Anemia is a frequent but insidious complication of cancer and its cytotoxic chemotherapy, contributing to debilitating fatigue, lethargy, cardiovascular problems, shortness of breath, and reduced cognitive function in individuals who often already have significant morbidity and diminished quality of life (QOL) as a consequence of their malignancy.[1,2] Although the complexities of cancer pathology can make it difficult to delineate the precise contribution of anemia to clinical outcome, associations with reduced treatment effectiveness, increased mortality, increased transfusion requirements, reduced performance and QOL, and increased cost have been observed.[3,4]
Erythropoietic support with recombinant human erythropoietin(Drug information on erythropoietin) (rHuEPO; epoetin alfa(Drug information on epoetin alfa) [Procrit] and epoetin beta) has become the standard of care for chemotherapy-induced anemia, by increasing hemoglobin (Hgb) levels with subsequent reductions in transfusion requirements and improvements in QOL.[5-11] Moreover, the introduction of darbepoetin alfa(Drug information on darbepoetin alfa) (Aranesp), a novel erythropoiesis-stimulating protein (ESP) with a longer terminal half-life, has lessened the effect of ESP support on patients without compromising efficacy.[12-17] However, despite widespread recognition that the appropriate management of anemia in patients with cancer is a crucial component of the treatment paradigm,[18-20] it is evident that many patients are not receiving timely intervention.[21,22] The articles in this supplement to ONCOLOGY summarize some of the key issues in the effective management of chemotherapy-induced anemia.
New data are emerging in the field of anemia management in patients with hematologic malignancies. Dr. David J. Straus addresses the utility of epoetin alfa and darbepoetin alfa in improving Hgb levels, with consequent improvements in QOL, fatigue, productivity, and cognitive function, and without adverse effects on clinical outcome. Interestingly, these effects are apparent even in patients with mild anemia, suggesting that physicians should carefully consider treating anemia in patients with Hgb levels between 11 and 12 g/dL. This is reflected in the overview of clinical guidelines for ESP use in chemotherapy-induced anemia provided by Dr. George M. Rodgers and by the review of evidence to support early intervention with ESPs from Dr. Gary H. Lyman. The most recent evidence-based practice guidelines (from the National Comprehensive Cancer Network) suggest a threshold Hgb level of 10 to 11 g/dL for commencing erythropoietic therapy with either epoetin alfa or darbepoetin alfa. These guidelines are based on an approximate 20% to 50% relative risk reduction in transfusion with ESP treatment. However, it appears that a similar magnitude of effect is seen when mild chemotherapy-induced anemia is treated with ESPs, suggesting that the focus of anemia management should possibly switch from correcting decreased Hgb levels to maintaining reasonable target Hgb levels. The impact of early intervention with ESPs on QOL and on the ability to maintain chemotherapy and radiotherapy schedules needs to be carefully weighed against other clinical and economic considerations.
Clinical guidelines for cancer- and chemotherapy-induced anemia also discuss the utility of iron supplementation in patients receiving erythropoietic therapy. Dr. David H. Henry discusses the possibility of augmenting response to ESPs with appropriate iron supplementation, based on several studies that have compared hematopoietic response rates in epoetin alfa-treated patients with iron deficiency receiving oral or intravenous iron or no iron. In addition, guidelines emphasize that one of the primary goals of increasing Hgb levels is to improve QOL and reduce fatigue. This point is reiterated by Dr. David Cella, who highlights the importance of establishing a patient's fatigue level at clinic visits by using appropriate and validated questionnaires to ensure that tangible improvements in QOL are being achieved.
There is constant tension between minimizing the effect of cancer therapy on patients and ensuring the best possible outcome. Recently, data have demonstrated that darbepoetin alfa can be effectively administered once every 3 weeks, which may allow the dosing of ESP therapy to be synchronized with standard chemotherapy cycles. Indeed, as Dr. John Glaspy explains, the hematopoietic and clinical responses observed with darbepoetin alfa given every 3 weeks are indistinguishable from results produced with weekly dosing, and are not compromised by synchronous cytotoxic treatment.
This has exciting implications for improving treatment convenience for patients, the importance of which is highlighted in the review from Dr. Barry Fortner. Reducing the number of clinic visits by synchronizing anemia treatment with existing chemotherapy may translate into considerable time savings for both the patient and caregiver, as well as a reduction in human resource time and costs at the medical clinic.
Finally, the risk-benefit profile of any treatment needs to be carefully considered. Concerns have been raised over a possible association between the use of ESPs and decreased survival, potentially as a consequence of a rapid rise in Hgb levels. Dr. Jeffrey Crawford discusses these concerns, providing evidence suggesting that there may be an improvement in survival with erythropoietic therapy. Five controlled trials of darbepoetin alfa, each with enrollments of between 600 and 1,000 patients, have been initiated to test the effect of treatment on survival, with meta-analysis of the five trials having 80% power to detect a hazard ratio for mortality as small as 1.15.