (months)
Patients treated with RT
after incomplete resection
Henke M etal: Lancet 2003; 362: 1255–60

53. 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

54. 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