Organ motion and early tumor response measurement during chemoradiotherapy for esophageal cancer.

We believe that the existing gap in knowledge on how to quantify target organ
motion of the esophageal tumor and to rationally define appropriate PTV margins
will provide clinically meaningful information in the design of subsequent
multi-institutional multimodality trials for esophageal cancer. The esophageal
tumor is rarely visible on conebeam CT (CBCT), however a fiducial gold marker
has good visibility on CBCT and movement of these markers can be used as the
surrogate for the esophageal tumor motion.
For optimal personalized treatment a combination of patient specific geometric
uncertainty and response prediction during treatment could lead to personalized
adaptive treatment.

It is our working hypothesis that quantifying geometrical uncertainties of
motion will be necessary to calculate appropriate PTV margins and that
upper/mid thoracic esophageal tumors have smaller geometric uncertainties due
to less respiratory motion compared to distal/GEJ tumors and therefore require
a smaller PTV margin, and that motion-corrected multimodal response evaluation
may better predict outcome.
Further we hypothesize that early imaging of the response at chemoradiotherapy
by MRI, PET or combined results could identify patients who will (not) respond
at this treatment and will (not) benefit from the planned treatment.

However, the distal border of a stenotic esophageal tumor cannot be reached by
the relatively thick EUS, but the much thinner gastro scope often can. During
insertion of the gold fiducial marker, the marker is pushed out of the stylet
and slides true a couple of mm of tissue. As other organs are in close
proximity of the esophagus, insertion of gold fiducials is only safe during EUS
visualization.

To quantify motion based variation of the target volume of the primary tumor
over the course of chemoradiotherapy in esophageal cancer patient, and to use
this information to calculate appropriate PTV (planning target volume) margins
according to the margins recipe for patients receiving trimodality (neoadjuvant
chemoradiation and surgery) or definitive chemoradiation in order to
personalize radiation treatment, resulting in either better target coverage or
a reduction in normal tissue radiation exposure.

A single center prospective observational study will be performed in esophageal
cancer patients. This study registers motion of the esophageal tumor, using 4D
planning CT scans and repeated 4D CBCT scanning. Motion of fiducial markers
inserted into the esophageal wall, will be used as a surrogate for tumor motion
in the limited image quality of CBCT scans.
Patients planned for trimodality treatment will additionally be imaged by
serial 4D PET CT and MRI in week 0 (before start chemoradiotherapy), week 3
(during chemoradiotherapy) and week 10 (just prior to surgery) to observe
(early) signs of tumor response.
Patients planned for definitive chemoradiation will not receive extra MRI
imaging during treatment because of the inability to correlate this imaging
with pathological response.

Placement of the fiducial markers will be performed during a regular staging
procedure (with informed consent). The duration of EUS will increase due to the
marker placement. No adverse events are expected by marker placement other than
the regular risks of EUS-FNA. EUS-FNA is considered a safe staging procedure
with a morbidity of < 1%
The variability of the position of the esophageal tumor will be quantified by
the standard 4D-CT scan during the radiotherapy treatment preparation phase and
repeated 4D-CBCT scans during the course of treatment. Accordingly to standard
procedures, CBCT scans will be made right before the first 3 fractions and
thereafter weekly 4D-CBCT scans will be made. For the patients within this
trial daily CBCT scanning will be performed.
Patients treated with trimodality will receive an extra FDG PET scan during
treatment. This requires the patient to fast 6 hours before scanning and gives
additional imaging dose. The total additional imaging dose associated with the
additional CBCT images and the additional FDG PET scan equals about 1% of the
treatment dose. This is similar to the calculation accuracy of state of the art
treatment planning systems and is thus considered to be negligible.
The additional PET scan and MRI scans will be combined with other appointments
in the hospital, but will take about 30 minutes per MRI scan and about 1,5
hours for the PET scan.