Patients suffering metastasized gastrointestinal cancer often receive ineffective treatments for prolonged periods of time as therapy non-response, which is hard to detect, cannot be determined earlier than nine weeks following start of therapy. Current therapy evaluation strategies primarily focus on morphological changes via RECIST criteria. However, morphological changes are subjected to prior physiological and metabolic alterations. Therefore, the MAESTRO project's ambition is to lay the foundations of a new area of research: the study of human biology using non-invasive chemistry imaging. For this, MAESTRO aims to unite two areas of research: metabolomics and magnetic resonance (MR). Metabolomics studies body functions through the measurements of metabolites; MR imaging (MRI) and spectroscopy (MRS) can provide 3D images of the body and measure metabolite and lipid content respectively. Previous studies show that phospholipid metabolites in particular the cell membrane precursors i.e. phosphomonoesters (PME), and the cell membrane degradation products i.e. phosphodiesters (PDE) are valuable biomarkers in therapy assessment. With this MAESTRO approach, the consortium aims at reducing the nine weeks period before therapy efficacy evaluation to three weeks or less. By validating the powerful new MRS(I)-visible biomarkers in a patient cohort, a non-invasive technology can be developed for dynamically mapping biochemical processes in the whole human body and pave the way for individualized medicine.
Patients with liver metastasis of gastrointestinal cancer, with histological or cytological proof of metastasis or a high suspicion on CT imaging.
Tumour size ≥ 1cm.
WHO-performance score 0-2.
Scheduled for first- or second-line palliative chemotherapy containing capecitabine combined with oxaliplatin (CAPOX) or fluorouracil combined with oxaliplatin and folinic acid (FOLFOX).
Any psychological, familial, sociological, or geographical condition potentially hampering adequate informed consent or compliance with the study protocol.
Contra-indications for MR scanning, including patients with a pacemaker, cochlear implant or neurostimulator; patients with non-MR compatible metallic implants in their eye, spine, thorax or abdomen; or a non-MR compatible aneurysm clip in their brain; patients with claustrophobia.
Single group
MRI/Spectroscopy
RadiationParticipants will undergo multiple 7T MR imaging sessions which include advanced 31P MRSI techniques, before start of palliative chemotherapy and during treatment until progression of disease or until week 54.
PME/PDE-ratio from Area Under the Curve (AUC): predictive
The primary outcome measure in this study is the PME/PDE-ratio (PME/PDE) resulting from the AUC of the metabolite peaks in the acquired metabolic images e.g. spectra. This measure is used to calculate changes in the metabolic phospholipid-ratios of PME and PDE (ΔPME/PDE) between baseline and after 2 weeks of therapy. In addition, this outcome measure is used to investigate secondary objectives including PME/PDE at baseline as a sole predictor (see Outcome Measure 3).
Change in PME/PDE (ΔPME/PDE): predictive
The second primary outcome measure to investigate the discriminative ability of PME/PDE is the ΔPME/PDE between baseline and after 2 weeks of therapy. This measure is used to investigate the primary objective whether biochemical imaging of change in the metabolic phospholipid-ratios of PME and PDE (ΔPME/PDE) between baseline and after 2 weeks of therapy are predictive for RECIST progression in gastrointestinal cancer patients after the first 9 week treatment period. In addition, this outcome measure is also used to investigate secondary objectives which includes different time periods over which ΔPME/PDE is measured.
PME/PDE at baseline: predictive
This secondary measure is used investigate the secondary objective whether biochemical imaging of PME/PDE at baseline of therapy is predictive for RECIST progression after the first 9-week treatment period, and for PFS and OS in gastrointestinal cancer patients. PME/PDE at baseline results from the AUC of the metabolite peaks in the acquired metabolic images e.g. specta (see also Outcome Measure 1).
Prediction model
Exploratory multi variable analysis for the development of a prediction model to predict resistance to treatment within 3 weeks after the start of chemotherapy with the use of all chemistry imaging data including all MR detectable nuclei and clinical parameters. Multi-variable analysis of clinically relevant data to investigate the feasibility of a dynamic prediction model will use all chemical imaging data, size measurements from CT, conventional 7T MR imaging scans, coded radiology reports, clinical patient data, e.g. chemotherapy details extracted from clinical notes which are coded before storage to preserve anonymity, choice of therapy, progression free survival (PFS) and overall survival (OS) and metastasis origin.
(Δ)PME/PDE predictive significance
To investigate to what extent baseline PME/PDE and (ΔPME/PDE) over all different time periods is predictive of PFS and OS, we will use standard survival analysis techniques (e.g. Cox regression, accelerated failure time models) and estimate the C-index as measure of discriminative ability.
Response to treatment
This outcome measure results from conventional therapy evaluation defined by RECIST progression. It is used in the primary and secondary objectives as the gold standard for the therapy evaluation predictors assessed in this study (ΔPME/PDE, PME/PDE, etc.)
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Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Lead sponsor
UMC Utrecht
Collaborator
