Multi-modality Imaging in the Prediction of Response to Systemic Treatment in Colorectal Cancer
Colorectal cancer is a frequently occurring cancer and about half of the patients develop
distant metastases to the liver. Only a subset of patients respond to systemic treatment,
which is potentially toxic and expensive. Therefore, predictive markers are needed to
determine treatment efficacy at an early stage. Preferably, they should provide insight into
the biology of colorectal cancer liver metastasis. In the past it has been shown that
several biomarkers as assessed with PET, MRI and MRS can serve as predictive markers.
Response to systemic therapy depends on several factors: delivery of the drug by the tumor
vascular system; cellular uptake, retention and metabolism; intrinsic sensitivity to a
specific drug. The relative contribution of these factors to response will be different for
different drugs. Since systemic treatment of colorectal cancer involves a combination of
drugs, predictive markers should be sensitive to a range of these factors. In this project
we propose the integrated analysis of noninvasive functional and molecular in vivo imaging
methods in order to predict the response to treatment in patients with liver metastases of
colorectal cancer. Tumor vascularity can be assessed by dynamic contrast enhanced magnetic
resonance imaging (DCE-MRI). The fluoropyrimidines FU and capecitabine - which are part of
standard treatment regimens - contain a fluorine atom which can be measured by fluorine-19
MR spectroscopy (19F MRS). The intracellular uptake and metabolism of drugs is an
energy-consuming process. 18F-Fluoro-2-deoxyglucose positron emission tomography (FDG-PET)
provides information on glucose uptake and hexokinase activity. Tumor characterization in
terms of grade and aggressiveness may give a relevant approximation to the intrinsic
sensitivity of a tumor to a drug. With 1H MRS the total amount of choline (tCho), a
precursor of cell membranes, can be measured. Tumor cellularity and extracellular matrix
composition can be assessed with diffusion weighted MRI (DWI).
The aim of this study is to obtain data on the biology data of colorectal cancer liver
metastasis, namely tumor vascularization (DCE-MRI), tumor cellularity (DWI), tumor (choline)
metabolism (1H MRS) and tumor glucose metabolism (FDG-PET). These data will be correlated
with the clinical outcome of patients and with drug uptake and metabolism (19F MRS). We will
study the relative contribution of each imaging method to predict the outcome of patients
with colorectal cancer at an early stage.
Research questions:
1. Do pre-treatment characteristics of liver metastases of colorectal cancer as assessed
by dynamic contrast enhanced MRI (DCE-MRI), diffusion weighted MRI (DWI), 1H MR
spectroscopy (MRS) and FDG-PET predict treatment outcome?
2. Do early changes (one week after start of treatment) in DCE-MRI, DWI, 1H MRS and
FDG-PET characteristics of liver metastases of colorectal cancer predict treatment
outcome?
3. Do 19F MRS parameters of fluoropyrimidine metabolism in liver metastases of colorectal
cancer predict treatment outcome at an early stage (one week after start of treatment)?
4. What is the relative contribution of each above mentioned imaging method to predict
treatment outcome of colorectal liver metastases? Design: 60 patients with liver
metastases of colorectal cancer treated with fluoropyrimidine-based therapy will
participate to the study. Baseline 1H MRS of the liver will be performed in a session
at 3 Tesla followed by DCE-MRI and DWI at 1.5 Tesla. FDG-PET will be added to the
standard baseline CT scan, using our clinical PET-CT scanner. DCE-MRI, DWI, 1H and 19F
MRS as well as FDG-PET of the liver will be repeated one week after start of treatment.
Clinical response will be evaluated after three treatment cycles by FDG-PET-CT. We will
assess the relative contribution of each imaging method as well as the integrated use
of these methods for the identification of predictive biomarkers for response to
treatment.
Relevance of this study: Since the response of a tumor to systemic drugs may be highly
variable between patients, a method that predicts the sensitivity of a tumor to treatment at
an early stage would enable individualization of therapy and consequently would protect
patients against the toxic effects of ineffective treatment. Preferably, those predictive
markers should also give us further insight into the biology of colorectal cancer. For this
reason we propose to study a combination of in vivo noninvasive imaging methods which allow
the monitoring of relevant biomarkers
Interventional
Intervention Model: Single Group Assignment, Masking: Open Label
Correlation early changes in imaging and treatment outcome
Correlation early changes in imaging and treatment outcome Week -2-0: PET-CT and MRI Week 0 Start chemotherapy Week 1 PET-CT and MRI Week 9 PET-CT onderzoek
imaging before start, week 1, week 9
No
C.J.A. Punt, Md PhD
Principal Investigator
Radboud University
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
MICC
NCT01292681
August 2009
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