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.
Pondicherry Call Girls Book Now 9630942363 Top Class Pondicherry Escort Servi...
Cancer related anemia
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
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)
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
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
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
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
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
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
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
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
Notas do Editor
In a recently published review on anemia Dr. Tefferi from mayo clinic defines anemia as…
Prevalence of anemia by cancer type. Liberal &lt;12g/dl, mod &lt;11g/dl and stringent &lt; 9g/dl
Recently published survey by European Cancer Anemia Survey has revealed a high prevalence of anemia in cancer patients sometime during their 6 months follow up. The prevalence being higher in hematological malignancies.
1011 erythrocytes are produced daily BFU-E committed erythroid progenitors takes 14 days to develop into a CFU-E which after a few divisions mature and at the end orthochromatic erythroblasts do not divide but enucleate to form reticulocytes. EPO is a better understood growth factor. Its effect allows BFU E to mature to morphologically committed CFUE which is stimulated to proliferate and differentiate into mature RBCS.
Signal transduction and activation transcription proteins are activated by EPO. Receptors maximum on CFU-E almost 1000/mol cells. With maturation the receptor density decreases.
1) CML, 2) ca colon 3) AIHA in CLL. No it is not. The reason is the varied nature of etiological factors that can cause anemia in these patients.
Cancer related anemia is multifactorial the main causes being blood loss, hemolysis, bone marrow tumor infiltration, hypersplenism and deficiency of folate and B12. Impaired erythropoeisis due to cytokine effect on iron metabolism. This is anemia of chronic disease which is charaterized by erythroid bone marrow hyperplasia, slightly decreased RBC survival, decreased reticulocytes, hypoferremia and low circulating EPO.
A study conducted in 400 patients concluded that fatigue was more important in patints’ mind as compared to the caregiver who believed pain was more important.
A study of 60 cancer pts 22 colorectal, 24 ling and 14 ovarian cancer. Three cycles of CT data collected prior to each cycle of CT. Pts with mild anemia (10-12 g) or no anemia were included in this study. MFI is multidimensional fatgue inventory (MFI 20) 20 item self report instrument
Relationship of fatigue with the level of Hb. in patients receiving chemotherapy.
A valuable commodity, may cause immune suppression with deleterious effect on survival, therefore in the absence of life threatening bleed should be avoided.
375 pts double blind RCT placebo vs EPO in pts with non myeloid malignancies 15-300u/kg of epoetin alfa TIW improvement in HRQOL elements seen12-24 wks. Figure 2. Comparison of health-related quality of life (HRQOL) mean
change scores (measured using a linear analog scale comprising energy
level, ability to carry out daily activities and overall quality of life) for
patients receiving epoetin α (rHuEPO) or placebo (HRQOL population).
All P values, which correspond to primary measures, are adjusted for
multiple comparisons (sequentially rejective Bonferroni procedure).
Reprinted with permission from the American Society of Clinical
Oncology, from Littlewood et al. [38].
of health related quality of life (HRQOL)
5 RCT on the use of Darbepoetin in patients receiving chemotheapy for various tumours. FACT functional assessment of cancer therapy
Figure 1. Mean change in FACT Fatigue subscale scores by hemoglobin respondera status. Error bars indicate 95% confidence intervals.
Functional iron deficiency enough stores of iron but slow mobilization.
175 patients randomized to receive EPO alfa and iron or no iron. Oral iron ferrous sulfate 325 mgbd vs, Iron dextran bolus prior to evry CT or Total dose iron therapy. At six weeks data were analysed for response. The results show an increased response rate at six weeks which would have otherwise been seen may be after 16 weeks of therapy. Graph showing percentage of responders and non responders in each group, responders were those who had elevation of Hb &gt;2g% …
Change in QOL related to iron therapy. Odd feature a decline in pts who recd EPO without iron. LASA linear analogue scale assessment.
This trial had many design flaws. All deaths occurred in the first 4 months after which the suv curves were parallel for 19 months.