Modelling the correlation between EGFr expression and tumour cell radiosensitivity, and combined treatments of radiation and monoclonal antibody EGFr inhibitors

Abstract

To estimate the effects of heterogeneity on tumour cell sensitivity to radiotherapy combined with radiosensitizing agents attributable to differences in expression levels of Epidermal Growth Factor Receptor (EGFr). Differences in radiosensitivity are not limited to cells of different cancer histotypes but also occur within the same cancer, or appear during radiotherapy if radiosensitizing drugs are combined with ionizing radiation. A modified biologically effective dose (MBED), has been introduced to account for changes in radiosensitivity parameters (α and α/β) rather than changes in dose/fraction or total dose as normally done with standard biologically effective dose (BED). The MBED approach was applied to cases of EGFr over-expression and cases where EGFr inhibitors were combined with radiation. Representative examples in clinical practice were considered. Assuming membrane EGFr over-expression corresponds to reduced radiosensitivity (αH = 0.15 Gy-1 and αH/βH = 7.5 Gy) relative to normal radiosensitivity (α = 0.2 Gy-1 and α/β = 10 Gy), an increased dose per fraction of 2.42 Gy was obtained through the application of MBED, which is equivalent to the effect of a reference schedule with 30 fractions of 2 Gy. An equivalent hypo-fractionated regime with a dose per fraction of 2.80 Gy is obtained if 25 fractions are set. Dose fractionations modulated according to drug pharmacokinetics are estimated for combined treatments with biological drugs. Soft and strong modulated equivalent hypo-fractionations result from subtraction of 5 or 10 fractions, respectively. During this computational study, a new radiobiological tool has been introduced. The MBED allows the required dose per fraction to be estimated when tumour radiosensitivity is reduced because EGFr is over-expressed. If radiotherapy treatment is combined with EGFr inhibitors, MBED suggests new treatment strategies, with schedules modulated according to drug pharmacokinetics.