Experimental and Clinical Therapeutics

Monday, October 17, 2005 3:00 PM-5:00 PM Exhibit Hall

(PP129) Targeting of the EGFR by C225 improves local control of FaDu hSCC by decreased repopulation and increased reoxygenation during fractionated irradiation.

Krause, Mechthild*,1, Ostermann, Gernot1, Petersen, Cordula1, Harstrick, Andreas2, Yaromina, Ala1, Thames, Howard3, Baumann, Michael1, 1 Dept. of Radiation Oncology, Dresden, Saxony, Germany2 Merck KG aA, Darmstadt, Hessen, Germany3 Dept. of Biomathematics, Houston, Texas, USA

ABSTRACT- Purpose: Specific targeting of the EGFR by C225 mAb during fractionated irradiation improves local control of head and neck squamous cell carcinoma (hSCC). Inhibition of repopulation and enhanced reoxygenation might contribute to this effect, however, so far this hypothesis has not been rigorously tested. The present study addresses this question in FaDu hSCC. For this tumor marked repopulation and incomplete reoxygenation during fractionated irradiation has previously been demonstrated in our laboratory, and C225 has been shown to significantly improve the results of fractionated irradiation in this tumor. Material and Methods: Using the same experimental design as in our previous study on repopulation and reoxygenation, FaDu tumors in nude mice were irradiated with 18 fractions in 18 days (18f/18d) or 18 fractions in 36 days (18f/36d). 3 Gy fractions were given either under ambient or under clamp hypoxic conditions. C225 or carrier was applied 4 times during the course of treatment. Fractionated irradiations were followed by graded top-up doses to obtain complete dose-response curves for local tumor control. Tumor control dose 50% (TCD50) was determined at day 120 after end of treatment. A total of 8 TCD50 assays were performed. Results: As in our previous studies, significant repopulation and reoxygenation occurred during fractionated RT of FaDu tumors, and application of C225 decreased significantly TCD50 (p= 0.035 for 18f/36d). Bootstrap analysis of the local tumor control data in the different experimental arms revealed that C225 decreased repopulation (in 84% of the comparisons) and progressively increased reoxygenation (in 65% of the comparisons after 18f/18d and in 80% of the comparisons after 18f/36d). Conclusion: Both decreased repopulation and increased reoxygenation contribute to the improvement of local control after targeting of the EGFR by C225 in FaDu hSCC.

Key words: EGFR, fractionated irradiation, repopulation, reoxygenation

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2005 RRS