Erythropoietin and darbepoetin were FDA-approved in 1993 and 2002, respectively, to treat chemotherapy-associated anemia in patients with non-myeloid malignancies. At that time of approval for erythropoietin, concerns were raised about venous thromboembolism (VTE) and tumor progression that might occur because of ESA treatment in these patients. Expression of erythropoietin and erythropoietin receptors has been shown in several human cancers. In certain cancer types, in vitro studies have shown that activation of erythropoietin/erythropoietin receptors leads to proliferation, antiapoptosis, and invasion. While systematic studies have confirmed VTE risks in humans, studies have not identified an association between treatment with ESAs and increased mortality risk.

The study described below evaluates VTE and mortality rates of ESA use in phase 3 trials comparing ESAs with placebo or standard of care treatment to treat chemotherapy-associated anemia in cancer patients. Data were extracted from trials reviewed in the Cochrane Collaboration (January 1, 1985 - April 1, 2005) and MEDLINE and EMBASE databases (April 1, 2005 - January 17, 2008).

Mortality risk was evaluated for 13,611 patients with cancer from 51 phase 3 trials and VTE risk was evaluated for 8,172 patients with cancer from 38 phase 3 trials. Trials differed with respect to study drug, patient numbers, treatment duration, concomitant treatments, and cancer diagnoses.

Once again, a significantly increased risk of VTE was found in patients treated with ESA (334 events / 4,610 patients) vs. control patients (173 events / 3562 control patients) (RR, 1.57; 95% CI, 1.31-1.87). Overall, the risk of mortality was also greater in ESA treated patients (HR 1.10; 95% CI 1.01-1.20). Although there was a trend towards increased mortality in each subset (ESA treatment in patients with the anemia of cancer or those with chemotherapy-induced anemia), in neither group did this reach a level of statistical significance (anemia of cancer; HR, 1.29; 95% CI, 1.00-1.67;P=.05), (chemotherapy-associated anemia; HR, 1.09;95%CI, 0.99-1.19).

Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. Bennett CL, Silver SM, Djulbegovic B, Samaras AT, Blau CA, Gleason KJ, Barnato SE, Elverman KM, Courtney DM, McKoy JM, Edwards BJ, Tigue CC, Raisch DW, Yarnold PR, Dorr DA, Kuzel TM, Tallman MS, Trifilio SM, West DP, Lai SY, Henke M. JAMA. 2008 Feb 27;299(8):914-24.

NAAC Expert Commentary:
Although the explanation for higher complications (including mortality) among cancer patients treated with ESAs remains unclear, the accumulated data, including that from this report warrant both strict compliance to newly established guidelines and additional study.

One concern regarding prior meta-analyses is that their findings are based primarily on aggregated data from a variety of different clinical situations. Data is commonly obtained from divergent studies that could involve chemotherapy, radiation therapy, or no treatment, and the use of various ESAs with different doses and target hemoglobin levels.

The current report takes a step forward from prior studies, since the investigators were able to discriminate between patients receiving ESAs for cancer-associated anemia and patients receiving ESAs for chemotherapy-associated anemia. The distinction is important in light of the analysis, which identified a trend toward higher mortality in both subsets; although a trend was observed, statistical significance was not reached for either subset.

The question remains as to whether strict compliance to current recommendations regarding ESA use will be associated with increased VTE and mortality. This question will be addressed in ongoing prospective randomized trials. Although the increased risk of VTE is of important consequence, it is unlikely to explain the higher rate of mortality experienced by ESA-treated cancer patients. One explanation might be that many cancers express erythropoietin receptors, which might be stimulated towards proliferation by exogenous ESA. As intuitive as this may seem, the data, including in vitro and animal studies, has been far from conclusive.

Thus, a number of unresolved issues remain. Yet, most clinicians would agree that the existing quality of life data, which is quite favorable with regard to ESA use in anemia that is associated with cancer treatment, must be balanced with those concerns raised by analyses that demonstrate increased risks, including mortality. For the short term, oncologists must rely on their clinical judgment as to which patients with anemia should be treated, and by what means (i.e., transfusion, ESA). Adherence to current guidelines, such as those forwarded by ASH/ASCO or the EORTC, is highly recommended.

Last Modified: June 4, 2008