Decreased repopulation as well as increased reoxygenation contribute to the improvement in local control after targeting of the EGFR by C225 during fractionated irradiation

Krause, Mechthild; Ostermann, Gernot; Petersen, Cordula; Yaromina, Ala; Hessel, Franziska; Harstrick, Andreas; van der Kogel, Albert J; Thames, Howard D; Baumann, Michael

doi:10.1016/j.radonc.2005.06.032

« Previous Next »Radiotherapy & Oncology
Volume 76, Issue 2 , Pages 162-167, August 2005

Decreased repopulation as well as increased reoxygenation contribute to the improvement in local control after targeting of the EGFR by C225 during fractionated irradiation

Mechthild Krause
- Department of Radiation Oncology, and
Gernot Ostermann
- Department of Radiation Oncology, and
Cordula Petersen
- Department of Radiation Oncology, and
Ala Yaromina
- Department of Radiation Oncology, and
Franziska Hessel
- Department of Radiation Oncology, and
Andreas Harstrick
- Merck KG aA, Darmstadt, Germany
Albert J van der Kogel
- Department of Radiation Oncology, University Medical Centre Nijmegen, The Netherlands
Howard D Thames
- MD Andersen Cancer Center, Houston, TX, USA
Michael Baumann
- Department of Radiation Oncology, and
- Experimental Centre, Medical Faculty Carl Gustav Carus, University of Technology Dresden, Germany
- Corresponding author. M. Baumann, Department of Radiation Oncology, Medical Faculty Carl Gustav Carus, University of Technology Dresden, Fetscherstr. 74, 01307 Dresden, Germany.

Received 3 May 2005; received in revised form 13 May 2005; accepted 18 June 2005. published online 18 July 2005.

Abstract

Background and purpose

Inhibition of repopulation and enhanced reoxygenation has been suggested to contribute to improvement of local tumour control after fractionated irradiation combined with inhibitors of the epidermal growth factor receptor (EGFR). The present study addresses this hypothesis in FaDu human squamous cell carcinoma. For this tumour model marked repopulation and incomplete reoxygenation during fractionated irradiation has previously been demonstrated. Furthermore, the anti-EGFR monoclonal antibody C225 has been shown to significantly improve the results of fractionated irradiation in this tumour.

Materials and methods

FaDu tumours in nude mice were irradiated with 18 fractions in 18 days (18f/18d) or 18 fractions in 36 days (18f/36d). Three Gy fractions were given either under ambient or under clamp hypoxic conditions. C225 or carrier was applied four times during the course of treatment. Fractionated irradiations were followed by graded top-up doses to obtain complete dose–response curves for local tumour control. Tumour control dose 50% (TCD₅₀) was determined at day 120 after end of treatment.

Results

Significant repopulation and reoxygenation occurred during fractionated irradiation of FaDu tumours (P-values between 0.028 and <0.001). Application of C225 significantly decreased TCD₅₀ for 18f/36d under ambient conditions (P=0.04). Bootstrap analysis revealed decreased repopulation and increased reoxygenation after application of C225 (P=0.06 for the combined effect). This was further corroborated by a significant effect of C225 on the ‘repopulated’ dose under ambient conditions which is influenced by both, reoxygenation and repopulation (P=0.012).

Conclusions

Our study provides evidence that both decreased repopulation as well as increased reoxygenation contribute to the improvement of local control after targeting of EGFR by C225 during fractionated irradiation of FaDu tumours.

Keywords: C225, EGFR inhibition, Molecular targeting, Repopulation, Reoxygenation, Fractionated irradiation, Squamous cell carcinoma, Local tumour control