Dose Response of Functionally Critical Brain Regions for Brain Radiotherapy

Research Question:

Our goal is to answer the following three research questions in this study:

1. What is the dose response curve (degree of radiation complications/radiological changes
vs. radiation dose) for brain regions involved in the processing of visual, language
and working memory functions?

2. What is the limiting dose for these functionally critical brain regions that can be
applied to radiotherapy treatment planning to minimize (e.g., less than 5%) the
possibility of radiation-induced injury?

3. Can brain fMRI be used to guide the radiotherapy treatment planning to minimize the
dose to functionally critical brain regions and evaluate treatment responses of these
regions?

Research Method:

Imaging before radiotherapy: For each patient, active stimulation and resting fMRI
examinations will be performed in addition to standard anatomic MRI for brain radiotherapy.
Activation maps of regions involved in visual, language and working memory functions will be
generated from the fMRI scans and the patient's responses on of the working memory task
(i.e., the N-Back task) will be recorded during the fMRI studies. The MRI and fMRI will,
combined, take approximately 90 minutes - 60 minutes for the standard MRI and 30 minutes for
the fMRI. The activation maps will be overlaid onto the FLAIR MRI images, imported into the
radiotherapy treatment planning system and co-registered with the simulation CT scan.

Radiotherapy and routine follow-up: Functionally critical areas in the fMRI activation maps
will be separately contoured as critical organs but will not be considered for plan
optimization. Dose volume histograms (DVHs) of functionally critically brain regions will be
calculated and documented. Each patient will receive fractionated brain radiotherapy
according to the treatment plan and will be followed up with every three months after
radiotherapy.

Follow-up evaluations: The 3MS examination will be administered prior to initiation of
treatment onset and every three months after treatment during routine follow-up to screen
neuropsychological functions. Anatomic MRI (standard) and brain fMRI (research) will be
acquired at 6 months after radiotherapy to determine the radiological and functional changes
in regions involved in the processing of visual, language and working memory functions.

Minimizing the interference of tumor recurrence or progression: Two actions will be taken to
minimize the interference of tumor recurrence or progression with the evaluation of
performance alterations caused by radiation. First, patient inclusion will be restricted to
patients with slow growing tumors, e.g., meningioma, low grade glioma and anaplastic
astrocytoma so that the chance for tumor recurrence or progression is small. Secondly,
patients who develop disease progression at any of the post-radiotherapy follow-ups will be
excluded from the study, as it would not be possible to distinguish the effects of disease
progression from radiotherapy side effects on the fMRI or the 3MS examination, and the
findings would not be interpretable.

Dose Response Analysis: Logistic regression analysis will be used to assess the likelihood
of complications to functionally critical brain regions as a function of radiation dose. The
dependent variable will be the binary indicator that identifies patients' manifesting
complications (decline of 3MS examination score and N-Back test, radiological/functional
changes identified on MRI and fMRI) attributed to radiation exposure. The logistic
regression model will include relevant subject level factors (e.g., age, gender, baseline
Karnofsky performance status, tumor location, recent seizures, anti-epleptic medications) as
covariates. The fitted logistic normal tissue complication probability (NTCP) model will
permit estimation of the probability of significant complications associated with any
radiation dose to the area, allowing the limiting dose to be calculated as the dose expected
to induce complication with an acceptable probability (e.g., 5%).

Incorporation of limiting dose for radiotherapy treatment planning: The limiting dose from
the above "Dose Response Analysis" will be used for IMRT re-planning considering the
functionally critical brain regions. The optimization goal is to minimize the dose to
functionally critical brain regions while maintaining similar PTV (planning target volume)
coverage and keeping dose to the critical structures within accepted tolerance. DVHs of the
functionally critical brain regions, PTV and all other critical structures will be compared
for both treatment plans with and without considering the functionally critical brain
regions. A Wilcoxon matched pair signed rank test will be performed to compare the plans in
terms of calculated NTCP of critical organs. The McNemar test will be used to compare plans
with and without dose constraints of functional areas in terms of yield rate (i.e., the
proportion of patients for whom the IMRT plan was successfully devised).

The primary study endpoint of this study is normal tissue complication. The primary
objective of this study is to determine the dose response curve and limiting dose for
functionally critically brain regions for brain radiotherapy. The second objective of this
study is to investigate the accuracy of active stimulation or resting state fMRI for
avoidance of the functionally critical brain regions for radiotherapy treatment planning of
brain tumors and for evaluating the treatment responses of these critical regions.

Inclusion Criteria:

- 1. Histologically confirmed diagnosis of slow growing brain tumors that requires
radiotherapy, e.g., meningioma, low grade glioma or anaplastic astrocytomas.

2. A diagnostic contrast enhanced CT/MRI demonstrating the lesion prior to
registration.

3. Karnofsky performance status ≥60. 4. Ability to undergo MR imaging with the use of
Gadolinium contrast. 5. Ability to undergo brain fMRI. 6. Patient must sign a study
specific informed consent form. Patients who cannot provide consent due to cognitive
impairment will not be enrolled in the study. The investigators will follow the
recently published guidelines (Binder & Guze, Am. J. Psy., 155, 1649-1650, 1998) to
assess the subject's understanding of the procedure and his/her decision making
capacity,.

Exclusion Criteria:

- 1. Any condition including allergy to Gadolinium contrast, metallic implants or
cardiac pace makers that makes the candidate ineligible for MR imaging. These
criteria will be determined by an MRI research screening form signed by the subject.

2. Any condition including taking anti-anxiety medicines such as Benzodiazepines or
requiring sedative to overcome claustrophobia that makes the candidate ineligible
brain fMRI.

3. Karnofsky performance status of ≤60 4. Prior history of radiation therapy to the
brain 5. Pregnancy 6. Significant medical or neurological disorders that would affect
the outcome of the evaluations and/or make a successful MRI/fMRI unduly difficult 7.
Major psychiatric conditions, whether medicated or unmedicated, as such conditions
can affect the validity of the evaluations