Improving Cancer Therapy by Doxorubicin and Granulocyte Colony-Stimulating Factor: Insights from a Computerized Model of Human Granulopoiesis

Neutropenia is a significant dose-limiting toxicity of cancer chemotherapy, especially in dose-intensified regimens. It is widely treated by injections of Granulocyte Colony-Stimulating Factor (G-CSF). However, optimal schedules of G-CSF administration are still not determined. In order to aid in identifying more efficacious and less neutropenic treatment protocols, we studied a detailed physiologically-based computer model of granulopoiesis, as affected by different treatment schedules of doxorubicin and/or Granulocyte Colony-Stimulating Factor (G-CSF). We validated the model as evident from accurate prediction of clinical data on human granulopoiesis in healthy individuals and in doxorubicin-treated cancer patients, with or without G-CSF support. Based on our model, we suggest new G-CSF administration regimens. These regimens include reduced G-CSF doses, optimally timed post-chemotherapy. Application of these regimens can lead to minimization of G-CSF side effects, as well as more cost-effective and less myelotoxic protocols. Currently clinical trials are being designed in order to test these new treatment regimens.