Multi-Tracer PET Assessment of Primary Brain Tumors
18 Years
N/A
Both
Brain Tumors, Cancer
Trial Information
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.
OBJECTIVES:
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
radiographic imaging.
- 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.
Inclusion Criteria:
Three different adult patient groups will be eligible for inclusion in this study:
- Adult patients with compelling evidence of primary brain tumor based on clinical and
MRI imaging characteristics that have not yet received surgery, histological
diagnosis, or any tumor-directed therapy. Such evidence will include: MRI or CT
scan-documented mass lesion within the brain, accompanied by anatomically appropriate
neurological signs and symptoms, in the absence of a probable competing diagnosis
such as brain abscess or primary intracranial hematoma. (Group 1)
- Newly diagnosed primary malignant brain tumors (WHO Grade II - IV glial-based
tumors) who have not had a complete surgical resection and by contrast MRI have
residual tumor greater than 1.0 cm in diameter and will be receiving radiotherapy
and/or chemotherapy. (Group 2)
- Patients with recurrent primary brain tumor as determined by standard clinical
criteria and MRI imaging. (Group 3)
- Patients must be 18 years or older for inclusion in this study. There is little
experience with the safety of [18F]FLT in children, and the risks associated
with radiation exposure may be increased for children under 18 years old as
well.
- Karnofsky performance status > 60%.
- Patients must document their willingness to be followed for at least 24 months
after recruitment by signing informed consent documenting their agreement to
have clinical endpoints and the results of histopathologic tissue analysis (when
tissue becomes available from routine care) entered into a research database.
- All patients, or their legal guardians, must sign a written informed consent and
HIPAA authorization in accordance with institutional guidelines.
- Determination of pregnancy status: Female patients that are not postmenopausal
or surgically sterile will undergo a serum pregnancy test prior to each set of
multi-tracer PET scans. A negative test will be necessary for such patients to
undergo research PET imaging.
- Pre-treatment laboratory tests for patients receiving [18F]FLT must be performed
within 21 days prior to study entry. These must be less than 2.5 times below or
above the upper or lower limit range for the respective laboratory test for
entry into the study. In those instances where a baseline laboratory value is
outside of this range, then such a patient will be ineligible for enrollment.
For the followup scanning sessions after therapy has been instituted, laboratory
testing will also be required due to the use of FLT. The patients have brain
tumors and will receive various forms of therapy; therefore many routine
laboratory tests may not be within the typical normal range. As such, a factor
of 4.0x above or below the upper or lower value for the normal range for any
laboratory test will be used to determine the acceptable range for the 2nd and
3rd imaging timepoints. The 4.0x value will be critical for liver function test
results which can be extremely variable, and a 4.0x above the upper normal range
is still acceptable for continued inclusion in this study. The baseline
laboratory testing will include liver enzymes (SGOT, SGPT, ALK Phos, GGT, LDH),
bilirubin (direct and total), amylase, serum electrolytes, CBC with platelets
and absolute neutrophil counts, prothrombin time, partial thromboplastin time,
BUN, creatinine, and urinalysis. For the assessments at subsequent imaging time
points the urinalysis will not be required however the remainder of the
laboratory tests as described for baseline assessment will again be obtained. A
negative HIV test will required at baseline. This is due to the previous
toxicity of FLT noted in this patient group.
Exclusion Criteria:
- Patients with clinically significant signs of uncal herniation, such as acute
pupillary enlargement, rapidly developing motor changes (over hours), or rapidly
decreasing level of consciousness, are not eligible.
- Patients with known allergic or hypersensitivity reactions to previously administered
radiopharmaceuticals. Patients with significant drug or other allergies or
autoimmune diseases may be enrolled at the Investigator's discretion.
- Patients who are pregnant or lactating or who suspect they might be pregnant. Serum
pregnancy tests will be obtained prior to each set of multi-tracer PET scans in
female patients that are not postmenopausal or surgically sterile.
- Adult patients who require monitored anesthesia for PET scanning.
- HIV positive patients due to the previous toxicity noted with FLT in this patient
group.
- Patients who have undergone surgery or receive any previous tumor-directed therapy
for their brain tumor.
Type of Study:
Observational
Study Design:
Observational Model: Case-Only, Time Perspective: Prospective
Outcome Measure:
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.
Outcome Time Frame:
December 2012
Safety Issue:
No
Principal Investigator
John M Hoffman, MD
Investigator Role:
Principal Investigator
Investigator Affiliation:
Huntsman Cancer Institute
Authority:
United States: Food and Drug Administration
Study ID:
HCI31335
NCT ID:
NCT00813566
Start Date:
December 2008
Completion Date:
December 2013
Related Keywords:
- Brain Tumors
- Cancer
- cancer
- imaging
- PET scanning
- Brain Neoplasms
Name | Location |
|---|---|
| Huntsman Cancer Institute | Salt Lake City, Utah 84112 |
