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

Piernicola Pedicini,Rocchina Caivano,Barbara Vischioni,Marta Cremonesi,Giovanni Storto,Antonio Nappi,Marcello Benassi,Lidia Strigari,Francesca Botta,Barbara Alicia Jereczek-Fossa,Roberto Orecchia,Daniela Alterio,Giuseppina Improta

doi:10.1186/1742-4682-9-23

Abstract

PurposeTo 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).Materials and methodsDifferences 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.ResultsAssuming 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.ConclusionsDuring 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.

Highlights

Radiobiology has been transformed thanks to new knowledge concerning cellular activation processes in response to an external stimulus
The modified biologically effective dose (MBED) allows the required dose per fraction to be estimated when tumour radiosensitivity is reduced because Epidermal growth factor receptor (EGFr) is over-expressed
If radiotherapy treatment is combined with EGFr inhibitors, MBED suggests new treatment strategies, with schedules modulated according to drug pharmacokinetics

Summary

Introduction

Radiobiology has been transformed thanks to new knowledge concerning cellular activation processes in response to an external stimulus. This knowledge has led to the identification of promising new drug therapies called "targeted therapy” [1]. The correlation between over-expression of EGFr and clinically aggressive malignant disease suggested that EGFr was a promising target for several epithelial tumours, which represent approximately two thirds of all human cancers. New radiobiology studies have focussed on identifying correlations between radiosensitization and biological agents. These effects have not been fully integrated into current radiobiological models [5,6,7,8]. One such model commonly used in clinical practice, is the BED obtained from the LQ model [9], given by the following equation (proliferation ignored): BED 1⁄4 D⋅

Objectives

Methods

Results

Conclusion