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The Oncologist, Vol. 10, No. 9, 762-763, October 2005; doi:10.1634/theoncologist.10-9-762
© 2005 AlphaMed Press

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Letter to the Editor

Response to "Effect of Patient Exclusion Criteria on the Efficacy of Erythropoiesis-Stimulating Agents in Patients with Cancer-Related Anemia"

Bertrand Coiffier

Hospices Civils de Lyon, Hematology, Pierre-Benite, France

Key Words. Anemia • Cancer • Epoetin • Erythropoiesis-stimulating agents

Correspondence: Bertrand Coiffier, M.D., Hospices Civils de Lyon, Hematology, Pierre-Benite, France. Telephone: 33-609-412414; Fax: 33-478-864355; e-mail: Bertrand.coiffier{at}chu-lyon.fr

Received August 2, 2005; accepted for publication September 15, 2005.

I read with interest the article by Dr. Littlewood and colleagues on the effect of patient exclusion criteria on the evaluation of efficacy of erythropoiesis-stimulating agents (ESAs) in patients with cancer-related anemia [1]. I agree completely that difficulties exist when comparing results of different clinical trials because of different entry criteria and response-measure definitions.

Therefore, despite inclusion of similar patients with lymphoid malignancies, the NeoRecormon Once Weekly (NOW) study, which had hemoglobin (Hb) response rates of 72% and 75% with once-weekly (QW) and three-times weekly (TIW) epoetin beta (NeoRecormon®; Hoffmann-La Roche, Basel, Switzerland, http://www.roche.com) treatment [2], might not be compared with an epoetin alfa (Eprex®/Epypo®; Ortho Biotech/Janssen-Cilag, High Wycombe, U.K., http://www.orthobiotech.co.uk; Procrit®; Ortho Biotech Products, L.P., Bridgewater, NJ, http://www.orthobiotech.com) study, which had an Hb response rate of 75% with TIW treatment [3]. Response rates might be influenced by the ESA and its schedule but also by patient characteristics, such as the number and type of previous treatments, disease status, baseline Hb level, and bone marrow infiltration. Nor might these results be compared with a similar study of darbepoetin alfa (Aranesp®; Amgen Inc., Thousand Oaks, CA, http://www.amgen.com) QW in patients with lymphoid malignancies, which had an Hb response rate of 60% [4]. Comparisons of the relative efficacies of ESAs can only be conducted through a prospective, randomized trial. Such a trial was recently reported, comparing epoetin alfa (40,000 IU QW) with darbepoetin alfa (200 µg every 2 weeks) in patients with solid tumors. That study showed similar improvements in Hb level with the two agents [5].

The NOW study demonstrated that a QW schedule of epoetin beta had the same efficacy and safety as the TIW schedule at the same overall weekly dose (30,000 IU weekly) in patients with lymphoid malignancies [2]. Littlewood et al. [1] suggested that the high response rates seen with epoetin beta in that study occurred as a result of strict inclusion criteria. However, the original phase III, placebo-controlled study of epoetin beta in transfusion-dependent, anemic patients with lymphoid malignancies confirmed a similar high Hb response rate of 67% with epoetin beta (~30,000 IU weekly divided into three doses) [6]. These results were obtained despite the patients being severely anemic at baseline (mean Hb level, 9.2 g/dl) and most patients (93.5%) having received transfusions in the 3 months before study entry.

Subsequent to the NOW study, preliminary reports of two recent studies have suggested that the QW 30,000 IU regimen of epoetin beta is also effective in patients with solid tumors [7, 8]. In contrast, there have been no prospective, randomized, phase III studies comparing different dosage regimens of epoetin alfa or darbepoetin alfa. Nevertheless, comparisons of individual studies with similar designs might suggest that a higher dose of epoetin alfa is required when this agent is given QW (40,000 IU weekly) [9, 10] compared with TIW [11]. The higher dose requirement with QW epoetin alfa is supported by the results of pharmacokinetic/pharmacodynamic studies, which show similar Hb changes in healthy adults treated with epoetin alfa at a dose of 150 IU/kg TIW or epoetin alfa at a dose of 40,000 IU QW [12]. Moreover, Storring et al. [13] showed differences in isoform composition and an enhanced in vivo to in vitro bioactivity ratio of epoetin beta compared with epoetin alfa. These findings, together with the delayed absorption of s.c. administered epoetin beta [14] and greater reticulocyte response with epoetin beta than with epoetin alfa [14], also support the lower dose requirement with QW epoetin beta compared with QW epoetin alfa.

In conclusion, comparison of different clinical trials of ESAs does not allow evaluation of the relative efficacy of each ESA. Recently, a retrospective chart review of ESA use in patients attending clinics in France confirmed that all the commercially available ESAs are effective in treating anemia in patients with cancer [15]. Although this survey was not a prospective, randomized study, it highlighted that, in the "real-life" setting, there may be some therapeutic advantages in using epoetin beta.


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Littlewood, Timothy J., Schenkel Brad, Liss Martin. Effect of Patient Exclusion Criteria on the Efficacy of Erythropoiesis-Stimulating Agents in Patients with Cancer-Related Anemia. The Oncologist 2005;10:357-360.[Abstract/Free Full Text] Littlewood, Timothy J., Schenkel Brad, Liss Martin. Response to a Letter to the Editor from Coiffier Regarding "Effect of Patient Exclusion Criteria on the Efficacy of Erythropoiesis-Stimulating Agents in Patients with Cancer-Related Anemia." The Oncologist 2005; 10:764-765.[Free Full Text]


This Article Has Been Cited by Other Articles

Littlewood, Timothy J., Schenkel Brad, Liss Martin. Response to a Letter to the Editor from Coiffier Regarding "Effect of Patient Exclusion Criteria on the Efficacy of Erythropoiesis-Stimulating Agents in Patients with Cancer-Related Anemia." The Oncologist 2005; 10:764-765.

 


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Dr. Coiffier has served as a consultant to F. Hoffmann-La Roche Ltd. and Ortho Biotech and has been a member of a speakers’ bureau sponsored by F. Hoffmann-La Roche Ltd.


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  1. Littlewood TJ, Schenkel B, Liss M. Effect of patient exclusion criteria on the efficacy of erythropoiesis-stimulating agents in patients with cancer-related anemia. The Oncologist 2005;10:357–360.
  2. Cazzola M, Beguin Y, Kloczko J et al. Once-weekly epoetin beta is highly effective in treating anaemic patients with lymphoproliferative malignancy and defective endogenous erythropoietin production. Br J Haematol 2003;122:386–393.[CrossRef][Medline]
  3. Littlewood TJ, Nortier J, Rapoport B et al. Epoetin alfa corrects anemia and improves quality of life in patients with hematologic malignancies receiving non-platinum chemotherapy. Hematol Oncol 2003;21:169–180.[CrossRef][Medline]
  4. Hedenus M, Adriansson M, San Miguel J et al. Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: a randomized, double-blind, placebo-controlled study. Br J Haematol 2003;122:394–403.[CrossRef][Medline]
  5. Schwartzberg LS, Yee LK, Senecal FM et al. A randomized comparison of every-2-week darbepoetin alfa and weekly epoetin alfa for the treatment of chemotherapy-induced anemia in patients with breast, lung, or gynecologic cancer. The Oncologist 2004;9:696–707.[Abstract/Free Full Text]
  6. Österborg A, Brandberg Y, Molostova V et al. Randomized, double-blind, placebo-controlled trial of recombinant human erythropoietin, epoetin beta, in hematologic malignancies. J Clin Oncol 2002;20:2486–2494.[Abstract/Free Full Text]
  7. Leonard R, Aapro M, Chan S et al. Once weekly epoetin beta in patients with metastatic breast cancer receiving anthracycline- or taxane-based chemotherapy. Ann Oncol 2004;15(suppl 3):iii.50 (Abstract 188P).
  8. Salles G, Facon T, Hunault-Berger M et al. Efficacy of epoetin beta (Neo-Recormon®) 30 000 IU once weekly in anemic patients with non-myeloid malignancies receiving chemotherapy. Haematologica 2005;90(suppl 2):446 (Abstract 1257).
  9. Gabrilove JL, Cleeland CS, Livingston RB et al. Clinical evaluation of once-weekly dosing of epoetin alfa in chemotherapy patients: improvements in hemoglobin and quality of life are similar to three-times-weekly dosing. J Clin Oncol 2001;19:2875–2882.[Abstract/Free Full Text]
  10. Witzig TE, Silberstein PT, Loprinzi CL et al. Phase III, randomized, double-blind study of epoetin alfa compared with placebo in anemic patients receiving chemotherapy. J Clin Oncol 2005;23:2606–2617.[Abstract/Free Full Text]
  11. Demetri GD, Kris M, Wade J et al. Quality-of-life benefit in chemotherapy patients treated with epoetin alfa is independent of disease response or tumor type: results from a prospective community oncology study. Procrit Study Group. J Clin Oncol 1998;16:3412–3425.[Abstract]
  12. Cheung W, Minton N, Gunawardena K. Pharmacokinetics and pharma-codynamics of epoetin alfa once weekly and three times weekly. Eur J Clin Pharmacol 2001;57:411–418.[CrossRef][Medline]
  13. Storring PL, Tiplady RJ, Gaines Das RE et al. Epoetin alfa and beta differ in their erythropoietin isoform compositions and biological properties. Br J Haematol 1998;100:79–89.[CrossRef][Medline]
  14. Halstenson CE, Macres M, Katz SA et al. Comparative pharmacokinetics and pharmacodynamics of epoetin alfa and epoetin beta. Clin Pharmacol Ther 1991;50:702–712.[Medline]
  15. Pujade-Lauraine E, Richard AJ, Sapède C et al. Erythropoietic agents in anaemic patients with cancer: a retrospective observational survey of epoetin alfa, epoetin beta and darbepoetin alfa use in routine clinical practice. Oncol Rep 2005;14:1037–1044.[Medline]



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T. J. Littlewood, B. Schenkel, and M. Liss
Response to a Letter to the Editor from Coiffier Regarding "Effect of Patient Exclusion Criteria on the Efficacy of Erythropoiesis-Stimulating Agents in Patients with Cancer-Related Anemia"
Oncologist, October 1, 2005; 10(9): 764 - 765.
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