Abstract P1-13-03: Grade of leukopenia predicts treatment effect in early breast cancer in patients treated with tailored epirubicin/cyclophosphamide chemotherapy
Authors: Lindman H , Poikonen-Saksela P , Ahlgren J , Andersson M , Bergh J , Blomqvist C 
Published: May 2019

Abstract
Background: Body surface based dosing of chemotherapy is unreliable due to marked inter-individual variations in pharmacokinetics/-dynamics. Multiple retrospective studies have demonstrated that hematological toxicity could be a surrogate marker for efficacy of chemotherapy. The SBG 2000-1 trial was the first adjuvant randomized trial designed to compare the same drugs and number of courses of individually dosed chemotherapy based on grade of toxicity vs. standard dosed chemotherapy in early breast cancer. The aim was to study the relations between dose of chemotherapy, leukopenia nadir grade and prognosis.
Methods: Women (n=1452) in Sweden and Denmark with early breast cancer aged 18-60 years, received the first cycle at a standard dose of FEC (fluorouracil 600 mg/m2, epirubicin 60 mg/m2, cyclophosphamide 600 mg/m2). Patients (n=1052) with nadir leukopenia grade 0-2 after first cycle were randomized between either 6 tailored FEC with increased doses of epirubicin and cyclophosphamide aimed at achieving grade 3 leukopenia or treatment with 6 standard FEC. Patients with nadir leukopenia grade 3-4 represented a second control group (registered group) treated with 6 standard FEC. Dose escalation did not significantly improve 10 year distant disease-free survival (HR 0.87, p=0.32, Eur J Cancer 13:79-86, 2018). In this report grade of leukopenia at course 3 (after final escalation) was assessed as a prognostic marker in a Cox regression model adjusted for chemotherapy doses.
Results: Eight-year distant disease-free survival (DDFS) was 73%, 77%, 78% and 83% for patients with leucocyte nadir grade 0, 1, 2 and 3-4 and overall survival (OS) 77%, 81%, 81% and 86% respectively. Cox regression analysis of leucocyte grade and DDFS showed a statistically significant hazard ratio (HR) of 0.84 (CI 0.74-0.96, p=0.008) per grade of leukopenia, with non-significant trend for OS (HR 0.88, CI 0.76-1.02, p=0.066). The correlations with DDFS and cumulative dose of epirubicin and cyclophosphamide were not significant with hazard ratios of 0.96 (0.91-1.014 p=0.15) and 1.002 (1.00-1.005 p=0.21) per mg cumulative dose per meter squared. Patients with grade 3 tumors had a significantly stronger impact of leukopenia on DDFS (HR 0.76, 95% CI 0.65-0.90 p&lt;0.001) and a test of interaction between the prognostic effect of grade and leukopenia was significant (p=0.026).
Conclusions: The grade of leukopenia predicts the individual treatment effect better than chemotherapy doses. The results of this prospective trial are in agreement with previous retrospective studies indicating that chemotherapy induced leukopenia is predictive for outcome in early breast cancer. Dose dependent toxicity should be monitored for optimal adjustment of the dosage of chemotherapy.
Citation Format: Lindman H, Poikonen-Saksela P, Ahlgren J, Andersson M, Bergh J, Blomqvist C. Grade of leukopenia predicts treatment effect in early breast cancer in patients treated with tailored epirubicin/cyclophosphamide chemotherapy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-13-03.