Erythropoiesis-stimulating Agents In Cancer Patients Research Articles

The Risk of Venous Thrombosis for Erythropoiesis Stimulating Agents and Blood Transfusions in Cancer Patients: A Nationwide Population-Based Study in Korea

Introduction: Several previous studies have indicated that both erythropoiesis-stimulating agents (ESAs) and blood transfusions elevate the risk of venous thrombosis in cancer patients. Nevertheless, there has been inconsistency in the evidence regarding whether ESAs or blood transfusions are more closely linked to thrombotic complications. To address this, nationwide population data was analyzed to explore the association between the use of ESAs, blood transfusions, and the risk of venous thrombosis in cancer patients. Methods: This study utilized a case-crossover design and analyzed the National Health Insurance Database of Korea. A total of 710,910 patients diagnosed cancer (ICD-10 code: C00.x-C26.x, C30.x-C34.x, C37.x-C41.x, C45.x-C58.x, C60.x-C76.x, C81.x-C85.x, C88.3, C88.7, C88.9, C90.0, C90.1, C91.x-C93.x, C94.0-C94.3, C94.5, C94.7, C95.x, C96.x) between January 1, 2011, and December 31, 2020 were included. Of these, 57,256 (8.03%) identified with venous thrombosis (ICD-10 code: I80.x). The hazard period, starting from the week of thrombosis and going back 12 weeks, was compared to an earlier 12-week control period separated by a 24-week gap. Secondary analyses were conducted with different durations for the hazard/control periods (8 and 4 weeks) to assess the robustness of the results. Patients served as their own controls, and time-dependent covariates such as granulocyte colony-stimulating factor and chemotherapy were evaluated for their association with thrombotic risk. Patients were categorized based on occurrences of inpatient hospitalization, red blood cell transfusion, platelet transfusion, central venous catheter placement, and major surgery during hazard and control periods, and these variables were compared using χ2 tests. Finally, conditional logistical regression was employed to compare the odds of exposure to ESAs, blood transfusions, and other thrombosis risk factors during the hazard period to the exposure odds during the control period. Results: There were similar rates of ESA use during the hazard period and the control period (0.88% vs. 0.28%; P = 0.477). However, red blood cell transfusions (6.85% vs. 1.79%; P <0.001), platelet transfusions (1.92% vs. 0.48%; P = 0.003), insertion of a central venous catheter (3.34% vs. 0.74%; P <0.001), hospitalizations (11.79% vs. 2.77%; P <0.001), and major surgery (5.70% vs. 2.00%; P <0.001) differed significantly between the two exposure periods. All of these factors were more frequent during the hazard period compared to the control period. In the crude conditional logistical regression model, the odds ratio (OR) for ESA use was significantly increased (OR = 3.14; 95% CI: 2.63, 7.75). However, after controlling for other covariates including red blood cell transfusions, platelet transfusions, central venous catheter insertion, hospitalization, and major surgery in an adjusted model, ESA use was found to be non-significant (OR = 1.12; 95% CI: 0.93, 1.36). In contrast to ESA use, red blood cell transfusion was associated with an increased risk of thrombosis in both the crude model (OR = 3.83; 95% CI: 3.58, 4.11) and the adjusted model (OR = 1.44; 95% CI: 1.32, 1.58). This study also investigated whether varying the lengths of the hazard and control periods (8 and 4 weeks) would affect the association between ESA use, red blood cell transfusions, and thrombotic events. The results showed that the association remained consistent regardless of the duration of the periods. Overall, these findings suggest that while there was an increased risk of thrombosis associated with red blood cell transfusions, the use of ESAs did not show a significant association with thrombotic events after adjusting for other relevant factors. Conclusions: This study revealed a stronger association between red blood cell transfusions and thrombotic complications in cancer patients. These findings suggest that red blood cell transfusions may have a higher thrombotic risk compared to ESAs in this particular patient population. Furthermore, the results indicate that the use of ESAs in cancer patients might not increase the risk of thrombotic complications depending on the exposure duration. Further studies are needed to assess the impact of ESAs and blood transfusions on thrombotic risk in different populations.

Does access to clinical study reports from the European Medicines Agency reduce reporting biases? A systematic review and meta-analysis of randomized controlled trials on the effect of erythropoiesis-stimulating agents in cancer patients.

Since 2010, the European Medicines Agency (EMA) has provided access to clinical study reports (CSRs). We requested CSRs for randomized controlled trials (RCTs) of erythropoiesis-stimulating agents (ESAs) in cancer patients from EMA and identified RCT publications with literature searches. We assessed CSR availability and completeness, the impact of unreported and unpublished data obtained from CSRs on the effects of ESAs on quality of life (QoL) of cancer patients, and discrepancies between data reported in the public domain and in CSRs. We used random-effects meta-analyses to evaluate the effect of ESAs on QoL measured with Functional Assessment of Cancer Therapy-Anemia (FACT-An), FACT-Fatigue (FACT-F) and FACT-Anemia Total (FACT-An Total) stratified by data source and the impact of discrepancies on QoL, mortality, adverse events, and clinical effectiveness outcomes. We identified 94 eligible RCTs; CSRs or other study documentation were available for 17 (18%) RCTs at EMA. Median report length was 1,825 pages (range 72–14,569). Of 180 outcomes of interest reported in the EMA documentation, 127 (71%) were publicly available. For 80 of those (63%) we noted discrepancies, but these had little impact on the pooled effect estimates. Of 27 QoL outcomes reported in the CSRs, 17 (63%) were unpublished. Including six unpublished comparisons (pooled mean difference [MD] 0.20; 95% confidence interval [CI] -1.93, 2.33) reduced the pooled effect of ESAs for FACT-An from MD 5.51 (95% CI 4.20, 6.82) in published data to MD 3.21 (95% CI 1.38, 5.03), which is below a clinically important difference (defined as MD ≥4). Effects were similar for FACT-F and FACT-An Total. Access to CSRs from EMA reduced reporting biases for QoL outcomes. However, EMA received documentation for a fraction of all RCTs on effects of ESAs in cancer patients. Additional efforts by other agencies and institutions are needed to make CSRs universally available for all RCTs.

Erythropoietin and cancer: the unintended consequences of anemia correction.

Until 1990, erythropoietin (EPO) was considered to have a single biological purpose and action, the stimulation of red blood cell growth and differentiation. Slowly, scientific and medical opinion evolved, beginning with the discovery of an effect on endothelial cell growth in vitro and the identification of EPO receptors (EPORs) on neuronal cells. We now know that EPO is a pleiotropic growth factor that exhibits an anti-apoptotic action on numerous cells and tissues, including malignant ones. In this article, we present a short discussion of EPO, receptors involved in EPO signal transduction, and their action on non-hematopoietic cells. This is followed by a more detailed presentation of both pre-clinical and clinical data that demonstrate EPO’s action on cancer cells, as well as tumor angiogenesis and lymphangiogenesis. Clinical trials with reported adverse effects of chronic erythropoiesis-stimulating agents (ESAs) treatment as well as clinical studies exploring the prognostic significance of EPO and EPOR expression in cancer patients are reviewed. Finally, we address the use of EPO and other ESAs in cancer patients.

Current Status of Use of Erythropoietic Agents in Cancer Patients

Anemia is frequently observed in cancer patients and can cause symptoms and result in red cell transfusions. The erythropoiesis stimulating agents (ESAs) have been shown to increase hemoglobin levels and reduce transfusion requirements in anemic subjects with cancer who are receiving chemotherapy. Initially, these benefits motivated broad use of the ESAs in oncology. Over the past 10 years, recognition of the adverse events that can be associated with ESA use in these patients, particularly venous thrombosis, has resulted in a rethinking of the issue of who are the correct candidates for treatment. Different health care systems have come to different conclusions based upon the available data and additional data are still being generated. This article will review the data concerning the safety of ESAs in cancer patients, including the results of additional trials published in the past 2 years. This will include a discussion of the potential of ESAs to impact tumor progression or survival. Thrombosis remains the most important and best documented adverse event associated with ESA therapy in oncology. The mechanism(s) through which ESAs alter thrombosis risk are still very poorly understood.

Impact of erythropoiesis-stimulating agents on red blood cell transfusion in Korea

Erythropoiesis-stimulating agents (ESAs) have been shown to reduce the need for red blood cell (RBC) transfusions and to improve quality of life for cancer patients with anaemia. However, increased risks of mortality and disease progression have been reported when using ESAs with excessive target haemoglobin levels. In 2007, the United States Food and Drug Administration and Korea Food and Drug Administration issued regulatory alerts for using ESAs in cancer patients. This retrospective study was performed to evaluate changes in ESA prescribing patterns between 2006 and 2010 and the impact on RBC transfusions in patients with solid tumours. The Seoul National University Hospital (SNUH) in Korea. This study includes adult patients with solid tumours who were diagnosed and treated in the SNUH from January 2006 to December 2010. The exclusion criterion was concomitant chronic renal failure. The patients' Hb levels and prescription data for ESAs and RBC transfusions were statistically analysed. The number of inpatient and outpatient solid-tumour patients was also analysed as a baseline. Main outcome measure Prescription data on ESAs and RBC transfusion. After adjusting for the number of patient visits, the monthly mean ESA doses dispensed decreased by an average of 1,192 mcg per quarter over the last 5 years, and the number of RBC transfusions ordered increased by 3.77 instances per quarter. After correcting for the number of patients, the mean doses of ESA dispensed each month decreased by 3,190 mcg per quarter, and the number of RBC transfusions ordered increased by 9.51 instances per quarter. During the last 5 years, the number of ESA doses dispensed at SNUH decreased and the number of RBC transfusions at SNUH increased, independent of the number of patients. The reduction in ESA use was thought to be due to the release of the safety alert letter in 2007. However, this study did not analyse other risk factors that may have influenced the number of RBC transfusions (e.g. metastatic cancer, comorbidities, surgery). Still, the results of this study suggest that the decreased ESA doses were relevant to the increased RBC transfusions.

Erythropoesis-stimulating agents – study of their use in cancer patients

BackgroundAnaemia is common, occurring in 30-90% of cancer patients. Erythropoiesis Stimulating Agents (ESAs) have shown to be effective in the correction of anaemia in oncohaematology.PurposeTo assess the use of ESAs...

Addition of iron to erythropoiesis-stimulating agents in cancer patients: a meta-analysis of randomized trials

Iron supplementation could improve the hematopoietic response of erythropoiesis-stimulating agents (ESAs) used for chemotherapy-induced anemia. We performed a meta-analysis of randomized, controlled trials by comparing parenteral or oral iron and no iron, when added to ESAs in anemic cancer patients, in order to calculate the relative risk (RR) of hematopoietic response and transfusions, the time required to reach this response, and toxicity. A total of 1,606 patients out of eight trials were available for meta-analysis. The RR of obtaining an hematopoietic response was 1.29 (P = 0.0001) with parenteral iron and 1.04 for oral iron (P = 0.59). The risk of transfusion was reduced with parenteral iron versus no iron (RR 0.77; P = 0.02) but not with oral iron (RR 0.68; P = 0.08). The time to reach hematopoietic response was 1 month shorter and no increased toxicity appeared with iron supplementation. Overall parenteral iron reduces the risk of transfusions by 23% and increases the chance of hematopoietic response by 29% when compared with ESAs alone. On the contrary, oral iron does not increase hematopoietic response nor transfusion rate. The significance of these results is that the proportion of non-responders to ESAs will have strongly improved and quality of life and cost ameliorated.

Erythropoiesis-stimulating agents in cancer patients: reflections on safety

Chemotherapy-induced anemia (CIA) is a frequent problem in cancer patients with a negative impact on prognosis and quality of life. Erythropoiesis-stimulating agents (ESAs) have proven efficacy in improving hemoglobin levels and reducing red blood cell transfusion needs of these patients. In several randomized studies in settings other than CIA (such as patients not receiving any chemotherapy, or studies on preventive use of ESAs to keep high hemoglobin levels), safety signals that ESA therapy may result in worse cancer outcome were documented. We review the evidence for these safety concerns, the different hypotheses to explain effects on outcome, the implications of the more restrictive guidelines on ESA therapy on daily practice and possible alternative treatments to consider.

Management of Anemia in Cancer Patients

Cancer-related anemia adversely affects quality of life and is associated with reduced overall survival. The correction of anemia in cancer patients has the potential to improve treatment efficacy and increase survival. A large number of studies demonstrate that treatment of anemia in cancer patients using erythropoiesis-stimulating agents (ESAs) significantly increases hemoglobin levels, decreases transfusion requirements and improves quality of life, predominantly by reducing fatigue. Some data on the use of ESAs in cancer patients indicate an increased risk of thromboembolic events and a possibly increased risk of mortality. However, there is ample evidence that when ESAs are used within current guidelines, they are valuable and safe drugs for the treatment of anemia in patients receiving radiotherapy and/or chemotherapy. There are increasing data from prospective, randomized trials demonstrating better responses to ESAs with the concurrent use of iron. Blood transfusions are also helpful in the management of anemia in cancer patients, especially when there is a need for immediate increases in hemoglobin levels. In this article, we discuss recent aspects relating to treatment modalities for anemia in cancer patients.

Outcomes of erythropoiesis-stimulating agents in cancer patients with chemotherapy-induced anemia

PurposeTo assess the clinical and economic outcomes among patients with chemotherapy-induced anemia (CIA) treated with United States Food and Drug Administration-approved fixed dosing regimens of erythropoiesis-stimulating agents (ESA).MethodsData were employed from the Dosing and Outcomes Study of Erythropoiesis-Stimulating Therapies (DOSE) registry to evaluate CIA patients who were initiated on either epoetin alfa (EPO) 40,000 Units (U) or darbepoetin alfa (DARB) 500 micrograms (mcg) between January 1, 2006 and May 8, 2009. Study measurements included ESA treatment dose and dose ratio, changes in hemoglobin (Hb) levels from baseline, and cumulative ESA costs.ResultsFive hundred forty patients treated in 44 clinical centers were evaluated, of which 420 were initiated on EPO 40,000 U and 120 were initiated on DARB 500 mcg. Both cohorts had similar baseline characteristics, although EPO patients were less likely than DARB patients to have received iron supplementation before ESA initiation (11.4% EPO vs. 20.0% DARB, p = 0.015). The EPO-to-DARB dose ratio based on cumulative ESA dose was 169:1 (U EPO: mcg DARB). EPO patients showed statistically greater Hb improvement compared to DARB patients, and compared to EPO patients, a greater proportion of DARB patients required a blood transfusion (13.9% EPO vs. 22.5% DARB, p = 0.026). Mean cumulative ESA cost was significantly lower for EPO patients than DARB patients ($4,261 EPO vs. $8,643 DARB, p < 0.0001).ConclusionsThese findings reported that patients with CIA achieved more favorable clinical and economic outcomes if initiated with EPO 40,000 U vs. DARB 500 mcg.

Usage of erythropoiesis‐stimulating agents in cancer patients at an academic cancer center and experience with specific care management tools for anemia

In 2007, the US Food and Drug Administration (FDA) issued regulatory alerts for use of erythropoiesis-stimulating agents (ESAs) in cancer patients with anemia after clinical trials and meta-analysis data found that high ESA doses were associated with adverse outcomes in patients. In response to these findings, specific patient management tools for anemia (consisting in an algorithm and prescribing order set) were developed by a multidisciplinary team at The University of Texas MD Anderson Cancer Center. A retrospective study consisted of 7117 patients aged 18 years and older with cancer malignancies who had received an ESA between January 2006 and December 2008 at MD Anderson. Changes in utilization of ESAs and packed red blood cells (PRBCs) were evaluated. The number of ESA doses dispensed each month decreased by 83% from January 2006 to December 2008 (P < .01), and the number of patients who received ESAs decreased by 80% (P < .01). The number of dispensed ESA doses for hemoglobin (Hb) levels ≥ 12 g/dL decreased significantly from 4% to 0% (P < .01), and the number for ≥ 10 g/dL decreased from 44% to 12% (P < .01). The PRBC transfusion rate remained stable in solid tumor patients (P > .05) but increased from 7% to 9% (P < .05) in patients with hematologic malignancies. The authors summarized their experience with use of ESAs in a tertiary oncology center. The implementation of their patient management tools for anemia might have facilitated the observed change at MD Anderson Cancer Center.

Erythropoiesis stimulating agents, blood transfusion, and the practice of medicine

Erythropoiesis stimulating agents, blood transfusion, and the practice of medicine

Erythropoietin in cancer-related anemia

Erythropoiesis-stimulating agents reduce the transfusion requirements of anemic cancer patients receiving chemotherapy. Risks associated with the use of erythropoiesis-stimulating agents in cancer patients have more recently been identified. Several recently published phase III trials and a meta-analysis have shown an increased risk of venous thromboembolism and a decreased survival in anemic cancer patients treated with erythropoiesis-stimulating agents. To minimize risks associated with erythropoiesis-stimulating agent use in cancer patients, the most recent American Society of Clinical Oncology/American Society of Hematology clinical practice guidelines and Food and Drug Administration recommendations should be followed.

Is intravenous iron supplementation with erythropoiesis-stimulating agents beneficial in cancer patients with anemia?

Chemotherapy-induced anemia is often an important problem for cancer patients, and this complication can be treated with erythropoiesis-stimulating agents (ESAs). This commentary discusses the findings of a study by Bastit et al., in which 396 patients with nonmyeloid malignancies and chemotherapy-induced anemia were treated with darbepoetin alfa with or without intravenous iron. This phase III trial showed that intravenous iron supplementation increases the hematopoietic response rates to ESAs in cancer patients; however, this study provides no information as to whether all cancer patients with anemia should receive intravenous iron as well as treatment with ESAs. Further data are needed to identify those patients who might benefit from intravenous iron supplementation in addition to ESAs, in order to avoid overtreatment of patients who are unlikely to benefit from the additional iron. As both ESAs and intravenous iron have known short-term and long-term risks, identification of reliable predictors of response that can guide these treatments is necessary before this strategy can be implemented into practice.

ESAs Further Restricted, but Debate Continues

T he best-selling oncology drugs in the United States, erythropoiesis-stimulating agents (ESAs), have been taken by about half of all U.S. cancer patients to treat chemotherapy-induced anemia — more than the number receiving radiation therapy. But that is changing. This summer, European and American regulatory authorities stringently restricted who should take ESAs, the most recent in a series of steps taken in response to clinical trials and basic research indicating that ESAs may harm cancer patients. Last year, the Centers for Medicare and Medicaid Services began denying coverage for the use of ESAs in cancer patients not undergoing chemotherapy and in those whose hemoglobin level is 10 g/dL or above. The center has further restricted use of darbepoetin, a second-generation, extendedrelease version, in patients undergoing chemotherapy. ESAs include epoetin alfa (Amgen’s Epogen and Procrit, which is manufactured by Amgen but licensed to Johnson & Johnson’s Ortho Biotech), Amgen’s longer-lasting darbepoetin alfa (Aranesp), and, in Europe, epoetin beta (NeoRecormon). The drugs are recombinant forms of erythropoietin (EPO), a naturally occurring hormone that is produced by the kidneys and controls red blood cell production. For the past 15 years, oncologists have prescribed ESAs to millions of anemic cancer patients in place of blood transfusions, hoping to improve their quality of life. Amgen scientists also reasoned that increasing anemic patients’ hemoglobin levels would help oxygenate tumors, thereby decreasing resistance to chemotherapy and radiation and improving outcomes. But a growing body of research on patients with head and neck, lymphoid, breast, cervical, and non – small-cell lung cancers and multiple myeloma indicates that patients taking ESAs have worse overall survival and tumor control when the drugs are given at hemoglobin levels higher than 12 g/dL. These patients are also more likely than patients who did not receive ESAs to have high blood pressure and thrombovascular events (TVEs). However, a study published in July in the Journal of Clinical Oncology suggested that patients with myelodysplastic syndrome treated long term with ESAs plus a white blood cell growth factor may have a survival advantage if they require few blood transfusions. But studies also show that ESAs reduce the need for transfusions only minimally, if at all, and that they usually do not imp rove patients’ quality of life. Ironically, the drugs were approved in 1993 as a safer alternative to blood transfusions just when the blood supply began to be screened for hepatitis B and C and human immunodeficiency virus, rendering blood much safer, while ESAs’ safety is now seriously questioned. The stakes in this controversy could hardly be higher: a large share of the profi ts of Amgen and Ortho Biotech; thousands of dollars of income for private practice oncologists who prescribe and administer these drugs; and, most important, the safety of cancer patients.

Cancer- and Chemotherapy-Induced Anemia

Anemia is a common condition in patients with cancer, and its correction through either transfusion with packed red blood cells or the administration of erythropoiesis-stimulating agents (ESAs) is a supportive care measure. The purpose of the guidelines is to operationalize the evaluation and treatment of anemia in cancer patients and to enable patients and clinicians to evaluate treatment options in the context of risks and benefits. The updated guidelines include a number of important changes that respond to new FDA recommendations limiting the use of ESAs in cancer patients. Updates also include new tables on the risks and benefits of ESAs versus red blood cell transfusion and recommendations for administering parenteral iron products. For the most recent version of the guidelines, please visit NCCN.org

Assessing adherence to the European Organization for Research and Treatment of Cancer (EORTC) guidelines for the use of erythropoiesis-stimulating agents in cancer patients

20696 Background: Anemia is a common symptom in cancer patients and has a considerable impact on patient quality of life (QoL). According to the European Cancer Anemia Survey, anemia was treated in only 38.9% of patients. Erythropoiesis-stimulating agents (ESAs) are widely used for the treatment of the chemotherapy-induced anemia (CIA). The European Organization for Research and Treatment of Cancer (EORTC) recently published guidelines for the use of ESAs in cancer patients, but actual adherence to these guidelines in clinical practice is unknown. Methods: Between March and July 2007, 16 working sessions were held and 179 Spanish oncologists were consulted to assess their adherence to the EORTC guidelines (update 2006)for the use of ESAs. In all sessions, a preliminary presentation about these guidelines was given, followed by a structured discussion that was facilitated by a moderator using an organized, brain storming work method (Metaplan). Results: Over 90% of oncologists agreed that the two major goals of ESA therapy are improvement of QoL and prevention of transfusions; 70% consider that CIA treatment with ESA should be initiated at a hemoglobin (Hb) level of 10–11g/dL. ESAs are administered every week (59%) or every three weeks (33%). In the opinion of 64% of respondents, the target Hb concentration should be 12–13 g/dL. Altogether 45% of oncologists use ESA in anemic patients with an Hb level of <11.9 g/dL to prevent a further decline in Hb. All participants agreed with the use of fixed doses of ESAs. Intravenous iron supplementation is low (5%). Conclusions: These study results show good adherence to the current EORTC guidelines in Spain, but action to increase adherence may improve patient outcomes. The main discrepancies are the use of intravenous iron and ESA in patients with Hb <11.9 g/dL. This study was supported by Amgen S.A. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen Amgen