Patients with cancer may have an absolute or functional iron deficiency as a result of their disease or its treatment. These conditions can lead to an insufficient supply of iron for incorporation into erythrocytes during supportive care with erythropoiesis-stimulating proteins for chemotherapy. The use of supplemental iron therapy is well established in patients with chronic kidney disease and anemia, but less well studied in the oncology/hematology setting. Furthermore, the use of oral iron formulations in patients with cancer and anemia is limited by poor absorption in the duodenum, arduous dosing requirements (three times a day), and a high likelihood of gastrointestinal side effects. Two recent studies have shown that intravenous (IV) iron (iron dextran or ferric gluconate) increases the hematopoietic response rates in cancer patients who were receiving chemotherapy and treated with epoetin alfa (Procrit) for anemia. The effects on hemoglobin levels and measures of iron metabolism were notably greater with IV iron formulations than with oral iron formulations. The results from several ongoing trials of IV iron in patients treated with epoetin alfa or darbepoetin alfa (Aranesp) for chemotherapy-induced anemia should lead to a greater understanding of the role of IV iron supplementation in improving the hematopoietic responses in these patients.
Use of IV Iron in Patients Treated With Chemotherapy
Two recent open-label randomized controlled studies evaluated the effects of iron therapy and its optimal administration route in the oncology/hematology setting.[31,32] In the first study, 157 patients with a histologic diagnosis of cancer, Hgb levels of 10.5 g/dL or less, and serum ferritin levels of 200 ng/mL or less (or ≤ 300 ng/mL with a TSAT ≤ 19%) were randomized to no iron, oral iron (ferrous sulfate) 325 mg twice a day, iron dextran 100 mg IV bolus at each visit to the calculated dose for iron replacement (based on a desired Hgb level of 14 g/dL), or a TDI of iron dextran. All patients were being treated with chemotherapy and with epoetin alfa 40,000 U once a week for their anemia, with no dose adjustments permitted.
After 6 weeks of therapy, there were significant increases in Hgb levels in all treatment groups in the intent-to-treat analysis (P < .001), with a clear greater benefit in the IV bolus and TDI groups (both P < .05 vs no iron and oral iron). Treatment group differences in Hgb response appeared to be independent of the pretreatment TSAT (< 15% vs ≥ 15%). Furthermore, there was a hematopoietic response (defined as an increase of ≥ 2g/dL in the Hgb level or an Hgb level ≥ 12 g/dL in the absence of red blood cell transfusions during the study) in significantly more patients treated with IV bolus or TDI iron than in those treated with no iron or oral iron (P < .01; Figure 1). There was also a trend toward a greater response in patients with a pretreatment ferritin level of less than 100 ng/mL than in those with a level of 100 ng/mL or higher.
Assessment of quality of life with the Linear Analog Scale Assessment showed improvements in energy, ability to perform daily activities, and overall quality of life in those treated with IV and TDI iron, no changes in those treated with oral iron, and decreases in those not treated with iron. Analysis of pooled data from all groups showed significant correlations between increases in Hgb levels and increases in energy (r = .32; P < .001), ability to perform daily activities (r = .30; P < .001), and overall quality of life (r = 0.31; P < .001). Seven possibly drug-related adverse events were reported (three each in the IV and TDI iron groups and one in the oral iron group), none of which necessitated discontinuation of treatment.
In the second study, 187 patients who were being treated with chemotherapy for nonmyeloid malignancies and who had Hgb levels less than 11 g/dL and serum ferritin levels greater than 100 ng/mL or TSAT greater than 15% were randomized to no iron, oral iron (ferrous sulfate) 325 mg three times a day, or IV ferric gluconate 125 mg once a week for 8 weeks. All patients were treated with epoetin alfa 40,000 U once a week, with dose adjustments permitted after 4 weeks. In the assessable population (n = 129; intent-to-treat population with no protocol deviations who completed ≥ 7 weeks of the study and were given ≥ 4 doses of epoetin alfa and ≥ 7 doses of ferric gluconate or ≥ 67% oral iron), there was an increase in Hgb levels of 2 g/dL or more in significantly more patients treated with IV ferric gluconate (73%) than in those treated with oral iron (46%; P < .01) and those not treated with iron (41%; P = .003). This benefit was greatest in patients with a pretreatment TSAT less than 20%.
Furthermore, the improvements in Hgb and ferritin levels and reticulocyte Hgb content were greater in the patients treated with IV ferric gluconate than in those treated with oral iron or no iron (Table 2). The TSAT values decreased in all treatment groups, suggesting that the dose of iron may have been insufficient even in the IV group. Drug-related adverse events were reported in 19 (31%) of 61 patients in the oral iron group, 4 of whom discontinued treatment, and in 8 (13%) of 63 patients in the IV ferric gluconate group, 2 of whom withdrew from treatment.
The findings in these two studies clearly suggest that using IV iron therapy increases the hematopoietic responses to epoetin alfa in cancer patients with anemia who are receiving chemotherapy, possibly by increasing the iron supply available for epoetin alfa-stimulated erythropoiesis.
Functional iron deficiency as a consequence of the underlying inflammatory component of cancer may translate clinically into a diminished response to erythropoietic therapy in patients receiving chemotherapy. Data suggest that IV iron improves measures of hematopoiesis and iron metabolism in patients with cancer and anemia who are treated with chemotherapy and epoetin alfa. Several other studies of IV iron in cancer patients treated with epoetin alfa or darbepoetin alfa for chemotherapy-induced anemia are underway, and as both drugs act on the same receptor with the same mechanism of action, it is expected that the iron response will be similar for both drugs in these studies. The study results should aid in understanding the role of IV iron supplementation in improving hematopoietic responses and quality of life in patients with cancer. Questions remain to be answered about the monitoring, timing, and cost-effectiveness of iron supplementation, as well as the potential for the use of iron in lowering ESP dosing requirements.
Financial Disclosure: Dr. Henry receives research grants from Watson Pharmaceuticals, Inc., and Ortho Biotech.
1. Groopman JE, Itri LM: Chemotherapy-induced anemia in adults: Incidence and treatment [erratum in J Natl Cancer Inst 92:497, 2000]. J Natl Cancer Inst 91:1616-1634, 1999.
2. Weiss G, Goodnough LT: Anemia of chronic disease. N Engl J Med 352:1011-1023, 2005.
3. 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.
4. 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.
5. 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.
6. 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 19:2865-2874, 2001.
7. 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 122:394-403, 2003.
8. 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.
9. 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 95:888-895, 2002.
10. Kotasek D, Steger G, Faught W, et al: Darbepoetin alfa administered every 3 weeks alleviates anaemia in patients with solid tumours receiving chemotherapy: Results of a double-blind, placebo-controlled, randomised study. Eur J Cancer 39:2026-2034, 2003.
11. 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.
12. Vadhan-Raj S, Mirtsching B, Charu V, et al: Assessment of hematologic effects and fatigue in cancer patients with chemotherapy-induced anemia given darbepoetin alfa every two weeks. J Support Oncol 1:131-138, 2001.
13. 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.
14. Patton J, Reeves T, Wallace J: Effectiveness of darbepoetin alfa versus epoetin alfa in patients with chemotherapy-induced anemia treated in clinical practice. Oncologist 9:451-458, 2004.
15. Berndt E, Kallich J, McDermott A, et al: Reductions in anaemia and fatigue are associated with improvements in productivity in cancer patients receiving chemotherapy. Pharmacoeconomics 23:505-514, 2005.
16. Henry DH, Dahl NV, Ferrlecit Cancer Study Group: Iron and B12 parameters in anemic cancer patients on chemotherapy presenting for epoetin alpha (EPO) therapy (abstract 747). Proc Am Soc Clin Oncol 23:747, 2004.
17. National Kidney Foundation: K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease: Update 2000 [erratum in Am J Kidney Dis 38:442, 2001]. Am J Kidney Dis 37(1 suppl 1):S182-S238, 2001.
18. Henry DH: Supplemental iron: A key to optimizing the response of cancer-related anemia to rHuEPO? Oncologist 3:275-278, 1998.
19. Kis AM, Carnes M: Detecting iron deficiency in anemic patients with concomitant medical problems. J Gen Intern Med 13:455-461, 1998.
20. Thomas C, Thomas L: Biochemical markers and hematologic indices in the diagnosis of functional iron deficiency. Clin Chem 48:1066-1076, 2002.
21. Suominen P, Punnonen K, Rajamaki A, et al: Serum transferrin receptor and transferrin receptor-ferritin index identify healthy subjects with subclinical iron deficits. Blood 92:2934-2939, 1998.
22. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Cancer and treatment-related anemia. Version 2.2005. Available at: http://www.nccn.org. Accessed August 22, 2005.
23. 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.
24. Nemeth E, Rivera S, Gabayan V, et al: IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest 113:1271-1276, 2004.
25. Andrews NC: Anemia of inflammation: The cytokine-hepcidin link. J Clin Invest 113:1251-1253, 2004.
26. Silverstein SB, Rodgers GM: Parenteral iron therapy options. Am J Hematol 76:74-78, 2004.
27. INFeD (iron dextran injection, USP) prescribing information. Morristown, NJ, Watson Pharma, 2001.
28. Parkkinen J, von Bonsdorff L, Peltonen S, et al: Catalytically active iron and bacterial growth in serum of haemodialysis patients after i.v. iron-saccharate administration. Nephrol Dial Transplant 15:1827-1834, 2000.
29. Danielson BG, Salmonson T, Derendorf H, et al: Pharmacokinetics of iron(III)-hydroxide sucrose complex after a single intravenous dose in healthy volunteers. Arzneimittelforschung 46:615-621, 1996.
30. Seligman PA, Dahl NV, Strobos J, et al: Single-dose pharmacokinetics of sodium ferric gluconate complex in iron-deficient subjects. Pharmacotherapy 24:574-583, 2004.
31. 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.
32. Henry DH, Dahl NV, Auerbach M, et al: Intravenous ferric gluconate (FG) for increasing response to epoetin (EPO) in patients with anemia of cancer chemotherapy-Results of a multicenter, randomized trial (abstract 3996). Blood 104:10b, 2004.