Pilot study to determine the effect of fractionated radiotherapy on expression of pro-angiogenic factors in oeshophagus carcinoma

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
pro-angiogenic 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.

Similar as described for tumour angiogenesis, radiotherapy has also been shown
to prime the immune system for both adaptive and innate antitumour responses.
With the emerging success of immunotherapy in the clinic it is thus vital to
explore how fractionated irradiation affects immune response signalling.

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.

Multi centre, non-randomized, interventional pilot study

Patients will undergo 2 extra endoscopic biopsies to collect tumour tissue. In
addition, on one timepoint a 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.

Enrolment in this study implies that the patient will undergo 2 extra
endoscopic biopsies of the oesophageal tumour and 1 extra venepuncture. As much
as possible, we will try to collect the extra blood sample together with
routine laboratory blood analysis. The biopsy may cause physical discomfort,
which will be equal to the discomfort at the diagnostic biopsy. The extra
biopsy will not give any additional risc factors for the patient, other than
the biopsy at the diagnostic procedure.
The addition of bevacizumab (3mg/kg/wk) has been proven to be clinically well
tolerable with low grade toxicities, when given together with the
chemoradiation in esophageal cancer. If not well tolerated, the bevacizumab
will be discontinued. Treatment of bevacizumab concurrent with chemoradiation
is known to increase the risk of gastro-intestinal perforations. Although no
data is available about the risk in esophageal cancer patients, the overall
incidence is between 1-4%. Therefore extra attention will be paid to the
clinical status of the patients treated with bevacizumab However, this study
uses a lower dose of bevacizumab that normally used for cancer patients, which
might reduce the risc of toxicities.
Results of this study will be used to design a following phase I/II clinical
trial, to test an optimal schedule for the combination treatment of
radiotherapy and angiostatic drugs.