Use Of Erythropoiesis-stimulating Agents In Patients Research Articles

The Effect of Erythropoiesis-Stimulating Agent on the Management of Chemotherapy-Induced Anemia and Tumor Growth in Diffuse Large B-Cell Lymphoma Patients

Bacground : Erythropoiesis stimulating agents (ESA) increase hemoglobin levels, reduce red blood cell (RBC) transfusion requirements and improve the quality of life (QoL) in patients with chemotherapy-associated anemia (CAA). The purpose of this study is to investigate the efficacy and safety of ESA for management of anemia caused by chemotherapy in patients with diffuse large B-cell lymphoma (DLBCL). And this study estimated quality of life as measured by Functional Assessment of Cancer Therapy Scales for anemia (FACT-An) additionally. Until now, several studies suggested that ESA can affect the progression of tumors. This study conducted experiments to confirm whether the results of previous studies were also applied to lymphoma cells.Patients and Methods : This prospective, multicenter, phase II study enrolled 50 Histologically confirmed DLBCL patients who were treated with rituximab, cyclophosphamide, doxorubicin, vincristin, and prednisolone (R-CHOP) chemotherapy. This study enrolled patients who were shown hemoglobin < 10.0 g/dL at least 3 cycles after starting R-CHOP, were planning to receive at least 4 times of darbepoetin, could read Quality of life as measured by FACT-An and agreed with informed consent. However, this study excluded patients who combined iron deficiency anemia, received erythropoietin at least one months before starting darbepoetin, serious pre-existing medical condition, and untreated primary or metastatic CNS(central nervous system) malignancy. This study was registered in clinicaltrial.gov, and more information can be found at NCT02890602. All patients received darbepoietin alfa at fixed dose of 360 mg once every 3 weeks and if the hemoglobin level exceeds 12 g/dL, administration of darbepoietin was stopped temporarily. In addition, DLBCL cell lines or primary DLBCL cells were tested in vitro to investigate if there were any adverse effects of ESAs on the cancer cell growth.Results : Fifty patients were enrolled between Sep 2012 and Oct 2016. The median age was 64.5 years (range: 34-79 years). The baseline clinical features were as follows: female sex, 68.0%; ECOG >1, 75.5%; stage III/IV, 80.0% and International Prognostic Index score (IPI) > 2, 53.3%, and mean serum ferritin level, 648.13±982.52. The baseline mean hemoglobin level was 9.24 g/dL and overall mean change in hemoglobin level was 1.54±1.3 g/dL at 16 weeks. 46% of total enrolled patients achieved an increase in Hb levels of at least 2 g/dL after 16 weeks of darbepoietin administration and median time to response was 8 weeks. The change of OoL was not significant from baseline to finish of ESA. Most adverse events were hematologic complications which were attributed to the primary disease or received chemotherapy. Only one patient had a thrombotic event which was Common Terminology Criteria for Adverse Events (CTCAE) grade I. Transfusion necessity was determined by clinical judgment and the transfusion rates were 18%. In in vitro study using DLBCL cells, erythropoietin or darbepoietin did not alter cancer cell viability nor rituximab-mediated cytotoxicity under the conditions we have tested.Conclusions : Our study has demonstrated that ESA is effective and safe for patients suffering from anemia after RCHOP chemotherapy. The use of ESA in patients with DLBCL did not deteriorate the quality of life of the patients during chemotherapy. Finally, our research have also shown that the use of ESA does not affect the growth of lymphoma cells. (EPOMA ClinicalTrials.gov number, NCT02890602) DisclosuresNo relevant conflicts of interest to declare.

A Single Institution Retrospective Analysis of the Effect of Erythropoiesis Stimulating Agents in Patients with Multiple Myleoma

Background: Erythropoiesis Stimulating Agents (ESAs) are FDA approved for chemotherapy induced anemia and anemia of chronic kidney disease. These indications are more frequent in patients with multiple myeloma. Use of ESAs has been associated with an increased risk of heart attack, stroke, venous thromboembolism (VTE), and all-cause mortality. In patients with cancer, ESA's have been associated with worse progression free survival (PFS) and overall survival (OS) Previous research regarding ESA use in patients with multiple myeloma has been limited and conflicting. In this study, we evaluate the effects of ESA use in patients with multiple myeloma. Additionally, we examined the frequency of ESA usage after the 2007 FDA safety update revising product labeling for ESAs.Methods: A retrospective chart review was conducted on patients diagnosed with active multiple myeloma between January 1st, 2000 and December 31st, 2015 at Gundersen Health System in La Crosse Wisconsin. Collected data include patient demographics, medications, lab tests, comorbidities, and the dates of any VTE, stroke, or myocardial infarction. Both a logistic regression and a matched case-control analysis were used to compare rates of complications in patients using ESAs to those that did not. ESA effect on median survival time was also calculated for each International Staging System (ISS) stage of disease.Results:There were 278 patients included for demographic analysis (Table 1), of which 268 were included in the logistic regression analysis and 124 (62 pairs) in the matched case-control analysis.A logistic regression model constructed via stepwise selection found that bone lesions at diagnosis (Odds Ratio (OR): 2.5 [1.2-5.1]), antiplatelet drug use (OR: 3.7 [1.2-11.3]) and ESA use (OR: 4.7 [2.2-9.9]) were associated with increased risk of VTE in our patient population. Use of an Angiotensin Converting Enzyme (ACE) inhibitor (OR: 0.4 [0.2-0.9]) was associated with a decreased risk of VTE. Increased odds of VTE with ESA usage (OR: 5.9 [1.9 - 18.8]) were also noted in the matched case-control analysis. There was no association found between rate of stroke and ESA usage in either logistic or matched case-control analysis. No significant association between ESA use and overall survival was noted in either logistic or matched case-control analysis.When comparing outcomes based upon pre and post FDA revised product labeling, we found a 50% reduction in ESA usage within our institution. In this same time period, the percentage of patients with multiple myeloma developing VTEs has been significantly reduced (18.6% vs 12.8% [p<0.007]).Conclusions: In our population, the use of ESAs in multiple myeloma patients was associated with increased risk of VTE. No significant association between ESA use and overall survival was noted. The observed decrease in both ESA use and rate of VTE in patients with myeloma after the 2007 revised safety labelling by the FDA may reflect practice changes in response to this revision at our institution. Further study in a prospective large multicenter dataset with further control of confounding variables is warranted. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The Impact of the Risk Evaluation Mitigation Strategy for Erythropoiesis-Stimulating Agents on Their Use and the Incidence of Stroke in Medicare Subjects with Chemotherapy-Induced Anemia with Lung and/or Breast Cancers.

Erythropoiesis-stimulating agents (ESAs), found to be effective in reducing anemia in chemotherapy-treated cancer patients, also are associated with an increased risk of cardiovascular events, including stroke. In an attempt to mitigate the risk, the Food and Drug Administration implemented a Risk Evaluation Mitigation Strategy (REMS) in February 2010. The purpose of this study is to evaluate change over time in the incidence of stroke among these patients before and after implementation of REMS. A retrospective data analysis using the Medicare 5% Sample Dataset, 2008-2011, was performed. Patients had to be 65 years of age or older at the start of at least 1 year of continuous enrollment and to have lung and/or breast cancers along with chemotherapy-induced anemia (CIA) in both pre-REMS and post-REMS periods (1Q2008 through 4Q2009 and 1Q2010 through 4Q2011, respectively). Logistic regression was used to evaluate differences in proportions of patients who received ESAs and experienced a stroke pre and post REMS. The pre-REMS cohort included 1252 eligible patients prescribed ESAs; the post-REMS cohort included 949 patients. No statistically significant change in stroke incidence was observed post REMS among patients with CIA who received ESAs. There was a 29.5% decrease in ESA use in patients with lung cancer and a 27.8% decrease in patients with breast cancer. Both were statistically significant. Results adjusted for baseline characteristics and comorbid conditions were similar. There was a statistically significant decrease in ESA use in patients with breast and/or lung cancers post REMS; no statistically significant reduction in the incidence of stroke was observed regardless of cancer type.

Safety and efficacy outcomes with erythropoiesis-stimulating agents in patients with breast cancer: a meta-analysis

New data on erythropoiesis-stimulating agents (ESAs) regarding overall survival and disease progression-related outcomes in patients with breast cancer receiving chemotherapy are presented in a meta-analysis of controlled trials of ESA use (epoetin α, epoetin β, darbepoetin α, biosimilars). A literature search identified reports from January 1997 through March 2014. We used company databases for Amgen, Inc., or Janssen studies and published data for other studies. Random-effects odds ratios (ORs) were calculated to compare results for patients randomized to ESA with those randomized to control. Deaths were reported for 571 of 2346 patients (24%) in the ESA groups and 523 of 2367 patients (22%) in the control groups [OR, 1.20; 95% confidence interval (CI) 1.03-1.40]. Sensitivity analyses were conducted to explore the effects of individual studies and exclusion of one study (BEST) resulted in an OR for death of 1.12 (95% CI 0.94-1.34). In seven studies reporting progression-related end points (N = 4197; ESA n = 2088; control n = 2109), the OR was 1.01 (95% CI 0.87-1.16) for ESA compared with control. After incorporating recent results of ESA use in patients with breast cancer, risks of survival and progression-free survival remain consistent with previously published data.

Anaemia management in patients with chronic kidney disease: Taiwan practice guidelines.

The introduction of erythropoiesis-stimulating agents (ESAs) markedly improved the lives of many anaemic patients with chronic kidney disease (CKD). In Taiwan, the strategy of management of anaemia in patients with CKD was different from many other parts of the world. In 1996, the National Health Insurance Administration of Taiwan applied a more restrictive reimbursement criteria for ESA use in patients with CKD. ESA is to be initiated when non-dialysis CKD patients have a serum creatinine >6 mg/dL and a hematocrit <28% to maintain a hematocrit level not exceeding 30%. The maximal dose of epoetin-α or β was 20 000 U per month. The target haemoglobin range and dose limitation for ESAs were the same for dialysis CKD patients. Thus, long before randomized controlled trials showing an increased risk for cardiovascular events at nearly normal haemoglobin concentrations and higher ESA doses in CKD, nephrologists in Taiwan had avoided the use of disproportionately high dosages of ESAs to achieve a haemoglobin level of 10-11 g/dL. Moreover, intravenous iron supplementation was encouraged earlier in Taiwan in 1996, when we reached consensus on the diagnostic criteria for iron deficiency (serum ferritin <300 ng/mL and/or transferrin saturation <30%). The experience of CKD anaemia management in Taiwan demonstrated that a reasonable haemoglobin target can be achieved by using the lowest possible ESA dose and intravenous iron supplementation.

Effect of Medicare Dialysis Payment Reform on Use of Erythropoiesis Stimulating Agents

In 2011, the Centers for Medicare and Medicaid Services (CMS) replaced fee-for-service reimbursement for erythropoiesis stimulating agents (ESAs) with a fixed-sum bundled payment for all dialysis-related care and pay-for-performance incentives to discourage maintaining patients' hematocrits above 36 percent. We examined the impact of the new payment policy on the use of ESAs. CMS's Renal Information Management System. Regression discontinuity design assessing the use of ESAs by hematocrit level before and after the implementation of the payment policy change. Secondary data from 424,163 patients receiving hemodialysis treatment between January 2009 and June 2011. The introduction of bundled payments with pay-for-performance initiatives was associated with an immediate and substantial decline in the use of ESAs among patients with hematocrit >36 percent and little change in the use of ESAs among patients with hematocrit ≤36 percent. In the first two quarters of 2011, the use of ESAs during dialysis fell by about 7-9 percentage points among patients with hematocrit levels >36 percent. No statistically significant differences in ESA use were observed at the thresholds of 30 or 33 percent. CMS's payment reform for dialysis care reduced the use of ESAs in patients who may not benefit from these agents.

Survival effects of erythropoiesis-stimulating agents (ESAs) in patients with breast cancer: A meta-analysis.

120 Background: New data are available from two trials of ESA use in patients with breast cancer receiving chemotherapy. We conducted a meta-analysis of trials of ESA use in this population. Methods: A literature search identified reports from 1997-2012 that included mortality data from controlled ESA trials (epoetin alfa, epoetin beta, darbepoetin alfa, biosimilars) in patients with breast cancer receiving chemotherapy. We used data from company databases for Amgen Inc. or Janssen Products LP studies and published data for other studies. Random-effects odds ratios (OR) were calculated to compare results for patients randomized to ESA to patients randomized to control. Analyses were stratified by metastatic stage; mixed stage or treatment; and adjuvant/neoadjuvant treatment. Results: We analyzed 9 studies (N = 4,713; ESA n = 2,346, control n = 2367) (Table).The overall stratified random-effects OR for death was 1.17 (95% confidence interval, 0.99-1.39). Details are presented in the Table. Conclusions: Overall survival OR remains consistent with prior data after including recent results. [Table: see text]

Survival effects of erythropoiesis-stimulating agents (ESAs) in patients with breast cancer: A meta-analysis.

e20616 Background: New data are available from two trials of ESA use in patients with breast cancer receiving chemotherapy. We conducted a meta-analysis of trials of ESA use in this population. Methods: A literature search identified reports from 1997-2012 that included mortality data from controlled ESA trials (epoetin alfa, epoetin beta, darbepoetin alfa, biosimilars) in patients with breast cancer receiving chemotherapy. We used data from company databases for Amgen Inc. or Janssen Products LP studies and published data for other studies. Random-effects odds ratios (OR) were calculated to compare results for patients randomized to ESA to patients randomized to control. Analyses were stratified by metastatic stage; mixed stage or treatment; and adjuvant/neoadjuvant treatment. Results: We analyzed 9 studies (N = 4713; ESA n = 2346, control n = 2367) (Table).The overall stratified random-effects OR for death was 1.17 (95% confidence interval, 0.99-1.39). Details are presented in the Table. Conclusions: Overall survival OR remains consistent with prior data after including recent results. [Table: see text]

The Effect of the APPRISE Mandate on Use of Erythropoiesis-Stimulating Agents and Transfusion Rates in Patients With Ovarian Cancer Receiving Chemotherapy

Objective Erythropoiesis-stimulating agents (ESAs) support chemotherapy-induced anemia in patients with epithelial ovarian cancer (EOC). In response to research demonstrating that ESAs increase tumor growth and shorten survival, the Food and Drug Administration mandated the new APPRISE (Assisting Providers and Cancer Patients with Risk Information for the Safe use of ESAs) guidelines for consenting patients before ESAs administration. We sought to quantify the change in ESA and red blood cell (RBC) transfusion use after the APPRISE mandate was instituted. Methods/Materials After institutional review board approval, a retrospective chart review compared patients with EOC undergoing chemotherapy before and after the APPRISE mandate. Abstracted data included patient demographics, chemotherapy treatment status and regimen, and number of patients requiring ESAs or RBCs. A cost savings analysis was also performed. Results Eighty-four patients who underwent 367 cycles of chemotherapy after the APPRISE guidelines were compared with a matched set of 88 patients receiving 613 cycles of chemotherapy before the APPRISE guidelines. There were no statistically significant differences between the groups. Most patients had advanced stage disease and received primary taxane-/platinum-based chemotherapy. Of 88 patients, 45 (51%) in the pre-APPRISE group received a total of 196 ESA injections compared with 0 patients in the post-APPRISE group. Red blood cell transfusion in the post-APPRISE group was similar to that in the pre-APPRISE group (8.3% vs 14.8%, P = 0.28). Omission of ESAs in the post-APPRISE group resulted in a roughly $700,000 savings in billable charges. Conclusions In our institution, the APPRISE guidelines have resulted in complete cessation of the use of ESAs in patients with primary or recurrent EOC, resulting in considerable cost savings. Importantly, RBC transfusion rates did not significantly increase after the guidelines were imposed.

The Effect of the APPRISE Mandate on Use of Erythropoiesis-Stimulating Agents and Transfusion Rates in Patients With Ovarian Cancer Receiving Chemotherapy

Erythropoiesis-stimulating agents (ESAs) support chemotherapy-induced anemia in patients with epithelial ovarian cancer (EOC). In response to research demonstrating that ESAs increase tumor growth and shorten survival, the Food and Drug Administration mandated the new APPRISE (Assisting Providers and Cancer Patients with Risk Information for the Safe use of ESAs) guidelines for consenting patients before ESAs administration. We sought to quantify the change in ESA and red blood cell (RBC) transfusion use after the APPRISE mandate was instituted. After institutional review board approval, a retrospective chart review compared patients with EOC undergoing chemotherapy before and after the APPRISE mandate. Abstracted data included patient demographics, chemotherapy treatment status and regimen, and number of patients requiring ESAs or RBCs. A cost savings analysis was also performed. Eighty-four patients who underwent 367 cycles of chemotherapy after the APPRISE guidelines were compared with a matched set of 88 patients receiving 613 cycles of chemotherapy before the APPRISE guidelines. There were no statistically significant differences between the groups. Most patients had advanced stage disease and received primary taxane-/platinum-based chemotherapy. Of 88 patients, 45 (51%) in the pre-APPRISE group received a total of 196 ESA injections compared with 0 patients in the post-APPRISE group. Red blood cell transfusion in the post-APPRISE group was similar to that in the pre-APPRISE group (8.3% vs 14.8%, P = 0.28). Omission of ESAs in the post-APPRISE group resulted in a roughly $700,000 savings in billable charges. In our institution, the APPRISE guidelines have resulted in complete cessation of the use of ESAs in patients with primary or recurrent EOC, resulting in considerable cost savings. Importantly, RBC transfusion rates did not significantly increase after the guidelines were imposed.

The effect of the APPRISE mandate on use of erythropoiesis-stimulating agents and transfusion rates in ovarian cancer patients.

5060 Background: Erythropoiesis-stimulating agents (ESAs) have long been used to support chemotherapy-induced anemia in patients with epithelial ovarian cancer (EOC). Recent studies have demonstrated that ESAs may lead to increased tumor growth and shorter survival. The FDA mandated new guidelines (APPRISE, for Assisting Providers and Cancer Patients with Risk Information for the Safe use of ESAs) for consenting patients before ESA administration. We sought to quantify the change in ESA use and RBC transfusion rates after the APPRISE mandate was instituted. Methods: A retrospective chart review identified patients with EOC undergoing chemotherapy after initiating the APPRISE mandate. A similar subset of patients treated prior to the APPRISE guidelines served as a control cohort. Abstracted data included patient demographics, primary or second line treatment status, chemotherapy regimen, number of patients requiring ESA or RBCs, or both, and a cost savings analysis. Results: 84 patients with EOC were identified as having undergone 367 cycles of first or second line chemotherapy after the APPRISE guidelines were instituted. A matched set of 88 patients receiving 613 cycles of chemotherapy within a year prior to institution of the APPRISE guidelines was analyzed for comparison. The two groups were statistically similar. Most patients in each group were initially diagnosed with advanced stage disease, were receiving primary chemotherapy, and were receiving taxane/platinum-based chemotherapy. 45 of 88 patients (51%) in the pre-APPRISE group received a total of 196 ESA injections compared to 0 of 84 patients (0%) in the post-APPRISE group. In spite of discontinuing the use of ESAs and no change in transfusion thresholds, RBC transfusion in the post-APPRISE group was similar to that in the pre-APPRRISE group (8.3% vs. 14.8%, p=.28). Omission of ESAs in the post-APPRISE group resulted in a cost-savings of an estimated $700,000 in billable charges. Conclusions: In our institution, the APPRISE guidelines resulted in complete cessation of ESA use in patients with EOC, resulting in considerable cost savings. Importantly, RBC transfusion rates did not increase after the guidelines were imposed.

Management of anaemia in CKD-the relative importance of erythropoietin and iron.

During an industry-sponsored symposium at the ERA–EDTA meeting in Munich 2010, four experts gathered to debate and provide an update on the treatment of anaemia in chronic kidney disease (CKD) patients, especially the relative contributions of erythropoiesis-stimulating agents (ESAs) and iron in its management. I chaired this symposium and invited these experts in collaboration with the sponsor to summarize their opinions. As the results of the largest of the ESA trial, TREAT, were available, many presenters focused on those results. The expert opinions were partly supported by available data, and there were, on occasions, differences in opinion between the experts on the interpretation of the data. For example, Dr Coyne’s statement that stroke risk is independent of ESA hyporesponsiveness is not a view that I share. I believe that the analysis of Solomon et al. in which Dr Coyne’s statement was based was simply not sufficiently powered to detect this relationship. Dr Locatelli states that the TREAT study was not a ‘placebo’ randomized controlled trial because the placebo group experienced an increase in haemoglobin (Hgb) over time. I disagree. The Hgb levels increased over time because the placebo group had a rescue feature which allowed administration of darbepoietin should Hgb fall below 9 g/dL. Dr Bhandari states that the profile of the ideal iron preparation should be capable of delivering sufficient quantities of intravenous iron to correct iron deficiency rapidly, with minimal potential side effects including low catalytic/labile iron release and negligible immunogenicity (risk of anaphylaxis). Yes, but I believe that the long-term safety of intravenous iron is the most important attribute which needs to be evaluated; long-term toxicity would trump any convenience afforded by the drug. Dr Kalra states that the drug should have reduced immunogenic potential and reduced risk for free iron toxicity. Although these claims may be true, they remain to be validated in larger safety studies especially among patients with multiple drug allergies. Below are opinions provided by the experts. There are several statements where consensus was not achieved. However, the experts do have a right to their opinions, and I present them below as they were presented to me, even when I am in disagreement. The highlights of this symposium, as I see it, are as follows: Normalizing Hbg among people with CKD is associated with cardiovascular and thrombotic risk. These risks can only be partially managed by correcting anaemia. Hyporesponsiveness to ESAs is associated with increased cardiovascular risk. Whether it is the dose of ESAs, poor response to ESA dose, a combination of the two or some other traits that confer this increased risk is unknown. Therefore, it should not be taken as a foregone conclusion that the dose of ESA is toxic. However, it is prudent to limit the dose of ESA to the minimum required to achieve a satisfactory Hbg response. The upper limit of ESA dose is unknown. Iron deficiency remains an important cause of ESA hyporesponsiveness. The diagnosis of iron deficiency among patients with CKD remains difficult. The pitfalls in making a diagnosis of iron deficiency anaemia are discussed. No gold standard is established. Therefore, when in doubt, a therapeutic trial of intravenous iron may be useful to establish a firm diagnosis. Among haemodialysis patients, the preferred route of iron administration is intravenous. However, it must be noted that patients with CKD who are not on haemodialysis can receive iron either orally or intravenously; there is no preference. The various parenteral irons, which are currently marketed, and their risks and benefits are discussed. Normalizing Hbg with ESAs in patients with CKD increases cardiovascular risk, whereas hyporesponsiveness to ESAs is associated with increased risk. Thus, it is logical to hypothesize that the cardiovascular risk of ESA use in patients with CKD may be mitigated with iron administration. Whether iron administration reduces ESA hyporesponsiveness or decreases or increases cardiovascular risk is currently unknown. The risk–benefit ratio of iron administration in CKD patients needs to be evaluated in well-designed prospective randomized controlled trials with cardiovascular and renal outcomes. Iron isomaltoside 1000 may be an attractive intravenous iron that may allow rapid repletion and theoretically a better safety profile.

Economic evaluation of erythropoiesis‐stimulating agents for anemia related to cancer

Erythropoiesis-stimulating agents (ESA) administered to cancer patients with anemia reduce the need for blood transfusions and improve quality-of-life (QOL). Concerns about toxicity have led to more restrictive recommendations for ESA use; however, the incremental costs and benefits of such a strategy are unknown. The authors created a decision model to examine the costs and consequences of ESA use in patients with anemia and cancer from the perspective of the Canadian public healthcare system. Model inputs were informed by a recent systematic review. Extensive sensitivity analyses and scenario analysis rigorously assessed QOL benefits and more conservative ESA administration practices (initial hemoglobin [Hb] <10 g/dL, target Hb < or =12 g/dL, and chemotherapy induced anemia only). Compared with supportive transfusions only, conventional ESA treatment was associated with an incremental cost per quality-adjusted life year (QALY) gained of $267,000 during a 15-week time frame. During a 1.3-year time horizon, ESA was associated with higher costs and worse clinical outcomes. In scenarios where multiple assumptions regarding QOL all favored ESA, the lowest incremental cost per QALY gained was $126,000. Analyses simulating the use of ESA in accordance with recently issued guidelines resulted in incremental cost per QALY gained of > $100,000 or ESA being dominated (greater costs with lower benefit) in the majority of the scenarios, although greater variability in the cost-utility ratio was present. Use of ESA for anemia related to cancer is associated with incremental cost-effectiveness ratios that are not economically attractive, even when used in a conservative fashion recommended by current guidelines.

Key insights into present and future treatments of anaemia in CKD patients

Key insights into present and future treatments of anaemia in CKD patients

Adherence to guidelines for use of erythropoiesis-stimulating agents in patients with chemotherapy-induced anemia: Results of a retrospective study of an electronic medical-records database in the United States, 2002–2006

Background: Chemotherapy-induced anemia (CIA) commonly occurs in cancer patients receiving conventional myelosuppressive chemotherapy. Two national guidelines regarding the use of erythropoiesis-stimulating agents (ESAs) in CIA were released in 2002. Because of poorer disease outcomes and increased risk of adverse events associated with ESAs in recent studies, the use of ESAs has been increasingly restricted in practice guidelines in the years 2007 and 2008. Objective: The aim of this study was to provide a baseline for adherence to national guidelines in the use of ESAs for CIA between 2002 and 2006. Methods: This retrospective study used the Varian Medical Oncology database (Varian Medical Systems, Inc., Palo Alto, California) of electronic medical records, representing 17 outpatient oncology organizations at 71 clinic locations in the United States. Adults diagnosed with any malignant neoplasm who started conventional cytotoxic chemotherapy between January 1, 2002, and September 30, 2006, were included. The proportion of patients receiving an ESA was calculated by hemoglobin (Hb) level during each chemotherapy cycle, stratified by line of chemotherapy and year. Logistic regression modeling identified predictors of ESA use in anemic patients during the first chemotherapy cycle. Results: The records of 17,731 cancer patients were evaluated. Median (SD) age was 61 (13) years, and 58.9% were female. Most patients (84.1%) had a solid tumor. Many patients (41.3%) received platinumcontaining chemotherapy and 74.4% received combination chemotherapy. During the first 5 cycles of first-line chemotherapy among patients with CIA (Hb <11 g/dL), ESAs were used by 55.8% of patients at cycle 1 and 68.9% at cycle 5. ESA use in CIA patients increased across lines of chemotherapy and time. Few patients (2.8%) received an ESA at Hb >13 g/dL. The statistically significant predictors of ESA use included age >65 years, eastern US residence, private health insurance, community-based care, and solid tumors, especially lung cancer. Conclusion: The patterns we observed were generally consistent with prevailing ESA labels and national guidelines during 2002 through 2006. Although ESA use in patients with CIA increased over chemotherapy cycles, lines of chemotherapy, and time, <70% of CIA episodes were treated with ESAs during the initial 5 chemotherapy cycles.

Tumor Progression Associated with Erythropoiesis-Stimulating Agents

To evaluate, characterize, compare, and critique trials reporting increased tumor progression in patients with cancer who are receiving erythropoiesis-stimulating agents (ESAs) that led to Food and Drug Administration (FDA) actions for black box warnings and labeling changes. Literature was accessed through MEDLINE (1950-August 2008) and PubMed (1975-August 2008) using the search terms recombinant erythropoietin, darbepoetin, epoetin, anemia, neoplasms, and disease progression. Articles cited in MedWatch alerts, Oncologic Drugs Advisory Committee meeting briefs, and bibliographies from identified articles were also reviewed. All studies published in English with data suggesting increased tumor progression or death due to disease progression in patients receiving ESAs were included. ESAs are approved for treatment of anemia in several different disease states, including chemotherapy-induced anemia. Ten trials investigating off-label use of ESAs in patients with cancer have reported an increased risk of tumor progression and/or treatment-associated death. Two of these trials reported worse overall survival with ESA treatment compared with placebo (28% vs 23% and 21.9% vs 16.4%), while another trial reported shorter time to death with treatment (68 vs 131 days; p = 0.04). Many of these studies had important limitations, including imbalanced groups at baseline and poor design. Moreover, none of these trials was designed to detect a statistically worse outcome with ESAs; thus, absolute conclusions regarding tumor progression cannot be drawn. As a result, better designed trials with safety as the primary outcome are ongoing. Additional studies are needed and being undertaken to qualify and quantify the possible risk of tumor progression with use of ESAs. Prudent practice dictates that until results of these trials are available, ESAs should be used in accordance with FDA labeling.