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Journal of Clinical Oncology, Vol 26, No 10 (April 1), 2008: pp. 1619-1625 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.12.2051 Randomized Trial of Intravenous Iron Supplementation in Patients With Chemotherapy-Related Anemia Without Iron Deficiency Treated With Darbepoetin Alfa
From the Oncologia Medica Falck, Ospedale Niguarda Ca Granda; Oncologia Medica, Polo Universitario Ospedale San Paolo; Dompé Biotec, Milano; Clinica Medica Generale e Terapia Medica, Università degli Studi di Sassari; Ospedale S. Giovanni di Dio, Frattaminore (NA); Ospedale San Giuseppe Moscati, Avellino; Medicina Oncologica, Ospedale Maggiore di Crema; IRCCS Ospedale Oncologico, Bari; Ospedale Oncologico A. Businco, Cagliari; Ospedale SS. Trinità, Soro (FR), Oncologia Medica, Ospedale O. Morgagni, Catania; Oncologia Medica, Ospedale San Martino, Genova; Oncologia Medica, Ospedale Civile di Vimercate, Milano; Istituto Regina Elena, Roma; Oncologia Medica, Ospedali Riuniti di Bergamo; and Oncologia Medica, Ospedale Careggi, Firenze, Italy Corresponding author: Paolo Pedrazzoli, MD, Divisione di Oncologia Medica Falck, Ospedale Niguarda Ca Granda, Piazza Ospedale Maggiore 20162, Milano, Italy; e-mail: paolo.pedrazzoli{at}ospedaleniguarda.it
Purpose Unresponsiveness to erythropoiesis-stimulating agents, occurring in 30% to 50% of patients, is a major limitation to the treatment of chemotherapy-related anemia. We have prospectively evaluated whether intravenous iron can increase the proportion of patients with chemotherapy-related anemia who respond to darbepoetin.
Patients and Methods Between December 2004 and February 2006, 149 patients with lung, gynecologic, breast, and colorectal cancers and Results Hematopoietic response by intention-to-treat analysis was 76.7% (95%CI, 65.4% to 85.8%) in the darbepoetin/iron group and 61.8% (95%CI, 50.0% to 72.7%) in the darbepoetin group (P = .0495). Among patients fulfilling eligibility criteria and having received at least four darbepoetin administrations, hematopoietic responses in the darbepoetin/iron group (n = 53) and in the darbepoetin-only group (n = 50) were 92.5% (95% CI, 81.8% to 97.9%) and 70% (95% CI, 55.4% to 82.1%), respectively (P = .0033). Increase of hemoglobin during treatment period showed a time profile favoring darbepoetin/iron with statistically significant effect from week 5 on. The safety profile was comparable in the two arms. Conclusion In patients with chemotherapy-related anemia and no iron deficiency, IV iron supplementation significantly reduces treatment failures to darbepoetin without additional toxicity.
Anemia is common in cancer patients, and is an important contributor to the morbidity of malignancy.1 The etiology of cancer-related anemia is multifactorial, but in most cases it is a consequence of the chronic disease process associated with malignancy, anemia of chronic disease (ACD).2,3 Key contributors to the pathogenesis of ACD are a shortened RBC life span and the failure of the bone marrow to increase RBC production. This occurs also through the inadequate production of erythropoietin for the grade of anemia.3,4 Anemia in cancer patients is exacerbated by chemotherapy, which further impairs erythropoietin production.5 The ability of recombinant erythropoiesis-stimulating agents (ESA)—epoetin alfa and beta and darbepoetin alfa (DA)—to correct chemotherapy-related anemia (CRA) and to reduce the need of blood transfusion in patients receiving chemotherapy has been well defined by several large clinical trials.6 When given according to evidence-based clinical practice guidelines,7,8 ESA can provide clinically meaningful improvements in overall health including physical, functional, and emotional well-being9,10 independent of tumor response.11 DA possesses comparable activity to epoeitins in CRA12 but, due to differences in the pharmacokinetic properties, it can be administered less frequently without changes in efficacy and safety.13 While epoetins and DA represent a remarkable advance in the treatment of CRA, approximately 30% to 50% of patients do not achieve a meaningful response to ESA.9,11,14 The reasons are mainly unknown, but some patients who fail to respond may have, or develop during treatment with ESA, functional iron deficiency (FID).2 The efficacy of intravenous (IV), not oral, iron to correct FID and improve anemia has been well documented in chronic kidney disease (CKD) during epoetin therapy.15 Despite these findings, clinicians have been reluctant to prescribe IV iron routinely for patients with CRA, probably because of the false perception that cancer patients do not have decreased iron stores (as measured by serum ferritin); the lack of clinical trials of ESA energetically pursuing iron usage in cancer patients and the risk of anaphylaxis associated with IV iron. However, the latter is an uncommon occurrence as the severe reactions rate with lower molecular weight iron dextran, iron sucrose, and ferric gluconate occurs in less than one in 200,000 patients.16 The effects of iron during epoetin therapy have been initially studied by Auerbach et al17 in anemic patients with cancer and iron deficiency. This study demonstrated that correcting functional, as well as absolute iron deficiency with iron supplementation will improve response to ESA. It also confirmed that iron supplement should be given IV rather then orally. However, a major point that remains to be elucidated in the field of ESA therapy for CRA is whether iron supplementation is capable to increase the fraction of patients who respond to epoetin and DA even in the absence of iron deficiency. This issue is clinically relevant because appropriate iron supplementation, apart from allowing more patients to benefit from ESA therapy, may represent a strategy to improve the cost-effectiveness of ESA in oncology as it has in nephrology.
Study Population Participants were recruited from 33 medical oncology institutions in Italy between December 2004 and February 2006. The independent ethics committee or central ethics committee for each of the institutions approved the protocol. All patients provided written informed consent before study participation. Randomization was conducted centrally to avoid selection bias.
For entry into the study, patients were required to have a diagnosis of breast, colorectal, lung, or gynecologic cancer and at least 12 additional weeks of planned cancer chemotherapy. Patients were eligible for the study if they were at least 18 years of age, had an Eastern Cooperative Oncology Group performance status
Protocol
Efficacy Assessment
Safety
Data Analysis and Statistical Methods Statistical analyses were performed using SAS statistical software version 8.2 (SAS Institute, Cary, NC). Descriptive statistics included frequencies and means (with standard deviation (SD) and 95% CI) for categoric and continuous variables, respectively. All analyses were performed on both intention to treat (ITT) and per protocol (PP) populations. ITT population was defined as all patients who were randomly assigned and received at least one administration of DA. PP population included patients meeting eligibility criteria and completing at least 4 weeks of treatment with DA.
The hypothesis of no difference in response rate between treatment groups was tested using the Pearson The safety analysis was performed on all patients who received at least one administration of study drug. Treatment-related AEs, according to NCI Common Terminology for Adverse Events Version 3.0, were tabulated according to seriousness and relation to the actual treatment received. Comparison between treatment groups was performed by means of Fisher's exact test.
Study Population Due to lower than expected accrual, 104 patients from nearly half of planned nstitutions were randomly assigned in 10 months. The steering committee and the sponsor decided, also based on favorable results from previous studies with a limited number of patients,13,17 to prolong the accrual for additional 4 months. No interim analysis was performed. A total of 149 patients were eventually enrolled and underwent random assignment to receive DA and IV iron (n = 73) or DA only (n = 76). Patients were well balanced in the two groups as for age, sex, tumor type, and disease stage. Relevant patients characteristics are presented in Table 1. Of the 149 patients randomized, 33 were subsequently excluded due to eligible criteria violations (evidence of baseline iron deficiency or no/incomplete data on iron profile in most cases). Among 116 patients strictly fulfilling inclusion criteria, 103 had completed at least 4 weeks of treatment with DA. The study profile is shown in Figure 1.
Efficacy Evaluations Hematopoietic response. Among randomly assigned subjects that had received at least one administration of DA (ITT population, n = 149), 56 of 73 (76.7%; 95% CI, 65.4% to 85.8%) in the DA/iron group and 47 of 76 (61.8%; 95% CI, 50.0% to 72.7%) in the DA-only group achieved hematopoietic response (P = .0495, Fig 2). In the PP population, response occurred in 49 of 53 patients (92.5%; 95% CI, 81.8% to 97.9%) in the DA/iron group and in 35 of 50 patients (70%; 95% CI, 55.4% to 82.1%) in the DA-only group (P = .0033, Fig 2).
The Hb profiles over time also favor DA/iron group in both ITT and PP populations (Fig 3). The time-adjusted Hb AUC5-12 confirms previous result with a significant increase (P = .025 and P = .023 in the ITT and PP populations, respectively) in AUC in the DA/iron group: ITT saw a 0.2 Hb increase in g · day/dL (95% CI, 0.095 to 0.305 Hb) and PP saw a 0.2 Hb increase in g · day/dL (95% CI, 0.08 to 0.32 Hb).
Median times to achievement of target Hb in the DA/iron and DA-only groups were 36 days(95% CI, 29 to 42 days) and 46 days(95% CI, 33 to 55 days), respectively (log-rank test, P = .0778) in the ITT population; and 35 days (95% CI, 28-42 days) and 42 days (95% CI, 29 to 56 days), respectively (log-rank test, P = .0305) in the PP population. RBC transfusions were required in two and five patients in the DA/iron and DA-only groups, respectively. The dose of DA was doubled for no response in 34.2% of patients the DA/iron group and in 31.5% of patients in the DA-only group. Exploratory analysis performed in this subset of patients showed that hematopoietic response occurred in 68.2% in the DA/iron group and in 32% in the DA-only group (P = .0199). This finding is expected if considering that avoidance of the development of FID is the mechanisms involved in hematopoietic response to iron supplementation in iron-replete patients receiving ESA. Any effect of IV iron in such patients is not likely to occur during the first weeks of ESA treatment (when the patient has enough iron to meet the increased iron needs of an expanding erythroid marrow) and therefore does not influence significantly early response to ESA. In fact, in our study DA dose was doubled at 4 weeks in the almost same percentage of patients in the two groups, but subsequently hematopoietic response occurred more frequently in the DA/iron group. Time to hematopietic response was shorter in the DA/iron group but it largely exceeded 4 weeks.
Safety Results
When patients with CRA are treated with ESA, an important response-limiting factor is represented by FID, an imbalance between iron needs in the erythropoietic marrow and iron supply.2 FID is well recognized in anemia of CKD where systematic IV iron supplementation is routinely utilized in course of ESA therapy24,25 resulting in improved efficacy of ESA and substantial cost savings.15 Surprisingly, oncologists have so far mostly ignored the issue of iron requirements during ESA therapy in despite this issue has been being raised by ASCO/ASH guidelines published in 2002.7 The use of iron supplementation has been investigated by Auerbach et al17 and, more recently, by Henry et al26 in patients with nonmyeloid malignancies receiving epoetin alfa for CRA, showing that IV iron improves hematopoietic response. However, the Auerbach study included only patients harboring iron deficiency (functional in most cases), while the Henry study had an unexpected low response rate (41%) in the epoetin-only arm, which might be related to having selected also patients not iron-replete (TSAT < 15% or ferritin < 100 ng/mL).26 The efficacy of IV iron in improving hematopoietic response to epoetin beta has been demonstrated by Hedenus et al27 in a limited series of 60 patients with lymphoproliferative malignancies. This study included moderately anemic patients not receiving chemotherapy who were considered iron-replete if having stainable iron in bone marrow aspirates. This method is not routinely applicable in patients with solid tumors where iron status is commonly assessed using serum ferritin and TSAT values. In our study, IV iron supplementation during therapy with DA significantly improved by 14.9% the proportion of patients in the ITT population achieving hematopoietic response, the primary efficacy parameter. The percentage of responders in the control group (62%) was comparable to rates reported in previous studies using DA.14,28 Most importantly, when looking at patients strictly fulfilling the eligibility criteria and having received at least four administrations of DA (PP population), the response rate in the IV iron group was greater than 90%, a magnitude never reached in previously published studies of ESA in CRA. Additional parameters of efficacy, including time to reach hematopoietic response, Hb profile over time and Hb AUC5-12 were also significantly better in the DA/iron arm. The favorable results obtained might be due to IV iron preventing the development of FID which otherwise could occur when the increased iron needs of an expanding erythroid marrow, stimulated by ESA, cannot be matched by sufficient mobilization, even in the presence of adequate iron stores.18,29 Darbepoetin and IV iron were well tolerated, with no safety concerns in either arms, in accordance with previous reports.6,16 No allergic reactions related to IV iron administration occurred, thus supporting the safety profile of both DA and iron gluconate.30 Concerns about the potential effect of iron on tumor stimulation, based on laboratory studies, have never been demonstrated in vivo in humans.31 In our study the amount of iron per patient administered (750 mg) was lower than that employed by others (up to 3000 mg in the study by Auerbach et al17). It also has to be considered that the transfusion of one RBC unit provides about 200 mg of iron. Multiple units of RBC are often given in unresponsive patients, thereby delivering similar amounts of iron, albeit more slowly available. Recent concerns that ESA may negatively alter patient survival32 are largely based on clinical trials in patients who were either nonanemic or not receiving chemotherapy. In contrast, a meta-analysis of ESA therapy in patients with the same clinical characteristics as those enrolled in the present study failed to show the same detrimental effect.6 In conclusion, we have demonstrated that IV iron supplementation significantly reduces treatment failures to DA in patients with CRA and normal iron status without additional toxicity. This is the only trial published so far which is based on iron-replete patients only with solid tumors and represents a major step forward in the optimization of ESA therapy in CRA. Based on our study, and the two other published papers,26,27 IV iron supplementation should become an integral and routine component of ESA therapy, and should be incorporated in clinical guidelines. Furthermore, the use of DA every three weeks and total dose infusion of iron, which are as effective as the dose and schedule utilized in our study,13,17 may well provide additional benefits for patients and health care providers. The potential health economic impact of IV iron supplementation in this setting for example, by decreasing the required doses of ESA, should be further examined in prospective trials.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. 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. Employment or Leadership Position: Enrico Crucitta, Dompé Biotec (C); Federica Apolloni, Dompé Biotec (C); Antonio Del Santo, Dompé Biotec (C) Consultant or Advisory Role: Paolo Pedrazzoli, Dompé Biotec (C); Teresa Gamucci, Dompé Biotec (C) Stock Ownership: None Honoraria: Giuseppe Colucci, Dompé Biotec; Roberto Labianca, Dompé Biotec; Francesco Di Costanzo, Dompé Biotec; Salvatore Siena, Dompé Biotec Research Funding: None Expert Testimony: None Other Remuneration: None
Conception and design: Paolo Pedrazzoli, Giuseppe Colucci, Roberto Labianca, Francesco Di Costanzo, Antonio Del Santo, Salvatore Siena Administrative support: Enrico Crucitta, Federica Apolloni Provision of study materials or patients: Paolo Pedrazzoli, Antonio Farris, Salvatore Del Prete, Filomena Del Gaizo, Daris Ferrari, Clara Bianchessi, Giuseppe Colucci, Alberto Desogus, Teresa Gamucci, Alessandro Pappalardo, Giuseppe Fornarini, Paola Pozzi, Alessandra Fabi, Roberto Labianca, Francesco Di Costanzo, Simona Secondino, Salvatore Siena Collection and assembly of data: Federica Apolloni Data analysis and interpretation: Paolo Pedrazzoli, Antonio Del Santo Manuscript writing: Paolo Pedrazzoli, Antonio Del Santo, Salvatore Siena Final approval of manuscript: Paolo Pedrazzoli, Antonio Farris, Salvatore Del Prete, Filomena Del Gaizo, Daris Ferrari, Clara Bianchessi, Giuseppe Colucci, Alberto Desogus, Teresa Gamucci, Alessandro Pappalardo, Giuseppe Fornarini, Paola Pozzi, Alessandra Fabi, Roberto Labianca, Francesco Di Costanzo, Simona Secondino, Enrico Crucitta, Federica Apolloni, Antonio Del Santo, Salvatore Siena
Steering Committee. Salvatore Siena, Giuseppe Colucci, Roberto Labianca, and Francesco Di Costanzo.
Participating Institutions.
We thank all patients who had the strength to fight their disease and help others to find better treatment options; all doctors and nurses and all investigators contributing to this trial; Guido Fedele and Giovanni Pappagallo for assistance in data analysis and statistical plan design; and Mario Cazzola for valuable suggestions.
Supported by Dompé Biotec. S.S. is recipient of a research contract supported in part by Oncologia Ca Granda ONLUS Fondazione. Authors disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Ludwig H, Fritz E: Anaemia in cancer patients. Semin Oncol 25:2-6, 1998 (suppl 7)[Medline] 2. Beguin Y: Prediction of response and other improvements on the limitations of recombinant human erythropoietin therapy in anemic cancer patients. Haematologica 87:1209-1221, 2002 3. Weiss G, Goodnough LT: Anemia of chronic disease. N Engl J Med 352:1011-1023, 2005 4. Miller CB, Jones RJ, Piantadosi S, et al: Decreased erythropoietin response in patients with the anemia of cancer. N Engl J Med 322:1689-1692, 1990[Abstract] 5. Groopman JE, Itri LM: Chemotherapy-induced anemia in adults: Incidence and treatment. J Natl Cancer Inst 91:1616-1634, 1999 6. Bohlius J, Wilson J, Seidenfeld J, et al: Recombinant human erythropoietin and cancer patients: Updated meta-analysis of 57 studies including 9353 patients. J Natl Cancer Inst 98:708-714, 2006 7. 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 8. Bokemeyer C, Aapro MS, Courdi A, et al: EORTC guidelines for the use of erythropoietic agents in anaemic patients with cancer: 2006 update. Eur J Cancer 43:258-270, 2007[CrossRef][Medline] 9. Glaspy J: The impact of epoetin alfa on quality of life during cancer chemotherapy: A fresh look at an old problem. Semin Hematol 34:20-26, 1997 (suppl 2)[Medline] 10. Cella D, Dobrez D, Glaspy J: Control of cancer-related anemia with erythropoietic agents: A review of evidence for improved quality of life and clinical outcomes. Ann Oncol 14:511-519, 2003 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 16:3412-3425, 1998[Abstract] 12. Glaspy J, Vadhan-Ray 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 20031025 study group trial. J Clin Oncol 24:2290-2297, 2006 13. 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 98:273-284, 2006 14. 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 94:1211-1220, 2002 15. Besarab A, Amin N, Ahsan M, et al: Optimization of epoetin therapy with intravenous iron therapy in hemodialysis patients. J Am Soc Nephrol 11:530-538, 2000 16. Chertow GM, Mason PD, Vaage-Nilsen O, Ahlmén J: Update on adverse drug events associated with parenteral iron. Nephrol Dial Transplant 21:378-382, 2006 17. 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 18. Beguin Y: Erytropoietic agents and iron, in Bokemeyer C and Ludwig H (eds): Anaemia in Cancer, ESO Scientific Updates, Vol 6, 2nd edition; Amsterdam, The Netherlands, Elsevier, 2005, pp199-220 19. 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 20. Shargel L, Wu-Pong S, Yu ABC: Review of mathematical fundamentals, in: Applied Biopharmaceutics and Pharmacokinetics, 5th Edition. New York, NY, McGraw-Hill, 2004, pp21-51 21. Cazzola M, Beguin Y, Kloczco 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 122:386-393, 2003[CrossRef][Medline] 22. Duh SM, Lefebvre P, Fastenau J, et al: Assessing the clinical benefits of erythropoietic agents using area under the hemoglobin change curve. Oncologist 10:438-448, 2005 24. Macdougall IC, Tucker B, Thompson J, et al: A randomized controlled study of iron supplementation in patients treated with erythropoietin. Kidney Int 50:1694-1699, 1996[Medline] 25. Fishbane S, Frei GL, Mesaka J: Reduction in recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation. Am J Kidney Dis 26:41-46, 1995[Medline] 26. Henry DH, Dahl NV, Auerbach M, et al: Intravenous ferric gluconate improves response to epoetin alfa versus oral iron of no iron in anemic patients with cancer receiving chemotherapy. Oncologist 12:231-242, 2007 27. Hedenus M, Birgegard G, Nasman P, et al: Addition of intravenous iron to epoetin beta increases hemoglobin response and decreases epoetin dose requirement in anemic patients with lymphoproliferative malignancies: A randomized multicenter study. Leukemia 21:627-632, 2007[Medline] 28. Hedenus M, Adriansson M, San Miguel J, et al: Darbepoetin Alfa 20000161 Study Group. Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: A randomized, double-blind, placebo-controlled study. Br J Haematol 122:394-403, 2003[CrossRef][Medline] 29. Brugnara C, Chambers LA, Malynn E, et al: Red blood cell regeneration induced by subcutaneous recombinant erythropoietin: Iron-deficient erythropoiesis in iron-replete subjects. Blood 82:1377, 1993 30. Auerbach M, Ballard H, Glaspy J: Clinical update: Intravenous iron for anaemia. Lancet 369:1502-1504, 2007[CrossRef][Medline] 31. Weinberg ED: The role of iron in cancer. Eur J Cancer Prev 5:19-36, 1996[Medline] 32. Khuri FR: Weighing the hazards of erythropoiesis stimulation in patients with cancer. N Engl J Med 356:2445-2448, 2007 Submitted April 23, 2007; accepted December 11, 2007.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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