Model-based optimization of G-CSF treatment during cytotoxic chemotherapy

• Published in: Journal of cancer research and clinical oncology 2018-02, Vol.144 (2), p.343-358
• Main Authors: Schirm, Sibylle, Engel, Christoph, Loibl, Sibylle, Loeffler, Markus, Scholz, Markus
• Format: Article
• Language: English
• Subjects: Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Bleomycin - administration & dosage; Bleomycin - adverse effects; Bone marrow; Breast cancer; Cancer Research; Chemotherapy; Cyclophosphamide - administration & dosage; Cyclophosphamide - adverse effects; Cytotoxicity; Doxorubicin - administration & dosage; Doxorubicin - adverse effects; Drug Administration Schedule; Etoposide - administration & dosage; Etoposide - adverse effects; Filgrastim - administration & dosage; Filgrastim - pharmacokinetics; Geriatrics; Granulocyte colony-stimulating factor; Granulocyte Colony-Stimulating Factor - administration & dosage; Granulocyte Colony-Stimulating Factor - pharmacokinetics; Granulocytes - drug effects; Granulocytes - pathology; Granulopoiesis; Hematology; Hematopoiesis - drug effects; Humans; Internal Medicine; Leukopenia; Leukopenia - chemically induced; Leukopenia - drug therapy; Lymphoma; Medicine; Medicine & Public Health; Models, Biological; Neoplasms - blood; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Oncology; Original Article – Clinical Oncology; Original – Clinical Oncology; Pharmacodynamics; Pharmacokinetics; Polyethylene Glycols - administration & dosage; Polyethylene Glycols - pharmacokinetics; Prednisone - administration & dosage; Prednisone - adverse effects; Procarbazine - administration & dosage; Procarbazine - adverse effects; Randomized Controlled Trials as Topic; Reproducibility of Results; Risk factors; Vincristine - administration & dosage; Vincristine - adverse effects
• ISSN: 0171-5216; 1432-1335
• DOI: 10.1007/s00432-017-2540-1

Purpose Although G-CSF is widely used to prevent or ameliorate leukopenia during cytotoxic chemotherapies, its optimal use is still under debate and depends on many therapy parameters such as dosing and timing of cytotoxic drugs and G-CSF, G-CSF pharmaceuticals used and individual risk factors of patients. Methods We integrate available biological knowledge and clinical data regarding cell kinetics of bone marrow granulopoiesis, the cytotoxic effects of chemotherapy and pharmacokinetics and pharmacodynamics of G-CSF applications (filgrastim or pegfilgrastim) into a comprehensive model. The model explains leukocyte time courses of more than 70 therapy scenarios comprising 10 different cytotoxic drugs. It is applied to develop optimized G-CSF schedules for a variety of clinical scenarios. Results Clinical trial results showed validity of model predictions regarding alternative G-CSF schedules. We propose modifications of G-CSF treatment for the chemotherapies ‘BEACOPP escalated’ (Hodgkin’s disease), ‘ETC’ (breast cancer), and risk-adapted schedules for ‘CHOP-14’ (aggressive non-Hodgkin’s lymphoma in elderly patients). Conclusions We conclude that we established a model of human granulopoiesis under chemotherapy which allows predictions of yet untested G-CSF schedules, comparisons between them, and optimization of filgrastim and pegfilgrastim treatment. As a general rule of thumb, G-CSF treatment should not be started too early and patients could profit from filgrastim treatment continued until the end of the chemotherapy cycle.