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

Authors' Affiliation: Office of Oncology Drug Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, White Oak, Maryland

Requests for reprints: Vinni Juneja, Food and Drug Administration, White Oak Building #22, 10903 New Hampshire Avenue, Silver Spring, MD 20993. Phone: 301-796-2288; E-mail: vinni.juneja{at}fda.hhs.gov.

Abstract

Purpose: Erythropoiesis-stimulating agents (ESA) are approved for the treatment of anemia in patients with nonmyeloid malignancies whose anemia is due to the effect of concomitantly administered chemotherapy. Since the 1993 approval of epoetin alfa in patients with cancer, the risk of thrombovascular events, decreased survival, and poorer tumor control have been increasingly recognized. The risks of ESAs in patients with cancer and the design of trials to assess these risks have been the topic of discussion at two Oncologic Drugs Advisory Committees in 2004 and 2007.

Experimental Design: Evaluation of randomized clinical trials comparing use of ESAs to transfusion support alone in patients with active cancer.

Results: Six studies (Breast Cancer Erythropoeitin Survival Trial, Evaluation of NeoRecormon on outcome in Head And Neck Cancer in Europe, Danish Head and Neck Cancer, Lymphoid Malignancy, CAN-20, and Anemia of Cancer) investigating ESAs in oncology patients showed decreased survival, decreased duration of locoregional tumor control, and/or increased risk of thrombovascular events. In these six studies, ESA dosing was targeted to achieve and maintain hemoglobin values in excess of current recommendations, and in three of the six studies, ESAs were administered to patients not receiving chemotherapy.

Conclusions: ESAs increase the risk of thrombovascular events and result in decreased survival and poorer tumor control when administered to achieve hemoglobin levels of 12 g/dL in patients with nonmyeloid malignancies. No completed or ongoing randomized, controlled trial has addressed safety issues of ESAs in patients with chemotherapy-associated anemia using currently approved dosing regimens in an epidermal tumor type. Additional studies are needed to better characterize these risks.