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61 EFFECTS OF EGFR-INHIBITION AND RADIOTHERAPY ON HYPOXIA, PROLIFERATION AND TUMOR GROWTH DELAY IN HUMAN TUMOR XENOGRAFTS
S21 excluded from the study, because the questionnaire wasn’t filled out completely. The Ex consisted of 49 patients and the rest 149 were included in the nonexercise group (nEx). Between the 2 groups the clinical characteristics of the study groups didn’t differ significantly. The median age and body mass index of the Ex and nEx was as follows {( ) shows the range} ; age 59 (31-76) years , 53 (28-80) years, BMI 21.8 (16.430.2), 21.6 (15.2-34.3), respectively. As we introduced hypo-fractionated radiotherapy in September 2010, we had 2 types of treatment schedules. The percentage of patients underwent the conventional one (50 Gy to the total breast + 0-10Gy boost for total of 5-6 weeks; 2Gy/fraction) and the hypo-fractionated one (43.2Gy to the total breast + 0-7.1G boost for total of 4 weeks; 2.7Gy/fraction) were 57% and 43% in the Ex and 56% and 44% in the nEx. Tangential field with 4MV X-ray was used and for the boost electron (6-10Mev, depend of the size of the breast) was used. The median exercise days per week and median duration time of each training in both groups were as follows: Ex; 3(2-7) days, 60 (20-180) minutes, nEx; 0 (0-7) days, 0 (0-240) minutes. The grade of acute skin toxicity of the two groups were as follows; Ex median 0 (0-2), nEx 1 (0-2). There was no higher than grade 2 acute skin toxicity. Grade 2 acute skin toxicity were observed in 1 of the Ex and 19 of the nEx (p=0.03). The patient with once a week 240 minute exercise was included in the nEx but did not showed a sever skin toxicity. However the patient with 10 minutes exercise every day, who was included into nEx, showed grade 2 skin toxicity. There were 2 patients who experience radiation pneumonitis. Both have not done any exercise during the radiotherapy period. The HAD (full score 18) of both group was as follows: anxiety; Ex 3 (0-8), nEx 5 (0-13) (p=0.04), depression Ex 2 (0-6), nEx 3 (0-18) (p=0.02). Conclusion: The patients of Ex group showed significantly lower rate of sever skin toxicity. Besides, their HAD scale for both anxiety and depression showed significantly lower scale. Exercise during the period of adjuvant radiotherapy for breast-conserving surgery has a possibility to be an effective method to prevent sever skin toxicity and in the same time relieve anxiety and depression in cancer patient. 61 EFFECTS OF EGFR-INHIBITION AND RADIOTHERAPY ON HYPOXIA, PROLIFERATION AND TUMOR GROWTH DELAY IN HUMAN TUMOR XENOGRAFTS H. Stegeman1, P. Span1, A.J. van der Kogel1, D. Wheeler2, J. Kaanders1, J. Bussink1 1 Department of Radiation Oncology, Radboud University Nijmegen MC, Nijmegen, The Netherlands 2 Department of Human Oncology, University of Wisconsin, School of Medicine and Public Health, USA Objective: The Epidermal Growth Factor Receptor (EGFR) and downstream signaling pathways are associated with major radiation resistance mechanisms, including hypoxia and proliferation. Inhibition of EGFR signaling improves the effect of radiotherapy significantly in head and neck cancer. However, a substantial proportion of these patients does not benefit from the addition of these new molecular targeted therapies. Identification of biological tumor characteristics that predict treatment response will
ICTR-PHE 2012 allow better selection of patients for these intensified treatments. Material and Methods: In search of predictive biological tumor characteristics, we treated four human larynx carcinoma xenograft lines (SCCNij), exhibiting distinct EGFR expression patterns, with radiotherapy (10 or 20 Gy), Cetuximab (C225, monoclonal antibody against EGFR), and concurrent C225 and radiotherapy treatment. Effects on tumor growth delay, hypoxia and proliferation were studied as well as proteins involved in the downstream signaling of the EGFR. Results: Concerning EGFR expression, we found SCCNij202>> SCCNij153 = SCCNij185>> SCCNij167. There was no correlation between EGFR and AKT activation (phospho-Akt) in these tumor lines. Using a growth delay assay, we observed that the tumor line with high EGFR expression (SCCNij202) was highly sensitive to C225, but showed only little growth delay in response to radiotherapy. In contrast, SCCNij167 tumors with low EGFR were resistant to C225 treatment, but particular radiosensitive. In both tumor lines no synergistic effect of C225 on radiosensitivity was observed. SSCNij185 and SCCNij153 tumors, with intermediate EGFR expression, were both insensitive to C225 alone, but showed opposing effects when C225 was combined with radiotherapy: no synergistic effect of C225 with radiotherapy in SCCNij153, while C225 strongly enhanced the effect of radiotherapy in SCCNij185. Molecular characterization of the tumor models by western blot suggested that expression of other growth factor receptors (including c-MET) in SCCNij153 tumors could be involved in this difference in response to C225 between the different tumor models. Additional immunohistochemical analyses were performed to study the effect of C225 and/or radiotherapy on hypoxia and proliferation. In SCCNij202, C225 decreased both hypoxia and proliferation. However, a single dose of radiotherapy alone (10 Gy) did not affect these parameters. On the other hand, radiotherapy caused a clear decrease in proliferation in SCCNij167 tumors. Both these treatment effects correspond to the results obtained in the tumor growth delay assay. Conclusions: We identified 4 xenograft models with distinct EGFR expression patterns, and diverse response patterns to treatment with EGFR-inhibition and/or radiotherapy. Differences in basal expression of growth factor receptors and the effects on hypoxia and proliferation correlate with response to treatment. Results of the effects of C225 and/or radiotherapy on hypoxia and proliferation in tumor lines with intermediate EGFR expression and effects on DNA repair, another radioresistance mechanism, will be presented. By studying multiple tumor models with similar origin and histology, we increase the understanding of the mechanisms involved in treatment response and provide a tool to improve patient selection and consequently treatment outcome. 62 TEST OF DIFFERENT PIXEL DETECTORS FOR LASER-DRIVEN ACCELERATED PARTICLE BEAMS S. Reinhardt1, C. Granja1, W. Assmann1, F. Krejci2 1 Ludwig-Maximilians University, München, Germany 2 Institute of Experimental and Applied Physics, Czech Technical University, Prague, Czech Republic
ICTR-PHE 2012 allow better selection of patients for these intensified treatments. Material and Methods: In search of predictive biological tumor characteristics, we treated four human larynx carcinoma xenograft lines (SCCNij), exhibiting distinct EGFR expression patterns, with radiotherapy (10 or 20 Gy), Cetuximab (C225, monoclonal antibody against EGFR), and concurrent C225 and radiotherapy treatment. Effects on tumor growth delay, hypoxia and proliferation were studied as well as proteins involved in the downstream signaling of the EGFR. Results: Concerning EGFR expression, we found SCCNij202>> SCCNij153 = SCCNij185>> SCCNij167. There was no correlation between EGFR and AKT activation (phospho-Akt) in these tumor lines. Using a growth delay assay, we observed that the tumor line with high EGFR expression (SCCNij202) was highly sensitive to C225, but showed only little growth delay in response to radiotherapy. In contrast, SCCNij167 tumors with low EGFR were resistant to C225 treatment, but particular radiosensitive. In both tumor lines no synergistic effect of C225 on radiosensitivity was observed. SSCNij185 and SCCNij153 tumors, with intermediate EGFR expression, were both insensitive to C225 alone, but showed opposing effects when C225 was combined with radiotherapy: no synergistic effect of C225 with radiotherapy in SCCNij153, while C225 strongly enhanced the effect of radiotherapy in SCCNij185. Molecular characterization of the tumor models by western blot suggested that expression of other growth factor receptors (including c-MET) in SCCNij153 tumors could be involved in this difference in response to C225 between the different tumor models. Additional immunohistochemical analyses were performed to study the effect of C225 and/or radiotherapy on hypoxia and proliferation. In SCCNij202, C225 decreased both hypoxia and proliferation. However, a single dose of radiotherapy alone (10 Gy) did not affect these parameters. On the other hand, radiotherapy caused a clear decrease in proliferation in SCCNij167 tumors. Both these treatment effects correspond to the results obtained in the tumor growth delay assay. Conclusions: We identified 4 xenograft models with distinct EGFR expression patterns, and diverse response patterns to treatment with EGFR-inhibition and/or radiotherapy. Differences in basal expression of growth factor receptors and the effects on hypoxia and proliferation correlate with response to treatment. Results of the effects of C225 and/or radiotherapy on hypoxia and proliferation in tumor lines with intermediate EGFR expression and effects on DNA repair, another radioresistance mechanism, will be presented. By studying multiple tumor models with similar origin and histology, we increase the understanding of the mechanisms involved in treatment response and provide a tool to improve patient selection and consequently treatment outcome. 62 TEST OF DIFFERENT PIXEL DETECTORS FOR LASER-DRIVEN ACCELERATED PARTICLE BEAMS S. Reinhardt1, C. Granja1, W. Assmann1, F. Krejci2 1 Ludwig-Maximilians University, München, Germany 2 Institute of Experimental and Applied Physics, Czech Technical University, Prague, Czech Republic