Level 2: Mid-level evidence
Anemia in cancer patients may be secondary to the disease or to the treatment. Concerns have been raised about the safety of erythropoiesis-stimulating agents (ESAs) for treating anemia in cancer patients, prompting the FDA in January 2008 to update a previous boxed warning.

Three recent reviews investigated the safety and efficacy of ESA use in cancer patients. Although two large systematic reviews showed an increase in overall mortality risk, a third smaller review and subgroups in the first two reviews showed no differences in analyses limited to patients treated with ESAs while on chemotherapy.

A review of 53 trials with 13,933 patients showed a significant increase in overall mortality in patients being treated with an ESA compared with controls (11.3% vs. 10.6%, P <.05) but no significant difference in an analysis of 10,441 patients on chemotherapy from 38 trials (10.7% vs. 10.3%) (Lancet. 2009;373:1532-1542).

A second large review also showed a significant increase in overall mortality with ESAs compared with control (13.6% vs. 13.1%, P <.05) in a meta-analysis of 28 trials with 6,525 patients. However, there were no significant differences in mortality with use of ESAs in treatment of chemotherapy-induced anemia (risk ratio 1.04, not significant) in an analysis of 23 trials involving 4,273 patients (CMAJ. 2009;180:E62-71; available at www .cmaj.ca/cgi/content/full/180/11/E62, accessed August 12, 2009).

The third review was a pooled analysis of individual patient data from six trials evaluating darbepoetin alfa with 2,112 chemotherapy patients. There were no significant differences in overall survival, progression-free survival, or disease progression (J Clin Oncol. 2009;27:2838-2847).

In all three reviews, ESAs were associated with significant reductions in the risk of transfusions.