Non-Ionizing Metabolic Imaging using robust phosphorus MRI to predict treatment efficacy.

Cell proliferation and energy metabolism are the main hallmarks of tumor
biology. State of the art imaging techniques can indirectly obtain insight in
cell proliferation using diffusion weighted MRI, while FDG-PET can obtain
information of glucose uptake hence reflecting energy demand. Here we will
investigate the use of 31P MRSI as a non-ionizing and more direct imaging
technique to detect cell proliferation and energy metabolism at once, aiming
for a better, faster, non-invasive and less expensive readout of treatment
effects.
Proof of principle studies in breast cancer in our center have demonstrated
that the accuracy of 31P MRSI in predicting non-responders to chemotherapy
improved from 75% to 96% when compared to biopsy histopathology and traditional
imaging. To make this technology widespread available and economically viable,
use of 31P MRSI should extend beyond exclusively breast cancer and also
potentially guide treatment for prostate, colon, rectum, pancreas, liver and
lung tumors.
In contrast to 31P breast MRSI, 31P MRSI of deeper laying (moving) organs
requires an array of 31P receivers, needs to be robust for motion artefacts,
and manage field non-uniformities. Leveraging on earlier investments in
hardware, we will design and investigate the use of snapshot 31P MRSI guided by
motion and field navigators to detect cell proliferation and energy metabolism
in tumors during treatments. Moreover, as 31P signals are basically unaffected
by traditional 1H MRI, novel scan merging technologies of Philips will be
implemented to obtain the 31P MRSI simultaneous with anatomical 1H MRI,
resulting in short scan sessions. In our study, we will target the most
challenging organs for MRI (i.e. pancreas and lung) to determine robustness of
31P MRSI and assess the effect size of predicting treatment efficacy in a pilot
study with patients scheduled for treatment of pancreas and lung cancer.

Primary objectives pancreatic cancer:
• In this clinical pilot study, we will assess the effect size to perform
a power calculation for a subsequent clinical trial. Therefore we want to
evaluate the ability of metabolic 7T MRI imaging to determine tumor response on
FOLFIRINOX chemotherapy in pancreatic cancer

Secondary objectives pancreatic cancer:
• To compare diagnostic accuracy of 7T MRI to conventional CT-imaging in
pancreatic cancer
• To predict surgical resectability of pancreatic cancer with metabolic 7T MRI
• To investigate the correlation of tumor characteristics (pathology result,
location of tumor, stage at diagnosis etc.) with measured levels of 31P
metabolites that are involved in energy metabolism and cell proliferation (e.g.
ATP, inorganic phosphate phosphocholine, phosphoethanolamine,
glycerolphosphocholine, glycerophosphoethanolamine) gained from the metabolic
7T MRI

Primary objective lung cancer:
• In this clinical pilot study, we will assess the effect size to perform a
power calculation for a subsequent clinical trial. Therefore, we want to
determine whether metabolic imaging at 7 Tesla is feasible and suitable to
detect changes in phospholipid metabolism and ATP levels in patients with
advanced non-small cell lung cancer after treatment with immune checkpoint
inhibitors to predict treatment outcome.

Secondary objectives lung cancer:
• In this study we will perform a baseline 31P MRI
• Determine the metabolic change caused by the systemic therapy with checkpoint
inhibitors in relation to the variance of metabolite levels between patients
prior to treatment.

• Relate metabolic signature to clinical outcome and occurrence of side-effects

In this single-centre observational cohort study, patients with (borderline)
resectable- or locally advanced pancreatic cancer treated with FOLFIRINOX yet
selected for surgery and patients with lung cancer treated with immunotherapy
will be asked for participation in the study. Additionally, 15 healthy
volunteers will be scanned once to perform a baseline for the metabolic ratio
of phospholipid metabolites (control group pancreatic cancer). After eligible
patients have signed informed consent, patients will continue to receive
standard treatment as scheduled. For patients with pancreatic cancer, a
standard CT-scan will be made after four courses of FOLFIRINOX, and will be
supplemented with NIMI-scans on the same day. The scans will be made before-,
after one cycle with FOLFIRINOX and after four cycles with FOLFIRINOX (Figure
1). Phosphorus MRSI combined with anatomical MRI will be obtained in the same
scan session.
Patients with lung cancer will be scanned twice, once just before
immunotherapy, and once 3 to 6 weeks after the start of the therapy (Figure 2).
The duration of the study depends on the inclusion of the required number of
subjects, with an expected overall duration of 24 months.

Patients will be asked for two or three hospital visits to undergo imaging
during approximately one hour. A healthy volunteer will be asked for one
hospital visit to undergo one MRI scan. To avoid an *extra* visit to the
hospital, we will try to plan the MRI scans on days that a patient already has
an appointment in the hospital. The patient will not have a direct benefit of
the study. Recently, many studies have investigated the safety of ultra-high
field MRI, such as 7 Tesla MRI, including potential side-effects35. Moreover,
in other countries these ultra-high field MRI*s have been used since the 90s.
Up until now, no negative effects have been found and the only reported
complaints are temporary vertigo and nausea during scanning. These side-effects
can be attributed to the fact that the vestibular system confuses the changing
magnetic field with movement.