The PLCRC substudy Ultra high field 7.0 Tesla MR Spectroscopy to monitor capecitabine metabolism in liver metastases - a proof of concept study

Capecitabine, an oral prodrug of 5-flouroracil (5FU), is the most widely used
chemotherapeutic agent in the treatment of metastatic colorectal cancer.
Response evaluation takes place nine weeks after start of treatment. This
results in unnecessary toxicity and costs for non-responding patients,
emphasizing the need to identify new markers that predict treatment response in
early stage.
In the search for predictive markers, 5FU drug trapping in tumor has been
correlated with tumor response. Capecitabine is developed to activate 5FU
preferentially in tumor, challenging the assessment of 5FU drug trapping
(non-invasively) and its use as a predictive marker in clinical practice. With
19F Magnetic resonance spectroscopy (19F MRS) it is possible to non-invasively
monitor the metabolism of fluorinated drugs at specific locations in the human
body. For capecitabine, previous pilot studies at 1.5 Tesla (T) and 3T showed
that it was possible to detect most of its metabolites in vivo. However,
further research in humans was hampered due to low sensitivity for metabolite
detection, difficulty of timing the MRS examinations due to inter-patient
variation in absorption and metabolism time and the use of RF surface coils
limiting spatial coverage. Recently ultra-high field 7.0 Tesla MRI has become
available for clinical research. By combining high field strength and multiple
coil elements, sensitivity and spatial coverage for the detection of
capecitabine metabolites is increased. With 7T 19F MRS it should be possible to
assess 5FU drug trapping in tumor by measuring changes in concentration of
capecitabine metabolites and calculate the retained fraction of 5FU.
Furthermore, by assessing 5FU drug trapping it should be possible to predict
efficacy of capecitabine therapy during early treatment in individual
colorectal cancer patients.

The primary objective of this feasibility/pilot study is to find the correct
scanning protocol to assess 5FU drug trapping in colorectal cancer liver
metastases using 7T MRS (phase 1). Secondary objectives will be assessed during
phase 2 of this study and include applying the developed scanning protocol to
explore the correlation between 5FU drug trapping in liver metastasis to the
efficacy of treatment according to the Response Evaluation Criteria In Solid
Tumors (RECIST) and to explore whether metabolite levels correlate to
perfusion, diffusion and acidity as determined by functional MRI. When both
phases of this study are completed, the results of this study will be used to
assess feasibility on a large continuing study investigating the correlation
between 5FU drug trapping and treatment efficacy using 7T MRS and if indeed
feasible, to perform sample size calculations.

This PLCRC sub-study is a proof of concept study in two phases. During phase 1
of this study we will include two times three patients to assess the optimal
time points for the accurate assessment of 5FU drug trapping. MRS examinations
for all patients will take place at day 14 during the first cycle of
capecitabine and bevacizumab. The proxy for 5FU drug trapping in metastasis is
the concentration of capecitabine or the precursor metabolite DFUR (input)
divided by the concentration of the breakdown products FBAL or FUPA
(ineffective output). In case DFUR and FUPA (shortest time in pharmacokinetics)
can be detected in one timepoint in 3 patients of phase 1, phase 2 of this
study will continue with a scanprotocol with one scan time point per patient.
Else, two time points will be selected based on maximizing sensitivity in
detecting capecitabine + DFUR and FBAL + FUPA. During phase 2 we will apply the
developed scan protocol in another 20 patients to serve the secondary
objectives. Phase 2 will be completed when all patients have received their
routine CT scan for treatment evaluation after completing three cycles of
capecitabine and bevacizumab.

Participating in this study will include one site visit at day 14 after start
of treatment for all included patients. During this visit patients will be
asked to undergo either one to three MRS examinations depending on the phase of
the study patients were included in. The total scan time for each of the three
scan sessions will be 30-35 minutes. To the best of our knowledge there are no
short- or long term risks involved in having an MRI or MRS scan.