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