Erythropoietin Use in Cancer Patients: A Matter of Life and Death?

It has now been 15 years since the first formal demonstration that recombinant human erythropoietin can ameliorate anemia associated with cancer. Since then, dozens of clinical trials in diverse groups of cancer patients have convincingly demonstrated the power of erythropoietin to increase hemoglobin (Hb) levels, and to reduce the need for potentially risky RBC transfusions. Three nonrandomized, community-based, open-label studies, enrolling more than 7,000 patients with nonmyeloid malignancy, and at least one randomized study, also suggested that erythropoietin can improve patients’ quality of life (QOL). A subsequent placebo-controlled study, however, indicated that this QOL benefit may be more modest than was initially hoped. Because recombinant erythropoietin is viewed by most clinicians as relatively nontoxic, and because erythropoietic agents are widely believed to have both objective and subjective benefits, the chief barriers to the universal use of this class of drugs have been relatively high cost, the lack of a uniform Hb response, clinical inertia, and patient inconvenience. In addition, there are several efficacy hurdles that, if cleared, could lead to a more robust recommendation for the use of erythropoietin in all patients with cancer: a clear demonstration that erythropoietin improves tumor response to therapy; an unequivocal demonstration that erythropoietin improves overall survival; and convincing evidence that erythropoietin therapy can benefit patients with normal or near-normal Hb levels, just as it helps those with moderate or severe anemia. Because improvement in overall survival is the gold standard for any drug treatment in people suffering from malignancy, trials were developed to try to demonstrate that recombinant erythropoietin could positively influence life expectancy in this group of patients. Improvement in cancer survival with erythropoietin therapy seemed a lofty goal but did not appear to be too much to ask. There was good reason to believe that successful treatment of anemia might augment the effectiveness of cancer therapy and prolong life, given that there is little question that the presence of moderate to severe anemia is associated with reduced survival in persons with a malignancy. It is less clear, however, whether anemia itself is the proximate cause of reduced survival or is instead a surrogate marker for other adverse prognostic features. Correction of Hb to near-normal levels with RBC transfusions might help clarify this question, but is not practical and has multiple potential toxicities. Thus, the possibility of improving survival by ameliorating anemia is best addressed by the use of recombinant erythropoietin. However, an important caveat with respect to erythropoietins is that the effects of this class of drugs on cancer outcomes from anemia correction alone may never be understood clearly because they appear to have biologic effects other than just increasing hemoglobin. Interest in a possible positive association between erythropoietin treatment and survival was fueled by a prospective, randomized, double-blind, allocation-concealed, multinational study of 375 anemic patients receiving chemotherapy for nonmyeloid cancer, which suggested a trend toward improved survival with erythropoietin use (median survival, 17 months with epoetin alfa, 11 months with placebo; Kaplan-Meier estimates, P .13, log-rank test). However, that study’s primary end points were transfusions, Hb response, and QOL; it was not powered to detect survival differences. A similar but also not statistically significant trend toward improved survival with erythropoietin was observed in the recently published, placebocontrolled epoetin alfa study of the North Central Cancer Treatment Group, which also enrolled anemic patients with nonmyeloid cancer receiving chemotherapy. Despite these two large trials and other smaller studies suggesting a potential survival benefit with the use of recombinant erythropoietin, a meta-analysis that included 19 studies in cancer patients (randomized trials published JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 25 SEPTEMBER 1 2005