Download - Cancer related anemia
Cancer Related Anemia
Dr. Shad Salim AkhtarMBBS, MD, MRCP(UK), FRCP (Edin), FACP (USA)Member AUICC FellowsConsultant Medical Oncologist & Medical DirectorPrince Faisal Oncology CenterKing Fahd Specialist HospitalBuraidah 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 ScalesAnemia grade Hb level
NCI WHO EORTCNo 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 7.5-9.5Severe anemia 6.5-8.0 6.5-8.0 5-7.5Very 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 15367 Cancer centers screened 748 Countries included 24 Time period 6 months Prevalence
• Hematological malignancies 72%• Solid tumors 66%
Hb level considered <12g/dlLudwig 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 5%• Multiple myeloma 90%
Average 30-86%
Knight K et al. Am J Med 2004;116:11s
Why do these pateints get anemia?
Normal erythropoeitic mechanismsAbnormalities 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 receptorCFU-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 cancer- Causes
Disease relatedTherapy relatedConcomitant factors
Disease related causes- Cytokine Mediated
Tumor Tumor cellscells
Activated immune & inflammatory system
CytokinesCytokines
Hepcidin levels ?
Other effects
Reduced erythropoietin production
Impaired iron utilization
TNF IFN-IL1
Down regulation of EPO-R
Suppression of BFU-E/ CFU-E
AnemiaAnemiaMercandante S et al: Cancer Treat Rev 2000;26:303-11
Shortened RBC survival
AnemiaAnemia
Blood loss
Disease related causes - others
Disrupted homeostatic mechanisms
Tumor Tumor cellscells
Reduced erythropoietin production
hematopoeitic cell clonal disorder
HemolysisHemophagocytosisHypersplenismMAHA
Marrow infiltration
Consumption
DeficienciesIntercurrent infections
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 causes-Treatment relatedRadiotherapy inducedChemotherapy inducedEffect of other drugs being usedTransient 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 responseCancer related fatigueIncreased mortalityEffect on treatment efficacy
Ferrario E et al: Cancer Treat Rev 2004; 30:563-75
Anemia-effect on the patient?
Physiological responseCancer related fatigue
• A common symptom (58-90% pts)• Associated with anemia?
Increased mortalityEffect 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%
• Fatigue• Patients’ belief61% vs 19%
Vogelzang NJ et al: Semin Hematol 1997; 34(s):4-12
Fatigue and anemia relationshipMFI-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 0.98Physical 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 1.00Mental 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<0.05P<0.01P<0.001Higher values indicate more fatigue Range (4-20)
Anemia 10-12 g/dl60 pts of cancer receiving 3 CT cycles
Level of hemoglobin Holzner B et al: Ann Oncol 2002;13:965-73
Ovarian LungColorectalAll *
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 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
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
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
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
EPO typesRecormon (erythropoietin)EPO beta-NeoRecormonEPO alpha-Eprex
Goodnough LT et al: N Engl J Med 1997; 336:933-38
Does it work??Cumulative metaanalysis 19 Randomized clinical trials includedDesign
• EPO vs no therapy or vs placeboTotal no of patients
• All patients 1896• Post 1995 1240
The number of patients requiring The number of patients requiring transfusiontransfusion
Clark O et al: BMC cancer 2002; 2:23 EPO Uncertainty Principle & CMA
Does it Does it work?work?
Clark O et al: BMC cancer 2002; 2:23 EPO Uncertainty Principle & CMA
EPO use does EPO use does reduce the reduce the number of number of patients requiring patients requiring transfusiontransfusion
What do What do youyou think?think?
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 alfa150-300u/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
• 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
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.
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
Auerbach M etal: J Clin Oncol 2004;22:1301-1307
175 pts RCT
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
Time (months)
Patients treated with RT after incomplete resection
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