Ida Netterberg, Elisabet I Nielsen, Henrik Lindman, Angelica Quartino, Mats O. Karlsson, Lena E. Friberg
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
Objectives: Myelosuppression is the dose-limiting toxicity for many chemotherapeutic agents. Febrile neutropenia (FN) is a common and life-threatening complication among patients treated with chemotherapeutic agents, and the frequency depends on patient factors and tumor type [1]. Neutropenic patients with an infection typically present no signs of infection other than fever. Therefore, it is desirable to identify predictors of FN, in order to initiate appropriate (prophylactic) treatment, e.g. antibiotics or granulocyte stimulating factor (G-CSF). Such predictors include patient or myelosuppressive factors [2] or infection biomarkers, e.g. interleukin 6 (IL6) and C-reactive protein (CRP). The objective of this study was to characterize the time-courses of CRP and IL6 after chemotherapy and assess variables as predictors of FN.
Methods: Measurements of IL6 and CRP in cycle 1 and 4 were collected from 49 breast cancer patients treated with adjuvant chemotherapy [3]. The IL6 and CRP concentration-time profiles were described by an indirect-response model where abrupt increases were captured by surge functions. Mixture models estimated the probability for observing a biomarker increase in each cycle. Predictors from the IL6- and CRP-models, an earlier characterization of neutrophil counts [3, 4], as well as patient factors, were evaluated in a logistic regression analysis of FN. The analysis was carried out using NONMEM 7.3.
Results: The peak time for IL6 was estimated to be shorter (3.9 days) than for CRP (7.8 days) which is in line with that physiologically IL6 stimulates the production of CRP. The probability of increased IL6 and CRP concentrations were estimated to 87 and 64 %, respectively. The data exploration clearly indicated a distinct connection between the magnitude of increased IL6 and CRP concentrations and FN. The combination of the estimated surge amplitude of CRP, IL6 baseline and age, significantly improved the prediction of FN. When only evaluating variables that would be available pre-chemotherapy, the estimated IL6 and neutrophil baseline were identified as significant predictors.
Conclusions: The magnitude of the increased CRP concentration, IL6 and neutrophil baseline and age, could be clinically valuable predictors of FN. This could potentially have an impact on the prophylactic therapy of patients at risk for developing FN.
References:
[1]Freifeld, AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, Raad II, Rolston KV, Young JAH and Wingard JR: Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: 2010 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2011, 52:e56-93
[2]Hansson EK, Friberg LE: The shape of the myelosuppression time profile is related to the probability of developing neutropenic fever in patients with docetaxel-induce grade IV neutropenia. Cancer Chemother Pharmacol. 2012, 69:881-90
[3] Quartino AL, Karlsson MO, Lindman H and Friberg LE: Characterization of endogenous G-CSF and inverse correlation to chemotherapy-induced neutropenia in patients with breast cancer using population modeling. Pharm Res. 2014, 12:3390-403 [4] Friberg, LE, Henningsson A, Maas H, Nguyen L, and Karlsson MO: Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. J. Clin. Oncol. 2002, 20:4713-4721
Reference: PAGE 24 (2015) Abstr 3583 [www.page-meeting.org/?abstract=3583]
Poster: Drug/Disease modeling - Oncology