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      Darbepoetin Versus Epoetin Alfa for the Correction of Anemia in Cancer Patients Receiving Radiotherapy or Chemoradiotherapy Treatment

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          Abstract

          Introduction

          Anemia is the most frequent hematological disturbance in cancer patients, with prevalence between 30% and 90%, depending on the type of tumor, the antitumor treatment, and other factors (infection, malnutrition, bleeding, tumor infiltration of the bone marrow). A number of erythropoietic agents have shown to be effective in increasing the hemoglobin (Hb) levels, reducing the requirements for transfusion, and improving quality of life. The objective of this study is to compare darbepoetin alfa and epoetin alfa when used to correct anemia in cancer patients who are receiving radiotherapy or radiochemotherapy.

          Material and methods

          A prospective study of 125 consecutive patients with anemia (Hb <13 g/dL in males or <12 g/dL in females) who were undergoing treatment with radiotherapy (RT) or radiochemotherapy (RCT) in our department were enrolled between March 2003 and March 2005. The treatment for the anemia was either darbepoetin alfa 150 mcg/week (62 patients, group 1) or epoetin alfa 40,000 IU/week (63 patients, group 2). Patients received iron supplements in both groups. Treatment was administered in a consecutive manner depending on tumor type. If the increase in Hb was <1 g/dL after 4 weeks of treatment, the dose was increased to 300 mcg/week in group 1 or to 60,000 IU/week in group 2. The treatment was terminated when a Hb value of ≥15 g/dL was reached during RT treatment, a Hb value of ≥14 g/dL was reached if the RT had been completed, or after 16 weeks of treatment whatever the Hb value. The mean age of patients was 63.36 ± 11.27 years, 67% were male. No significant differences were observed between the 2 groups in tumor type or stage, previous treatments, or intent to treat with RT or RCT.

          Results

          Comparing group 1 and group 2 by intent to treat, the mean Hb at the start of treatment with the study drug was 12.1 g/dL vs 11.8 g/dL, the proportion of patients whose dose was increased was 19.7% vs 24.6%, the need for transfusion was 3.2% in each group, the duration of erythropoietic treatment was 6.5 weeks in both groups, and 2 patients in group 2 restarted treatment with epoetin alfa. The percentage of patients who responded (defined as an increase in the Hb ≥ 2 g/dL in the absence of transfusions) was of 72.6% and 66.7%, respectively. Four vascular adverse events were observed, 2 in each group. No significant differences were observed with respect to the baseline, week 4, and week 12 levels of endogenous erythropoietin, serum iron,% saturation, and ferritin. The increase in Hb 1 month after the final administration of the study drug was 2.21 g/dL in group 1 and 2.46 g/dL in group 2 (p = ns).

          Conclusions

          The results of our study demonstrate that both treatments are equally effective in correcting anemia in cancer patients undergoing RT or RCT.

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          Most cited references39

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          Prevalence and outcomes of anemia in cancer: a systematic review of the literature.

          Anemia is common in patients with cancer. This systematic literature review of reports published in 1966 through February 2003 identified the prevalence of anemia in specific cancers and assessed the impact of anemia on survival and quality of life (QOL). Studies about chemotherapy-induced anemia were excluded. Anemia prevalence varied widely; most studies found that between 30% and 90% of patients with cancer had anemia. Prevalence was affected strongly by the definition of anemia: 7% of patients with Hodgkin disease had anemia when the condition was defined as a hemoglobin level <90.0 g/L; as many as 86% of patients had anemia when it was defined as a hemoglobin value <110.0 g/L. Prevalence varied by cancer type and disease stage: 40% of patients with early-stage colon tumors and nearly 80% of patients with advanced disease had anemia. Patients with anemia had poorer survival and local tumor control than did their nonanemic counterparts in 15 of 18 studies. In 8 of 12 studies, patients without anemia (most treated with epoetin) needed fewer transfusions. QOL was positively correlated with hemoglobin levels in 15 of 16 studies. There was no significant difference in treatment toxicity between patients with and without anemia. Tumor hypoxia, which has been associated with resistance to radiation therapy and chemotherapy, may stimulate angiogenesis, leading to poor local control of tumors and increased morbidity and mortality. Treatment of anemia may have a significant impact on patient survival and QOL. However, a standard definition of anemia is needed, as is research about the effect of anemia on cancer progression.
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            Impact of tumor hypoxia and anemia on radiation therapy outcomes.

            Local recurrence remains a major obstacle to achieving cure of many locally advanced solid tumors treated with definitive radiation therapy. The microenvironment of solid tumors is hypoxic compared with normal tissue, and this hypoxia is associated with decreased radiosensitivity. Recent preclinical data also suggest that intratumoral hypoxia, particularly in conjunction with an acid microenvironment, may be directly or indirectly mutagenic. Investigations of the prognostic significance of the pretreatment oxygenation status of tumors in patients with head and neck or cervical cancer have demonstrated that increased hypoxia, typically designated in these studies as pO(2) levels below 2.5-10 mm Hg, is associated with decreased local tumor control and lower rates of disease-free and overall survival. Hypoxia-directed therapies in the radiation oncology setting include treatment using hyperbaric oxygen, fluosol infusion, carbogen breathing, and electron-affinic and hypoxic-cell sensitizers. These interventions have shown the potential to increase the effectiveness of curative-intent radiation therapy, demonstrating that the strategy of overcoming hypoxia may be a viable and important approach. Anemia is common in the cancer population and is suspected to contribute to intratumoral hypoxia. A review of the literature reveals that a low hemoglobin level before or during radiation therapy is an important risk factor for poor locoregional disease control and survival, implying that a strong correlation could exist between anemia and hypoxia (ultimately predicting for a poor outcome). While having a low hemoglobin level has been shown to be detrimental, it is unclear as to exactly what the threshold for "low" should be (studies in this area have used thresholds ranging from 9-14.5 g/dl). Optimal hemoglobin and pO(2) thresholds for improving outcomes may vary across and within tumor types, and this is an area that clearly requires further evaluation. Nonetheless, the correction of anemia may be a worthwhile strategy for radiation oncologists to improve local control and survival.
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              Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy.

              Patients receiving chemotherapy often develop anemia. Darbepoetin alfa (Aranesp(TM)) is an erythropoiesis-stimulating glycoprotein that has been shown, in dose-finding studies, to be safe and clinically active when administered to patients with cancer every 1, 2, or 3 weeks. This phase III study compared the safety and efficacy of darbepoetin alfa with placebo in patients with lung cancer receiving chemotherapy. In this multicenter, double-blind, placebo-controlled study, 320 anemic patients (hemoglobin or=25% improvement; mean difference = 13%; 95% CI = 2% to 23%, P =.019) than patients receiving placebo. Patients receiving darbepoetin alfa did not appear to have any untoward effect in disease outcome and did not develop antibodies to the drug. Adverse events were similar between the groups. Patients with chemotherapy-associated anemia can safely and effectively be treated with weekly darbepoetin alfa therapy. Darbepoetin alfa decreased blood transfusion requirements, increased hemoglobin concentration, and decreased fatigue. Although no conclusions can be drawn about survival from this study, the potential salutary effect on disease outcome warrants further investigation in a prospectively designed study.
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                Author and article information

                Journal
                Clin Med Oncol
                101467911
                Clinical Medicine. Oncology
                Libertas Academica
                1177-9314
                2008
                19 May 2008
                : 2
                : 393-399
                Affiliations
                Department of Oncological Radiotherapy Hospital Central de la Defensa, Madrid, Spain
                Author notes
                Correspondence: Dr. Pilar Ma Samper Ots, Department of Oncological Radiotherapy, Hospital Central de la Defensa, Glorieta del Ejercito s/n, 28047 Madrid. Fax: 91 422 86 55; Email: psampero@ 123456hotmail.com
                Article
                cmo-2-2008-393
                3161674
                21892305
                9129014d-03ce-4fcc-927a-28bb37407d86
                © 2008 the author(s), publisher and licensee Libertas Academica Ltd.

                This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license http://creativecommons.org/licenses/by/3.0/).

                History
                Categories
                Original Research

                Oncology & Radiotherapy
                epoetin alfa,radiotherapy,anemia,darbepoetin alfa,radiochemotherapy
                Oncology & Radiotherapy
                epoetin alfa, radiotherapy, anemia, darbepoetin alfa, radiochemotherapy

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