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Chemotherapy Versus Oral Iron or No Iron in Anemic Patients with Cancer Receiving Intravenous Ferric Gluconate Significantly Improves Response to Epoetin Alfa
| Content Provider | Semantic Scholar |
|---|---|
| Author | David Henry Naomi Bechdolt, Burley V. Dahl Auerbach, Michael Tchekmedyian, Simon |
| Copyright Year | 2007 |
| Abstract | Purpose. To evaluate the safety and efficacy of intravenous (IV) sodium ferric gluconate complex (FG), oral ferrous sulfate, or no iron to increase hemoglobin (Hb) in anemic cancer patients receiving chemotherapy and epoetin alfa. Patients and Methods. In this open-label, multicenter trial, 187 patients with chemotherapy-related anemia (Hb <11 g/dl; serum ferritin >100 ng/ml or transferrin saturation >15%) scheduled to receive chemotherapy and epoetin alfa (40,000 U subcutaneously weekly) were randomized to 8 weeks of 125 mg of IV FG weekly, 325 mg of oral ferrous sulfate three times daily, or no iron. The primary outcome was a change in Hb from baseline to endpoint, first whole-blood or red blood cell transfusion, or study withdrawal. Results. One hundred twenty-nine patients were evaluable for efficacy (FG, n 41; oral iron, n 44; no iron, n 44). Mean increase in Hb was 2.4 g/dl (95% confidence interval [CI], 2.1–2.7) for FG (p .0092 vs. oral iron; p .0044 vs. no iron), 1.6 g/dl (95% CI, 1.1– 2.1) for oral iron (p .7695 vs. no iron), and 1.5 g/dl (95% CI, 1.1–1.9) for no iron. Hb response (increase >2 g/dl) was 73% for FG (p .0099 vs. oral iron; p .0029 vs. no iron), 46% for oral iron (p .6687 vs. no iron), and 41% for no iron. FG was well tolerated. Conclusion. For cancer patients with chemotherapyrelated anemia receiving epoetin alfa, FG produces a significantly greater increase in Hb and Hb response compared with oral iron or no iron, supporting more aggressive treatment with IV iron supplementation for these patients. The Oncologist 2007;12:231–242 INTRODUCTION Anemia is a common complication of cancer and its treatment. The prevalence of anemia (hemoglobin [Hb] 12 g/dl) approaches 50% in patients with cancer and may increase to more than 90% in patients with certain types of cancer and in those undergoing chemotherapy or radiation therapy [1]. Recombinant human erythropoietin (epoetin alfa) is an effective treatment for chemotherapy-related anemia. In multicenter, randomized clinical trials and community-based studies in patients with chemotherapy-related anemia, epoetin alfa produced significant increases in Hb levels, significant decreases in transfusion requirements, and significant improvements in quality of life [2–5]. However, approximately 30%–50% of patients reCorrespondence: David H. Henry, M.D., Joan Karnell Cancer Center, Pennsylvania Hospital, 230 West Washington Square, Philadelphia, PA 19106, USA. Telephone: 215-829-6311; Fax: 215-829-6104; e-mail: dhhenry@juno.com Received June 20, 2006; accepted for publication October 7, 2006. ©AlphaMed Press 1083-7159/2007/$30.00/0 doi: 10.1634/theoncologist.12-2-231 The Oncologist Symptom Management and Supportive Care The Oncologist 2007;12:231–242 www.TheOncologist.com by gest on M arch 5, 2014 http://thologist.alpham edpss.org/ D ow nladed from ceiving epoetin alfa therapy for chemotherapy-related anemia do not achieve a clinically meaningful hematologic response [2–5]. The lack of response to erythropoietic therapy is poorly understood but has been attributed to a functional iron deficiency in that the high rate of erythropoietic agent-induced erythropoiesis exceeds the delivery of usable iron, despite adequate iron stores [6]. Absolute iron deficiency, in contrast, occurs when iron delivery is impaired because iron stores are depleted (in healthy subjects, serum ferritin 100 ng/ml and transferrin saturation [TSAT] 20%) [7]. Patients with functional iron deficiency require supplementation of usable iron to optimize response to erythropoietic therapy, which might not be accomplished with oral iron [7]. In a recent prospective, open-label trial, patients receiving epoetin alfa for chemotherapy-related anemia who were treated with intravenous (IV) iron dextran had a significantly greater Hb response compared with those receiving oral iron [8]. Sodium ferric gluconate complex (FG) (Ferrlecit; Watson Pharma, Inc., Morristown, NJ, http://www. watsonpharm.com) is safe and effective in optimizing response to erythropoietic therapy in patients undergoing hemodialysis [9–11]. However, its efficacy in patients with chemotherapy-related anemia receiving erythropoietic therapy has not been well characterized. This 12-week, multicenter, randomized trial compared the efficacy of FG, oral iron, and no iron in increasing Hb levels in iron-replete patients with chemotherapy-related anemia receiving epoetin alfa. PATIENTS AND METHODS Study Design and Patients This was an open-label, randomized, controlled, multicenter, prospective trial. Randomization was conducted centrally to avoid selection bias. Patients received study treatment for 8 weeks followed by a 4-week follow-up period. Eligible patients were at least 18 years old, were about to start a cycle of chemotherapy, and had a nonmyeloid malignancy, Hb 11 g/dl, a life expectancy 24 weeks, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2. Patients were also required to have a serum ferritin level 100 ng/ml or TSAT 15% and to have received no epoetin alfa or IV iron therapy within 30 days and no oral iron therapy ( 27 mg/day) within 7 days before enrollment. Patients were excluded for hemolysis, gastrointestinal bleeding, folate or vitamin B12 deficiency, elevated serum ferritin ( 900 ng/ml) or TSAT ( 35%), pregnancy or lactation, liver dysfunction (grade 2 based on National Cancer Institute Common Toxicity Criteria), renal dysfunction (serum creatinine 2.0 mg/dl), active infection requiring systemic antibiotics, personal or family history of hemochromatosis, comorbidities precluding study participation, hypersensitivity to FG or its components, contraindication to epoetin alfa therapy, red blood cell (RBC) transfusion within the past 2 weeks, or any investigational agent within 30 days before enrollment. Patients were not allowed to take any vitamin, mineral, or herbal supplements containing 27 mg/day of iron or 100 mg/day of vitamin C during the study or follow-up. Blood transfusions were permitted at the investigator’s discretion if Hb decreased to 8 g/dl. Changes to the chemotherapy plan were permitted. Written informed consent was provided by all patients before study participation, and the protocol and supporting documents were approved by the institutional review board at each participating institution. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice as contained in the U.S. Code of Federal Regulations that governs the protection of human subjects and the obligations of clinical investigators. Treatment Eligible patients were randomized in a 1:1:1 ratio to 8 weeks of treatment with 125 mg of FG intravenously once weekly (q.w.), 325 mg of ferrous sulfate (tablets or liquid if clinically indicated) orally three times daily (t.i.d.), or no iron treatment (Fig. 1). FG was either diluted in 100 ml of normal saline and infused over 1 hour or administered undiluted as an IV push over 10 minutes at the discretion of the investigator. During the first clinic visit ( 4 days from the initiation of the chemotherapy cycle), patients randomized to FG received their first 125-mg dose, and patients randomized to oral iron received—and were instructed to immediately begin taking—their medication. Oral iron was dispensed weekly, with adherence monitored via tablet count. If TSAT increased to 50%, FG was withheld until TSAT decreased to 50% and then restarted at the original dose. Epoetin alfa treatment was initiated at the first clinic visit and was continued for 12 weeks. The initial dose was 40,000 U administered subcutaneously q.w. If after 4 weeks Hb did not increase by 1 g/dl, the dose was increased to 60,000 U q.w. If Hb increased 1.3 g/dl in any 2-week period, the dose was reduced by 25%. If Hb increased to 13 g/dl, epoetin alfa was discontinued until Hb decreased to 12 g/dl and then resumed at 75% of the previous dose. Assessments Within 7 days before the start of a chemotherapy cycle, eligible patients underwent a comprehensive assessment, in232 Iron and Epoetin for Chemotherapy-Related Anemia by gest on M arch 5, 2014 http://thologist.alpham edpss.org/ D ow nladed from cluding medical and oncologic history, physical examination, vital signs, laboratory assessment, fecal occult blood test, and ECOG performance status assessment. Laboratory assessments included Hb, serum ferritin, reticulocyte Hb content (CHr), reticulocyte count, transferrin, TSAT, serum iron, total iron binding capacity, percentage of hypochromic RBCs (%HYPO), red cell indices, white blood cell count with differential, platelet indices, and serum chemistries. At the first clinic visit (week 1; baseline), a blood sample was obtained for laboratory assessments, vital signs and concomitant medications were recorded, and study treatment commenced. Patients attended weekly clinic visits for treatment and assessment and returned for follow-up visits at weeks 10 and 12, which included a complete physical examination. Adverse events were assessed at each clinic visit until study completion or withdrawal and during the 30 days following the last study-related procedure. Statistical Analysis Results from previous clinical investigations were used to determine the sample size, based on using two-tailed t tests to detect a significant difference in change in Hb from baseline between treatment groups while using a Bonferroni correction to control the maximum experiment-wise type I error rate ( .05). Using this adjustment for two comparisons (i.e., FG to no iron and FG to oral iron), the significance level for each comparison is .025. On the basis of previous clinical investigations in hemodialysis patients, it was anticipated that FG would have a 1.00-g/dl greater mean change in Hb from baseline than would the no-iron comparator and that the expected standard deviation would be 1.50. Using these calculations, a sample size of 45 patients per group was needed to detect a significant dif |
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| Alternate Webpage(s) | http://citeseerx.ist.psu.edu/viewdoc/download;jsessionid=A03B1675CB1E00FF5BF59D36A7844835?doi=10.1.1.534.3063&rep=rep1&type=pdf |
| Language | English |
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| Content Type | Text |
| Resource Type | Article |
