Erythropoiesis stimulating agents: a personal journey.

I write this editorial in deference to the many experts who devote their careers to this important field. In this editorial, I simply report the journeyman route of a medical oncologist who is desperately trying to improve the outcomes of women suffering from breast cancer. At the end of the 1990s, there was much hope that erythropoie-sis stimulating agents (ESAs) would improve the survival of cancer patients. It was all so very obvious. Elegant partial oxygen pressure (pO2) histograms showed differential oxygenation between normal and malignant tissues, and patients with higher tumoral pO2 were demonstrated to have improved survival (1,2). Beverly Teicher had shown the oxygen-dependency of cancer and had published oxygen enhancement ratios for the representative members of the key mechanistic classes of anticancer agents. Preclinical models had shown that erythropoietin restored the anemia-induced reduction in antineoplastic cytotoxicity, eg, cyclophosphamide (3). Hence, the ESAs, by raising hemoglobin levels, improving oxygenation, and increasing cytotoxicity of our antineoplastics, simply must improve survival! ESAs even improved antitumor immune response (4) and increased radiosensitivity (5,6). Many of my friends and colleagues will remember slide sets that I showed, listing various references to the beneficial effects of ESAs on tumor regression in a variety of tumor types (7–10). Then along came the famous Glaser et al. data (11) of epoetin increasing hemoglobin levels and improving prognosis in anemic patients with head and neck cancer and the Littlewood trial (12) that showed an improvement in 12-month survival from 49% to 60% for epoetin vs placebo and even an increase in overall survival from 11 to 17 months. Put all of this together and one could not have a better background for our own BEST INT76 (13) and Henke trials (14). Even the names were optimistic: Breast cancer Erythropoietin Survival Trial (BEST), the Breast Cancer-Anemia and the Value of Erythropoietin Trial (BRAVE). The rest is, as they say, history. So where do we stand now? In August 2003, I wrote a letter to Lancet Oncology (15), refer-encing the imbalance of risk factors between treatment groups and other issues in INT76 and documenting several methodological issues that hindered interpretation of both the BEST and Henke trials, with a conclusion that they " generated more questions than answers. " Ten years later, in my humble opinion, there is no doubt: virtually all of the meta-analyses, including three of the most recent: the Tonelli et al. 2009 meta-analysis (16) …