Characterization of Serial Magnetic Resonance Spectroscopy Imaging in Patients With Malignant Glioma Undergoing Radiotherapy
Malignant glioma is the most common primary brain tumor in adults. Despite aggressive
therapy, less than 40% of these patients are expected to live beyond 5 years. External beam
radiotherapy following maximal surgical resection is the mainstay of treatment for this
group of patients. Recent intensification of local therapy with focused radiotherapy
planning has resulted in successful escalation of dose. Further improvement in the
therapeutic index of therapy is desirable.
Radiologic characterization of glial tumors relies predominantly on CT and MRI images; these
studies provide good anatomic information regarding the size and location of the tumor, as
well as surrounding structures, but are unable to evaluate viability or proliferative
activity of tumors. Thus, the enhancing lesion on CT or MRI may not correspond precisely to
areas of viable tumor, especially after surgery and radiotherapy. Also, because contrast
enhanced MRI relies on regions of blood brain barrier (BBB) breakdown, it is not tumor
specific, thus non-neoplastic processes may lead to findings similar to disease progression.
This phenomenon can make conventional radiologic follow-up difficult in patients who have
received radiotherapy, as such imaging techniques are limited in their ability to discern
radiotherapy effect and necrosis from recurrence and progression. Finally, because they do
not discriminate viable tumor, CT and MRI are of limited usefulness in assessing response to
therapy, and are unable to effectively predict outcome. Magnetic Resonance Spectroscopy
(MRS) is a relatively new technology which may be able to address these issues.
The objective of the current study is to investigate the changes that occur in tumor related
magnetic resonance (MR) spectra over the course of radical radiotherapy for malignant
glioma. The primary endpoint for the study will be to identify characteristic evolving
metabolite patterns on MRSI, before, during, and after radiotherapy that correlate with
overall survival, and progression-free survival in high grade gliomas. Secondary endpoints
will involve correlation of MRSI metabolite patterns with time to progression and Karnofsky
- Patients must be older than 18 years of age.
- Patients must have histologically proven malignant glioma of the brain.
- Patients must have bi-directionally measurable enhancing residual disease by T1
- Patients must be willing to undergo high dose radiotherapy to the brain for the
treatment of their glial tumor.
- Patients must be willing and able to comply with all study requirements.
- The patient or legally authorized representative must fully understand all elements of
informed consent, and sign the consent document.
Ineligibility criteria include:
- History of previous RT to the head and neck region
- History of lupus, scleroderma or RT hypersensitivity
- Co-existing medical condition precluding radiotherapy
- Psychiatric conditions precluding informed consent.
- Medical or psychiatric conditions precluding MR studies (eg. pacemaker, aneurysm clips,
neuro stimulator, cochlear implant, severe claustrophobia/anxiety)
Patients will be approached for study participation at the time of their initial radiation
oncology consultation in the outpatient department of the Cross Cancer Institute (CCI).
Patients who wish to participate, and satisfy the eligibility and exclusion criteria, will
be required to review and sign the consent form at that time. Patients will then undergo
regular staging investigations, construction of an immobilizing shell, treatment planning
MRI, and CT simulation. These studies are typically completed 2 weeks after the initial
consult. Radiotherapy will commence approximately 3-4 weeks after the initial consult. At
week 0 of RT, prior to beginning therapy, the patient will undergo the baseline MRS. The
mid-RT MRS study will be performed during week 4 of RT. The post therapy scan will take
place 2 months post-therapy. From then on, patients will be seen in clinic every 2-4 months
for follow-up, and will undergo MRI and MRS scans with each visit for 1 year.
Data Collection and Statistical Analysis:
The height of each MRS metabolite peak will be measured from voxels within the enhancing MRI
lesion and from voxels in normal brain for each patient. Relative metabolite values
(normalized to the value in normal brain) will then be generated, as well as relative
metabolite ratios (eg. relative choline/relative NAA) for each time point (week 0, week 4,
and post-RT, at follow-up). For each patient, the relative metabolite levels (and ratios)
will be plotted over time. Patients will then be partitioned into groups, based on similar
evolving MRS pattern. For each of the groups, curves of survival and disease free
progression will be generated by the Kaplan-Meier method. The curves will be analyzed for
statistical significance by the log-rank method.
The investigators plan to accrue 30 patients for the present study. They are confident 30
patients will be sufficient to generate statistically significant results. In a study of
the effects of brain tumor radiotherapy on normal brain as imaged by NMR spectroscopy,
Urtasun et al were able to find statistically significant metabolite changes on proton MRS
images with only 10 patients. In addition, the data to be utilized in the retrospective
aspect of the study contains information on approximately 30 patients and their MRS scans.
The trends found in this data will be used to guide data analysis for the prospective study.
Finally, given the relative distribution and frequency of histologies seen in the new
patient CNS clinic at the CCI, the investigators feel the target accrual of 30 patients is
feasible within the time restraints of the project.
Observational Model: Cohort, Time Perspective: Prospective
Wilson Roa, MD
Alberta Health Services
Canada: Health Canada
CNS-09-0022 / ethics 21388