Efficacy and Safety Analysis of Epoetin Alfa in Patients With Small-Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Trial

Erythropoiesis-stimulating agents (ESA) used for the treatment of chemotherapy-induced anemia in cancer patients have been associated with adverse outcomes of enhanced tumor progression and impaired survival in a series of recent clinical trials. As clinical practice guidelines for ESA administration in cancer patients have evolved to improve safety, the mechanisms underlying the adverse outcomes and whether ESAs exert direct and/or indirect effects in primary tumors to modulate tumor cell growth, survival, and chemoradiotherapy responses remain uncertain. Erythropoietin receptor (EpoR) expression in tumor cells has raised the simplistic possibility that Epo signaling mediated via a functional cellular receptor may contribute to tumor progression in a direct manner. However, Epo biology in cancer is likely to be complex and an interplay of multiple factors is potentially involved in the overall tumor response to exogenous Epo. Optimization of ESA use as an important supportive therapy modality in cancer patients, and further investigation of the role of Epo-EpoR in cancer biology will require a combination of carefully designed preclinical and clinical studies designed to ascertain not only the effect of ESA therapy on clinical outcomes such as tumor response, progression-free, and overall survival but also to investigate the potential effects of Epo on biomarkers of EpoR activation and factors related to tumor biology and chemoradiation responsiveness.

Section: Recent Clinicaltrials Of Esasöwhat Canwe Learn?supporting

confidence: 68%

Erythropoiesis-Stimulating Agent Use in Cancer: Preclinical and Clinical Perspectives

Arcasoy

2008

“…In summary, there have been a large number of trials investigating ESAs for the treatment of CIA in cancer patients (5,(10)(11)(12)(13)(14)(15)32). In several trials, an increase in thrombotic events was seen in the ESA arm (6,8,11,54).…”

Section: Discussionmentioning

confidence: 99%

Recombinant Human Erythropoietin in Combination with Chemotherapy Increases Breast Cancer Metastasis in Preclinical Mouse Models

Hedley

Chu

Ormond

et al. 2011

Purpose: Erythropoiesis-stimulating agents (ESA) are used clinically for treating cancer-related anemia. Recent clinical trials have reported increased adverse events and reduced survival in ESA-treated breast cancer patients receiving chemotherapy, potentially related to erythropoietin (EPO)-induced cancer progression. However, minimal preclinical data are available about the impact of EPO on metastatic cell behavior and/or the metastatic process, and this was the goal of our study.Experimental Design: Breast cancer cell lines were treated with recombinant human EPO (rHuEPO) and screened for expression of EPO receptors (EPOR). MDA-MB-231 and MDA-MB-435 cell lines were used for functional assays in vitro (two-dimensional/three-dimensional growth and survival) and in vivo (tumorigenicity and metastasis), in the presence or absence of EPO and/or cytotoxic agents.Results: A large variation in EPOR expression across cell lines was observed. In vitro, rHuEPO had a protective effect on radiation-treated MDA-MB-435 cells (P < 0.05); however, rHuEPO treatment alone or combined with chemotherapy or hypoxia did not influence cell survival. In vivo, rHuEPO increased lung metastases in immunocompromised mice injected with MDA-MB-231 or MDA-MB-435 cells and treated with chemotherapy relative to mice treated with chemotherapy alone (P < 0.05).Conclusions: The lack of an in vitro effect of rHuEPO highlights the importance of in vivo studies to delineate the effects of EPO on the metastatic process. These studies may begin to uncover the underlying functional explanation for the observed EPO-related adverse events and decreased survival in ESA-treated metastatic breast cancer patients undergoing chemotherapy.

“…The study met its noninferiority end point, ruling out a potential decrease in response rate of >6% in the ESA-treated arm compared with controls. Survival was not significantly different [Hazard Ratio (HR), 1.17; 95% confidence interval (95% CI), 0.89-1.55] in the epoetin alfa and placebo-treated arms, respectively (12).…”

Section: Overview Of Current Trials Addressing Risks Of Tumor Promotionmentioning

confidence: 99%

Continuing Reassessment of the Risks of Erythropoiesis-Stimulating Agents in Patients with Cancer

Juneja

Keegan

Gootenberg

et al. 2008