The role of iron in the management of chemotherapy-induced anemia in cancer patients receiving erythropoiesis-stimulating agents.
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ABSTRACT:
SUBMITTER: Mhaskar R
PROVIDER: S-EPMC8765740 | biostudies-literature | 2016 Feb
REPOSITORIES: biostudies-literature
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The role of iron in the management of chemotherapy-induced anemia in cancer patients receiving erythropoiesis-stimulating agents.
Mhaskar Rahul R Wao Hesborn H Miladinovic Branko B Kumar Ambuj A Djulbegovic Benjamin B
The Cochrane database of systematic reviews 20160204
<h4>Background</h4>Erythropoiesis-stimulating agents (ESAs) are commonly used to treat chemotherapy-induced anemia (CIA). However, about half of patients do not benefit.<h4>Objectives</h4>To evaluate the benefits and harms related to the use of iron as a supplement to ESA and iron alone compared with ESA alone in the management of CIA.<h4>Search methods</h4>We searched for relevant trials from the Cochrane Central Register of Controlled Trials (CENTRAL) (issue 1 January 2016), MEDLINE (1950 to F ...[more]
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Project description:Erythropoisis stimulating agent (ESA) use was addressed in Food and Drug Administration (FDA) Oncology Drug Advisory Committee (ODAC) meetings between 2004 and 2008. FDA safety-focused regulatory actions occurred in 2007 and 2008. In 2007, black box warnings advised of early death and venous thromboembolism (VTE) risks with ESAs in oncology. In 2010, a Risk Evaluation Strategies (REMS) was initiated, with cancer patient consent that mortality and VTE risks were noted with ESAs. We report warnings and REMS impacts on ESA utilization among Veterans Administration (VA) cancer patients with chemotherapy-induced anemia (CIA). Data were from Veterans Affairs database (2003-2012). Epoetin and darbepoetin use were primary outcomes. Segmented linear regression was used to estimate changes in ESA use levels and trends, clinical appropriateness, and adverse events (VTEs) among chemotherapy-treated cancer patients. To estimate changes in level of drug prescription rate after policy actions, model-specific indicator variables as covariates based on specific actions were included. ESA use fell by 95% and 90% from 2005, for epoetin and darbepoetin, from 22% and 11%, respectively, to 1% and 1%, respectively, among cancer patients with CIA, respectively (p<0.01). Following REMS in 2010, mean hematocrit levels at ESA initiation decreased from 30% to 21% (p<0.01). Black box warnings preceded decreased ESA use among VA cancer patients with CIA. REMS was followed by reduced hematocrit levels at ESA initiation. Our findings contrast with privately- insured and Medicaid insured cancer patient data on chemotherapy-induced anemia where ESA use decreased to 3% to 7% by 2010-2012. By 2012, the era of ESA administration to VA to cancer patients had ended but the warnings remain relevant and significant. In 2019, oncology/hematology national guidelines (ASCO/ASH) recommend that cancer patients with chemotherapy-induced anemia should receive ESAs or red blood cell transfusions after risk-benefit evaluation.
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Project description: Not available
| S-EPMC10985414 | biostudies-literature
Project description:Anemia, complicating the course of chronic kidney disease, is a significant parameter, whether interpreted as subjective impairment or an objective prognostic marker. Renal anemia is predominantly due to relative erythropoietin (EPO) deficiency. EPO inhibits apoptosis of erythrocyte precursors. Studies using EPO substitution have shown that increasing hemoglobin (Hb) levels up to 10-11 g/dL is associated with clinical improvement. However, it has not been unequivocally proven that further intensification of erythropoiesis stimulating agent (ESA) therapy actually leads to a comprehensive benefit for the patient, especially as ESAs are potentially associated with increased cerebro-cardiovascular events. Recently, new developments offer interesting options not only via stimulating erythropoeisis but also by employing additional mechanisms. The inhibition of activin, a member of the transforming growth factor superfamily, has the potential to correct anemia by stimulating liberation of mature erythrocyte forms and also to mitigate disturbed mineral and bone metabolism as well. Hypoxia-inducible factor prolyl hydroxylase inhibitors also show pleiotropic effects, which are at the focus of present research and have the potential of reducing mortality. However, conventional ESAs offer an extensive body of safety evidence, against which the newer substances should be measured. Carbamylated EPO is devoid of Hb augmenting effects whilst exerting promising tissue protective properties. Additionally, the role of hepcidin antagonists is discussed. An innovative new hemodialysis blood tube system, reducing blood contact with air, conveys a totally different and innocuous option to improve renal anemia by reducing mechanical hemolysis.
| S-EPMC5592888 | biostudies-other
Project description:PurposeTo update the American Society of Clinical Oncology (ASCO)/American Society of Hematology (ASH) recommendations for use of erythropoiesis-stimulating agents (ESAs) in patients with cancer.MethodsPubMed and the Cochrane Library were searched for randomized controlled trials (RCTs) and meta-analyses of RCTs in patients with cancer published from January 31, 2010, through May 14, 2018. For biosimilar ESAs, the literature search was expanded to include meta-analyses and RCTs in patients with cancer or chronic kidney disease and cohort studies in patients with cancer due to limited RCT evidence in the cancer setting. ASCO and ASH convened an Expert Panel to review the evidence and revise previous recommendations as needed.ResultsThe primary literature review included 15 meta-analyses of RCTs and two RCTs. A growing body of evidence suggests that adding iron to treatment with an ESA may improve hematopoietic response and reduce the likelihood of RBC transfusion. The biosimilar literature review suggested that biosimilars of epoetin alfa have similar efficacy and safety to reference products, although evidence in cancer remains limited.RecommendationsESAs (including biosimilars) may be offered to patients with chemotherapy-associated anemia whose cancer treatment is not curative in intent and whose hemoglobin has declined to < 10 g/dL. RBC transfusion is also an option. With the exception of selected patients with myelodysplastic syndromes, ESAs should not be offered to most patients with nonchemotherapy-associated anemia. During ESA treatment, hemoglobin may be increased to the lowest concentration needed to avoid transfusions. Iron replacement may be used to improve hemoglobin response and reduce RBC transfusions for patients receiving ESA with or without iron deficiency. Additional information is available at www.asco.org/supportive-care-guidelines and www.hematology.org/guidelines.
| S-EPMC6482353 | biostudies-literature
Project description:BackgroundAnemia 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 methodsWe 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.ResultsA 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.ConclusionsIntravenous 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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Project description:A specific cause of anemia cannot be identified in many elderly patients. Erythropoiesis-stimulating agents (ESAs) may play a role in treating these patients with anemia of unknown etiology (AUE). This study examines hemoglobin and cardiovascular outcomes among elderly anemic patients treated with ESAs. We conducted a retrospective cohort study that included all anemic patients older than age 60 years who had erythropoietin (EPO) measured between 2005 and 2013 at a single center. Three independent reviewers used defined criteria to assign each patient's anemia to 1 of 4 groups: chronic kidney disease (CKD), myelodysplastic syndrome, AUE, or other etiology. Logistic regression was used to compare treatment response (defined per the International Working Group response criteria in myelodysplasia). Adjusted Cox regression analysis was used to calculate the cardiovascular event hazard ratios associated with ESA treatment. A total of 570 patients met the inclusion criteria, of whom 101 received ESAs. There was a nonstatistically significant but quantitatively better response in AUE (47%) and CKD (54%) compared with other etiologies (22%). The adjusted odds ratio for response in AUE compared with other etiologies was 3.3 (95% confidence interval, 0.838-13.0). A baseline EPO level <200 IU/L independently predicted treatment response. There was no statistically significant difference in cardiovascular events or cardiovascular event-free survival between the treated and untreated groups after adjusting for confounders. Our results suggest that ESAs may effectively treat AUE, and responses may be similar to those in CKD. We could not detect a statistically significant increase in cardiovascular events in the studied cohort.
| S-EPMC5728467 | biostudies-literature
Project description:Patients with renal anemia are frequently treated with erythropoiesis-stimulating agents (ESAs), which are dynamically dosed in order to stabilize blood hemoglobin levels within a specified target range. During typical ESA treatments, a fraction of patients experience hemoglobin 'cycling' periods during which hemoglobin levels periodically over- and undershoot the target range. Here we report a specific mechanism of hemoglobin cycling, whereby cycles emerge from the patient's delayed physiological response to ESAs and concurrent ESA dose adjustments. We introduce a minimal theoretical model that can explain dynamic hallmarks of observed hemoglobin cycling events in clinical time series and elucidates how physiological factors (such as red blood cell lifespan and ESA responsiveness) and treatment-related factors (such as dosing schemes) affect cycling. These results show that in general, hemoglobin cycling cannot be attributed to patient physiology or ESA treatment alone but emerges through an interplay of both, with consequences for the design of ESA treatment strategies.
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Project description:BackgroundErythropoiesis-stimulating agents are used to treat anemia in patients with cancer. However, their safety and effectiveness is controversial. We did a systematic review of the clinical efficacy and harms of these agents in adults with anemia related to cancer or chemotherapy.MethodsWe conducted a systematic review of published and unpublished randomized controlled trials (RCTs) using accepted methods for literature searches, article selection, data extraction and quality assessment. We included RCTs involving anemic adults with cancer. We compared the use of erythropoiesis-stimulating agents with nonuse and assessed clinical outcomes (all-cause mortality, cardiovascular events and hypertension, health-related quality of life, blood transfusions and tumour response) and harms (serious adverse events) between groups.ResultsWe identified 52 trials (n = 12 006) that met our selection criteria. The pooled all-cause mortality during treatment was significantly higher in the group receiving erythropoiesis-stimulating therapy than in the control group (relative risk [RR] 1.15, 95% confidence interval [CI] 1.03 to 1.29). Compared with no treatment, use of erythropoiesis-stimulating agents led to clinically detectable improvements in disease-specific measures of quality of life. It also reduced the use of blood transfusions (RR 0.64, 95% CI 0.56 to 0.73). However, it led to an increased risk of thrombotic events (RR 1.69, 95% CI 1.27 to 2.24) and serious adverse events (RR 1.16, 95% CI 1.08 to 1.25).InterpretationUse of erythropoiesis-stimulating agents in patients with cancer-related anemia improved some disease-specific measures of quality of life and decreased the use of blood transfusions. However, it increased the risk of death and serious adverse events. Our findings suggest that such therapy not be used routinely as an alternative to blood transfusion in patients with anemia related to cancer.
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Project description:Pharmacovigilance (PV) is the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or other problems related to medical products after they have been licensed for marketing. The purpose of PV is to advance the safe use of marketed medical products. Regulatory agencies and license holders collaborate to collect data reported by health care providers, patients, and the public as well as data from systematic reviews, meta-analyses, and individual clinical and nonclinical studies. They validate and analyze the data to determine whether safety signals exist, and if warranted, develop an action plan to mitigate the identified risk. Erythropoiesis-stimulating agents (ESAs) provide an example of how PV is applied in reality. Among other approved indications, ESAs may be used to treat anemia in patients with chemotherapy-induced anemia. ESAs increase hemoglobin levels and reduce the need for transfusions; they are also associated with a known increased risk of thromboembolic events. Starting in 2003, emerging data suggested that ESAs might reduce survival. As a result of PV activities by regulatory agencies and license holders, labeling for ESAs addresses these risks. Meta-analyses and individual clinical studies have confirmed that ESAs increase the risk of thromboembolic events, but when used as indicated, ESAs have not been shown to have a significant effect on survival or disease progression. Ongoing safety studies will provide additional data in the coming years to further clarify the risks and benefits of ESAs.
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Project description:The increased risks of death and adverse events with erythropoiesis-stimulating agent (ESA) therapy targeting a higher hemoglobin level are established. It is uncertain whether the adverse effects of ESA therapy are related to dose and are mitigated when a fixed low ESA dose is used. We conducted a multicenter, prospective randomized open-label, blinded-endpoint (PROBE) trial to evaluate fixed low versus high dose ESA therapy on patient outcomes. We intended to recruit 2104 hemodialysis patients >18 years with anemia or receiving ESA treated at dialysis clinics in Italy. The intervention was fixed low (4000 IU epoetin alfa equivalent weekly) or high (18,000 IU epoetin alfa equivalent weekly) dose ESA for 12 months. Primary outcomes were serum transferrin, ferritin, albumin, C-reactive protein and ESA dose. Secondary outcomes were the composite of death or cardiovascular event, all-cause mortality, cardiovascular mortality, myocardial infarction, stroke, cardiovascular hospitalization, and quality of life. Study recruitment was terminated after inclusion of 656 participants with convergence of ESA dose between groups during follow up. Fixed low dose ESA had uncertain effects on serum ferritin (delta of delta (DD) 3.9 ng/ml, 95% CI -85.0 to 92.8), transferrin (9.2 mg/dl, -6.3 to 24.8), transferrin saturation (3.7%, -5.0 to 12.3), serum albumin (-0.03 g/dl, -0.2 to 0.1), or C-reactive protein (-0.6 mg/l, -3.3 to 2.1). In addition, fixed dose therapy had inconclusive effects on the composite endpoint of mortality and cardiovascular events (hazard ratio [HR] 0.95, 95% CI 0.66 to 1.37), death (0.98, 0.64 to 1.52), nonfatal myocardial infarction (0.52, 0.18 to 1.52), nonfatal stroke (no events), hospital admission for cardiovascular causes (0.93, 0.50 to 1.72) or health-related quality of life. A fixed low ESA dose in hemodialysis patients has uncertain effects on serum parameters, mortality, cardiovascular events, and quality of life. Hemoglobin targets may be so entrenched in nephrology practice that a trial of ESA dose is no longer possible.
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