Can Granulocyte-Colony Stimulating Factor Worsen Anemia?

Neutropenia is the major dose-limiting toxicity in patients with cancer who are treated with myelosuppressive chemotherapy. The incidence of chemotherapy dose reductions or treatment delays, which can impact overall dose intensity and compromise treatment outcomes, may be reduced by the prophylactic use of granulocyte colony-stimulating factor (G-CSF). In this issue, Papaldo et al report on the effects of G-CSF on hemoglobin in 506 patients with stage I-II breast cancer who received adjuvant epirubicin and cyclophosphamide (EC) at 120 mg/m and 600 mg/m, respectively. This study utilized a 2 2 factorial design in which patients were randomly assigned to receive EC alone or with lonidamine to enhance the activity of anthracyclines and were also randomly assigned to receive G-CSF or not, thereby yielding four treatment assignments. Another aspect of the trial was that they tested five schedules of G-CSF. It was given as (1) 480 g days 8 to 14; (2) 480 g days 8, 10, 12, and 14; (3) 300 g days 8 to 14; (4) 300 g days 8, 10, 12, and 14; and (5) 300 g days 8 and 12. Specifically with regard to G-CSF, the study aims were to compare the mean hemoglobin level in patients assigned to receive G-CSF compared with those in the control group and also to compare the mean hemoglobin levels in patients on the five different schedules of G-CSF. These G-CSF schedules were not randomly assigned but were accrued sequentially in cohorts. The authors report that from the third cycle of EC onward, the mean hemoglobin value was statistically significantly lower in the G-CSF treatment group (overall) when compared with controls at each weekly time point of each cycle (P .0001). Exploratory analysis showed no difference in the hemoglobin level in patients who received no G-CSF when compared with those receiving just two doses of G-CSF (schedule 5). However, from the second cycle onward, the mean hemoglobin level was lower in patients receiving more than two doses of G-CSF (schedules 1-4) compared with those who received just two doses of G-CSF (schedule 5). Again, overall the study showed that the rate of grade 2 or worse anemia was higher in the G-CSF group than in the controls (38.8% v 26.2%, P .005). Thus, Papaldo et al concluded that G-CSF dose-related effect may play a role in the worsening of anemia in patients receiving adjuvant EC. The potential effect of G-CSF on erythropoiesis is not clearly understood. Papaldo et al address several of the theoretical ways by which G-CSF might have an impact on erythropoiesis, including the hypotheses that the granulopoietic and erythropoietic lineages may compete for differentiating stem cells, that G-CSF may induce stem cells to differentiate into more committed hematopoietic cells, thereby directly leading to a decline in erythropoiesis, or that the inhibition of erythropoiesis may occur at a late level of differentiation. Their clinical findings support, but cannot prove, the hypothesis that there is competition for common stem cells. Even if the hypothesis is correct, the results provided by Papaldo et al may not apply to current practice. Following the availability of G-CSF not only was dose escalation made feasible, but we were also able to shorten the intertreatment interval (dose density). In theory, the latter maneuver increases chemotherapy efficacy by increasing the proportion of chemotherapy sensitive cells exposed to each successive treatment cycle. Recently, the results of an Intergroup study coordinated by the Cancer and Leukemia Group B (C9741) in which dose density was explicitly tested were updated. Improved outcomes were maintained with no increase in toxicity at a median follow-up of 6.5 years. In this trial, the incidence of grade 2 anemia was highest in the dose dense and concurrent treatment group (23%) with 13% of patients requiring packed RBC transfusions. Subsequently, Burstein et al reported that there was no need for RBC transfusion in any patients receiving darbepoetin for hemoglobin values of 12 g/dL or less while receiving dose-dense doxorubicin plus C followed by paclitaxel with pegfilgrastim. This suggests that if there is a steal, its impact can be abrogated with a second growth factor. In addition, this suggests that any G-CSF effect on red cell lineage must be qualitative and reversible and therefore must occur after an adequate number of stem cells are committed to the red cell lineage. This somewhat undermines the steal hypothesis. With improved long-term outcomes demonstrated using dosedense chemotherapy when compared with standard regimens in various cancers, it is important to reemphasize the goal of care in the adjuvant setting: cure. We may be far more flexible and cost tolerant in this setting as compared with the palliative setting. To better understand this issue, and as suggested by the authors, a cost-effectiveness analysis would be valuable with regard to both G-CSF and erythropoietic growth factor use associated with dose-dense regimens. Such an analysis will likely show that growth factors increase acute health care costs if used to prevent treatment induced anemia, but this may be especially worthwhile in the curative setting. For clinicians, the bottom line is that this study provides a hint that G-CSF may worsen anemia caused by chemotherapy but additional prospective studies, including tests of schedule of administration, are needed before any practices are changed.