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[ "Drug", "Design,", "Development", "and", "Therapy", "Dovepress", "open", "access", "to", "scientific", "and", "medical", "research", "O", "ri", "g", "i", "n", "al", "R", "esearch", "Open", "Access", "Full", "Text", "Article", "Intravenous", "iron", "monotherapy", "for", "the", "treatment", "of", "non-iron-deficiency", "anemia", "in", "cancer", "patients", "undergoing", "chemotherapy:", "a", "pilot", "study", "This", "article", "was", "published", "in", "the", "following", "Dove", "Press", "journal:", "Drug", "Design,", "Development", "and", "Therapy", "29", "August", "2013", "Number", "of", "times", "this", "article", "has", "been", "viewed", "Hikmat", "Abdel-Razeq", "1", "Salah", "Abbasi", "1", "Iyad", "Saadi", "1", "Rana", "Jaber", "2", "Hazem", "Abdelelah", "1", "Department", "of", "Internal", "Medicine,", "Department", "of", "Pharmacy,", "King", "Hussein", "Cancer", "Center,", "Amman,", "Jordan", "1", "2", "of", "patients", "and", "may", "have", "a", "negative", "effect", "on", "overall", "survival.", "Aims:", "To", "assess", "the", "efficacy", "and", "feasibility", "of", "intravenous", "iron", "therapy", "in", "patients", "with", "cancer", "who", "have", "non-iron-deficiency", "anemia", "and", "who", "are", "undergoing", "treatment", "with", "chemotherapy", "without", "the", "use", "of", "erythropoiesis-stimulating", "agents.", "Methods:", "Adult", "patients", "with", "solid", "cancers", "and", "non-iron-deficiency", "anemia", "were", "included.", "Ferric", "sucrose", "at", "a", "dose", "of", "200", "mg", "was", "given", "in", "short", "intravenous", "infusions", "weekly", "for", "a", "total", "of", "12", "weeks.", "Hemoglobin", "level", "was", "measured", "at", "baseline,", "every", "3", "weeks,", "and", "2", "weeks", "after", "the", "last", "iron", "infusion", "(week", "14).", "Adverse", "events", "related", "to", "intravenous", "iron", "were", "prospectively", "reported.", "Results:", "Of", "25", "patients", "included,", "19", "(76.0%)", "completed", "at", "least", "three", "iron", "infusions", "and", "14", "(56.0%)", "finished", "the", "planned", "12", "weeks", "of", "therapy.", "The", "mean", "hemoglobin", "level", "of", "the", "25", "patients", "at", "baseline", "was", "9.6", "g/dL", "(median,", "9.9", "g/dL;", "range,", "6.9", "g/dL­10.9", "g/dL).", "The", "mean", "change", "in", "hemoglobin", "level", "for", "the", "15", "patients", "who", "completed", "at", "least", "9", "treatments", "was", "1.7", "g/dL", "(median,", "1.1", "g/dL;", "range,", "−1.9", "g/dL", "to", "3.2", "g/dL);", "it", "reached", "2.1", "g/dL", "(median,", "1.3", "g/dL;", "range,", "−0.2", "g/dL", "to", "4.6", "g/dL;", "P", "=", "0.0007)", "for", "the", "14", "patients", "who", "completed", "all", "12", "weekly", "treatments.", "Five", "(20.0%)", "patients", "were", "transfused", "and", "considered", "as", "treatment", "failures.", "No", "treatment-related", "adverse", "events", "were", "reported.", "Conclusion:", "Intravenous", "iron", "treatment", "alone", "is", "safe", "and", "may", "reduce", "blood", "transfusion", "require-", "ments", "and", "improve", "hemoglobin", "level", "in", "patients", "with", "cancer", "who", "are", "undergoing", "anticancer", "therapy.", "Further", "randomized", "studies", "are", "needed", "to", "confirm", "these", "findings.", "Keywords:", "anemia,", "cancer,", "chemotherapy,", "intravenous", "iron,", "transfusion", "Introduction", "Correspondence:", "Hikmat", "Abdel-Razeq", "Department", "of", "Internal", "Medicine,", "Section", "of", "Hematology", "and", "Medical", "Oncology,", "King", "Hussein", "Cancer", "Center,", "Amman", "11194,", "Jordan", "Tel", "+962", "6", "530", "0460", "Email", "habdelrazeq@khcc.jo", "submit", "your", "manuscript", "|", "www.dovepress.com", "Dovepress", "http://dx.doi.org/10.2147/DDDT.S45674", "Anemia", "is", "a", "common", "complication", "of", "cancer", "and", "its", "treatment.", "It", "occurs", "in", "more", "than", "50%", "of", "patients", "and", "may", "reach", "90%", "in", "certain", "types", "of", "cancers,", "especially", "in", "patients", "undergoing", "chemotherapy", "and/or", "radiation", "therapy.", "1", "Anemia", "is", "defined", "as", "an", "inadequate", "circulating", "level", "of", "hemoglobin", "(Hb)", "(Hb", ",12", "g/dL)", "and", "may", "arise", "as", "a", "result", "of", "the", "underlying", "disease,", "bleeding,", "poor", "nutrition,", "chemotherapy,", "or", "radiation", "therapy.", "Preliminary", "studies", "suggest", "that", "survival", "and", "loco-regional", "control", "after", "radiation", "therapy,", "especially", "in", "head", "and", "neck", "cancers,", "may", "be", "compromised", "by", "anemia.", "2–4", "Drug", "Design,", "Development", "and", "Therapy", "2013:7", "939–944", "939", "©", "2013", "Abdel-Razeq", "et", "al,", "publisher", "and", "licensee", "Dove", "Medical", "Press", "Ltd.", "This", "is", "an", "Open", "Access", "article", "which", "permits", "unrestricted", "noncommercial", "use,", "provided", "the", "original", "work", "is", "properly", "cited.", "Dovepress", "Abdel-Razeq", "et", "al", "Anemia", "often", "worsens", "symptoms", "such", "as", "fatigue,", "weakness,", "and", "dyspnea,", "and", "thus", "may", "have", "a", "negative", "effect", "on", "quality", "of", "life", "(QOL)", "and", "performance", "status", "in", "patients", "with", "cancer.", "Thus,", "to", "improve", "physical", "functioning,", "QOL,", "and", "prognosis", "in", "patients", "with", "cancer,", "it", "would", "be", "reasonable", "to", "take", "a", "proactive", "approach", "in", "identifying", "populations", "who", "need", "treatment", "for", "cancer-associated", "anemia", "(CAA)", "and", "provide", "timely", "management.", "Blood", "transfusion", "is", "an", "effective", "way", "to", "replace", "depleted", "Hb", "within", "a", "short", "period,", "but", "the", "effect", "is,", "unfortunately,", "temporary", "and", "can", "cause", "serious", "adverse", "risks", "and", "increased", "mortality.", "In", "randomized", "clinical", "trials", "in", "patients", "with", "CAA,", "erythropoiesis-stimulating", "agents", "(ESAs)", "produced", "significant", "increases", "in", "Hb", "level,", "decreased", "transfusion", "requirements,", "and", "improved", "QOL.", "5–7", "However,", "30%–50%", "of", "patients", "do", "not", "respond", "to", "such", "agents.", "In", "addition,", "the", "use", "of", "ESAs", "often", "causes", "concern", "about", "severe", "adverse", "reactions.", "6,8", "In", "several", "studies,", "ESAs", "were", "found", "to", "shorten", "overall", "survival", "time,", "or", "time", "to", "tumor", "progression", "in", "patients", "whose", "Hb", "level", "reached", "more", "than", "12", "g/dL.", "These", "studies", "included", "patients", "with", "different", "primary", "cancers,", "such", "as", "breast,", "lung,", "head", "and", "neck,", "cervix,", "and", "lymphomas.", "9–11", "The", "lack", "of", "response", "to", "erythropoietin", "stimulation", "in", "patients", "with", "cancer", "is", "partly", "attributed", "to", "the", "functional", "iron", "defi-", "ciency", "state,", "in", "which", "the", "high", "rate", "of", "erythropoiesis", "exceeds", "the", "delivery", "of", "usable", "iron,", "despite", "adequate", "iron", "stores.", "12", "Absolute", "iron", "deficiency,", "in", "contrast,", "occurs", "when", "iron", "delivery", "is", "impaired", "because", "iron", "stores", "are", "depleted", "(serum", "ferritin,", ",100", "ng/mL;", "transferring", "saturation,", ",20%).", "13", "Hepcidin,", "a", "peptide", "hormone", "produced", "by", "the", "liver,", "is", "up-", "regulated", "in", "chronic", "inflammatory", "states", "including", "cancer.", "Hepcidin", "inhibits", "iron", "transport", "across", "cell", "membranes,", "thus", "decreasing", "the", "accessibility", "of", "stored", "iron", "and", "gastro-", "intestinal", "absorption", "of", "dietary", "iron,", "leading", "to", "an", "increased", "frequency", "of", "iron-restricted", "erythropoiesis.", "14–16", "Many", "randomized", "trials", "examined", "the", "role", "of", "intravenous", "(IV)", "iron", "in", "addition", "to", "ESAs", "in", "the", "treatment", "of", "anemia", "in", "patients", "with", "cancer.", "Many", "of", "these", "studies", "showed", "improve-", "ment", "in", "ESA", "response,", "time", "to", "maximal", "response,", "reduction", "in", "ESA", "dose,", "and", "improvement", "in", "QOL", "parameters", "(when", "measured)", "in", "favor", "of", "the", "combination", "over", "ESAs", "alone.", "The", "observed", "benefit", "was", "independent", "of", "baseline", "iron", "parameters.", "17–21", "One", "study", "found", "a", "36%", "reduction", "in", "the", "number", "of", "patients", "transfused.", "21", "This", "pilot", "study", "assessed", "the", "efficacy", "and", "feasibility", "of", "IV", "iron", "monotherapy", "in", "patients", "with", "cancer", "who", "have", "anemia", "and", "who", "are", "undergoing", "treatment", "with", "chemotherapy", "and/or", "radiation", "therapy", "without", "the", "use", "of", "ESAs.", "940", "submit", "your", "manuscript", "|", "www.dovepress.com", "Dovepress", "Patients", "and", "methods", "Study", "design", "Patients", "received", "the", "study", "treatment", "for", "12", "weeks", "followed", "by", "a", "4-week", "follow-up", "period.", "Eligible", "patients", "were", "at", "least", "18", "years", "old,", "about", "to", "start", "a", "cycle", "of", "chemotherapy", "and/or", "radiation", "therapy", "within", "1", "week", "of", "inclusion,", "and", "had", "a", "nonmyeloid", "malignancy,", "Hb", "levels", "of", "11.0", "g/dL", "or", "less,", "a", "life", "expectancy", "of", "more", "than", "24", "weeks,", "and", "an", "Eastern", "Cooperative", "Oncology", "Group", "performance", "status", "of", "0–2.", "Patients", "were", "also", "required", "to", "have", "a", "serum", "ferritin", "level", "of", "100", "ng/mL", "or", "higher", "or", "transferrin", "saturation", "(TSAT)", "levels", "of", "15%", "or", "higher", "and", "to", "have", "received", "no", "ESAs", "or", "IV", "iron", "therapy", "within", "30", "days", "and", "no", "oral", "iron", "therapy", "(27", "mg/day", "or", "more)", "within", "7", "days", "before", "enrollment.", "Patients", "were", "excluded", "for", "leukoerythroblastic", "features", "on", "blood", "film,", "hemolysis,", "gastrointestinal", "bleeding,", "folate", "or", "vitamin", "B12", "deficiency,", "elevated", "serum", "ferritin", "($900", "ng/mL)", "or", "transferrin", "saturation", "(TSAT)", "($35%)", "levels,", "pregnancy", "or", "lactation,", "liver", "dysfunction", "(grade", "2", "or", "higher", "based", "on", "National", "Cancer", "Institute", "Common", "Toxicity", "Criteria),", "renal", "dysfunction", "(serum", "creatinine", "levels", "$2.0", "mg/dL),", "active", "infection", "requiring", "systemic", "antibiotics,", "personal", "or", "fam-", "ily", "history", "of", "hemochromatosis,", "comorbidities", "precluding", "study", "participation,", "hypersensitivity", "to", "IV", "iron,", "red", "blood", "cell", "transfusion", "within", "the", "last", "2", "weeks,", "or", "any", "investiga-", "tional", "agent", "within", "30", "days", "before", "enrollment.", "Patients", "were", "not", "allowed", "to", "take", "any", "vitamin,", "mineral,", "or", "herbal", "supplements", "containing", "27", "mg", "or", "more", "of", "iron", "per", "day", "or", "100", "mg", "vitamin", "C", "per", "day", "during", "the", "study", "or", "follow-up", "period.", "Blood", "transfusions", "were", "permitted", "at", "the", "primary", "physician's", "discretion", "if", "Hb", "levels", "decreased", "to", "8", "g/dL", "or", "less,", "and", "such", "patients", "were", "considered", "treatment", "failures.", "Changes", "to", "the", "chemotherapy", "plan", "were", "permitted.", "Written", "informed", "consent", "was", "provided", "by", "all", "patients", "before", "study", "participation,", "and", "the", "protocol", "and", "supporting", "docu-", "ments", "were", "approved", "by", "the", "institutional", "review", "board", "of", "King", "Hussein", "Cancer", "Center.", "The", "study", "was", "conducted", "in", "accordance", "with", "the", "Declaration", "of", "Helsinki", "and", "Good", "Clinical", "Practice", "as", "contained", "in", "the", "US", "Code", "of", "Federal", "­Regulations", "that", "governs", "the", "protection", "of", "human", "subjects", "and", "the", "obligations", "of", "clinical", "investigators.", "Treatment", "Patients", "received", "200", "mg", "ferric", "hydroxide", "sucrose", "diluted", "in", "100", "mL", "normal", "saline", "and", "infused", "over", "the", "course", "of", "1", "hour", "weekly", "for", "a", "total", "of", "12", "weeks.", "The", "first", "dose", "was", "given", "during", "the", "first", "clinic", "visit", "(±4", "days", "from", "the", "initiation", "of", "chemotherapy", "or", "radiation", "therapy).", "TSAT", "was", "monitored,", "Drug", "Design,", "Development", "and", "Therapy", "2013:7", "Dovepress", "as", "protocol", "mandated", "withholding", "iron", "therapy", "when", "TSAT", "levels", "were", "higher", "than", "50%.", "Assessment", "At", "the", "first", "clinic", "visit", "(week", "1;", "baseline),", "a", "blood", "sample", "was", "obtained", "for", "laboratory", "assessments", "before", "the", "study", "treat-", "ment", "was", "started.", "Patients", "attended", "weekly", "clinic", "visits", "for", "treatment", "and", "assessment;", "and", "returned", "for", "follow-up", "visits", "at", "week", "14", "which", "included", "a", "complete", "physical", "examination.", "Complete", "blood", "count", "and", "TSAT", "were", "done", "every", "3", "weeks,", "and", "again", "2", "weeks", "after", "last", "treatment", "(week", "14).", "Complete", "laboratory", "assessment", "(Hb,", "serum", "ferritin,", "reticulocyte", "count,", "transferrin,", "TSAT,", "serum", "iron,", "total", "iron", "binding", "capacity,", "red", "cell", "indices,", "white", "blood", "cell", "count", "with", "differential,", "platelet", "count,", "and", "serum", "chemistries)", "were", "done", "at", "week", "1", "and", "at", "week", "14", "(end", "of", "study).", "Adverse", "events", "were", "assessed", "at", "each", "clinic", "visit", "until", "study", "completion", "or", "withdrawal,", "and", "during", "the", "30", "days", "after", "the", "last", "study", "treatment.", "Statistical", "analysis", "Hb", "test", "results", "were", "presented", "as", "mean,", "median,", "and", "range", "through", "all", "12", "weeks.", "The", "same", "was", "done", "to", "show", "the", "changes", "of", "Hb", "level", "every", "3", "weeks.", "Comparison", "between", "means", "of", "Hb", "level", "were", "made", "between", "the", "baseline", "Hb", "and", "Hb", "levels", "in", "the", "following", "weeks,", "using", "t-test.", "A", "significance", "criterion", "of", "P", ",", "0.05", "was", "used", "in", "the", "analysis.", "All", "analyses", "were", "performed", "using", "SAS", "version", "9.1", "(SAS", "Institute", "Inc,", "Cary,", "NC,", "USA).", "Intravenous", "iron", "therapy", "for", "cancer-associated", "anemia", "Table", "1", "Characteristics", "of", "the", "25", "patients", "with", "cancer", "who", "received", "intravenous", "iron", "therapy", "for", "non-iron-deficiency", "anemia", "Patient", "Sex", "Age,", "years", "Type", "of", "cancer", "Treatment", "1", "2", "3", "4", "5", "Male", "Female", "Female", "Female", "Female", "65", "48", "50", "41", "72", "Chemotherapy", "Chemotherapy", "Chemotherapy", "Chemotherapy", "Chemotherapy", "6", "7", "8", "9", "10", "Female", "Male", "Male", "Female", "Female", "57", "71", "62", "67", "70", "11", "12", "13", "14", "Female", "Male", "Male", "Female", "50", "56", "77", "27", "15", "16", "17", "18", "Female", "Female", "Female", "Male", "33", "61", "44", "54", "Hodgkin's", "lymphoma", "Neuroblastoma", "Breast", "cancer", "High", "grade", "sarcoma", "Non-small", "cell", "lung", "cancer", "Breast", "cancer", "Prostate", "cancer", "Leg", "leiomyosarcoma", "Breast", "cancer", "Endometrial", "adenocarcinoma", "Uterine", "sarcoma", "Bladder", "cancer", "Colon", "cancer", "Neuroendocrine", "tumor", "Osteosarcoma", "Breast", "cancer", "Ewing", "sarcoma", "Renal", "cell", "carcinoma", "19", "Female", "66", "20", "21", "22", "Female", "Female", "Male", "55", "53", "66", "23", "24", "Female", "Male", "69", "51", "25", "Female", "31", "Uterine", "leiomyosarcoma", "Breast", "cancer", "Gastric", "cancer", "Rectal", "cancer", "Breast", "cancer", "Desmoplastic", "round", "cell", "Breast", "cancer", "Chemotherapy", "Chemotherapy", "Chemotherapy", "Chemotherapy", "Chemotherapy", "Chemotherapy", "Chemotherapy", "Chemotherapy", "Chemotherapy", "Chemotherapy", "Chemotherapy", "Chemotherapy", "Sunitinib", "and", "radiotherapy", "Chemotherapy", "Chemotherapy", "Chemotherapy", "Chemotherapy", "and", "radiotherapy", "Chemotherapy", "Chemotherapy", "Chemotherapy", "Results", "Twenty-five", "patients", "(17", "women", "and", "8", "men)", "were", "eligible,", "consented,", "and", "included", "in", "the", "study;", "their", "mean", "age", "(standard", "deviation,", "[SD])", "was", "56", "years", "(13.0", "years).", "All", "patients", "were", "receiving", "active", "chemotherapy,", "and", "two", "were", "also", "receiving", "active", "radiotherapy.", "Chemotherapy", "varied", "according", "to", "the", "primary", "cancer", "and", "included", "anthracycline,", "platinum,", "tax-", "anes,", "cyclophosphamide,", "high-dose", "ifosfamide,", "vincristine,", "vinblastine,", "bleomycin,", "and", "others.", "Many", "of", "the", "included", "patients", "had", "their", "chemotherapy", "treatment", "as", "second-", "or", "third-line", "therapy.", "Patients'", "characteristics,", "including", "age,", "primary", "tumor,", "and", "active", "anticancer", "treatment", "are", "sum-", "marized", "in", "Table", "1.", "One", "patient", "died", "during", "the", "study", "from", "his", "tumor", "(after", "week", "2),", "and", "five", "patients", "withdrew", "from", "the", "study", "because", "of", "inconvenience", "(three", "after", "week", "3,", "and", "two", "after", "week", "4).", "Nineteen", "(76.0%)", "patients", "completed", "a", "minimum", "of", "three", "treat-", "ments,", "15", "(60.0%)", "completed", "nine", "treatments,", "and", "14", "(56.0%)", "completed", "all", "twelve", "planned", "weekly", "treatments.", "Drug", "Design,", "Development", "and", "Therapy", "2013:7", "As", "seen", "in", "Table", "2,", "the", "mean", "Hb", "level", "of", "the", "25", "patients", "at", "baseline", "was", "9.6", "g/dL", "(median,", "9.9", "g/dL;", "range,", "6.9", "g/dL–10.9", "g/dL).", "For", "the", "15", "patients", "who", "completed", "at", "least", "nine", "treatments,", "the", "mean", "change", "in", "their", "Hb", "level", "was", "1.7", "g/dL", "(median,", "1.1", "g/dL;", "range,", "−1.9", "g/dL", "to", "3.2", "g/dL).", "For", "the", "14", "patients", "who", "completed", "the", "whole", "treatment", "period", "(12", "weeks),", "the", "mean", "Hb", "level", "change", "was", "2.1", "g/dL", "Table", "2", "Means", "and", "medians", "of", "hemoglobin", "levels", "(g/dL)", "of", "the", "25", "patients", "with", "cancer", "Baseline", "(week", "1)", "Week", "3", "Week", "6", "Week", "9", "Week", "12", "Patients,", "n", "Mean", "g/dL", "(SD)", "Median", "g/dL", "(minimum,", "maximum)", "25", "19", "15", "15", "14", "9.6", "(1.06)", "10.5", "(1.28)", "10.5", "(1.12)", "11.3", "(1.37)", "11.7", "(1.22)", "9.9", "(6.90,10.9)", "10.7", "(6.80,12.1)", "10.5", "(9.10,12.0)", "11.55", "(8.90,13.2)", "11.35", "(9.80,13.7)", "Abbreviations:", "n,", "number;", "SD,", "standard", "deviation.", "submit", "your", "manuscript", "|", "www.dovepress.com", "Dovepress", "941", "Dovepress", "Abdel-Razeq", "et", "al", "(median,", "1.3", "g/dL;", "range,", "−0.2", "g/dL", "to", "4.6", "g/dL;", "P", "=", "0.0007).", "Eight", "(42.1%)", "of", "the", "19", "patients", "who", "completed", "at", "least", "three", "iron", "infusions", "had", "a", "more", "than", "1", "g/dL", "increase", "in", "their", "Hb", "level.", "Hemoglobin", "level", "changes", "for", "the", "14", "patients", "who", "completed", "twelve", "iron", "infusions", "are", "shown", "in", "Figure", "1.", "No", "IV", "iron-related", "adverse", "events", "were", "reported", "among", "patients", "during", "the", "study", "or", "the", "follow-up", "period.", "TSAT", "was", "monitored", "during", "the", "study", "period,", "and", "no", "patients", "had", "TSAT", "levels", "increase", "to", "more", "than", "50%.", "The", "highest", "ferritin", "level", "among", "patients", "who", "completed", "at", "least", "nine", "IV", "iron", "treatments", "was", "1,170", "ng/mL;", "the", "mean", "level", "at", "the", "end", "of", "study", "period", "for", "the", "whole", "group", "was", "379", "ng/mL.", "Five", "(20.0%)", "patients", "received", "blood", "transfusions", "and", "were", "considered", "treatment", "failures", "(three", "after", "week", "3,", "transfused", "at", "Hb", "levels", "of", "6.9", "g/dL,", "7.8", "g/dL,", "and", "5.4", "g/dL;", "one", "after", "week", "4,", "transfused", "at", "an", "Hb", "level", "of", "8.2", "g/dL;", "and", "one", "after", "week", "9,", "transfused", "at", "an", "Hb", "level", "of", "7.2", "g/dL).", "The", "decision", "for", "transfusion", "was", "made", "by", "the", "primary", "treating", "physician.", "Discussion", "Anemia", "is", "extremely", "common", "in", "patients", "with", "cancer.", "Low", "Hb", "levels", "are", "associated", "with", "diminished", "QOL", "and", "possibly", "decreased", "overall", "survival.", "2", "Successful", "treatment", "of", "anemia", "has", "undeniable", "benefits", "for", "patients,", "often", "yielding", "dramatic", "symptomatic", "improvement.", "Although", "the", "role", "of", "ESAs", "is", "well-established", "in", "treating", "CAA,", "big", "concerns", "were", "recently", "raised", "about", "the", "negative", "effect", "of", "ESAs", "on", "survival", "in", "some", "patients", "with", "cancer.", "9–11", "Concerns", "about", "the", "risk", "for", "throm-", "boembolism", "in", "patients", "with", "cancer", "with", "higher", "Hb", "levels", "who", "are", "receiving", "ESA", "were", "also", "addressed", "in", "many", "trials.", "22,23", "In", "addition,", "the", "possible", "immunosuppressive", "effects", "of", "blood", "product", "transfusions", "that", "may", "have", "relevance", "to", "neoplasia", "progression", "were", "addressed", "before.", "24,", "25", "In", "our", "pilot", "study,", "we", "tested", "the", "feasibility", "of", "using", "iron", "supplementation", "alone", "to", "treat", "anemia", "in", "patients", "with", "cancer", "who", "are", "undergoing", "chemotherapy", "without", "the", "use", "of", "ESAs", "or", "blood", "transfusion,", "which", "could", "be", "a", "valid", "alternative,", "especially", "for", "patients", "with", "curable", "cancers.", "Oral", "iron", "is", "easier", "to", "administer", "and", "relatively", "inexpen-", "sive,", "but", "low", "patient", "adherence,", "poor", "enteral", "absorption,", "and", "poor", "tolerance", "because", "of", "a", "wide", "range", "of", "troublesome", "gas-", "trointestinal", "adverse", "effects", "limit", "its", "overall", "effectiveness.", "26", "Anemia", "of", "chronic", "disease", "may", "occur", "in", "patients", "with", "cancer", "and", "is", "associated", "with", "an", "increase", "in", "hepcidin", "lev-", "els,", "which", "decreases", "oral", "iron", "absorption", "and", "bone", "marrow", "iron", "use,", "negating", "any", "possible", "effect", "of", "regular", "doses", "of", "oral", "iron.", "15", "IV", "iron", "therapy", "significantly", "improves", "response", "to", "epo-", "etin", "alfa", "when", "compared", "with", "oral", "iron", "or", "no", "iron", "in", "anemic", "patients", "with", "cancer", "who", "are", "receiving", "chemotherapy.", "17–21", "Oral", "iron", "supplements", "with", "ESAs", "showed", "no", "significant", "benefit", "over", "ESAs", "alone", "in", "treating", "CAA.", "21", "Sodium", "ferric", "gluconate", "and", "iron", "sucrose", "appear", "to", "have", "more", "favorable", "safety", "profiles", "over", "iron", "dextran.", "A", "large", "prospective", "safety", "comparison", "trial", "failed", "to", "show", "serious", "anaphylactoid", "reactions,", "27", "which", "is", "confirmed", "in", "our", "study,", "in", "which", "no", "patients", "developed", "reactions", "and", "no", "patients", "withdrew", "from", "the", "study", "because", "of", "adverse", "effects.", "Given", "that", "the", "mean", "Hb", "increase", "using", "ESAs", "with", "IV", "iron", "in", "one", "large", "controlled", "trial", "was", "2.4", "g/dL,", "21", "the", "results", "obtained", "in", "our", "study", "are", "clinically", "significant.", "These", "findings", "should", "be", "further", "confirmed", "and", "better", "assessed", "in", "larger", "studies,", "in", "which", "questions", "such", "as", "the", "optimal", "timing", "of", "IV", "iron", "therapy", "with", "respect", "to", "chemo-", "therapy", "and", "the", "optimal", "total", "dose", "of", "IV", "iron", "should", "be", "determined.", "16", "14", "12", "Hb", "level", "10", "8", "6", "4", "2", "0", "Baseline", "Week", "3", "Week", "6", "Week", "9", "Week", "12", "Figure", "1", "Hemoglobin", "(Hb)", "level", "changes", "for", "the", "14", "patients", "who", "completed", "12", "iron", "infusions", "(dotted", "lines)", "and", "their", "mean", "hemoglobin", "level", "change", "(solid", "line).", "942", "submit", "your", "manuscript", "|", "www.dovepress.com", "Dovepress", "Drug", "Design,", "Development", "and", "Therapy", "2013:7", "Dovepress", "The", "use", "of", "IV", "iron", "monotherapy", "was", "recently", "reviewed", "by", "a", "group", "in", "Germany", "that", "studied", "the", "use", "of", "ferric", "car-", "boxymaltose", "to", "replace", "ESA", "and", "blood", "transfusions", "as", "a", "treatment", "for", "CAA.", "Iron-deficient", "patients", "treated", "with", "ferric", "carboxymaltose", "alone", "(n", "=", "233)", "had", "a", "median", "of", "1.4", "g/dL", "increase", "in", "hemoglobin", "levels", "compared", "with", "those", "receiving", "additional", "treatment", "with", "ESAs", "(n", "=", "46;", "median,", "1.6", "g/dL).", "Our", "study,", "however,", "is", "peculiar", "in", "using", "iron", "therapy", "in", "a", "non-iron-deficiency", "state.", "28", "Iron", "overload", "after", "IV", "iron", "therapy,", "with", "potential", "con-", "cerns", "about", "the", "risk", "of", "developing", "secondary", "cancers", "and", "infection,", "might", "be", "raised.", "The", "highest", "serum", "ferritin", "level", "in", "the", "present", "study", "in", "patients", "who", "completed", "at", "least", "9", "weeks", "of", "IV", "iron", "therapy", "was", "1,170", "ng/mL.", "Most", "of", "the", "literature", "addressing", "cancer", "and", "infections", "in", "iron-overloaded", "patients", "comes", "from", "patients", "with", "hemochromatosis", "or", "patients", "who", "are", "undergoing", "hemodialysis.", "Published", "reviews", "report", "an", "increase", "in", "hepatocellular", "only", "in", "patients", "with", "hemochromatosis", "after", "they", "develop", "cirrhosis.", "29", "Similarly", "data", "supporting", "the", "association", "between", "IV", "iron", "therapy", "and", "higher", "infection", "rate", "are", "weak", "and", "not", "well-supported.", "30", "In", "fact,", "anemia", "itself", "is", "a", "risk", "factor", "for", "infections", "in", "patients", "receiving", "hemodialysis.", "31", "A", "multivariate", "analysis", "of", "associa-", "tions", "between", "iron", "and", "mortality", "in", "more", "than", "58,000", "patients", "receiving", "hemodialysis", "reported", "no", "increased", "death", "rate", "from", "serum", "ferritin", "levels", "as", "high", "as", "1,200", "ng/mL.", "30", "The", "increasing", "cost", "of", "therapy", "in", "patients", "with", "cancer", "is", "of", "grave", "concern,", "which", "could", "be", "an", "additional", "benefit", "of", "IV", "iron", "over", "the", "use", "of", "ESAs", "in", "such", "patients.", "To", "further", "address", "many", "of", "the", "questions", "raised,", "our", "team", "is", "planning", "a", "bigger", "trial", "for", "IV", "iron", "in", "patients", "with", "cancer", "who", "have", "anemia", "to", "confirm", "the", "results", "discussed", "in", "this", "pilot", "trial.", "In", "addition,", "we", "will", "be", "looking", "into", "predictors", "of", "response", "to", "IV", "iron,", "such", "as", "serum", "hepcidin", "level.", "Conclusion", "IV", "iron", "therapy", "alone", "is", "safe", "and", "may", "be", "effective", "in", "improv-", "ing", "Hb", "levels", "in", "patients", "with", "cancer", "who", "are", "undergoing", "active", "anticancer", "therapy.", "Further", "randomized", "trials", "are", "needed", "to", "address", "many", "of", "the", "questions", "raised", "in", "our", "pilot", "study.", "Disclosure", "The", "authors", "report", "no", "conflicts", "of", "interest", "in", "this", "work.", "References", "1.", "Henry", "DH.", "Supplemental", "iron:", "a", "key", "to", "optimizing", "the", "response", "of", "cancer-related", "anemia", "to", "rHuEPO?", "Oncologist.", "1993(4):275–278.", "Drug", "Design,", "Development", "and", "Therapy", "2013:7", "Intravenous", "iron", "therapy", "for", "cancer-associated", "anemia", "2.", "Knight", "K,", "Wade", "S,", "Balducci", "L.", "Prevalence", "and", "outcomes", "of", "anemia", "in", "cancer:", "a", "systematic", "review", "of", "the", "literature.", "Am", "J", "Med.", "2004;", "116(Suppl", "7A):11S–26S.", "3.", "Cella", "D,", "Kallich", "J,", "McDermott", "A,", "Xu", "X.", "The", "longitudinal", "relationship", "of", "hemoglobin,", "fatigue", "and", "quality", "of", "life", "in", "anemic", "cancer", "patients:", "results", "from", "five", "randomized", "clinical", "trials.", "Ann", "Oncol.", "2004;15(6):", "979–986.", "4.", "Harrison", "LB,", "Chadha", "M,", "Hill", "RJ,", "Hu", "K,", "Shasha", "D.", "Impact", "of", "tumor", "hypoxia", "and", "anemia", "on", "radiation", "therapy", "outcomes.", "Oncologist.", "2007(6):", "492–508.", "5.", "Demetri", "GD,", "Kris", "M,", "Wade", "J,", "Degos", "L,", "Cella", "D.", "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.", "6.", "Gabrilove", "JL,", "Cleeland", "CS,", "Livingston", "RB,", "Sarokhan", "B,", "Winer", "E,", "Einhorn", "LH.", "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.", "2001;19(11):", "2875–2882.", "7.", "Littlewood", "TJ,", "Bajetta", "E,", "Nortier", "JW,", "Vercammen", "E,", "Rapoport", "B;", "Epoetin", "Alfa", "Study", "Group.", "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.", "2001;19(11):2865–2874.", "8.", "Glaspy", "J,", "Bukowski", "R,", "Steinberg", "D,", "Taylor", "C,", "Tchekmedyian", "S,", "Vadhan-Raj", "S.", "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.", "1997;15(3):1218–1234.", "9.", "Henke", "M,", "Laszig", "R,", "Rübe", "C,", "et", "al.", "Erythropoietin", "to", "treat", "head", "and", "neck", "cancer", "patients", "with", "anaemia", "undergoing", "radiotherapy:", "randomised,", "double-blind,", "placebo-controlled", "trial.", "Lancet.", "2003;362(9392):", "1255–1260.", "10.", "Leyland-Jones", "B;", "BEST", "Investigators", "and", "Study", "Group.", "Breast", "can-", "cer", "trial", "with", "erythropoietin", "terminated", "unexpectedly.", "Lancet", "Oncol.", "2003;4(8):459–460.", "11.", "Bohlius", "J,", "Langensiepen", "S,", "Schwarzer", "G,", "et", "al.", "Recombinant", "human", "erythropoietin", "and", "overall", "survival", "in", "cancer", "patients:", "results", "of", "a", "comprehensive", "meta-analysis.", "J", "Natl", "Cancer", "Inst.", "2005;97(7):", "489–498.", "12.", "Macdougall", "IC.", "Strategies", "for", "iron", "supplementation:", "oral", "versus", "intra-", "venous.", "Kidney", "Int", "Suppl.", "1999;69:S61-S66.", "13.", "KDOQI.", "KDOQI", "Clinical", "Practice", "Guideline", "and", "Clinical", "Practice", "Recommendations", "for", "anemia", "in", "chronic", "kidney", "disease:", "2007", "update", "of", "hemoglobin", "target.", "Am", "J", "Kidney", "Dis.", "2007;50(3):471–530.", "14.", "Cazzola", "M,", "Mercuriali", "F,", "Brugnara", "C.", "Use", "of", "recombinant", "human", "erythropoietin", "outside", "the", "setting", "of", "uremia.", "Blood.", "1997;89(12):", "4248–4267.", "15.", "Weiss", "G,", "Goodnough", "LT.", "Anemia", "of", "chronic", "disease.", "N", "Engl", "J", "Med.", "2005;352(10):1011–1023.", "16.", "Andrews", "NC.", "Anemia", "of", "inflammation:", "the", "cytokine-hepcidin", "link.", "J", "Clin", "Invest.", "2004;113(9):1251–1253.", "17.", "Hedenus", "M,", "Birgegård", "G,", "Näsman", "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.", "2007;21(4):", "627–632.", "18.", "Pedrazzoli", "P,", "Farris", "A,", "Del", "Prete", "S,", "et", "al.", "Randomized", "trial", "of", "intravenous", "iron", "supplementation", "in", "patients", "with", "chemotherapy-related", "anemia", "without", "iron", "deficiency", "treated", "with", "darbepoetin", "alpha.", "J", "Clin", "Oncol.", "2008;26(10):1619–1625.", "19.", "Bastit", "L,", "Vandebroek", "A,", "Altintas", "S,", "et", "al.", "Randomized,", "multicenter,", "controlled", "trial", "comparing", "the", "efficacy", "and", "safety", "of", "darbepoetin", "alpha", "administered", "every", "3", "weeks", "with", "or", "without", "intravenous", "iron", "in", "patients", "with", "chemotherapy-induced", "anemia.", "J", "Clin", "Oncol.", "2008;26(10):", "1611–1618.", "submit", "your", "manuscript", "|", "www.dovepress.com", "Dovepress", "943", "Dovepress", "Abdel-Razeq", "et", "al", "20.", "Auerbach", "M,", "Silberstein", "PT,", "Webb", "RT,", "et", "al.", "Darbepoetin", "alfa", "300", "or", "500", "µg", "once", "every", "3", "weeks", "with", "or", "without", "intravenous", "iron", "in", "patients", "with", "chemotherapy-induced", "anemia.", "Am", "J", "Hematol.", "2010;85(9):", "655–663.", "21.", "Henry", "DH,", "Dahl", "NV,", "Auerbach", "M,", "Tchekmedyian", "S,", "Laufman", "LR.", "Intravenous", "ferric", "gluconate", "significantly", "improves", "response", "to", "epoetin", "alfa", "versus", "oral", "iron", "or", "no", "iron", "in", "anemic", "patients", "with", "cancer", "receiving", "chemotherapy.", "Oncologist.", "2007;12(2):231–242.", "22.", "Steensma", "DP.", "Management", "of", "anemia", "in", "patients", "with", "cancer.", "Curr", "Oncol", "Rep.", "2004;6(4):297–304.", "23.", "Wun", "T,", "Law", "L,", "Harvey", "D,", "Sieracki", "B,", "Scudder", "SA,", "Ryu", "JK.", "Increased", "incidence", "of", "symptomatic", "venous", "thrombosis", "in", "patients", "with", "cervical", "carcinoma", "treated", "with", "concurrent", "chemotherapy,", "radiation,", "and", "erythropoietin.", "Cancer.", "2003;98(7):1514–1520.", "24.", "Shao", "W,", "Edelman", "LS,", "Sullivan", "DJ,", "Nelson", "EW,", "Shelby", "J.", "Long-term", "cytokine", "alterations", "following", "allogeneic", "blood", "transfusion.", "J", "Investig", "Med.", "1998;46(4):161–167.", "25.", "Santin", "AD,", "Bellone", "S,", "Parrish", "RS,", "et", "al.", "Influence", "of", "allogeneic", "blood", "transfusion", "on", "clinical", "outcome", "during", "radiotherapy", "for", "cancer", "of", "the", "uterine", "cervix.", "Gynecol", "Obstet", "Invest.", "2003;56(1):28–34.", "26.", "Fishbane", "S,", "Frei", "GL,", "Maesaka", "J.", "Reduction", "in", "recombinant", "human", "erythropoietin", "doses", "by", "the", "use", "of", "chronic", "intravenous", "iron", "supplementation.", "Am", "J", "Kidney", "Dis.", "1995;26(1):41–46.", "27.", "Fishbane", "S.", "Safety", "in", "iron", "management.", "Am", "J", "Kidney", "Dis.", "2003;", "41(Suppl", "5):18–26.", "28.", "Steinmetz", "T,", "Tschechne", "B,", "Harlin", "O,", "et", "al.", "Clinical", "experience", "with", "ferric", "carboxymaltose", "in", "the", "treatment", "of", "cancer-", "and", "chemotherapy-", "associated", "anaemia.", "Ann", "Oncol.", "2013;24(2):475–482.", "29.", "Kowdley", "KV.", "Iron,", "hemochromatosis,", "and", "hepatocellular", "carcinoma.", "Gastroenterology.", "2004;127(5", "Suppl", "1):S79–S86.", "30.", "Besarab", "A,", "Frinak", "S,", "Yee", "J.", "An", "indistinct", "balance:", "the", "safety", "and", "efficacy", "of", "parenteral", "iron", "therapy.", "J", "Am", "Soc", "Nephrol.", "1999;10(9):2029–2043.", "31.", "Kalantar-Zadeh", "K,", "Regidor", "DL,", "McAllister", "CJ,", "Michael", "B,", "Warnock", "DG.", "Time-dependent", "associations", "between", "iron", "and", "mortality", "in", "hemodialysis", "patients.", "J", "Am", "Soc", "Nephrol.", "2005;16(10):", "3070–3080.", "Dovepress", "Drug", "Design,", "Development", "and", "Therapy", "Publish", "your", "work", "in", "this", "journal", "Drug", "Design,", "Development", "and", "Therapy", "is", "an", "international,", "peer-", "reviewed", "open-access", "journal", "that", "spans", "the", "spectrum", "of", "drug", "design", "and", "development", "through", "to", "clinical", "applications.", "Clinical", "outcomes,", "patient", "safety,", "and", "programs", "for", "the", "development", "and", "effective,", "safe,", "and", "sustained", "use", "of", "medicines", "are", "a", "feature", "of", "the", "journal,", "which", "has", "also", "been", "accepted", "for", "indexing", "on", "PubMed", "Central.", "The", "manu-", "script", "management", "system", "is", "completely", "online", "and", "includes", "a", "very", "quick", "and", "fair", "peer-review", "system,", "which", "is", "all", "easy", "to", "use.", "Visit", "http://www.dovepress.com/testimonials.php", "to", "read", "real", "quotes", "from", "published", "authors.", "Submit", "your", "manuscript", "here:", "http://www.dovepress.com/drug-design-development-and-therapy-journal", "944", "submit", "your", "manuscript", "|", "www.dovepress.com", "Dovepress", "Drug", "Design,", "Development", "and", "Therapy", "2013:7" ]

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