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      Treatment of anemia in cancer patients undergoing chemotherapy with intravenous ferric carboxymaltose without erythropoiesis-stimulating agents

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          Abstract

          Background:

          Anemia is commonly encountered in cancer patients receiving active chemotherapy. Due to adverse events and presumed negative effects on disease-progression and survival, erythropoiesis-stimulating agents are not frequently used. In this study, we assess the efficacy and safety of intravenous ferric carboxymaltose (FCM) to treat cancer-induced anemia (CIA).

          Patients and Methods:

          We recruited adult cancer patients on active chemotherapy with a hemoglobin (Hb) level ⩽11.0 g/dL. Based on serum ferritin (sFr) and transferrin saturation (TSAT), patients were divided into 3 groups: group I (absolute iron deficiency, n = 26) with sFr < 30 ng/mL and TSAT < 20%; group II (functional iron deficiency, n = 24) with sFr 30–800 ng/mL and TSAT < 20%; and patients with TSAT ⩾ 20% were placed in group III as “others” ( n = 34). All patients were treated with intravenous FCM. Serum hepcidin and C-reactive protein were used as biomarkers to predict response.

          Results:

          A total of 84 patients with a median age (SD) of 53.8 (10.6) were recruited. Baseline median Hb level was 10.2 (range: 8.3–11.0) gm/dL. At week 12, there was a significant increment in Hb level for patients in groups I and II (median increment: 2.35 and 1.5 gm/dL, respectively), with limited response observed in group III, and most of the increment noted as early as week 3 (⩾1.0 g/dL). Responders tended to have lower levels of hepcidin. No clinically significant adverse events were reported; however, asymptomatic hypophosphatemia was observed in 39 (46.4%) patients.

          Conclusions:

          Intravenous FCM is a safe and effective treatment option for the management of a subgroup of patients with CIA.

          The study was registered at ClinicalTrials.gov [Identifier: NCT04246021]

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          Most cited references34

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          Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial.

          Anaemia is associated with poor cancer control, particularly in patients undergoing radiotherapy. We investigated whether anaemia correction with epoetin beta could improve outcome of curative radiotherapy among patients with head and neck cancer. We did a multicentre, double-blind, randomised, placebo-controlled trial in 351 patients (haemoglobin <120 g/L in women or <130 g/L in men) with carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. Patients received curative radiotherapy at 60 Gy for completely (R0) and histologically incomplete (R1) resected disease, or 70 Gy for macroscopically incompletely resected (R2) advanced disease (T3, T4, or nodal involvement) or for primary definitive treatment. All patients were assigned to subcutaneous placebo (n=171) or epoetin beta 300 IU/kg (n=180) three times weekly, from 10-14 days before and continuing throughout radiotherapy. The primary endpoint was locoregional progression-free survival. We assessed also time to locoregional progression and survival. Analysis was by intention to treat. 148 (82%) patients given epoetin beta achieved haemoglobin concentrations higher than 140 g/L (women) or 150 g/L (men) compared with 26 (15%) given placebo. However, locoregional progression-free survival was poorer with epoetin beta than with placebo (adjusted relative risk 1.62 [95% CI 1.22-2.14]; p=0.0008). For locoregional progression the relative risk was 1.69 (1.16-2.47, p=0.007) and for survival was 1.39 (1.05-1.84, p=0.02). Epoetin beta corrects anaemia but does not improve cancer control or survival. Disease control might even be impaired. Patients receiving curative cancer treatment and given erythropoietin should be studied in carefully controlled trials.
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            Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia.

            The erythropoiesis-stimulating agents (ESAs) erythropoietin and darbepoetin are licensed to treat chemotherapy-associated anemia in patients with nonmyeloid malignancies. Although systematic overviews of trials have identified venous thromboembolism (VTE) risks, none have identified mortality risks with ESAs. To evaluate VTE and mortality rates associated with ESA administration for the treatment of anemia among patients with cancer. A published overview from the Cochrane Collaboration (search dates: January 1, 1985-April 1, 2005) and MEDLINE and EMBASE databases (key words: clinical trial, erythropoietin, darbepoetin, and oncology), the public Web site of the US Food and Drug Administration and ESA manufacturers, and safety advisories (search dates: April 1, 2005-January 17, 2008). Phase 3 trials comparing ESAs with placebo or standard of care for the treatment of anemia among patients with cancer. Mortality rates, VTE rates, and 95% confidence intervals (CIs) were extracted by 3 reviewers from 51 clinical trials with 13 611 patients that included survival information and 38 clinical trials with 8172 patients that included information on VTE. Patients with cancer who received ESAs had increased VTE risks (334 VTE events among 4610 patients treated with ESA vs 173 VTE events among 3562 control patients; 7.5% vs 4.9%; relative risk, 1.57; 95% CI, 1.31-1.87) and increased mortality risks (hazard ratio, 1.10; 95% CI, 1.01-1.20). Erythropoiesis-stimulating agent administration to patients with cancer is associated with increased risks of VTE and mortality. Our findings, in conjunction with basic science studies on erythropoietin and erythropoietin receptors in solid cancers, raise concern about the safety of ESA administration to patients with cancer.
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              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.

              This randomized, double-blind, placebo-controlled clinical trial assessed the effects of epoetin alfa on transfusion requirements, hematopoietic parameters, quality of life (QOL), and safety in anemic cancer patients receiving nonplatinum chemotherapy. The study also explored a possible relationship between increased hemoglobin and survival. Three hundred seventy-five patients with solid or nonmyeloid hematologic malignancies and hemoglobin levels or = 1.5 g/dL per cycle since starting chemotherapy, were randomized 2:1 to epoetin alfa 150 to 300 IU/kg (n = 251) or placebo (n = 124) three times per week subcutaneously for 12 to 24 weeks. The primary end point was proportion of patients transfused; secondary end points were change in hemoglobin and QOL. The protocol was amended before unblinding to prospectively collect and assess survival data 12 months after the last patient completed the study. Epoetin alfa, compared with placebo, significantly decreased transfusion requirements (P =.0057) and increased hemoglobin (P <.001). Improvement of all primary cancer- and anemia-specific QOL domains, including energy level, ability to do daily activities, and fatigue, was significantly (P <.01) greater for epoetin alfa versus placebo patients. Although the study was not powered for survival as an end point, Kaplan-Meier estimates showed a trend in overall survival favoring epoetin alfa (P =.13, log-rank test), and Cox regression analysis showed an estimated hazards ratio of 1.309 (P =.052) favoring epoetin alfa. Adverse events were comparable between groups. Epoetin alfa safely and effectively ameliorates anemia and significantly improves QOL in cancer patients receiving nonplatinum chemotherapy. Encouraging results regarding increased survival warrant another trial designed to confirm these findings.
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                Author and article information

                Contributors
                Journal
                Ther Adv Med Oncol
                Ther Adv Med Oncol
                TAM
                sptam
                Therapeutic Advances in Medical Oncology
                SAGE Publications (Sage UK: London, England )
                1758-8340
                1758-8359
                9 September 2020
                2020
                : 12
                : 1758835920953292
                Affiliations
                [1-1758835920953292]Department of Medical oncology, King Hussein Cancer Center, 202 Queen Rania Al-Abdullah, Amman, 11941, Jordan
                [2-1758835920953292]School of Medicine, University of Jordan, Amman, Jordan
                [3-1758835920953292]Department of Medical oncology, King Hussein Cancer Center, Amman, Jordan
                [4-1758835920953292]Department of Medical oncology, King Hussein Cancer Center, Amman, Jordan
                [5-1758835920953292]Department of Medical oncology, King Hussein Cancer Center, Amman, Jordan
                [6-1758835920953292]Department of Medical oncology, King Hussein Cancer Center, Amman, Jordan
                [7-1758835920953292]Department of Pharmacy, King Hussein Cancer Center, Amman, Jordan
                [8-1758835920953292]Department of Nursing, King Hussein Cancer Center, Amman, Jordan
                [9-1758835920953292]Office of Scientific Affairs and Research, King Hussein Cancer Center, Amman, Jordan
                Author notes
                Author information
                https://orcid.org/0000-0003-2833-6051
                https://orcid.org/0000-0002-1052-9093
                Article
                10.1177_1758835920953292
                10.1177/1758835920953292
                7485004
                32952616
                798cbd9e-5abb-44c6-8464-bbfd5291da91
                © The Author(s), 2020

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                : 6 May 2020
                : 6 August 2020
                Categories
                Original Research
                Custom metadata
                January-December 2020
                ts1

                anemia,cancer,ferric carboxymaltose,hepcidin
                anemia, cancer, ferric carboxymaltose, hepcidin

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