Angiogenic factor expression during fractionated irradiation

Evidence is emerging that the effect of radiotherapy might be enhanced by angiostatic drugs. Whereas preclinical results
are promising, clinical trials have shown only moderate effect so far. This is most likely due to suboptimal scheduling;
both modalities have to be precisely dosed and scheduled to gain the optimal effect, with the lowest possible toxicity. Our
results show that fractionated irradiation in vitro and in vivo induces a fast and significant up-regulation of pro-angiogenic
factors. These results indicate that the long term anti-tumour effects of radiotherapy might be enhanced by inhibiting the
pro-angiogenic response induced during the course of radiotherapy. Whether and when this pro-angiogenic response to
radiotherapy occurs in patients remains elusive. Therefore, it is important to determine the time point at which the proangiogenic
response during fractionated radiotherapy develops in patients. Furthermore, it is important to determine
whether this up-regulation can be inhibited by the administration of bevacizumab, a monoclonal antibody against VEGF.
In this way an optimal dose schedule could be designed for the combination treatment of angiostatic drugs and
radiotherapy.

This study has 2 primary objectives:
1) To determine the time point of induction of VEGF expression in the tumour tissue of oesophagus carcinomas during
chemoradiation.
2) To determine whether the tumour promoting effects of this induction of VEGF expression can be inhibited by
administration of bevacizumab.

Before chemoradiation
during chemoradiation
after chemoradiation
surgery

Patients will undergo 1 extra endoscopic biopsy to collect tumour tissue. In addition, on four time points blood samples
will be collected. The time point of this biopsy and blood collection depends on the study cohort. The patients in the final
cohort will receive bevacizumab (3mg/kg/wk) starting at the identified time point of induction. Bevacizumab administration
will be discontinued 4 weeks before the surgical resection of the tumour.