Parenteral Iron Improves Darbepoetin Responses in Non-Iron Deficient Chemotherapy Treated Patients
Parenteral Iron Improves Darbepoetin Responses in Non-Iron Deficient Chemotherapy Treated Patients
Abstract & Commentary
By William B. Ershler, MD, Editor
Synopsis: In a randomized, prospective trial, anemic chemotherapy-receiving patients received either darbepoetin alone or darbepoetin with intravenous ferric gluconate. The group that received the added ferric gluconate had a significantly higher rate of achieving objective criteria for anemia improvement. The iron infusions were associated with no observed toxicity.
Source: Pedrazzoli P, et al. Randomized trial of intravenous iron supplementation in patients with chemotherapy-related anemia without iron deficiency treated with darbepoetin alfa. J Clin Oncol. 2008;26:1619-1625.
Erythropoiesis-stimulating agents (ESA) are commonly prescribed for cancer patients who develop anemia while receiving chemotherapy. Such has been shown to effectively reduce the sense of fatigue and improve quality of life.1-3 Yet, as many as 50% of treated patients do not achieve a meaningful response.3,4 In the current report, Pedrazzoli and colleagues report a prospective trial aimed to assess whether intravenous iron supplementation given to chemotherapy treated patients without iron deficiency would augment ESA response.
For this, 149 patients with lung, gynecologic, breast, and colorectal cancers and ³ 12 weeks of planned chemotherapy were enrolled at 33 institutions. Enrollment criteria included a hemoglobin concentration of ≤ 11 g/dL and no absolute or functional iron deficiency. All patients received darbepoetin alfa 150ug subcutaneously once weekly for 12 weeks and were randomly assigned to sodium ferric gluconate 125 mg intravenously weekly for the first 6 weeks (n=73) or no iron (n=76). Primary end point of the study was the percentage of patients achieving hematopoietic response (hemoglobin concentration of ³ 12 g/dL or ³ 2 g/dL increase from baseline).
Erythroid response, by intention-to-treat analysis was 76.7% (95% confidence interval [CI], 65.4% to 85.4%) in the darbepoetin/iron group and 61.8% (95% CI, 50.0% to 72.7%) in the darbepoetin only group (P = 0.0495). Among patients fulfilling eligibility criteria and having received at least four darbepoetin treatments, responses in the darbepoetin/iron group (n=53) were achieved in 92.5% (95% CI, 81.8%-97.9%) compared with 70% (95% CI, 55.4%-82.1%) in the darbepoetin only group (P=0.0033). The safety profile was the same for both groups.
Commentary
The anemia that is so commonly observed in cancer patients is a composite of many factors, not the least of which are the marrow inhibitory effects of both inflammation and chemotherapy. Anemia is common in patients with both acute and chronic inflammatory disease and it has long been held that inflammatory cytokines have an inhibitory role on erythropoiesis.5,6 The mechanism whereby inflammatory cytokines or other components of the inflammatory process produce anemia is incompletely understood. Inflammation-associated hypoproliferative anemia has much overlap with iron deficiency but typically iron stores are within normal limits or elevated.7 Inflammatory cytokines stimulate liver production of hepcidin which in turn reduces intestinal iron absorption and decreased iron release from macrophages.8 Thus, the underlying mechanism for inflammation-associated anemia is coming to light.
Although typically, cancer patients are iron-replete, because of the associated inflammatory processes, iron utilization is reduced and "functional" iron deficiency accounts for the microcytic hypoproliferative anemia observed. Iron administered alone is not usually effective in overcoming the functional iron deficiency of inflammation, but the current report indicates a significant potential for combined iron and ESA for overcoming these inhibitory forces and improving anemia. Because the inflammatory-hepcidin pathway is associated with reduced gastrointestinal iron absorption,9 it is unlikely the results observed with parenteral iron would be matched if oral iron supplementation had been tested. This, however, is a worthwhile question because of the lower cost and ease of administration of the oral preparation.
The current report marks an advance of immediate clinical importance. The findings suggest ESA treatment can be safely enhanced by administration of iron. Further studies will be needed to determine whether iron should be routinely prescribed to all receiving ESA or only to those patients proving refractory.
References
1. Cella D, et al. Control of cancer-related anemia with erythropoietic agents: a review of evidence for improved quality of life and clinical outcomes. Ann Oncol. 2003;14(4):511-519.
2. Cella D, et al. Epoetin alfa treatment results in clinically significant improvements in quality of life in anemic cancer patients when referenced to the general population. J Clin Oncol. 2003;21(2):366-373.
3. Demetri GD, 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(10):3412-3425.
4. Vansteenkiste J, et al. Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy. J Nat Can Inst. 2002;94(16):1211-1220.
5. Campioni D, et al. Evidence for a role of TNF-related apoptosis-inducing ligand (TRAIL) in the anemia of myelodysplastic syndromes. Am J Pathol. 2005;166(2):557-563.
6. Zamai L, et al. TNF-related apoptosis-inducing ligand (TRAIL) as a negative regulator of normal human erythropoiesis. Blood. 2000;95(12):3716-3724.
7. Weiss G. Pathogenesis and treatment of anaemia of chronic disease. Blood Rev. 2002;16(2):87-96.
8. Andrews NC. Anemia of inflammation: the cytokine-hepcidin link. J Clin Invest. 2004;113(9):1251-1253.
9. Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood. 2003;102(3):783-788.
In a randomized, prospective trial, anemic chemotherapy-receiving patients received either darbepoetin alone or darbepoetin with intravenous ferric gluconate. The group that received the added ferric gluconate had a significantly higher rate of achieving objective criteria for anemia improvement. The iron infusions were associated with no observed toxicity.Subscribe Now for Access
You have reached your article limit for the month. We hope you found our articles both enjoyable and insightful. For information on new subscriptions, product trials, alternative billing arrangements or group and site discounts please call 800-688-2421. We look forward to having you as a long-term member of the Relias Media community.