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Journal of Clinical Oncology, Vol 24, No 15 (May 20), 2006: pp. 2233-2236 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.05.7794
Epoetin Alfa and Darbepoetin Alfa Go Head to HeadMayo Clinic College of Medicine, Rochester, MN Since July 2002, when the US Food and Drug Administration approved the use of darbepoetin alfa for treatment of chemotherapy-associated anemia in patients with nonmyeloid malignancies, American oncologists have had two recombinant erythropoietic agents from which to choose when trying to ameliorate anemia in patients suffering from cancer.1 Darbepoetin alfa and epoetin alfa share the same native protein sequence, but the molecules have distinct glycosylation patterns, resulting in a three-times longer serum half-life and a modestly reduced erythropoietin receptor affinity for darbepoetin compared with its predecessor, epoetin.2 Darbepoetin is currently marketed by its manufacturer as having "increased potency and longer half-life" compared with epoetin, which purportedly "allows for less-frequent dosing than the previous standard of care."3 However, until recently, there have been few reports of clinical trials directly comparing darbepoetin alfa and epoetin alfa administered in the doses and schedules that are now commonly used in clinical oncology practice. Most of the larger published comparative analyses to date have been retrospective, have been limited to historical controls, or were pilot studies using multiple dose levels of darbepoetin.4-7 This issue features an important prospective study by Glaspy et al8 comparing two doses and schedules of these erythropoietic agents frequently used in oncology clinics (once weekly subcutaneous epoetin alfa initiated at a fixed dose of 40,000 U v darbepoetin alfa administered subcutaneously once every 2 weeks, beginning at a fixed dose of 200 µg). Both treatment groups were permitted a 50% dose escalation at week 5 for nonresponse, which was defined as failure to achieve a hemoglobin increment of at least 1 g/dL above the baseline measurement. This study, as with other community-based erythropoietin treatment protocols organized by Glaspy et al,9 is remarkable first of all for its size, and the authors are to be congratulated for completing accrual so rapidly. To our knowledge, the present trial is the largest randomized study of erythropoietic agents in cancer-associated anemia; 1,209 patients received protocol therapy. The study was sponsored by the manufacturer of darbepoetin (Amgen, Inc, Thousand Oaks, CA), and the report includes an industry coauthor. The outcome in terms of the primary end point, which was the proportion of patients who required RBC transfusion, was similar between treatment groups, with 21% of patients in the darbepoetin arm receiving transfusion between week 5 and the end of study (27% from beginning to end) compared with 16% of patients in the epoetin group (22% from beginning to end). For comparison, the historical control transfusion rate for a similar group of placebo-treated patients with a comparable degree of chemotherapy-associated anemia is approximately 40% to 45%. The investigators' predefined cutoff for declaring inferiority of one regimen was an absolute proportional difference in transfusion rate of 11.5%; because the upper limit of the CI of the 5% observed difference (ie, 16% for epoetin v 21% darbepoetin) favoring epoetin was 10.8%, the authors conclude that these two regimens are equivalent from the standpoint of a noninferiority analysis. Equivalence is a formal statistical term, and equivalent should not be seen as semantically equal to identical. In fact, in some respects, the results of this study could be interpreted as suggesting that weekly epoetin might be slightly superior to every-2-week darbepoetin, at least in the doses chosen for the trial. The transfusion end point, although not quite meeting the predefined inferiority cutoff, did favor weekly epoetin, whereas the CIs for the proportion of patients transfused narrowly missed refuting the noninferiority hypothesis. The mean hemoglobin increment from baseline, especially around week 9, was superior for the epoetin-treated group, albeit again not statistically significant. From week 5 until the end of the study, more patients on the epoetin arm were within the stated goal hemoglobin range of 11 to 13 g/dL (see Fig 3 of the report). Additionally, the rate of increase of hemoglobin seems to have been slightly greater with the weekly epoetin regimen, which is a scheduling phenomenon that has been observed in a few other studies, including those comparing various darbepoetin doses and schedules with each other (increasing the drug dose seems to be more effective at augmenting hemoglobin rapidly than does increasing the dosing frequency7). One might argue about whether a rapid increase in hemoglobin is always a good thing; after all, the package inserts for recombinant erythropoietins were modified in 2004 to warn about an excessive rate of hemoglobin increase because of concerns about a possible association between rapid increase of hemoglobin and risk of thromboembolic events raised by several studies. However, if a patient has severe anemia and is in danger of needing a transfusion soon, a rapid hemoglobin increase is likely to be beneficial.10-13 In contrast, the trend in the study in terms of quality-of-life (QOL) changes favored darbepoetin. QOL has proven to be a rather variable, complex, and inconsistent factor in past analyses of erythropoietic agents,14,15 so it is difficult to know just what to make of this finding. The study was not double blinded, which could influence QOL comparisons, but it is also possible that the advantage of receiving an injection less frequently is a component of QOL. If so, that could favor every-2-week darbepoetin, as used in the study by Glaspy et al.8 Overall, all of the differences (transfusions, hemoglobin, and QOL) between groups were small, so there seems little reason for clinicians to change whatever they are already doing. Instead, this study provides us with some reassurance that both weekly epoetin and every-2-week darbepoetin remain reasonable choices for our anemic patients.
The study by Glaspy et al8 is not the only randomized, head-to-head comparison of darbepoetin and epoetin. For instance, in September 2005, Waltzman et al16 (sponsored by Ortho Biotech, Bridgewater, NJ; a subsidiary of Johnson & Johnson and the marketer of epoetin alfa in the United States) published the results of a study comparing the same two regimens used by Glaspy et al,8 albeit in a smaller number of patients (n = 358). In that analysis, weekly epoetin-treated patients achieved a The dose and schedule of the erythropoietic agent chosen may be a more important determinant of the RBC response than the specific drug itself. Along these lines, the North Central Cancer Treatment Group recently compared weekly epoetin with every-3-week epoetin maintenance therapy (120,000 U) in cancer-associated anemia. Hemoglobin end points were slightly superior in the weekly therapy arm, whereas the transfusion and QOL outcomes were similar between the two treatment groups.20 Other ongoing and planned trials will compare standard weekly epoetin with epoetin administered once every 3 weeks from the time of treatment initiation, rather than only in the maintenance phase after an initial hemoglobin response has been achieved. Direct comparisons with darbepoetin administered in a similar schedule will be important. Front loading of darbepoetin also seems to be an effective strategy that deserves further exploration,21 and data are accumulating on the effects of darbepoetin administered once every 3 weeks, usually at a fixed dose of 500 µg, which seems to be comparable to a darbepoetin schedule of 2.25 µg/kg once weekly.22 Although higher dose regimens may be more costly in terms of drug expenditure than conventional dosing, they may be associated with a greater overall response rate, as has been demonstrated for epoetin when administered at a dose of 60,000 U once weekly to patients whose anemia did not respond to 40,000 U of epoetin weekly.23,24 This could result in net savings if the difference in response rate and transfusion needs were large enough between dosing regimens. Thus far, the toxicity observed with higher dose erythropoietin regimens has been comparable to the toxicity seen with more typical doses, as long as excessive hemoglobin levels are avoided. The article by Glaspy et al8 comes with an unusual notice about a leak to the business press that was identified and appropriately reported to the Journal of Clinical Oncology by the study's lead author, an event that was apparently out of both the authors' and sponsors' control. Jokes about governmental inability to keep secrets notwithstanding, it is perhaps not surprising that the premature data release associated with this study involved a US government agency, specifically, the Center for Medicare and Medicaid Services (CMS), because CMS has considerable interest in the most cost-effective use of recombinant erythropoietins. Before Medicare Part D coverage became effective in early 2006, erythropoietic agents were consistently the top drug expense for CMS (although some of this expense is for anemia associated with renal failure, rather than cancer anemia).25 For some years, CMS has expressed a desire to see the results of a large trial or series of trials comparing multiple doses and schedules of darbepoetin and epoetin in cancer-associated anemia. A conference of interested parties was even held in Bethesda for this purpose in 2002, which was attended by both authors (D.P.S. and C.L.L.). Yet, a check of the Web site www.clinicaltrials.gov on January 30, 2006, revealed no such ongoing studies registered, and thus far, all of the largest published comparative studies, including those conducted by cooperative groups, have been at least partially sponsored by industry, rather than by a potentially more independent and objective organization, such as a government payer. We do not mean to suggest here that industry-sponsored studies are somehow suspect. In the past, we have worked on clinical trial development with both companies that market erythropoietic agents in the United States, and without exception, we have found their representatives to be interested in conducting high-quality, clinically meaningful studies with integrity and transparency. But corporate leaders have obligations to shareholders to minimize risks and increase profits, and this responsibility, understandably, can diminish their enthusiasm for approving certain types of studies where the results could potentially put their products in a poor light. Clinicians may ask legitimate questions that industry sponsors may not be eager to answer. We believe that the postmarketing studies that have long been of interest to CMS still need to be performed, regardless of the ultimate sponsor. The remaining questions regarding epoetin and darbepoetin are clinically important because decisions about which erythropoietic agent to use and how and when to administer it are made in clinics across the globe thousands of times each day based on a limited evidence pool.24 Although almost all oncologists have now moved on from administering epoetin three times per week (the original US Food and Drug Administration–approved schedule, which was approved in 1989 for treatment of anemia of renal failure), we still need to know whether there are meaningful differences between epoetin and darbepoetin when administered in comparable doses once weekly, once every 2 weeks, or once every 3 weeks to patients with cancer-associated anemia. An adequately powered six-arm study, for instance, would go a long way towards sorting this out. The present study by Glaspy et al8 will prove valuable as a benchmark for comparison with future results, and the findings suggest that differences between at least two of the arms in such a six-arm trial would be relatively small. Beyond dose and schedule issues, there are a number of other key questions about erythropoietic agents that also remain incompletely answered.26 When is the best time (ie, ideal hemoglobin range) to start an erythropoietic drug for a cancer patient with anemia? What is the optimal target hemoglobin in terms of QOL and adverse events, and what benefits can really be expected in terms of QOL? Both epoetin and darbepoetin are approved by the US Food and Drug Administration specifically for anemia associated with chemotherapy. But, is there really any meaningful difference in the efficacy of these drugs between cancer patients who are or are not receiving active antitumor therapy, as the US Food and Drug Administration continues to insist? Can the response to recombinant erythropoietins be augmented with concomitant administration of parenteral iron27 or other agents, and is there any potential harm in doing so for cancer patients, who often have functional iron deficiency despite elevated total-body iron stores? Does recombinant erythropoietin therapy truly alter tumor behavior or patient survival?28 What biologic activities do epoetin and darbepoetin have that are physiologically and clinically relevant, beyond merely supporting the developing erythron?29 From our perspective, a task equally important to optimizing use of existing erythropoietic agents is advancing the cause of novel agents that might also benefit some of the 30% to 40% of patients with cancer-associated anemia who do not respond to epoetin or darbepoetin as they are currently used, including the 15% to 20% of patients who require transfusions despite receiving erythropoietin therapy. Fortunately, a number of erythropoiesis-stimulating agents, including several that are orally bioavailable, are in the late stages of development. Drugs in the pipeline include a continuous erythropoietin receptor activator that is now in phase III clinical trials,30 several molecules that operate through the hypoxia-inducible factor/von Hippel-Lindau oxygen-sensing pathway, pegylated versions of existing molecules,31 hyperglycosylated erythropoietins (eg, AMG 114), erythropoietic agents manufactured in human cells instead of animal cells (eg, epoetin delta), and several others. Additionally, recent discoveries about the biology of erythropoiesis, including novel inhibitory proteins, promise more targeted agents to come. All of these new agents will need to be compared with the best current standard regimens. It would be of great value to define that optimal standard regimen (or regimens) as soon as possible. Author Contributions
Author’ Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required
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Clin Ther 25:2781-2796, 2003[CrossRef][Medline] 7. Glaspy JA, Jadeja JS, Justice G, et al: Darbepoetin alfa given every 1 or 2 weeks alleviates anaemia associated with cancer chemotherapy. Br J Cancer 87:268-276, 2002[CrossRef][Medline] 8. Glaspy J, Vadhan-Raj S, Patel R, et al: Randomized comparison of every-2-weeks darbepoetin alfa and weekly epoetin alfa for the treatment of chemotherapy-induced anemia: The 20030125 Study Group trial. J Clin Oncol 24:2290-2297, 2006 9. Glaspy J, Bukowski R, Steinberg D, et al: Impact of therapy with epoetin alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice: Procrit Study Group. J Clin Oncol 15:1218-1234, 1997 10. Leyland-Jones B: Breast cancer trial with erythropoietin terminated unexpectedly. Lancet Oncol 4:459-460, 2003[CrossRef][Medline] 11. Henke M, Laszig R, Rube C, et al: Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: Randomised, double-blind, placebo-controlled trial. Lancet 362:1255-1260, 2003[CrossRef][Medline] 12. Steensma DP: Management of anemia in patients with cancer. Curr Oncol Rep 6:297-304, 2004[Medline] 13. Campos SM, Duh MS, Lefebvre P, et al: Benefits associated with an early hemoglobin response to epoetin alfa therapy in the treatment of chemotherapy-related anemia. J Natl Compr Canc Netw 3:807-816, 2005[Medline] 14. 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 23:2606-2617, 2005 15. Seidenfeld J, Piper M, Flamm C, et al: Epoetin treatment of anemia associated with cancer therapy: A systematic review and meta-analysis of controlled clinical trials. J Natl Cancer Inst 93:1204-1214, 2001 16. Waltzman R, Croot C, Justice GR, et al: Randomized comparison of epoetin alfa (40,000 U weekly) and darbepoetin alfa (200 microg every 2 weeks) in anemic patients with cancer receiving chemotherapy. Oncologist 10:642-650, 2005 17. Case AS, Rocconi RP, Kilgore LC, et al: Effectiveness of darbepoetin alfa versus epoetin alfa for the treatment of chemotherapy induced anemia in patients with gynecologic malignancies. Gynecol Oncol doi:10.1016/j.ygyno.2005.11.027 18. 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. Oncologist 9:696-707, 2004 19. Senecal FM, Yee L, Gabrail N, et al: Treatment of chemotherapy-induced anemia in breast cancer: Results of a randomized controlled trial of darbepoetin alfa 200 microg every 2 weeks versus epoetin alfa 40,000 U weekly. Clin Breast Cancer 6:446-454, 2005[Medline] 20. Steensma DP, Molina R, Sloan JA, et al: Phase III randomized trial of two different dosing schedules of erythropoietin in anemic patients with cancer. J Clin Oncol 24:1079-1089, 2006 21. Glaspy JA, Jadeja JS, Justice G, et al: A randomized, active-control, pilot trial of front-loaded dosing regimens of darbepoetin-alfa for the treatment of patients with anemia during chemotherapy for malignant disease. Cancer 97:1312-1320, 2003[CrossRef][Medline] 22. Canon JL, Vansteenkiste J, Bodoky G, et al: Results of a randomised, double-blind, active-controlled trial of darbepoetin alfa administered once every 3 weeks for the treatment of anaemia in patients receiving multicycle chemotherapy. Proceedings of the 10th Congress of the European Hematology Association, Stockholm, Sweden, June 2-5, 2005 (abstr 0471) 23. 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 19:2875-2882, 2001 24. 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. J Clin Oncol 20:4083-4107, 2002 25. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Oncologic Drugs Advisory Committee: Minutes of the meeting of Tuesday, May 4, 2004. Gaithersburg, MD, 2004 26. 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 100:2303-2320, 2002 27. Auerbach M, Ballard H, Trout JR, et al: Intravenous iron optimizes the response to recombinant human erythropoietin in cancer patients with chemotherapy-related anemia: A multicenter, open-label, randomized trial. J Clin Oncol 22:1301-1307, 2004 28. Steensma DP, Witzig TE: Does treatment with recombinant human erythropoietin affect the survival of anemic patients with cancer? Nat Clin Pract Oncol 2:444-445, 2005[CrossRef][Medline] 29. Maiese K, Li F, Chong ZZ: New avenues of exploration for erythropoietin. JAMA 293:90-95, 2005 30. Macdougall IC: CERA (Continuous Erythropoietin Receptor Activator): A new erythropoiesis-stimulating agent for the treatment of anemia. Curr Hematol Rep 4:436-440, 2005[Medline] 31. Tillmann HC, Kuhn B, Kranzlin B, et al: Efficacy and immunogenicity of novel erythropoietic agents and conventional rhEPO in rats with renal insufficiency. Kidney Int 69:60-67, 2006[CrossRef][Medline] Related Article
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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1 g/dL hemoglobin increase significantly earlier than patients receiving every-2-week darbepoetin (median time, 35 v 46 days, respectively), and the mean increase in hemoglobin above the baseline was also greater at all key time points (ie, at week 5, week 9, and end of study) with epoetin. Additionally, the number of units transfused per patient was significantly lower for the epoetin group than for the darbepoetin group, although the total proportion of patients transfused was low overall (12.9% v 17.8%, respectively), and the proportional difference was not statistically significant. Another smaller study (n = 123) in patients with gynecologic tumors compared these same two erythropoietic regimens and suggested a slight benefit for weekly epoetin over every-2-week darbepoetin in terms of a transfusion end point.
