Cancer related anemia

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Information about Cancer related anemia

Published on December 16, 2016

Author: DrShadSalimAkhterAkh

Source: slideshare.net

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

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