Evaluation of treatment-related acute myeloid leukemia or myelodysplastic syndrome risk following standard chemotherapy versus dose-intensified chemotherapy plus granulocyte colony-stimulating factor.
Authors: Lyman GH , Dale DC , Wolff D , Culakova E , Poniewierski MS , Crawford J 
Published: December 2010

Abstract #6135

Background Retrospective studies of the risk of acute myeloid leukemia or myelodysplastic syndrome (t-ML) in cancer patients receiving granulocyte colony-stimulating factor (G-CSF) have reported conflicting findings. To evaluate the impact of chemotherapy with G-CSF support on both overall survival (OS) and the risk of t-ML in patients with breast cancer, an exhaustive literature review and meta-analyses were conducted of prospective, randomized, controlled clinical trials.&#x2028; Methods Electronic databases including Medline, EMBASE, BIOSIS were searched through January 2008 identifying 5410 articles for initial screening. Eligibility criteria included: patients with non-myeloid malignancies receiving chemotherapy (CT) with or without G-CSF (filgrastim or pegfilgrastim) with adequate follow-up (≥2 years). Of the 65 publications identified, 6 were from unique, prospective, randomized, controlled trials in patients with breast cancer. Excluded reports consisted of retrospective studies, duplicate reports and studies with either no control group or with stem cell transplantation. Meta-analyses were performed based on the method of Mantel and Haenszel with summary estimates [±95% CLs] provided for both relative risk (RR) and risk difference (RD). Any asymmetry in the associated funnel plots was assessed utilizing the Egger regression intercept.&#x2028; Results A total of 2848 and 2839 patients were randomized to receive CT with G-CSF support versus standard CT, respectively. In the only trial to randomize breast cancer patients receiving the same CT to prophylactic G-CSF versus no primary or secondary prophylactic G-CSF, t-ML was reported in 1/254 (0.4%) receiving CT plus G-CSF compared to 0/243 in those not receiving G-CSF. The remaining 5 studies compared treatment with different CT intensities permitting dose intensification with G-CSF support. Meta-analyses for both OS and t-ML were performed comparing dose intensified CT with G-CSF support to standard CT without G-CSF. No significant heterogeneity was observed across trials for both outcomes. A significant increase in OS was found among patients receiving CT with G-CSF support (RR=0.88; 0.80-0.98; P=.020). A non-significant increase in the incidence of t-ML was observed among patients receiving dose intensified CT with G-CSF support (RR=1.94; 0.89-4.22; P=.097 and RD=.003; P=.090). Funnel plot analysis revealed evidence for a publication bias for t-ML reporting studies (t=3.69; 2 sided P=.034).&#x2028; Conclusions Of over 5000 studies reviewed, 1 prospective study with the same CT in both study arms found no significant increase in the risk of t-ML with G-CSF support. Meta-analyses demonstrated that chemotherapy with G-CSF support results in a significant improvement in OS with a non-significant increase in t-ML. There is insufficient data to definitively examine the role of G-CSF on t-ML risk independent of the concomitant use of dose intensified chemotherapy.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6135.