If Only It Were Simple
Authors: Rodger J. Winn
Journal: Journal of the National Comprehensive Cancer Network (2005)

If Only It Were SimpleFatigue is one of the most common and most bothersome symptoms experienced by cancer patients, with chemotherapy-induced anemia one of the major causes.Erythropoietic therapy corrects anemia, and because improved quality of life 1 and functional status 2 have been shown as a result of improved hemoglobin levels, treatment with these stimulating agents is warranted.In reality, however, biologic systems are not that simple.If the effect of erythropoietin and darbopoietin was solely limited to raising hemoglobin levels, current clinical trials would have answered most of the searing questions and unqualified recommendations for usage could be made with a comfortable degree of certitude.However, the biologic end-point of raising hemoglobin to 12 to 14 g/dL has other impacts on vascular and hematologic systems, with possible rheologic consequences leading to an increased risk of thrombovascular events.Of concern is the possibility that raising hemoglobin levels adversely affects survival.A decrease in survival for erythropoietin-treated patients was noted in 2 randomized trials: one in head and neck cancer and one in metastatic breast cancer. 3In both of these trials, the incidence of serious thrombotic events was greater in the treatment arms.Probably, one of the few certainties in medicine is that one trial can never answer all the questions.Even more basically, the perfect trial design-one that does not lead to post-hoc alternative interpretation or raise further questions-probably cannot be achieved.Human biology is complex and the factors that must be considered are myriad.Leyland Jones et al. 3 discussed the possibility that raising hemoglobin levels to 14 g/dL or too rapidly are factors in an increase in thrombosis.This must be balanced against the Campos et al. article in this issue showing that patients with a rapid response to erythropoietin have better responses, improved quality of life, and less use of the agents.To complicate matters further, as might be expected, the effect of erythropoietin is not only on hemoglobin-forming cells.As is comprehensively documented by Glaspy in this issue, erythropoietin receptors exist on a variety of cells, including tumor cells, raising the specter of promoting tumor growth.To date, most, but not all, laboratory data available do not support this hypothesis.A meta-analysis of overall cancer survival does not show a negative effect for erythropoietin administration 4 and might even suggest a benefit.Clearly, however, we cannot dismiss the possibility of a harmful effect on tumor progression out of hand.Since we must proceed in the face of imperfect knowledge, Steensma and Loprinzi 5 elegantly summarized the prudent approach: judicious guideline recommendations in situations with data we are fairly comfortable accepting (e.g., titrating to levels of 12 g/dL as recommended in the NCCN guidelines) and further research for situations with significant persistent questions.Although research in the phase IV mode is difficult, we owe it to patients being treated in accordance with guidelines to continue refining our recommendations.