CLINICAL PRACTICE OF RECOMBINANT HUMAN ERYTHROPOETIN IN CANCER RELATED ANEMIA

CLINICAL PRACTICE OF RECOMBINANT HUMAN ERYTHROPOETIN IN CANCER RELATED ANEMIA

S. Vijaya Kumar*¹ and G. K. Thilaka ²

Department of Botany and Microbiology, A.V.V.M. Pushpam College ¹, Poondi, Thanjavur, Tamil Nadu, India

Department of Biotechnology, D.G. Vaishnav College ², Chennai, Tamil Nadu, India

ABSTRACT:Anemia is a complication commonly encountered in malignancy, especially of hematological origin, either at presentation or during the course of treatment.  Anemia of chronic disease, a condition characterized by disordered iron metabolism, shortened RBC half-life and inefficient erythropoiesis, is the major contributor to cancer anemia. Anemia effects up to 90% of Cancer patients with more than 60% requiring blood transfusion during or after treatment with the advent of recombinant human Erythropoietin (rHuEPO), an alternative to red blood cell transfusion has become available rHuEPO is now widely used in Cancer patients, as it improves hematocrit, lowers blood transfusion requirements and improves quality of life.  So far, three drugs have been approved for the treatment of anemia in patients with malignancies (epoetin Alfa epoetin Beta and darbopoetin Alfa).  New concepts for the cure of erythropoietin in cancer patients include 3 and 4 weekly dosing, as well as loading dose concepts.  Although three rHuEPOs act on the same erythropoietin receptors, there are some variations on the degree of glycolylation, which lead to the differences in the pharmacokinetics and pharmacodynamics among the RhuEPOs. The cost effectiveness and medical justification of the administration of RHuEPO in tumor patients with respect to its positive effects on tumor oxygenation, tumor growth inhibition and support of chemo and radiotherapy is still a matter of debate.  The largest systematic review on the use of erythropoietin in cancer patients undergoing treatment indicates a suggestive but not significant survival advantage of erythropoietin treated patients.  Besides highlighting both the historical and functional aspects of RHuEPO, this review discusses the applications of RHUEPO in oncology.

INTRODUCTION: Anemia defined, as an inadequate number of hemoglobin containing red blood cells, is a widely prevalent complication among cancer patients and varies by type of neoplasia and cytotatic treatment ^1-3.  Apartfrom the physical symptoms and diminished quality of life ⁴ patients with anemia experience, there is some evidence that anemia; with the consequence of increased tumor hypoxia might result in a poorer response to radiotherapy ^5-9 or chemotherapy.  Besides the overall quality of life, low Hb levels may negatively influence the patient’s physical performance. Although blood transfusion in the fastest means to alleviate symptoms associated with anemia, there are short and long-term risks associated with this treatment such as transmission of infections agents, transfusion reactions, alloimmunization, and overtransfusion ¹⁰. The development of increasingly more aggressive antineoplastic treatments that may lead to anemia has increased the need for blood transfusions and has promoted oncologists to weigh advantages and disadvantages of transfusion ^{11, 12}.

With the introduction of human erythropoietin rHuEPO in oncology about 10 years ago, an alternative to RBC transfusion becomes available.  Two forms of rHuEPO, epoeitin α and epoetin β both with similar clinical efficiency are available to treat anemia and have been tested in randomized controlled trials.  Recently, a novel long acting erythropoietin variant (novel erythropoeitics stimulating protein – NESP) or (darbopoetin-a) has been introduced into clinical practice.

In order to give a frame work for EPO therapy, the American Society of Clinical oncology CASCO) and American Society of Hematology (ASM) and more necessarily, the European Organization for Research and Treatment of Cancer (EORTC), developed evidence – based guidelines on the use of epoetin in cancer patients ^{13, 14}. To increase treatment efficiency and to improve patient compliance, a number of different administration regimes for rHuEPO are currently under evaluation, including less frequent dosing and loading dose concepts. In addition with longer half-life has become available owing mainly to economical considerations; the ¹⁵ general use of recombinant erythropoietin has not become common practice in oncological setting.

Anaemia in Cancer Patients: Many Cancer patients suffer from anemia, which has a major detrimental effect on their quality of life.  Tumor associated factors can be acute or chronical tumor bleeding, hemolytic, deficiency in folic acid and vit B12, as well as infiltration of the bone marrow Immune cell activation triggers the release of several cytokines, affecting the proliferation of progenitor cells or the production of Erythropoietin. Tumor necrosis factor – (a) recreated by monocytes & macrophages in inhibits the proliferation of the erythroid precursors BFU-e and EFV-e. In addition, activation of MQs can lead to a shorter erythrocyte half-life & to a decrease in iron utilization.

Released cytokines also inhibit the production of erythropoietin in the Kidney, resulting in relatively low levels of the hormone, compared with the grade of anemia observed. Depending on the drug & schedule used, cytostatic therapy has a major impact on the incidence of anemia in cancer ^{16, 17} patients contributing factors include the inhibition of EPO production by nephrotoxin platinum compounds & the myelo suppressive effects on the erythroid precursor cells. Dose-intensified treatment negimusor shortened treatment intervals; as well as multimode therapies are associated with a higher degree of anemia.  In addition some vinonelbine are strongly myelo suppressive & cause high degrees of anemia ¹⁷.

Some groups of cancer patients show particularly high incidences of anemia during/after cytotoxin therapy.  This is the case for 70% of myeloma patients & 50% of lung & ovarian cancer patients ¹⁸. Anemia is also observed frequently in patients with head & neck tumors, breast cancer genito urinary tumors & lymphomas ¹⁷.

Erythropoietin – Mechanism of Action: The human body generates 2.5 million new red blood cells (RBCs) per second from the bone marrow to replenish the continuous removal of effect RBCs.  The production of RBCs (Erythropoiesis) is controlled by an intricate interaction between various human factors and cytokines.  A specific cytokine, a siaglycoprotein known as erythropoietin, which acts directly on certain RBC progenitors and precursors in the bone marrow, controls the proliferation, differentiation and maturation of RBCs. The expression of erythropoietin is markedly increased in kidneys during hypoxic state, a condition mediated by the transcription factor HIF-I ¹⁹. (The ultimate effect is to increase erythropoiesis in an attempt to maintain O₂ delivery to vital organs).

Synthesized in the kidney and to a minor degree in the liver, EPO, the native glycoprotein hormone has a molwt of 34 KDa & consists of 165 aa. About 40% of the molecular mass is composed of carbohydrates ²⁰. Glycosylation itself does not influence the biological activity, but delays the clearance of the hormone from the plasma ²¹ particularly important in this aspect are the sialic acid residues bound to four of the carbohydrate hydrate side chains, leading to a biological half-life of the molecules ~ 8.5 h ²².

The response to a decrease in tissue oxygenation, EPO is released into the plasma & binds to EPO receptors on the surface of red blood cell precursors (BFU – e, CFU – e, erythroblasts) located in the bone marrow.  As well as prolonging their survival, EPO inhibits apoptosis of the precursor cells, there by inducing their proliferation and differentiation ²³.

Recombibnant Human Epos: Three Epos have been approved for the treatment of anemia in cancer patients: epoetin α, epoeitin β and darbopoetin. Epoetin and darbopoetin are approved for patients with solid tumors and non-myeloid malignancies under chemotherapy in general.  The indication for epoetin   is restricted to patients with solid tumors undergoing platinum containing chemotherapy ^{24, 25, 26}.

Modifications of RHuEPO: As the N-glycosylation confers the biological activity of RHuEPO, an increase in the number of glycosylation site may enhance its activity. A hyper glycosylated RHuEPO, known as NESP (Novel Erythropoiesis stimulating protein; Darbopoetin) has recently been introduced ²⁷ by using a process called “Site Mutagenesis”, the polypeptide backbone of the RHuEPO is modified, leading to the creation of 5 N – glycosylation sites (compared with other RHUEPO).  7 compared with the RHuEPOs, NESP has a higher negative charge and 3 fold longer half-life.  It requires a less frequent dosing schedule and produces a similar clinical outcome and safety profile as RHuEPOs in treating anemia of malignancy ^28,29,30.

Another strategy to enhance the biological activity of RHuEPO is to provide a “protective vehicle” so as to decrease the rate of elimination, thus prolonging the half-life RHuEPO. Methods such as micro encapsulation and pegylation to RHuEPO are currently being assessed.

Treatment of Cancer related Anaemia with EPO: More than half of cancer patients have a low serum level of EPO ³¹. RHuEPO has been employed in connecting the anemia, either as supportive or preventive treatment, with an excellent safety profile.  Interestingly, RHuEPO has recently been shown capable to induce apotopsis in myeloma cell culture, suggesting it’s anti tumor activity ³². In general, anemia could be correlated in about 50% of patients when RHUEPO is given after chemotherapy.

A higher proportion of anemia correction could be achieved in patients who received platinum based chemotherapy ^{33, 34}.

When RHUEPO is applied before chemotherapy, it prevents the decline in hemoglobin and decreased the requirement of blood transfusion during the course of chemotherapy ^{35, 36}.Nowrosian has suggested that when given substaneously at a dose of 150 μl/kg three times a week in selected patients, rHuEPO can produce a response rate of up to 80%. In a large prospective community study, the use of rHuEPO increased the functional capacity and the quality of life of patients.  It also improved the level of Hemoglobin and minimized blood transfusion requirements ³⁸.

The positive outcomes correlated with the hemoglobin level but independent of the tumor response. Recent clinical studies have demonstrated that a normal or near normal level of hemoglobin before radiotherapy with/without chemotherapy could improve the treatment outcome ³⁹.

In recent multicentre, randomized study in patients with pelvic malignancies the addition of rHuEPO to the treatment course of radiotherapy improved both treatment response rate and potential survival ⁴⁰.

Furthermore, a recent analysis of 2 large scale studies involving 4382 patients, has revealed that patients with solid tumors received RHUEPO had a significant improvement in quality of life occurring b/w hemoglobin levels from 80 - 140g ⁴¹. The most noticeable benefit, from an incremental increase in hemoglobin, occurred when there was a change in Hb from 110-120 g/l.

Hematological Malignancy/Pre-Lukaemic Stem Cell Disorder: Multiple myeloma, lympho proliferative diseases and chronic lymphocytic leukemia are those hematological disorders that benefit significantly from rHuEPO therapy, with an average response rate of 60% whether RHUEPO is given as supportive (post-chemotherapy), preventive (pre- treatment) or maintenance (optimization of hemoglobin while not on treatment) therapy, it increases the hemoglobin and minimizes the requirement for blood transfusions  ^42-45. However, a delay in treatment response of up to 4 weeks may occur.

Darbepoetin: Data on the use of darbopoetin in the oncological setting are more scare than for the other Epos.  This is due to the fact that so far most trials are dose – finding studies, investigating the efficiency and safety of different regimens uses a dose – finding study on the weekly administration of dar- in patients with solid tumors receiving chemotherapy indicated that the most efficient weekly dose is 4-5μ g/kg ⁴⁷. Compound with recommended dose of 2.25μ g/kg per week after 12 weeks of therapy, this dose resulted in an earlier on set of response (7 versus 10 weeks) as well as higher response rates (76% vs. 52%) & a more rapid increase of Hb levels (2.7 vs. 1.5 μg/dl).  The same study showed that administration of 9μ g/kg per week.

In most phase III studies using darbepoetin, a starting dose of 2.25 μg/kg/week was used. One example is the applient trial for patients with solid tumor, enrolling 320 patients with lung cancer who had Hb levels < 11g/dl ⁴⁷ patients received db-d or placebo for a period of 12 weeks during platinum containing chemotherapy. In addition to a significant reduction in the proportion of patients transfused during weeks 5-12 patients under db- had a higher haematopeitic response, achieving a Hb level of 12g/dl.  Improvement in fatigue symptoms was better in the db - but did not quite reach statistical significance. This might in part be due to the delayed increase in the average H bevel after 4 & after 12 weeks, respectively ⁴⁶. A dose escalation to 4.5 μg/week was applied in 43% of patients.

A recent phase III swtudy by Hydenusetal ⁴⁷ in patients with lymphoma & myeloma gave cleaner, better results. In a close finding study ⁴⁷, db- was administered every 3 weeks.  Doses of 4.5, 6.75, 9, 12, 13.5 & 15μ g/kg as well as placebo were given for 12 weeks.  Patients with solid tumors & a base line Hb level of < 11μg/dl were included.  The best results were observed in the group receiving 12μ g/kg, which showed a response rate of 71% & a final increase in Hb of 2.64 g/dl.  Similar results were observed in another dose – finding study for the administration of db - every 4 weeks, comparing placebo & doses of 9, 12, 15 &18 g/kg in 145 patients.  While the highest response rate & increase in Hb was achieved with a dose of 15 μg/kg, a dose of 18 μg/kg gave worse results.

CONCLUSIONS: Anemia caused by the tumor itself or by cytotoxic treatment, is frequently observed in cancer patients, negatively influencing their over all QoL and also worsening prognosis.  This review analyzed the effectiveness of EPO in the treatment of cancer patients. With the development of rHuEPOs, well-tolerated alternative to RBC transfusions have now become available.  Treatment with epoetins has been shown to be effective in reducing transfusion rates. There is strong and consistent evidence that treatment with rHuEPO may reduce the need for red blood cell transfusion and increase hemotologic response rates, there by improving the QOL & large systematic review analyzing date published before 2002 hints towards a possible influence of epoetins on survival.

In order to improve efficiency and convenience of EPO treatment, a number of different administration regimens are currently being tested, ranging from lies frequent application of higher doses to loading dose and early intervention concepts.  Although initial promising results have been observed, the value of these concepts still has to be shown in larger randomized trials. Comparing the efficiency of the different epoetins is difficult due to lack of large randomized head to head studies. Clinical trials with EPO aimed at correction of Hb levels beyond anemia indicated a higher risk of thrombovascular events.  Larger meta-analysis is needed to fully elucidate the impact of epoetin and Hb levels on outcome.

REFERENCES:

1. T ng, Gmarx 2, T little wood et al.  Recombinant erythropoietin in clinical practice.  Postgraduate Medical Journal 2003; 79: 367 – 376.
2. A. Engert Recombinant Human erythropoietin in oncology: Current status.  Annals of oncology 2005 16 (10): 1584 – 1595.
3. Knightk, wades, Balducci L Prevalence and Outcomes of anaemia in cancer: a systematic review of the literature.  AM J Medical 2004; 116 (suppl.7A): 115 – 265.
4. Enger t A.  Recombinant human erythropoietin as an alternative to blood transfusion in cancer related anaemia. Disease management and Health outcomes 2000; 8:259-72.(cross ref.)
5. Frommhold H, Guttenberger R, Henke M.  The impart of blood Hemoglobin content on the outcome of radiotherapy.  Strahilentherapic and oncologic 1998; 174 (suppl IV): 31-4.
6. Hockel N, Knoop C, Schlenger K, Vormdran B, Bowssmann E, Mithe M, et al.  Intratumoral PO2 predicts survival in advanced cancer of the uterine cervix.  Radio ether oncol 1993; 26: 45 – 50 (cross ref) (ISI) (Medicine).
7. Knocke TH, Writmann HD, Feldman HJ, Selher E, Potter R. Intratumoral PO2 measurements as predictive essay in the treatment of carcinoma of the uterine cervix.  Radio ether oncol 1999; 53:99-104 (cross ref) (ISI) (Medicine).
8. Glacer CM, Millesi W, Konnek GV, Lang S, Schult B, Watzinger F et al. Impact of hemoglobin level and use of recombinant erythropoietin on efficiency of preoperative chemoradiation therapy for squamous cell carcinoma of the oral cavity and oropharynx. Int I Radial oncalBiOLPhys 2001; 50:705-15 (cross ref.) (ISI) (Medicine).
9. Silver DF, Piner MS. Effects of recombinant human erythropoietin on the anti tumor effect of cisplatin in SC1D Mice bearing human ovarian cancer: a possible oxygen effect.  Gynicol. Oncol 1999:73:280-4 (cross ref) (ISI) (Medicine)
10. Goodnough LT. Risks of blood transfusion. Crit cane med 2003; 31 (12 suppl): S678-86. (Cross ref) (ISI) (Medicine)
11. Halstemson CE, Macries M, Katz SA, Schnieders JR, Watanable M, Sobota JT, et al. Comparative pharma kinetics and pharmaeodynamics of epoetinalfa and epoetin beta.  Clinpharmacalther 1991; 50:702-12. (ISI) (Medicine).
12. Storring PL, Tiplady RJ, Gaines Das RE, stenning BE, Lamikanra A, Rafferty B. Epoetin and B differs in their EPO isoform compositions & biological properties. Br J Haematol 1998; 100:79-89. (Cross ref) (ISI) (Medicine).
13. Pizzo JD, Lichtin AE, Woolf SH et al.  Use of epoetin in patients with cancer. Evidence – based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hemotology.  J clinoncol 2002; 19:4083 – 4107.
14. Bokemeyer C, Aapro MS, Courdi A et al.  EORTC guidelines for the use of erythropoieticproteins in anemic patients with cancer. Eur J cancer 2004; 40:2201-2216 (cross ref) (ISI) (Medicine).
15. Egrie JC, Browne JK. Development & characterization of darbepoetinalfa. Oncology 2002; 16 (suppl): 13-22.
16. Dalton JD, Bailey NP, Bonnet – Lee PJ et al.   Multicenter UK audit of anaemia in patients receiving cytotoxic chemotherapy.  Proc Am socclinoncol 1998; 17:418a (abstr 1611).
17. Groopman JE, Atria LM. Chemotherapy – induced anaemia in adults: Incidence and treatment. J Nat, cancer Inst 1999; 91: 1616 – 1634 (Abstract/Free full text)
18. Nowrousian MD. Recombinant human EPO in the treatment of cancer related chemotherapy – induced anaemia in patients with solid tumors. Med oncol 1998; 15 (suppl): 19 – 28 (Medline).
19. Macdougall IC. An overview of the efficiency and safety of novel erythropoiesis of stimulating protein (NESP) Nehru Dial Transplant 2001; 16 (suppl 39: 14-21) (Abstract/Free full text)
20. Locatell F, Olivanes J, Walker R, et al.  Novel erythropoiesis stimulating protein for the treatment of anaemia in chronic renal insufficiency Kidney Int 2001; 60; 2:741 – 7
21. Glaspy J, Jadija JS, Justice G. et al.  A dose finding and safety study of novel erythropoiesis stimulating protein (NESP) for the treatment of anaemia in patients receiving multicycle chemotherapy.  BrJ cancer 2001; 84 (Suppl I) : 17-23.
22. Smith RE Jr, Jaiyesimi IA, Meza LA, et al.  Novel erythropoietic stimulating protein (NESP) for the treatment of anaemia of chronic disease associated with cancer.  Br J cancer 2001; 84 (suppl I): 24-30. (Cross ref)
23. Lai PH, Euerett R, Wang FF et al.  Structural characterization of human erythropoietin. J. BiochemChem 1986; 261: 3116 – 3121.
24. Dordal MS, Wang FF, Gold wasser E.  The role of carbohydrate in erythropoietin action.  Endocrinology 1985; 116: 2293 – 2299. (Abstract).
25. Gold wasser E, Kung CK, Eliason J. On the mechanism of erythropoietin induced differentiation. 13.  The role of sialic acid in erythropoietin action. J Bio chem. 1974; 249: 4204 – 4206. (Abstract/Free full text).
26. Faulds D, Sorkim EM. Epoetin (recombinant Human erythropoietin) A review of its pharmacodynamic & pharma-cokinetics proportions & therapeutic potential in anaemia and the stimulation of erythropoiesis.  Drugs 1989; 38: 836-899. (ISI) (Medline)
27. Ortho Biotech, Inc. package Inset 2003.
28. Hoffmann – La Roche Ltd. Package Inset 2004
29. Amgen Inc. package Insert 2003
30. Miller CB, Jones RJ, Piontadosi S, et al. Decreased erythropoietin response in patients with the anaemia of cancer.  N Engl J Med 1990; 322:1689-92 (Abstract)
31. Mittleman M, Newmann D, Peled A, et al.  Erythropoietin induces tumor regression &anti tumor immune responds in murine myeloma models.  ProcNatiAcadSci USA 2001; 98:5181-6 (Abstract/Free full Text).
32. Case DC Jr, Bwhomski RM, Caney RW et al.  Rec human EPO therapy for anaemia cancer patients on combination therapy J Nat1 cancer Ins. 1993; 85:8016
33. Casinu S, Fedeli A, Del Ferrot, et al. Recombinant human erythropoietin in ceplation associated anaemia a randomized, double-blinded trial with placebo J lioncels 1994; 12:1058-68 (Abstract/Free Full Text).
34. Del Mastro L, Venturini M, Lionetoo R, et al.  Randomized phase III trial evaluating the role of EPO in the prevention of chemotherapy – induced anaemia J clinoncol 1997; 15: 2715-21 (Abstract).
35. Ten BokkelHuimink WW, de swart CA, Van Toorn DW, et al. Controlled Multi center study of the influence of subcutaneous recombinant EPO on anaemia and transfusion dependency in patients with Ovarian carcinoma treated with platinum based chemotherapy. Med oncol 1998; 15: 174-82. (Medline)
36. Newrousian MR Recombinant human EPO in the treatment of cancer related or chemotherapy – induced anaemia in patients with solid tumors. Med oncol 1998; 15 (suppl 1): S19 – 28
37. Demetri GD, Kris M, Wade J, et al. Quality of life benefit in chemotherapy patients treated with epoetin - is independent of disease response or tumor type results from a prospective community oncology study, Procrit study group J clinoncol 1998; 16:3412 – 25 (ABSTRACT)
38. Little wood TJ. The impact of hemoglobin levels on treatment outcomes in patients with cancer. Seminoncol 2001; 28 (2 suppl 8): 49-53
39. Antonodou D, Cardamakis E, Puglisi M, et al. EPO enhance radiation treatment efficiency in- patient with pelvic malignancies. Final results of randomized phase III study.  Eur J cancer 2001; 37 (suppl 6): 144. (cross ref)
40. Crawford J, Cella D, Cleland CS, et al. Relation ship b/w changes in hemoglobin level and quality of life during chemotherapy in anemic cancer patients receiving epoetin therapy. Cancer 2002; 95: 888-95. (Cross ref) (Medline).
41. Rose T, Raik, Rericki D et al.  Clinical and health states assessment in anemic chronic lymphatic leukemia (C22) patients treated with epoetin   (epo).  Journal of the American Society of Hemotology 1994; 84:5269.
42. Dammaco F, Silvertrins F, Castoldi GL, et al.  The effectiveness and tolerability of epoetin   in patients with multiple nefrautory to chemotherapy.  Int J clin Lab Res 1998; 26:127-34 (cross ref) (Medline)
43. Glaspy JA, Jandja JS, Justice G. Darbepoetin    given every 1 or 2 weeks alleviates anaemia associated with cancer chemotherapy.  Br J cancer 2002; 87: 268 – 276. (Cross ref) (ISI) (Medline).
44. Vanstunki J, Pinker R, Massuti B et al.  Double blind, placebo – controlled randomized phase III trial of darbepoetin    in lung cancer patients receiving chemotherapy, J Nat1 cancer Inst. 2002; 94: 1211 – 1220. (Abstract/Free full text).
45. Pirker R, Vansteedkiste J, Gateley J et al.  A Phase III double blind, placebo-controlled, randomized study of novel erythropoiesis stimulating protein (NESP) in patients undergoing platicum – treatment for lung cancer.  Proc Am Socclinoncol 2001; (Abstract 1572).
46. Hedenus M, Adriansson M, Miguel JJ et al.  Efficacy & safety of darbepoietin   in anaemia patients with lymphoproliferative malignancies: a randomized, double blind, placebo-controlled study. Br J Haematol 2003; 122:394-403 (cross ref) (ISI) (Medline).
47. Coates D, Albertisson M, John Mackey J et al.  Randomized, double blind, placebo – controlled, dose finding study of darbepoetinalfa administered once every 3 (Q3W) 0.4 (Q4W) weeks in patients with solid tumors. Proc AM socclinoncol 2002; (Abstract 1421).
    

    ---