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Published on 1 September 2007

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Erythropoietin-stimulating agents in the treatment of anaemia of cancer and chemotherapy

teaser

George M Rodgers
MD PhD

Professor of Medicine and Pathology

Huntsman Cancer Institute
University of Utah Health Sciences Center
Salt Lake City
USA

E: george.rodgers@hsc.utah.edu

While anaemia is commonly associated with cancer and its treatment, many cancer patients in the USA receive no supportive therapy for their anaemia. A US survey published in 2002 reported that the annual number of cancer patients receiving chemotherapy was about 800,000; of these, only about 200,000 (25%) received anaemia treatment.1 Thus, cancer or treatment-related fatigue is underrecognised and suboptimally managed; one study reported that cancer patient fatigue occurred at least a few days of each month in 76% of chemotherapy patients.(1,2)

This article will review strategies for evaluating the anaemic cancer patient and will summarise recent data on optimal management of these patients. The treatment approach is based on recent guidelines recommendations issued by the US National Comprehensive Cancer Network (NCCN) Anemia Panel.(3) The role of parenteral iron therapy will be �discussed, as well as potential adverse effects of ESA therapy which have led to limitation of their recommended use in the USA.

The results of recent clinical studies involving cancer patients treated with ESAs will also be discussed, as well as the impact of these study results on ESA prescribing recommendations.

Initial laboratory evaluation
For purposes of this discussion, anaemia is defined as a haemoglobin (Hb) level of <11g/dl. Anaemia in cancer patients may result from bleeding associated with thrombocytopenia related to the tumour or its treatment, nutritional deficiency of vitamin B12 or folic acid, haemolysis, or as a result of the “chronic disease” or chemotherapy state. Before it is assumed that anaemia in a cancer patient is due to chemotherapy or “chronic disease”, other treatable causes should first be excluded. Otherwise, patients may have a suboptimal response to ESAs. An appropriate initial laboratory evaluation includes iron studies (serum iron, total iron binding capacity, ferritin), vitamin B12 and folic acid levels, a chemistry panel to include lactate dehydrogenase and bilirubin, and a Coombs test to exclude haemolysis. Evaluation of the patient’s peripheral blood smear may also be helpful.

If this baseline laboratory evaluation does not suggest another aetiology, then a diagnosis of “anaemia of cancer or chemotherapy” is suggested.

Pathophysiology
Figure 1 depicts mechanisms contributing to the anaemia of cancer or chemotherapy. Similar mechanisms are seen in the “anaemia of chronic disease” associated with renal failure, inflammation, etc. In these anaemias, inflammatory cytokines such as interleukin-1 or tumour necrosis factor elaborated from activated mononuclear cells suppress erythropoiesis and inhibit endogenous erythropoietin production. Red blood cell survival is usually shortened in these patients. Although serum iron levels in these patients are low, bone marrow iron stores are adequate or increased, indicating a defect in iron utilisation. This state has been termed “functional iron deficiency”.

[[HPE34_Fig1_57]]

Treatment options
The reasons to treat anaemia in this setting include reducing complications of severe anaemia (ischaemia) and improving quality of life (QOL). Previous standard treatment consisted of packed red blood cell transfusions for symptomatic relief of anaemic symptoms.

While efficacious in relieving symptoms, chronic transfusion may lead to problems, including iron overload, alloimmunisation leading to diminished transfusion response and viral infection risks.

Appreciation of the mechanisms contributing to the anaemia of cancer or chemotherapy (see Figure 1) suggests alternative treatment options, specifically erythropoietin-stimulating agents (ESAs) and iron therapy.

The positive results of clinical studies using ESAs that took into consideration QOL issues as an endpoint have dramatically changed the supportive care of cancer patients with anaemia.

The first trial reporting the effects of an ESA, epoetin alfa, on both reducing red cell transfusion requirements and improving anaemia-specific QOL in cancer patients receiving chemotherapy was published by Littlewood et al.(4) Similar results were demonstrated with darbepoetin alfa.(5)

Subsequent studies have confirmed beneficial effects of ESA therapy, and the treating physician has several treatment options to manage cancer patients with anaemia.(3)

The target haemoglobin for ESA therapy
ESAs are very active in increasing haemoglobin, haematocrit and red cell mass in cancer patients. However, excessive improvement or normalisation of haemoglobin levels may lead to hypertension, thrombosis and even death. Consequently, guidelines for these drugs strongly recommend that physicians target haemoglobin levels less than those typically considered normal. The data on which the recommended target haemoglobin level is based are taken from an analysis of two large community oncology trials in which epoetin alfa was the ESA used.(6)

Results of this analysis indicated a positive correlation between improving haemoglobin levels and improving QOL scores. Maximum QOL gain occurred at a haemoglobin level of 12g/dl. The greatest incremental gain in QOL occurred when haemoglobin levels increased from 11g/dl to 12g/dl.(6) Thus, most guidelines for ESA therapy recommend initiating treatment at a haemoglobin level <11g/dl and targeting a level of 12g/dl.(7)

FDA-approved regimens for ESAs in chemotherapy-related anaemia
Table 1 summarises the recommended regimens for darbepoetin alfa and epoetin alfa as of June 2007. Epoetin alfa is approved for weekly subcutaneous dosing both in a weight-based and standard dosage format (150U/kg TIW or 40,000U/wk). If there is no haemoglobin response after four weeks, dose escalation is recommended (300U/kg TIW or 60,000U/wk).

[[HPE34_Tbl1_58]]

Clinical trials supporting the epoetin alfa regimens have been published.(3)

Darbepoetin alfa is approved for both weekly and every-three-week dosing regimens: 2.25g/kg/wk and 500g Q 3 wk, respectively.(5,8) Dose escalation for the weekly regimen is approved for 4.5g/kg/wk if there is no haemoglobin response by four weeks.

Commonly used off-label ESA regimens
Both epoetin alfa and darbepoetin alfa have been studied in cancer patients treated every two weeks.9,10 An every-three-week epoetin alfa regimen has also been investigated.(11)

Initiation of ESA therapy
The American Society of Clinical Oncology/American Society of Hematology anaemia guidelines were published in 2002; recommendations were based on the literature up until 1999. This guideline recommended a haemoglobin value <10g/dl to initiate treatment with ESAs.(12) Subsequent appreciation of QOL issues in cancer patients led to more recent guideline recommendations for the threshold haemoglobin to be <11g/dl for treatment initiation.(3) This higher threshold haemoglobin value is supported by a meta-analysis that included data from 1999-2004.(13) Results of this analysis suggested a clinical benefit associated with initiating treatment at a haemoglobin >10g/dl; such intervention significantly reduced the relative risk of red cell transfusion and a subsequent haemoglobin decline below 10g/dl. Significant QOL benefits were also associated with early intervention.(13)

Monitoring of iron stores
Current recommendations of the NCCN Anemia Panel are to measure serum ferritin levels as well as serum iron/total iron binding capacity prior to initiation of ESA therapy.(3) If the serum ferritin is <100ng/ml or the transferrin saturation is <20%, functional iron deficiency likely exists and the patient will probably benefit from parenteral iron therapy in combination with an ESA. The Auerbach study that investigated the effectiveness of oral vs IV iron therapy in anaemic cancer patients receiving chemotherapy had treatment iron value criteria of ferritin at or lower than 200ng/ml, or ferritin at or lower than 300ng/ml with a transferrin saturation at or lower than 19%.(14)

While the patient continues to receive ESA therapy, iron studies should be monitored on a regular basis to ensure that functional iron deficiency will not occur and diminish the patient’s response to ESA therapy.

Adverse events associated with ESAs
Use of epoetin alfa and darbepoetin alfa in cancer patients is associated with potential risks. Compared with placebo-treated patients, cancer patients who received either ESA were more likely to experience the following adverse events: oedema, diarrhoea, hypertension and thrombosis. In terms of the thrombosis risk, the largest clinical trial comparing the two drugs head-to-head in cancer patients found that 6% of darbepoetin alfa and 7% of epoetin alfa patients experienced cardiovascular/thromboembolic events.(15) No cases of neutralising antibodies to erythropoietin were found, nor were cases of pure red cell aplasia.(15)

New safety concerns of ESA therapy
In early 2007, the FDA issued a healthcare alert to provide new safety data for ESAs. Results of four studies were presented to the FDA; these studies in anaemic cancer patients found a higher risk of serious adverse events or death with ESA use.(16)

One study was the Danish Head and Neck Cancer Study Group trial (DAHANCA 10), in which patients with advanced head and neck cancer were treated with radiotherapy vs radiotherapy plus darbepoetin. A higher than recommended haemoglobin concentration was targeted (14.0-15.5g/dl). There was a significant risk of progressive disease and a trend toward worse survival (nonsignificant) in the darbepoetin group, and this trial was terminated.

Another study was an anaemia of cancer trial in which cancer patients not receiving chemotherapy were treated with darbepoetin vs placebo. Not only did the ESA group not have a decreased risk of transfusion, but there was also decreased survival in the ESA group.

A third study with epoetin alfa in lung cancer patients evaluating a QOL endpoint was prematurely terminated after an interim safety evaluation found a higher mortality rate in the ESA group.

A fourth study with an unapproved ESA (pegylated epoetin beta) in anaemic lung cancer patients was also terminated early after an interim analysis identified increased mortality in the ESA group.

These cumulative data led the FDA to issue a safety alert about ESA therapy. A new “black-box warning” has been added to ESA product labels summarising the increased risks of ESA therapy in cancer patients. The FDA further recommended that:

  • The lowest possible dose of ESAs should be used to gradually increase haemoglobin levels.
  • Haemoglobin levels should be measured twice weekly for 2-6 weeks after any dosage adjustment.
  • ESA therapy should be withheld if the haemoglobin increase exceeds 12g/dl or rises by 1g/dl in any two-week period.
  • ESA therapy should not be used in anaemic cancer patients not receiving chemotherapy.

As a consequence of the FDA actions, the US Centers for Medicare and Medicaid Services (CMS) as well as other insurers, have limited reimbursement for ESA use in cancer patients to those patients who have chemotherapy-induced anaemia.

Controversial issues with ESA therapy
Are epoetin alfa and darbepoetin alfa equivalent?
The clinical equivalence of the two ESAs in cancer patients has been investigated in both retrospective studies (medication use evaluations, chart audits), as well as prospective trials.

Endpoints of these studies have included red cell transfusion rates, change in haemoglobin level, time to target haemoglobin, necessity for dose escalation and drug safety.

Two recent reviews surveyed the medical literature on the subject of comparative trials of the two ESAs in chemotherapy-related anaemia.(17,18) Both trials concluded that the drugs have equivalent efficacy and safety.

One study calculated the odds ratio (OR) for transfusions; for epoetin alfa, the OR for transfusion was 0.44 (95% CI 0.35-0.55), and for darbepoetin alfa, the OR for transfusion was 0.41 (95% CI 0.31-0.55).(20) Thus, the preponderance of the data at this time indicates that the two ESAs are equivalent. The decision as to which drug to use is based on patient and physician preference (dose schedules) and cost.

Do ESAs affect survival in cancer patients receiving chemotherapy?
A recent meta-analysis of 57 clinical trials in which epoetin or darbepoetin therapy were compared with placebo was reported.(20) The authors concluded that:

  • ESAs reduce the relative risk for red cell transfusion.
  • There is suggestive evidence that these drugs improve QOL.
  • ESAs increase the relative risk of thromboembolism (RR 1.67).
  • No definitive effect of erythropoietic drugs on cancer patient survival can be demonstrated, favorably or unfavourably.

However, this meta-analysis did not include data from clinical trials recently submitted to the FDA.

In May 2007, the FDA convened a meeting of its Oncologic Drugs Advisory Committee to review all clinical data on ESA use in chemotherapy-induced anaemia.

While this data review confirmed the known risk of thrombosis, the analysis showed a neutral effect on overall cancer patient survival and tumour progression, while demonstrating a benefit in terms of reducing the need for blood transfusion.(20) The updated meta-analysis using all ESAs in 35 studies of chemotherapy-induced anaemia involved more than 8,500 patients and indicated no effect on survival (hazard ratio 1.033, 95% CI: 0.922-1.158; see Figure 2).

[[HPE34_Fig2_60]]

Conclusions
ESAs are useful drugs in supportive care management of the cancer patient receiving chemotherapy. In this setting, ESAs reduce the need for red cell transfusion, improve QOL and have a neutral effect on survival.

However, in the anaemia of cancer setting (no chemotherapy), recent data suggest that ESA use is associated with decreased patient survival. These new data have led to restrictions in FDA-approved indications as well as in reimbursement for ESAs in cancer patients.

In the USA, based on current information, recommendations are to use ESAs only in cancer patients receiving chemotherapy, targeting a haemoglobin level of 11-12g/dl.

New ESAs are under development and are undergoing clinical trials in cancer patients. It will be important for these novel erythropoietic drugs to be carefully evaluated for their effects on cancer patient survival.

References
1. Tchekmedyian NS. Anemia in cancer patients: significance, epidemiology, and current therapy. Oncology 2002;16(9 Suppl 10):17-24.
2. Curt GA, Breitbart W, Cella D, et al. Impact of cancer-related fatigue on the lives of patients: new findings from the Fatigue Coalition. Oncologist 2000;5:353-60.
3. Rodgers GM, Cella D, Chanan-Khan A, et al. Cancer- and treatment-related anemia. J Natl Compr Canc Netw 2005;3:772-89.
4. Littlewood TJ, Bajetta E, Nortier JW, et al. Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomized, double-blind, placebo-controlled trial. J Clin Oncol 2001;19:2865-74.
5. Vansteenkiste J, Pirker R, Massuti B, et al. Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy. J Natl Cancer Inst 2002;94:1211-20.
6. Crawford J, Cella D, Cleeland CS, et al. Relationship between changes in hemoglobin level and quality of life during chemotherapy in anemic cancer patients receiving epoetin alfa therapy. Cancer 2002;95:888-95.
7. Rodgers GM. Guidelines for the use of erythropoietic growth factors in patients with chemotherapy-induced anemia. Oncology 2006;20 Suppl 6:12-5.
8. Canon JL, Vansteenkiste J, Bodoky G, et al. Randomized, double-blind, active-controlled trial of every-3-week darbepoetin alfa for the treatment of chemotherapy-induced anemia. J Natl Cancer Inst 2006;98:273-84.
9. Thames WA, Smith SL, Scheifele AC, et al. Evaluation of the US Oncology Network’s recommended guidelines for therapeutic substitution with darbepoetin alfa 200 microg every 2 weeks in both naive patients and patients switched from epoetin alfa. Pharmacotherapy 2004;24:313-23.
10. Henry DH, Gordan LN, Charu V, et al. Randomized, open-label comparison of epoetin alfa extended dosing (80000 U Q2W) vs weekly dosing (40000 U QW) in patients with chemotherapy-induced anemia. Curr Med Res Opin 2006;22:1403-13.
11. Patton J, Kuzur M, Liggett W, et al. Epoetin alfa 60,000 U once weekly followed by 120,000 U every 3 weeks increases and maintains hemoglobin levels in anemic cancer patients undergoing chemotherapy. Oncologist 2004;9:90-6. Erratum in: Oncologist 2004;9:240.
12. Rizzo 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 Hematology. Blood 2002;100:2303-20.
13. Lyman GH, Glaspy J. Are there clinical benefits with early erythropoietic intervention for chemotherapy-induced anemia? A systematic review. Cancer 2006;106:223-33.
14. Auerbach M, Barker L, Bahrain H, et al. Intravenous iron optimizes the response to erythropoietin in patients with anemia of cancer and chemotherapy: results of a multicenter, open-label, randomized trial. Blood 2001;98:799a (abstract).
15. Glaspy J, Vadhan-Raj S, Patel R, et al. Randomized comparison of every-2-week darbepoetin alfa and weekly epoetin alfa for the treatment of chemotherapy-induced anemia: the 20030125 Study Group Trial. J Clin Oncol 2006;24:2290-7.
16. US Food & Drug Administration. Information on Erythropoiesis Stimulating Agents (ESA) (marketed as Procrit, Epogen, and Aranesp). Rockville MD: FDA; 2007. Available at: http://www.fda.gov/cder/drug/infopage/RHE/default.htm17. Ross SD, Allen IE, Henry DH, et al. Clinical benefits and risks associated with epoetin and darbepoetin in patients with chemotherapy-induced anemia: a systematic review of the literature. Clin Ther 2006;28:801-31.
18. Cersosimo RJ, Jacobson DR. Epoetin alfa versus darbepoetin alfa in chemotherapy-related anemia. Ann Pharmacother 2006;40:58-65.
19. Amgen Inc. Safety of erythropoiesis-stimulating agents (ESAs) in oncology: background information for Oncologic Drugs Advisory Committee. Thousand Oaks CA: Amgen; 2007. Available at: http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4301b2-01-01-Amgen.pdf
20. Bohlius J, Wilson J, Seidenfeld J, et al. Erythropoietin or darbepoetin for patients with cancer. Cochrane Database Syst Rev 2006;3:CD003407.



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