Personalising docetaxel and G-CSF schedules in cancer patients by a clinically validated computational model

Abstract

Background: This study was aimed to develop a new method for personalising chemotherapeutic and granulocyte colony-stimulating factor (G-CSF) combined schedules, and use it for suggesting efficacious chemotherapy with reduced neutropenia. Methods: Clinical data from 38 docetaxel (Doc)-treated metastatic breast cancer patients were employed for validating a new pharmacokinetic/pharmacodynamics model for Doc, combined with a mathematical model for granulopoiesis. An optimisation procedure was constructed and used for selecting improved treatment schedules. Results: The combined model accurately predicted observed nadir timing ( r =0.99), grade 3 or 4 neutropenia (86% success) and neutrophil counts over time in individual patients ( r =0.63), and showed robustness to CYP3A-induced variability in Doc clearance. For average patients, the predicted optimal support for the standard chemotherapy regimen, Doc 100 μ g m −2 tri-weekly, is G-CSF, 300 μ g, Q1D × 3, starting day 7 post-Doc. This regimen largely moderates chemotherapy-induced neutrophil nadir and neutropenia duration. The more intensive Doc dose, 150 mg m −2 , is optimally supported by the slightly less cost-effective G-CSF 300 μ g, Q1D × 4, 5 days post-Doc. The latter regimen is optimal for borderline patients (2000 neutrophils per μ l) under Doc, 100–150 mg m −2 tri-weekly. Conclusions: The new computational method can serve for tailoring efficacious cytotoxic and supportive treatments, minimising side effects to individual patients. Prospective clinical validation is warranted.

Docetaxel enhances apoptosis and G2/M cell cycle arrest by suppressing mitogen-activated protein kinase signaling in human renal clear cell carcinoma

“…Cytotoxicity, especially peripheral neurotoxicity and hematopoietic side effects, are significant and inevitable side effects of DOX treatment (Maggioni et al, 2010;Vainas et al, 2012). In addition, during cancer metastases, drug resistance can develop through a variety of mechanisms, including inhibition of apoptosis and activation of extracellular signal-related PI3 kinase/Akt survival pathways (Jiang et al, 2009).…”

A Review of Mixed‐Effects Models of Tumor Growth and Effects of Anticancer Drug Treatment Used in Population Analysis

“…27, the authors suggest that the model can be used to individualize low-grade glioma patient therapy based on the analysis of tumor size data collected before treatment onset. Other models developed under a population context [48][49][50] or for individual patients are also of use for patient treatment individualization. 49 Regarding the development of models for preclinical data, efforts are currently under way to develop models that account for the effect of immunotherapy, [51][52][53][54] models that account for combinations of drugs, 32,52,55 models to account for intracellular dynamics in combined systems biology/pharmacometric models, 56 and models to translate preclinical results into clinical findings.…”

Feasibility and safety of a reduced duration of therapy of colony-stimulating factor in a dose-dense regimen

“…Generally, the correct G-CSF prophylaxis should consider three factors: (i) day of chemotherapy administration, (ii) day of nadir onset (iii) and FN risk factors [18]. …”

“…Their method could reduce neutropenia by tailoring efficacious cytotoxic and supportive treatments, while minimizing side effects [18]. …”