Multi-Tracer PET Assessment of Primary Brain Tumors
Positron emission tomography (PET) is a molecular imaging modality that can probe various
aspects of tumor function using a variety of radio-labeled imaging agents ("tracers").
Oncologic PET imaging has seen a dramatic rise in clinical utilization over the past decade
for cancer detection, staging, and evaluating residual or recurrent disease following
therapy. These clinical scans use the tracer [18F]fluoro-2-deoxy-D-glucose (FDG), which
accumulates in cells in proportion to GLUT transporter and hexokinase activity. FDG thus
provides a measure of tissue glucose metabolism. Concurrent with this clinical growth, a
number of other PET tracers have received significant attention in research for a variety of
imaging targets. Of special interest are the tracers 3'-deoxy-3'-[18F]fluorothymidine
(FLT), 1-[11C]-acetate (ACE), and [15O]water (H2O). The uptake, retention/washout, and
ultimate biodistribution of these tracers are each related to different functional or
molecular processes. As such, each can be used to probe a different aspect of tumor
function: FLT directly assesses tumor proliferation, ACE provides a measure of tumor growth
related to fatty acid and membrane synthesis, and H2O quantifies tumor perfusion.
This study has two primary objectives: a translational objective in which a new PET imaging
technology will be translated from experimental development (with simulations and in
animals) to the first use in human subjects; and an exploratory objective in which the
complementary value of multiple PET tracers will be investigated. Each of these objective
is described below, where the study design has been carefully setup to fulfill both
objectives in the same study population.
The translational objective of this study is to implement and evaluate a new imaging
technology for rapid, single-scan multi-tracer PET imaging of these tracers. Current PET
technology prohibits imaging of more than one tracer in a single scan since the imaging
signals from each tracer cannot be distinguished by normal techniques; as such, separate
scans with each tracer currently need to be acquired hours or days apart. Our group has
developed techniques and algorithms for recovering individual-tracer images from
rapidly-acquired multi-tracer PET data using dynamic imaging techniques. These methods have
been tested through extensive simulations and verified experimentally in a canine model with
spontaneously-occurring tumors. Refinement of the methods with more advanced algorithms is
ongoing. The patient imaging studies of this protocol will be implemented in two phases.
In Phase A, separate single-tracer imaging of each tracer will be performed. The data from
these scans will be co-registered and combined to "emulate" multi-tracer scans, which will
then be processed by the multi-tracer signal-separation algorithms. This will permit a
direct comparison of imaging biomarkers from multi-tracer vs. single-tracer scans for each
tracer. Such comparison techniques have been established by the investigators and have been
accepted by peer review for testing multi-tracer signal-separation algorithms. Once
statistically-significant evidence is obtained that multi-tracer scans can accurately
provide the same imaging biomarkers as separate single-tracer scans, the imaging will
transition to Phase B—in which actual multi-tracer scans will be performed.
The objectives of this exploratory study is to preliminarily evaluate the complementary
value of FDG, FLT, ACE, and H2O PET in patients with primary glial neoplasms. Multi-tracer
PET profiles with these four tracers will be obtained in 20 patients with primary glial
neoplasms at up to three timepoints: (1) at "baseline" prior to surgery or immediately
after surgery providing a complete surgical resection was not possible and confirmed by a
post-operative contrast MRI scan where residual tumor greater than 1.0 cm in diameter was
present and prior to any tumor-directed therapy; (2) at the conclusions of the initial (~6-8
weeks) chemoradiotherapy; and (3) at the time of MRI-documented recurrence within 2 years.
In addition, patients with a known primary brain tumor who have previously undergone
treatment and have recurred based on standard clinical and imaging criteria will be eligible
for the study. A number of quantitative and pseudo-quantitative imaging biomarkers for each
tracer will be computed at each imaging timepoint, and the change in each biomarker between
timepoints will also be computed. These data will be compared with clinical endpoints
(survival, time to progression), and with tumor biologic information (histology, WHO grade,
vascularity, Ki-67, VEGF, EGFR, p53) in cases when tumor tissue becomes available from
standard care. These data will provide pilot information into the potential value of
concurrent multiple PET biomarkers for predicting tumor behavior prior to the start of
therapy, for improved prognostication, for more efficient and effective tumor surveillance,
and/or for more appropriate assignment of patients to conventional, aggressive, or
investigational therapies early in their clinical courses.
The driving hypothesis for the overall line of research is that multiple PET imaging
biomarkers obtained in conjunction can provide improved image-guided personalized care of
patients with primary glial neoplasms. The term "personalized care" is used here to broadly
include the prediction of tumor behavior prior to the start of therapy, tumor surveillance,
prognostication, and individualized assignment of patients to conventional, aggressive, or
investigational therapies early in their clinical courses. This pilot project will obtain
initial data on the value of these PET biomarkers for such image-guided personalized care.
Specific hypotheses to be tested include:
- HYPOTHESIS I a: Rapid, single-scan multi-tracer PET imaging can recover PET imaging
biomarker information of each tracer that are not significantly different from those
obtained from conventional, single-tracer scans of each tracer.
- HYPOTHESIS II b: Multi-tracer PET biomarkers, obtained in conjunction, are better able
to predict tumor aggressiveness than individual-tracer biomarkers or conventional
- HYPOTHESIS III b: Multi-tracer PET biomarkers, obtained in conjunction, are better
able to detect functional changes in tumor state that occur in response to therapy than
individual-tracer biomarkers or conventional radiographic imaging.
- HYPOTHESIS IV b: Characterization of multiple aspects of tumor function (glucose
metabolism, proliferation, membrane growth, and perfusion) provides new insight into
tumor status that can guide selection of the most appropriate therapy.
a Sufficient statistical power is expected to be obtained under this protocol to validate
the extensive simulations and experimental evaluations performed previously and concurrently
with these patient imaging studies.
b Pilot data regarding these three hypotheses will be obtained in this work by studying the
correlation of PET imaging biomarkers with clinical outcomes and tumor biologic information.
Though high statistical power cannot be expected from the limited number of patients in
this pilot study, underlying trends in the data will be identified, permitting the
formulation of formal hypotheses to be tested in future rigorous trials.
Observational Model: Case-Only, Time Perspective: Prospective
Rapid, single-scan multi-tracer PET imaging can recover PET imaging biomarker information of each tracer that are not significantly different from those obtained from conventional, single-tracer scans of each tracer.
John M Hoffman, MD
Huntsman Cancer Institute
United States: Food and Drug Administration
|Huntsman Cancer Institute||Salt Lake City, Utah 84112|