Clinical trial NCT01991977
Conditions: Malignant Glioma
Sponsor: Mayo Clinic
Start date: 2013-12-01; Completion date: 2024-07-15
Enrollment: 91 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well fluorine F 18 fluorodopa (18F-DOPA)-positron emission tomography (PET) works in finding tumors in patients with newly diagnosed gliomas undergoing radiation therapy. Comparing results of diagnostic procedures done before and during radiation therapy may help doctors predict a patient's response to treatment and help plan the best treatment.

Detailed description:
PRIMARY OBJECTIVES:

I. Compare confirmed-progression free survival at 6 months for grade IV MGMT unmethylated glioma patients after radiation therapy targeting volumes designed with both 18F-DOPA PET and conventional magnetic resonance (MR) image information with historical controls from Mayo Clinic Rochester patients, including those treated on North Central Cancer Treatment Group (NCCTG) clinical trials.

SECONDARY OBJECTIVES:

I. Compare progression free survival at 12 months for grade III patients after radiation therapy targeting volumes designed with both 18F-DOPA PET and conventional MR image information with historical controls from Mayo Clinic Rochester patients, including those on NCCTG clinical trials.

II. Compare patient overall survival after radiation therapy targeting volumes designed with both 18F-DOPA PET and conventional MR image information with historical controls from Mayo Clinic Rochester patients, including those on NCCTG clinical trials.

III. Evaluate quality of life after radiotherapy treatment targeting dose escalated volumes defined to include high 18F-DOPA PET uptake.

IV. Determine acute and late effect toxicity after radiotherapy treatment targeting dose escalated volumes defined to include high 18F-DOPA PET uptake.

V. Compare confirmed-progression free survival at 12 months for grade IV MGMT methylated patients after radiation therapy targeting volumes designed with both 18F-DOPA PET and conventional MR image information with historical controls from Mayo Clinic Rochester patients, including those on NCCTG clinical trials.

VI. Compare confirmed-progression free survival in grade IV MGMT un-methylated patients with similar historical controls from Mayo Clinic Rochester patients, including those on NCCTG clinical trials.

VII. Compare confirmed-progression free survival in grade IV MGMT methylated patients with similar historical controls from Mayo Clinic Rochester patients, including those on NCCTG clinical trials.

TERTIARY OBJECTIVES:

I. Compare radiation therapy (RT) treatment volumes defined by MR only with RT treatment volumes defined with both PET and MR information for grade IV glioma patients.

II. Compare timing of accurate identification of progression defined by 18F-DOPA PET, perfusion magnetic resonance imaging (pMRI) and conventional MRI for grade IV glioma patients.

III. Compare patterns of failure after radiation therapy targeting volumes defined with target volumes designed to with both 18F-DOPA PET and conventional MR image information with patterns of failure for historical controls from Mayo Clinic Rochester patients, including those on NCCTG clinical trials.

IV. Compare RT treatment volumes defined by MR only with RT treatment volumes defined with both PET and MR information for grade III glioma patients.

V. Evaluate intra- and inter-observer variability with vs. without the addition of 18F-DOPA PET uptake for radiotherapy target volume delineation.

VI. Compare timing of accurate identification of progression defined by 18F-DOPA PET, pMRI and conventional MRI for grade III glioma patients.

VII. Compare predictive capabilities of 18F-DOPA PET, pMRI and diffusion tensor imaging (DTI) for localization of recurrences for patients treated with 18F-DOPA PET-guided RT dose escalation.

OUTLINE:

Patients undergo 18F DOPA-PET, pMRI, and DTI within 14 days before radiation therapy, 3-6 weeks after radiation therapy, and during follow-up. Patients also undergo intensity-modulated radiation therapy (IMRT) over 30 fractions and receive temozolomide.

After completion of study treatment, patients are followed up periodically for up to 5 years.

Arms: arm 1: Patients undergo 18F DOPA-PET, pMRI and DTI within 14 days before radiation therapy, 3-6 weeks after radiation therapy, and during follow-up. Patients also undergo IMRT over 30 fractions and receive temozolomide.
Interventions: intervention 1: Diffusion Weighted Imaging intervention 2: Fluorine F 18 Fluorodopa intervention 3: Intensity-Modulated Radiation Therapy intervention 4: Perfusion Magnetic Resonance Imaging intervention 5: Positron Emission Tomography intervention 6: Quality-of-Life Assessment intervention 7: Temozolomide
Intervention descriptions: intervention 1: Undergo DTI intervention 2: Undergo 18F-DOPA-PET intervention 3: Undergo IMRT intervention 4: Undergo pMRI intervention 5: Undergo 18F-DOPA-PET intervention 6: Ancillary studies intervention 7: Receive temozolomide

Protocol documents:
Prot_SAP_000.pdf: 




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Table of Contents 
EVALUATING THE IMPACT OF 18F-DOPA-PET ON RADIOTHERAPY PLANNING FOR 
NEWLY DIAGNOSED GLIOMAS .......................................................................................................... 1 
PROTOCOL RESOURCES ...................................................................................................................... 2 
TABLE OF CONTENTS ........................................................................................................................... 3 
SCHEMA ..................................................................................................................................................... 4 
1.0 
BACKGROUND ............................................................................................................................... 5 
2.0 
GOALS ......................................................................................................................................... 14 
3.0 
PATIENT ELIGIBILITY .................................................................................................................. 15 
4.0 
TEST SCHEDULE .......................................................................................................................... 17 
5.0 
GROUPING FACTORS: .................................................................................................................. 18 
6.0 
REGISTRATION/RANDOMIZATION PROCEDURES ........................................................................ 18 
7.0 
PROTOCOL TREATMENT .............................................................................................................. 20 
8.0 
DOSAGE MODIFICATION BASED ON ADVERSE EVENTS .............................................................. 25 
9.0 
ANCILLARY TREATMENT/SUPPORTIVE CARE: NONE. ................................................................. 25 
10.0 
ADVERSE EVENT (AE) REPORTING AND MONITORING .............................................................. 25 
11.0 
EVALUATION CRITERIA .............................................................................................................. 31 
12.0 
DESCRIPTIVE FACTORS ............................................................................................................... 35 
13.0 
FOLLOW–UP DECISION AT EVALUATION OF PATIENT ................................................................. 35 
14.0 
BODY FLUID BIOSPECIMENS - NONE. .......................................................................................... 36 
15.0 
DRUG INFORMATION ................................................................................................................... 36 
16.0 
STATISTICAL CONSIDERATIONS AND METHODOLOGY ............................................................... 37 
17.0 
PATHOLOGY CONSIDERATIONS/TISSUE BIOSPECIMENS: N/A ..................................................... 46 
18.0 
RECORDS AND DATA COLLECTION PROCEDURES ....................................................................... 47 
19.0 
BUDGET ...................................................................................................................................... 49 
20.0 
REFERENCES ............................................................................................................................... 50 
APPENDIX I ECOG PERFORMANCE STATUS ................................................................................ 54 
APPENDIX II FOLSTEIN MINI MENTAL STATE EXAMINATION (MMSE) ............................. 55 
APPENDIX III PATIENT INFORMATION SHEET........................................................................... 58 
APPENDIX IV MDASI - BT.................................................................................................................... 59 
APPENDIX V CONTOURING CNS AND H/N .................................................................................... 61 
APPENDIX VI IMAGING GUIDELINES ............................................................................................. 63 
 


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Schema 
 
Registration 
 
 
 
Standard of care CT simulation1 
 
 
 
Cycle 1 
18F-DOPA PET, 
standard and advanced MRI Imaging 
(scans no more than 2 weeks prior to RT) 
then Radiation Treatment (RT) 
 
 
 
Cycle 2 
18F-DOPA PET, 
standard and advanced MRI Imaging 
(scans 3-6 weeks post-RT) 
 
 
 
Cycles 3+ 
18F-DOPA PET, 
At every clinically indicated standard and  
advanced MRI Imaging follow-up  
surveillance appointment for 5 years or until progression. 
 
 
Event Monitoring 
 
 
 
1CTsimulation can be done prior to or after registration 
 
 


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1.0 
Background 
1.1 
Conventional imaging is inadequate to differentiate high- and low-grade gliomas 
and normal tissue: 
Image-guided techniques have assumed a central role in maximizing the therapeutic 
benefit of first-line multi-modal treatment for gliomas. However there are significant 
deficiencies associated with conventional contrast enhanced magnetic resonance imaging 
(CE-MRI), the current standard of care for image-guided radiotherapy (RT) of brain 
tumors. MRI findings typically include a heterogeneous area of CE solid tumor 
surrounded by a large area of vasogenic edema. CE on T1-weighted images is used to 
identify regions of highest tumor density/grade or malignant potential for radiotherapy 
planning. However, approximately one-third of high-grade gliomas demonstrate no 
contrast enhancement (NCE), while benign tumors, such as pilocytic astrocytomas, 
infection, demyelination, and treatment effect commonly enhance [1]. Although used to 
define the extent of tumor infiltration relative to normal neuro-anatomic structures, 
abnormal T2/FLAIR signal is known to contain both regions of non-tumoral vasogenic 
edema and non-uniform tumor infiltration [2, 3]. Recent spectroscopic data suggest that 
the infiltration of tumor cells is not necessarily uniform with some areas of T2 change 
more likely to be edema and other areas more likely to have tumor infiltration [3]. 
Furthermore, tumor infiltration has been found to extend beyond areas that demonstrate 
abnormal T2/FLAIR or enhancement [4]. There is a critical need to incorporate imaging-
based techniques to guide therapy that address these deficiencies of CE-MRI. Molecular 
imaging techniques provide visual information about biological processes and have the 
potential to improve the accuracy of RT tumor delineation and image-guided dose 
escalation, which impact the overall course of treatment and prognosis for brain tumor 
patients. 
 
1.2 
Amino acid PET tracer 18F-DOPA PET appears promising for gliomas: 
In contrast to the most commonly used tracer 18-Fluoro-deoxyglucose (18F-FDG), which 
is taken up in both the tumor and normal brain glucose-metabolizing tissues, amino acid 
PET tracers such as 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (18F-DOPA), show a 
high uptake in tumor tissue and low uptake in normal brain tissue [5-7]. 18F-DOPA 
transport is independent of the blood-brain barrier breakdown, allowing uptake to occur 
in both enhancing and non-enhancing tumor with CE-MRI.  Limited studies evaluating 
the sensitivity of 18F-DOPA indicated that although FDG PET demonstrated a higher 
absolute standard uptake value (SUV) compared with 18F-DOPA, the sensitivity for 
detection of low- or high-grade tumors was 96% for 18F-DOPA versus 61% for 18F-
FDG [6, 8]. The most studied amino acid tracer is 11C-methionine (11C-MET PET) [9]. 
Discrepancies of high 11C-MET PET uptake extending up to 4.5 cm beyond the CE 
region on CE-MRI for glioma patients have been reported [10], with high MET uptake 
also reported extending beyond the abnormal T2 signal area [10]. Several studies have 
indicated MET-PET altered resection planning for a majority of both low- and high-grade 
gliomas [11, 12]. A comparison of the performance of 18F-DOPA with 11C-MET 
concluded that 18F-DOPA provided equivalent visual and quantitative SUV information 
when imaging cerebral lesions [13]. The short physical half-life of 11C limits the ability 
to image patients at a facility without a cyclotron. Therefore, labeling an amino acid 
tracer with 18F would increase the physical half-life and increase the feasibility of multi-
institutional use.  Unfortunately, labeling methionine with 18F is not chemically feasible.  
The sensitivity for differentiating tumor from normal brain, compelling literature 
evidence for amino acid tracers to detect additional tumor beyond conventional CE-MRI, 


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and the feasibility of multi-institutional use all substantiate the need to further investigate 
the value of 18F-DOPA PET in the clinical management of gliomas.  
 
1.3 
18F-DOPA-PET for gross and clinical target volume delineation 
Manual delineation of target volumes based on the PET data using different window-
level settings and lookup tables is highly operator-dependent and subject to large inter-
observer variability [14-25]. Several image segmentation approaches have been 
developed and used in the clinical setting, such as thresholding, region growing, edge 
detection, deformable models, clustering, and many more [15-24, 26-41]. A study by 
Grosu et al. demonstrated a reduction in interobserver variability defining the gross tumor 
volume (GTV) with agreement in more than 80% of the outlined volume from 1 in 5 
patients to 5 in 10 patients with the inclusion of MET-PET [25]. Reports in the literature 
have demonstrated the significant volume delineation differences between MRI alone 
and MET- PET/MRI fusion.  A study by Matsuo et al. concluded that based on 19 
patients with 95 brain metastases, for GTV-MRI volumes greater than 0.5 mL, the GTV- 
MET-PET volumes were larger, and that a 2 mm margin outside the GTV-MRI 
significantly improved coverage of the GTV-PET [42]. A study by Grosu et al. found 
that of 39 patients undergoing radiation therapy planning for malignant gliomas after 
surgical resection, 74% had a MET-PET tumor volume (up to 4.5 cm) larger than the 
contrast-enhanced T1-weighted MRI-defined volume [ 10 ] . Also shown, for 18 
patients who underwent both T2-weighted MRI and MET- PET, there was a 50% 
increase in MET uptake extended beyond the abnormal T2 signal area. Given the studies 
that demonstrate the significance of 11C-MET PET to adequately delineate tumor volume, 
using 18F-DOPA-PET as a surrogate is anticipated to play an important role in the 
planning of radiation treatment of gliomas. 
 
1.4 
Re-visiting dose escalation incorporating biological imaging-based treatment 
volumes: 
Previous studies have clearly defined the role for RT in controlling high grade gliomas 
[43]. Previous dose escalation studies without chemotherapy up to 90 Gy to a 0.5 cm 
PTV margin from the contrast-enhancing lesion did not alter the median survival benefit, 
with treatment failures within the high dose RT IMRT fields remaining at over 90%, 
although no significant treatment toxicities occurred [44, 45]. In 2004, a randomized 
phase III trial reported improved median and 2-year survival in GBM patients treated 
with concomitant and adjuvant temozolomide (TMZ) and conformal RT with 60 Gy in 30 
fractions [46].  Unfortunately, subsequent studies not only reported patterns of failure 
within the high dose (60 Gy) treatment field in over 90% of patients with GBM, but also 
showed an increase in distant failures [47, 48]. A dose escalation retrospective analysis 
with TMZ did not show a survival benefit or a reduction of in-field failures, but did show 
tolerable doses up to 78 Gy with only 8% experiencing RTOG grade 3 acute CNS 
toxicity and 0% grade 4 [49]. While these results appear to be discouraging, we believe 
they highlight the deficiencies of conventional imaging modalities in RT treatment 
planning.  To date, the MRI CE lesion plus resection cavity have been used to define the 
dose escalation volume. However, a recent imaging study with the amino acid tracer, 11C 
MET PET, revealed tracer uptake outside the high-dose region defined by CE-MRI was 
correlated with non-central recurrences [50]. Another recent study showed that dose 
escalation to the MRI CE lesion of up to 75 Gy in 30 fractions decreased central 
recurrences, and did not cause radiation necrosis or any late CNS toxicities [51].  These 
studies suggest that re-visiting dose escalation strategies by incorporating biological 


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imaging-based treatment volumes in the era of 3D-conformal and intensity modulated RT 
with added radiosensitizing chemotherapy (TMZ) could reveal improved patient 
outcomes without added acute or late toxicities.  We will evaluate the impact of 
integrating molecular imaging into RT for guidance of tumor delineation and dose 
escalation.  We expect that dose escalation of the combined 18F-DOPA PET uptake and 
CE-MRI volumes with adjuvant TMZ will lead to a reduction in both in-field and central 
failures, and improve patient outcomes without additional acute or late toxicities. 
 
1.5 
Advanced MRI for tumor delineation and assessment of recurrence: 
Advanced MRI techniques, including Perfusion MRI (pMRI) and Diffusion Tensor 
Imaging (DTI), provide physiologic information that complements anatomical 
information from CE-MRI [52-56]. The pMRI method employs dynamic susceptibility 
contrast-enhanced (DSC) MRI and rapid bolus injection of gadolinium-based (Gd) 
contrast agent to measure relative cerebral blood volume (rCBV) as an estimate of tissue 
microvasculature [52-54]. Based on inherent differences in microvasculature, relCBV has 
been used to distinguish high-grade and low-grade components of non-enhancing and 
enhancing gliomas at the time of surgical biopsy [57, 58] and to distinguish high-grade 
glioma recurrence from pseudoprogression and radiation necrosis [59, 60]. 
Diffusion Tensor Imaging (DTI) is based on the use of multi-directional magnetic 
gradients to detect Brownian diffusion of tissue water, which is directionally specific in 
the brain, due to white matter tracts [55, 56]. Preliminary studies comparing DTI with 
CE-MRI indicate that DTI can more accurately distinguish tumor margins and tumor 
infiltration along white matter tracts [61, 62]. 
These advanced MRI techniques for differentiating tumor extent and grade are sensitive 
to the contrast administration technique, acquisition protocol, and method of additional 
post-processing [63-66]. However, use of these advanced techniques in oncology has 
been reported, suggesting they may differentiate regions of tumor into various degrees of 
aggressiveness, provide information about tumor infiltration and predict treatment 
efficacy [57, 58, 61, 62]. Accordingly, in addition to each PET scan acquired for this 
study, pMRI and DTI data will be acquired and compared with 18F-DOPA PET in for 
impact on RT planning and for differentiation of tumor recurrence from pseudo-
progression during follow-up imaging.   
 
1.6 
Preliminary Data 
18F-FDOPA-PET has been in production at Mayo Clinic Rochester since 2001, used to 
image Parkinson’s patients to study the 18F-FDOPA uptake in the caudate nucleus and 
putamen. More recently we have been using 18F-FDOPA-PET to image gliomas prior to 
neurosurgery on our open IRB-approved pilot study (MC1078), where the trajectory of 
the biopsy will be planned per the co-registered PET and MR images, targeting the 
maximum PET uptake as well as any discordant regions, e.g. MR-enhancing but no PET 
uptake. Below are some preliminary findings from the first subset of patients accrued to 
the pilot study. 






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Figure 5: Biopsy sample grade vs. ratios of 18F-DOPA  
PET tumor SUVmax to SUVmean of the contralateral normal  
brain tissue (T/N), excluding oligodendroglioma samples. 
 
Figure 4: 18F-DOPA PET-CT, T1 MRI, H&E staining (40x magnification), and Ki-67 (10x 
magnification) staining (from left to right) for biopsy samples located in (A) CE+PET+ 
(purple), (B) CE-PET+ (blue), and (C) CE-PET- (green).  
stereotactic biopsy planning, especially in NCE tumors. We will be evaluating 
correlations between image-guided, spatially accurate tissue samples across a range of 
SUVs over a large cohort in concurrent trial (MC#TBD). 
Preliminary results – 18F-DOPA PET correlations with cellularity, proliferation 
index and thresholds: MRI CE is targeted during neurosurgical planning and RT 
delineation of the boost dose volume based on the presumption that this region contains 
the highest density of tumor and/or highest grade disease. Histopathological markers of 
cellularity and Ki-67 proliferative index were analyzed for the 20 positive biopsy 
samples, and assessed with SUVmean. SUVmean was chosen for correlation as it is more 
representative of the entire cellular area used in calculations of both cellularity and Ki-67 
compared to a single value at SUVmax. Our results show that both cellularity (p = 0.03) 
and proliferative activity (p < 0.001) significantly correlate with 18F-DOPA PET 
SUVmean. This is evident in Figure 4 comparing SUVmean with stained nuclei for 3 
samples from the same patient. These Ki-67 results agree with previous 18F-DOPA PET 
correlations between Ki-67 and SUVmean (p = 0.001) in newly diagnosed gliomas [67]. 
      
18F-DOPA PET 
thresholds were 
computed based on 
ratios of SUVmax of 
the tumor to 
SUVmean of the 
contralateral normal 
brain tissue (T/N) to 
facilitate future 
delineation of high 
density regions from 
the entire 18F-DOPA 






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1.7 
Adverse event assessment 
Based on preliminary data of 18F-DOPA trials in glioma patients at Mayo Clinic, no 
adverse events related to the agent have been reported. As of 09Jun2015, 82 glioma 
patients have received at least one injection and a total of 174 injections have been 
administered. Although, the most likely adverse event would be allergic reaction to the 
agent, no such reaction has been seen to date. If allergic reaction were to occur, it would 
happen shortly after injection of the agent. Based on our data, we are reducing the 
observation time required post-injection from one hour to the duration the patient is in the 
PET suite for dosing and imaging (approximately 15-20 minutes). This change will 
reduce the time the patients must wait after their scans are completed and will not 
compromise patient safety (based on no adverse events seen in the five years this agent 
has been studied in glioma patients). 
 
1.8 
Rationale for Addendum 8: 
Addendum 8 was required to solve several issues. The first solution is to no longer enroll 
Grade-III patients. The enrollment of Grade-III patients was proceeding slower than 
expected; therefore the anticipated sample size at the end of the study would no longer be 
sufficient for many of the Grade-III related endpoints. The second solution is to redefine 
our endpoint based on the Grade-IV MGMT un-methylated patients. This is necessary 
due to the markedly different progression free survival depending on MGMT methylation 
status, and the change in distribution of MGMT status for patients accrued to this study 
due to the competing study A071102, a large cooperative group study opened by the 
Alliance which is/was enrolling only Grade-IV MGMT Methylated patients. During the 
period (8/1/2015-1/25/2017) only three Grade-IV MGMT Methylated patients were 
enrolled to this study compared to 14 Grade-IV MGMT un-methylated patients.  Third, 
we added the option to deliver the radiation in our regional Radiation Oncology sites 
which have matched treatment machines and share the same beam model in our treatment 
planning system.  All of the advanced imaging and treatment planning must still take 
place in Rochester, but this will be more convenient for patients who live closer to one of 
our regional sites.  We have had several patients who were interested in this study but 
chose not to participate because the did not want to come to Rochester for their daily 
radiation treatments. 
 
 


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2.0 
Goals 
2.1 
Primary 
Compare confirmed-progression free survival at 6 months for Grade IV MGMT un-
methylated glioma patients after radiation therapy targeting volumes designed with both 
18F-DOPA PET and conventional MR image information with historical controls from 
Mayo Clinic Rochester patients, including those treated on North Central Cancer Treatment 
Group (NCCTG) clinical trials. 
2.2 
Secondary 
2.21 
Compare progression free survival at 12 months for Grade III patients after 
radiation therapy targeting volumes designed with both 18F-DOPA PET and 
conventional MR image information with historical controls from Mayo Clinic 
Rochester patients, including those on NCCTG clinical trials. 
2.22 
Compare patient overall survival after radiation therapy targeting volumes 
designed with both 18F-DOPA PET and conventional MR image information 
with historical controls from Mayo Clinic Rochester patients, including those on 
NCCTG clinical trials. 
2.23 
Evaluate quality of life after radiotherapy treatment targeting dose escalated 
volumes defined to include high18F-DOPA PET uptake. 
2.24 
Determine acute and late effect toxicity after radiotherapy treatment targeting 
dose escalated volumes defined to include high18F-DOPA PET uptake. 
2.25 
Compare confirmed-progression free survival at 12 months for Grade IV MGMT 
Methylated patients after radiation therapy targeting volumes designed with both 
18F-DOPA PET and conventional MR image information with historical controls 
from Mayo Clinic Rochester patients, including those on NCCTG clinical trials. 
2.26 
Compare confirmed-progession free survival in grade IV MGMT un-methylated 
patients with similar historical controls from Mayo Clinic Rochester patients, 
including those on NCCTG clinical trials. 
2.27 
Compare confirmed-progession free survival in grade IV MGMT methylated 
patients with similar historical controls from Mayo Clinic Rochester patients, 
including those on NCCTG clinical trials. 
 
2.3 
Correlative Research 
2.31 
Compare RT treatment volumes defined by MR only with RT treatment volumes 
defined with both PET and MR information for Grade IV glioma patients.  
2.32 
Compare timing of accurate identification of progression defined by 18F- DOPA 
PET, pMRI and conventional MRI for Grade IV glioma patients.  
2.33 
Compare patterns of failure after radiation therapy targeting volumes defined 
with target volumes designed to with both 18F-DOPA PET and conventional MR 
image information with patterns of failure for historical controls from Mayo 
Clinic Rochester patients, including those on NCCTG clinical trials. 


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2.34 
Compare RT treatment volumes defined by MR only with RT treatment volumes 
defined with both PET and MR information for Grade III glioma patients. 
2.35 
Evaluate intra- and inter-observer variability with vs. without the addition of 
18F-DOPA PET uptake for radiotherapy target volume delineation. 
2.36 
Compare timing of accurate identification of progression defined by 18F-DOPA 
PET, pMRI and conventional MRI for Grade III glioma patients. 
2.37 
Compare predictive capabilities of 18F-DOPA PET, pMRI and DTI for 
localization of recurrences for patients treated with 18F-DOPA PET-guided RT 
dose escalation. 
 
 
3.0 
Patient Eligibility 
 
3.1 
Inclusion Criteria 
 
3.11 
Age ≥18 years. 
 
3.12 
Histologically confirmed newly diagnosed grade IV malignant glioma.  
Note: as of addendum 8, Grade III patients are no longer being enrolled. 
 
3.13 
CT simulation, immobilization, MRI and PET imaging, treatment planning, and 
all follow-up MRI and PET scans to be performed at Mayo Clinic Rochester. 
Note: The actual radiation therapy treatments and follow-up other than imaging 
can be performed at Mayo Clinic Rochester, Northfield, LaCrosse, Mankato, Eau 
Claire, or Albert Lea. 
 
3.14 
Provide written informed consent.  
 
3.15 
Ability to complete questionnaire(s) by themselves or with assistance. 
 
3.2 
Exclusion Criteria 
 
3.21 
Patients diagnosed with anaplastic oligodendroglioma 
 
3.22 
Unable to undergo MRI scans with contrast (e.g. cardiac pacemaker, defibrillator, 
kidney failure). 
 
3.23 
Unable to undergo an 18F-DOPA PET scan (e.g., Parkinson’s Disease, taking 
anti-dopaminergic, or dopamine agonist medication or less than 6 half-lives from 
discontinuance of dopamine agonists).  
 
NOTE: Other potentially interfering drugs: amoxapine, amphetamine, 
benztropine, buproprion, buspirone, cocaine, mazindol, methamphetamine, 
methylphenidate, norephedrine, phentermine, phenylpropanolamine, selegiline, 


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paroxetine, citalopram, and sertraline. If a patient is on any of these drugs, list 
which ones on the On-Study form. 
 
3.24 
Any of the following: 
• 
Pregnant women 
• 
Nursing women 
• 
Men or women of childbearing potential who are unwilling to employ 
adequate contraception 
 


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4.0 
Test Schedule 
 
Baseline 
Active Monitoring 
 
Until PD or patient 
refusal 
Tests and procedures 
≤21 days 
prior to 
registration 
Cycle 1 
Pre-RT 
Scans 
Cycle 1 
RT 
Cycle 2 
Post RT Scans 
≤42
5
 days after 
RT 
At every clinically 
indicated follow-up 
MR scan  
(end of each new 
cycle) 
Physical exam, wt, 
ECOG PS 
X 
 
 
 
 
Neuro history and exam 
X 
 
 
X 
X 
MMSE
4
 
 
X
12
 
 
X 
X 
CT simulation for 
radiotherapy planning 
X
8,9
 
 
 
 
 
Pregnancy test 
 
X
1,R
 
 
X
1,R
 
X
1,R
 
18F-DOPA-PETR 
 
X
8
 
 
X 
X
3
 
MRI with contrast/ 
RANO Assessment 
 
X
6,8
 
 
X 
X
3
 
Advanced MRI 
 
X
7,8
 
 
X 
X
3
 
18F-DOPA adverse 
event assessment 
 
X
2
 
 
X
2
 
X
2
 
Adverse event 
assessment11 (See 
Section 10.3) 
X 
 
X
10
 
X 
X 
QOL assessment4 
 
X
12
 
 
X 
X 
Concurrent Steroids and
Anticonvulsants  
 
X
12
 
 
X 
X 
MGMT Methylation 
Status 
X
13
 
 
 
 
 
 
1. For women of childbearing potential only. Must be done ≤48 hours prior to injection of study drug. 
Note: For a positive pregnancy test prior to the pre-RT 18F-DOPA injection the patient will not 
undergo the 18F-DOPA PET scan and will instead be taken off study with no follow-up. For any post-
RT 18F-DOPA injection, the patient will not undergo the 18F-DOPA PET scan and will instead move 
to event monitoring. 
2. 
18F-DOPA post-injection assessment: done approximately 15-20 minutes post injection of 18F-DOPA 
and if AE observed a second AE assessment is required ≤24 hours post injection. 
3. All follow-up serial imaging after initial treatment until progression up to 5 years.  Note a typical 
grade IV follow-up schedule will include follow-up scans every 2 months for the first year after 


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radiation therapy, every 3 months for the second year, every 4 months for the third year, every 6 
months after that. The actual timing of the follow-up scans for an individual patient will be per the 
clinician’s discretion, e.g. if the clinician suspects possible progression, they may schedule more 
frequent follow-up imaging. While it is extremely unlikely (as current time to progression is 6 to 9 
months), if a grade IV patient did not progress for 5 years, they may have up to 16 follow-up visits. 
4. Patient will complete a maximum of 6 post-baseline QOL/MMSE evaluations  
5. Post RT scans to occur 3 to 6 weeks after RT is complete, to coordinate with first follow-up 
appointment 
6. Pre-treatment measurement 
7. For patients who have had a 3T glioma protocol MR scan post-operatively at this institution prior to 
consenting for this study, research funds will be used to repeat the advanced MR scans prior to RT for 
this study. 
8. Must be done ≤14 days prior to start of RT 
9. CT simulation can be done prior to or after registration. 
10. Max grade of Adverse Events experienced during RT to be recorded at the end of RT. 
11. To be assessed by Radiation Oncologist at baseline and during RT, and Medical Oncologist for 
Cycle 2 and subsequent cycles. 
12. Baseline MMSE, QOL, Concurrent Steroids and Anticonvulsants assessments can occur prior to 
registration and are to be completed prior to the first 18F-DOPA injection. 
13. MGMT Testing Results can be submitted at any time prior to, or after, registration. 
R Research funded (see Section 19.0) 
 
5.0 
Grouping Factors:  
Group 1: Grade IV patients vs. 
Group 2: Grade III glioma patients: Note: as of addendum 8, Grade III patients are no longer 
being enrolled. 
 
6.0 
Registration/Randomization Procedures 
6.1 
To Register a Patient 
To register a patient, access the Mayo Clinic Cancer Center (MCCC) web page and enter 
the registration/randomization application. The registration/ randomization application is 
available 24 hours a day, 7 days a week. Back up and/or system support contact 
information is available on the Web site. 
If unable to access the Web site, call the MCCC Registration Office at 
 
between the hours of 8 a.m. and 4:30 p.m. Central Time (Monday through Friday). 
The instructions for the registration/randomization application are available on the MCCC 
web page
 and detail the process for completing 
and confirming patient registration. Prior to initiation of protocol treatment, this process 
must be completed in its entirety and a MCCC subject ID number must be available as 
noted in the instructions. It is the responsibility of the individual registering the patient to 
confirm the process has been successfully completed prior to release of the study agent. 
Patient registration via the registration/randomization application can be confirmed in any 
of the following ways: 
• 
Contact the MCCC Registration Office 
. If the patient was fully 
registered, the MCCC Registration Office staff can access the information from the 
centralized database and confirm the registration. 


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• 
Refer to “Instructions for Remote Registration” in section “Finding/Displaying 
Information about A Registered Subject.” 
6.2 
IRB Approval 
Documentation of IRB approval must be on file in the Registration Office before an 
investigator may register any patients. 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office (fax: 
).  If the necessary documentation is not submitted in advance of 
attempting patient registration, the registration will not be accepted and the patient may 
not be enrolled in the protocol until the situation is resolved. 
When the study has been permanently closed to patient enrollment, submission of annual 
IRB approvals to the Registration Office is no longer necessary. 
6.3 
Verification prior to registration 
Prior to accepting the registration, the remote registration application will verify the 
following: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information 
 
6.4 
Radiation therapy on this protocol must be performed at Mayo Clinic Rochester, 
Northfield, LaCrosse, Mankato, Eau Claire, or Albert Lea under the supervision of a 
radiation oncologist. 
 
6.5 
Tests and procedures (Section 4.0) must be completed within the guidelines specified on 
the test schedule. 
 
6.6 
Patients may be registered by the treating physician or healthcare provider. 
 
6.7 
Patient questionnaire booklet is available on site; copies are not acceptable for this 
submission. 
 


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7.0 
Protocol Treatment 
7.1 
CT simulation 
The patient will be immobilized and a CT dataset acquired of the patient for treatment 
planning as per standard of care during the CT simulation appointment. 
7.2 
PET Scanning 
7.21 
Timing of PET scanning:  
PET scans will be acquired prior to and after completion of radiotherapy.  The 
PET scan to be used for radiation treatment planning should be acquired no 
more than 14 days prior to beginning radiation treatments.  The post-RT PET 
scan should be acquired 3-6 weeks after completing radiation treatments, to 
correspond with the first follow-up appointment. Follow-up PET scans will also 
be acquired at each clinically indicated appointment per the standard of care 
follow-up regimen at Mayo Clinic Rochester until progression (up to 5 years). 
7.22 
Patient preparation for PET scan:  
A negative urine pregnancy test must be done ≤48 hours prior to each 18F-DOPA 
injection for women of child-bearing potential only. For a positive pregnancy test 
prior to any post-RT 18F-DOPA injection, the patient will not undergo the 18F-
DOPA PET scan and will instead move to event monitoring. 
Patients will be instructed to follow a four hour food fast prior to the 18F-DOPA 
PET scan. Liberal hydration 24 hours before the exam will be encouraged. 
Carbidopa, used for Parkinson’s patients to inhibit decarboxylation of the 18F-
DOPA tracer, is not necessary for brain tumor imaging. 
7.23 
18F-DOPA PET:  
A total of 5.0 + 10% mCi of 18F-DOPA will be intravenously injected. A scout 
image will be acquired in order to prescribe the scan range for the image 
acquisition. CT images will be obtained and used for attenuation correction of 
the PET data and, at 10 minutes after injection of 18F-DOPA, a 3D PET 
acquisition will be acquired for no more than 30 minutes. The PET data will also 
be acquired concurrently in list mode; this data will be used to salvage a scan 
should the patient move. The PET sinograms will be reconstructed with a fully 
3D-OSEM algorithm into a 300 mm field of view with a pixel size of 1.17mm 
and slice thickness of 1.96mm. All images will be transferred to a Radiation 
Oncology workstation. 
 
7.3 
Advanced MRI Scanning 
7.31 
Screening for advanced MR eligibility: 
The subject will undergo MRI screening for contraindications to scanning and 
contrast agent administration as per routine clinical protocol at Mayo Clinic. 
7.32 
Timing of advanced MR scanning: 
Advanced MRI will be acquired at the time of the standard CE-MRI examination 
on a 3.0 Tesla field strength scanner, no more than 14 days prior to beginning 
radiation treatments, 3 to 6 weeks after completing radiation treatments 
(corresponding with the first follow-up appointment), and for all follow-up serial 
imaging after final RT treatment until progression (up to 5 years). The estimated 


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additional time of advanced MRI (Perfusion MRI and Diffusion Tensor Imaging) 
will be approximately 10 minutes). 
7.33 
Perfusion MRI: 
The pMRI DSC acquisition will be acquired as per standard perfusion DSC 
clinical protocol of the Radiology Department at Mayo Clinic. The DSC 
acquisition time is approximately 3 minutes.   
The single dose of Gd-based contrast agent gadobutrol (Gadavist) (0.10 
mmol/kg) to be administered for each MR exam is current standard of care for 
the Radiology Department at Mayo Clinic. Recent literature has linked the 
development of a conditional called Nephrogenic Systemic Fibrosis (NSF) with 
administration and dosage of Gd-based contrast agents in patients with renal 
failure or insufficiency. Per standard of care at Mayo Clinic, we will screen all 
patients for renal failure/insufficiency to ensure normal renal function. There 
have been no reports in the literature of the occurrence of NSF in patients with 
normal renal function [62, 69].  
7.34 
Diffusion MRI: 
DTI data will be acquired as per standard DTI clinical protocol of the Radiology 
Department at Mayo Clinic. 
7.4 
Radiation Treatment  
7.41 
Target delineation: 
Following informed consent and co-registration of the PET and MRI datasets 
with the planning CT acquired during the standard of care CT simulation 
appointment, the radiation oncologist will define the target volumes to use for 
radiation treatment planning. The pre-RT 18F-DOPA PET scan and standard of 
care MRI will be co-registered with the treatment planning CT.   
Target delineation will be based both on MRI and PET imaging, defining each 
gross tumor volume (GTV), clinical target volume (CTV), planning target 
volume (PTV) and associated dose as in Table 1. The MR criteria used in the 
definition of GTV5100_MR and GTV6000_MR will be identical to the historical 
standard of care at Mayo Clinic and NCCTG, but volumes encompassing both 
low and high signal PET disease (GTV5100_PET) and only high signal PET 
disease (GTV6000_PET) will also be included in the treatment volumes. 
GTV5100_MR, GTV5100_PET, GTV6000_MR and GTV6000_PET will be 
expanded by 1 cm to accommodate sub-clinical disease spread, modified per MD 
discretion as needed (see Figure 8). These CTVs will then be combined for each 
dose level, and CTV5100 and CTV6000 will be expanded by 0.3 cm to 
accommodate random setup uncertainty. These expansion values and doses being 
delivered to PTV5100 and PTV6000 conform to the Mayo standard of care and 
are the same expansion definitions used in NCCTG clinical trials N0177, N057K, 
N0874 and N0877.  
Beyond these standard treatment doses, we plan to boost the MR- and PET-
defined high density disease (GTV7600=GTV6000) with no expansion for sub-
clinical disease to a total dose of 76 Gy. Boost volumes will be based on post-
operative 18F-DOPA imaging. For patients that also were included on the 
corresponding neurosurgical trial (MC1373), post-operative 18F-DOPA will be 
required for any patients that have undergone any surgical procedure other than 
biopsy only. 


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Delineation of normal structures should follow the “Contouring CNS and Head 
and Neck” in Appendix V. 
 
Table 1. Target delineation for MRI and PET Imaging 
 
Dose 
GTV/CTV/PTV definition: 
GTV_MR definition: 
GTV_PET definition: 
51 Gy 
GTV5100 = GTV5100_MR + 
GTV5100_PET 
CTV5100_MR = GTV5100_MR + 1 cm 
(modified as needed) 
CTV5100_PET = GTV5100_PET + 1 cm 
(modified as needed) 
CTV5100 = CTV5100_MR + 
CTV5100_PET 
PTV5100 = CTV5100 + 0.3 cm  
GTV5100_MR =  
Boolean (T1_GAD + 
FLAIR) + T1_Cavity  
GTV5100_PET = 
gold_PET 
60 Gy 
GTV6000 = GTV6000_MR + 
GTV6000_PET 
CTV6000_MR = GTV6000_MR + 1 cm 
(modified as needed) 
CTV6000_PET = GTV6000_PET + 1 cm 
(modified as needed) 
CTV6000 = CTV6000_MR + 
CTV6000_PET 
PTV6000 = CTV6000 + 0.3 cm  
GTV6000_MR =  Boolean 
(T1_GAD + T1_Cavity) 
GTV6000_PET = 
Boolean (HGG 
Threshold and 
gold_PET) 
76 Gy 
GTV7600 = GTV7600_MR + 
GTV7600_PET 
CTV7600_MR = GTV7600_MR + 0 cm 
CTV7600_PET = GTV7600_PET + 0 cm 
CTV7600 = CTV7600_MR + 
CTV7600_PET 
PTV7600 = CTV7600 + 0.3 cm  
GTV7600_MR = 
GTV6000_MR   
GTV7600_PET = 
GTV6000_PET   
Table 1: Radiotherapy doses and definitions of the volumes to be targeted with those doses, with the 
gold_PET contour reviewed and approved by either 
 or 
, and the HGG 
Threshold contour derived from a tumor to normal brain ratio (T/N)>2.0 determined initially from 
preliminary studies (Figure 5). 
 
7.42 
Treatment planning and delivery: 
Patients will receive intensity modulated RT delivered over 30 fractions with 
either photons or protons per MD discretion, with concurrent and adjuvant TMZ. 
 




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7.5 
Follow-up protocol 
7.51 
Response Assessment:  
Post-treatment tumor recurrence will be monitored through follow-up imaging, 
using standard of care MRI to assess tumor response based on the Response 
Assessment in Neuro-Oncology (RANO) Working Group criteria until 
progression of disease (up to 5 years) [70]. 
7.52 
Patterns of Failure: 
For those who recur, follow-up imaging at progression will be co-registered with 
pre-treatment imaging in MIM Maestro™, and patterns of failure will be 
analyzed in the Eclipse treatment planning software (Varian Medical Systems, 
Palo Alto, CA) by determining the portion of the recurrence volume (RecVol) 
that falls within the 95% isodose line of the boost dose from the delivered RT 
plan and classifying each recurrence as either ‘central’ (>95%), ‘in field’ (80 - 
95%), ‘marginal’ (20 - <80%), or ‘distant’ (<20%).  
7.53 
Follow-up Imaging: 
Once the full course of radiotherapy is complete, an 18F-DOPA-PET scan will be 
obtained in addition to the standard of care MRI along with state-of-the-art pMRI 
and DTI sequences, to use as a baseline for follow-up imaging. 18F-DOPA PET 
imaging has been demonstrated to differentiate recurrence from pseudo-
progression [6, 9]. Accordingly, at every standard of care glioma follow-up 
imaging regimen appointment scheduled at Mayo Clinic Rochester until 
progression (up to 5 years), in addition to standard of care MRI, an 18F-FDOPA-
PET scan as well as perfusion MRI and DTI sequences will be obtained. pMRI 
and DTI sequences will be compared against 18F-DOPA PET data to evaluate 
earliest accurate differentiation of tumor progression versus treatment response. 
7.54 
Outcomes: 
Outcomes for patients treated prospectively with the addition of 18F-DOPA PET 
image-guided dose escalation will be determined and compared against patients 
treated at Mayo Clinic on NCCTG trials as described in Sections 7.41 and 16.11.  
7.55 
Acute and Late Toxicity Monitoring:  
Using the dose escalation approach described above, previous studies have 
successfully dose escalated to 76 – 80 Gy without significant increases in acute 
or late adverse effects [51]. Nonetheless, both acute (available at 
http://ctep.cancer.gov) and late [71] toxicity will be monitored continuously as 
each patient is accrued and follow-up data are accumulated, and the PTV3 dose 
level will be adjusted if necessary. 
 
7.6 
Quality of life – patient reported outcome:  
Quality of life (QOL) will be compared to high-grade glioma patients treated on previous 
Radiation Therapy Oncology Group (RTOG) protocols. QOL and cognitive function will 
be evaluated with the MD Anderson Symptom Inventory Brain Tumor Module (MDASI-
BT) and Mini-Mental Status Exam (MMSE) questionnaires. Every patient will be asked 
to complete the whole form packet at baseline and at each MRI evaluation for a 
maximum of 6 evaluations. These time points are selected to capture the quality of life 
profile and correlate findings with radiologic and clinical progression as well as time 
points used on prior studies to allow historical comparisons. 
 
 


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8.0 
Dosage Modification Based on Adverse Events 
If a patient develops an allergic reaction during injection of 18F-DOPA, the patient is not to 
receive any additional tracer and will not undergo PET imaging and will go off study. 
 
9.0 
Ancillary Treatment/Supportive Care: None. 
 
10.0 
Adverse Event (AE) Reporting and Monitoring 
10.1 
Adverse Event Characteristics 
CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site (http://ctep.cancer.gov). 
10.11 Adverse event monitoring and reporting is a routine part of every clinical trial. 
First, identify and grade the severity of the event using a copy of the CTCAE 
v4.0. Next, determine whether the event is expected or unexpected (refer to 
Sections 10.2 and 15.0) and if the adverse event is related to the medical 
treatment or procedure (see Section 10.3). With this information, determine 
whether an adverse event should be reported as an expedited report (see Section 
10.2) or as part of the routinely reported clinical data. Important: All AEs 
reported via expedited mechanisms must also be reported via the routine data 
reporting mechanisms defined by the protocol (see Sections 10.6 and 18.0). 
Expedited and routine reports are to be completed within the timeframes and via 
the mechanisms specified in Sections 10.4 and 10.6. All expedited AE reports 
must also be sent to the local Institutional Review Board (IRB) according to local 
IRB’s policies and procedures. 
10.2 
Expected vs. Unexpected 
• 
The determination of whether an AE is expected is based on agent- specific adverse 
event information provided in Section 15.0 of the protocol. 
• 
Unexpected AEs are those not listed in the agent-specific adverse event information 
provided in Section 15.0 of the protocol.  
NOTE: “Unexpected adverse experiences” means any adverse experience that is neither 
identified in nature, severity, or frequency of risk, in the information provided for 
IRB review nor mentioned in the consent form. 
10.3 
Assessment of Attribution  
Patients will be observed for adverse events for approximately 15-20 minutes post 18F-
DOPA injection by the Nuclear Medicine health professionals administering the scan. 
Post therapy 18F-DOPA scans will have pre-existing conditions documented prior to 18F-
DOPA injection in order delineate causality for pre and post 18F-DOPA AEs.  
Patients will be regularly evaluated by a radiation oncology health professional per 
standard clinical practice throughout their course of external beam radiation therapy. 
When assessing whether an adverse event is related to a medical treatment or procedure, 
the following attribution categories are utilized:  


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Definite - The adverse event is clearly related to PET scanning and 18F-DOPA 
injection 
Probable - The adverse event is likely related to PET scanning and 18F-DOPA 
injection 
Possible - The adverse event may be related to PET scanning and 18F-DOPA 
injection 
Unlikely - The adverse event is doubtfully related to PET scanning and 18F-DOPA 
A injection  
Unrelated - The adverse event is clearly NOT related to PET scanning and 18F-
DOPA injection 
 
Definite - The adverse event is clearly related to RT dose escalation 
Probable - The adverse event is likely related to RT dose escalation 
Possible - The adverse event may be related to RT dose escalation 
Unlikely - The adverse event is doubtfully related to RT dose escalation 
Unrelated - The adverse event is clearly NOT related to RT dose escalation 
 
Events determined to be possibly, probably or definitely attributed to a medical 
treatment suggest there is evidence to indicate a causal relationship between the 
drug/treatment and the adverse event. 
 
10.31 AEs Experienced Utilizing Investigational Agents and Commercial Agent(s) on 
the SAME Arm 
NOTE: When a commercial agent(s) is (are) used on the same treatment arm as 
the investigational agent/intervention (also, investigational drug, biologic, 
cellular product, or other investigational therapy under an IND), the entire 
combination (arm) is then considered an investigational intervention for 
reporting. 
Routine Reporting 
• Routine AE reporting for Phase 1 and Phase 2 clinical studies using an 
investigational agent /intervention in combination with a commercial agent is stated 
in the protocol. See Section 10.6. 
• Routine AE reporting for Phase 3 clinical studies using an investigational 
agent/intervention and a commercial agent in combination must be reported as 
defined by the general guidelines provided by sponsors, Groups, Cancer Centers, 
or Principal Investigators. See Section 10.6. 
Expedited Reporting 
• An AE that occurs on a combination study must be assessed in accordance with the 
guidelines for investigational agents/interventions in Section 10.4, and where 
indicated, an expedited report must be submitted. 
• An AE that occurs prior to administration of the investigational agent/intervention 
must be assessed as specified in the protocol. In general, only Grade 4 and 5 AEs 
that are unexpected with at least possible attribution to the commercial agent require 
an expedited report. Refer to Section 10.4 for specific AE reporting requirements or 
exceptions. 
• Commercial agent expedited reports must be submitted to the FDA via MedWatch. 






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Report an expected event that is greater in severity or specificity than expected as 
an expedited event. 
10.5 
Other Required Reporting 
10.51 Persistent or Significant Disabilities/Incapacities 
Any AE that results in persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions (formerly referred to as disabilities), congenital 
abnormities or birth defects, must be reported immediately if they occur at any time 
following treatment with an agent under an IND/IDE since they are considered to be a 
serious AE and must be reported to the sponsor as specified in 21 CFR 312.64(b). 
10.52 Death 
The reporting period for 18F-DOPA for this study is 1 day. 
The reporting period for radiation dose escalation for this study is 30 days. 
Any death occurring within 1 day after 18F-DOPA agent was last administered 
or within 30 days of the last radiation dose, regardless of attribution requires 
expedited reporting within 24-hours. 
Any death occurring greater than 1 day after the last 18F-DOPA agent was 
administered with an attribution of possible, probable, or definite requires 
expedited reporting within 24-hours. 
Any death occurring greater than 30 days after the last radiation dose was 
administered with an attribution of possible, probable, or definite requires 
expedited reporting within 24-hours. 
Reportable categories of Death  
• 
Death attributable to a CTCAE term. 
• 
Death Neonatal:  A disorder characterized by cessation of life during the 
first 28 days of life. 
• 
Death NOS: A cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5. 
• 
Sudden death NOS: A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5. 
• 
Death due to progressive disease should be reported as Grade 5 
“Neoplasms benign, malignant and unspecified (incl cysts and polyps) 
– Other (Progressive Disease)” under the system organ class (SOC) of 
the same name.  Evidence that the death was a manifestation of underlying 
disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) 
should be submitted. 
10.53 Secondary Malignancy 
• 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, radiation 
or chemotherapy).  A secondary malignancy is not considered a metastasis of 
the initial neoplasm. 
• 
All secondary malignancies that occur following treatment with an agent under 
an IND/IDE will be reported. Three options are available to describe the event: 


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o Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myeloctyic Leukemia [AML]) 
o Myelodysplastic syndrome (MDS) 
o Treatment-related secondary malignancy 
• 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol. 
10.54 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy). Second malignancies require ONLY 
routine reporting. 
10.6 
Required Routine Reporting 
Adverse events related to PET scanning and PET tracer injection to be graded if 
detected during observation post injection, or if noted within 24-hour post PET 
tracer injection per the CTCAE v4.0 grading. Adverse events related to dose 
escalation will be graded at baseline, assessed during RT and reported at the end 
of RT, and during every clinically indicated MR follow-up during Active 
Monitoring until progression. 
 
Category 
(CTCAE SOC) 
Adverse 
event/Symptoms 
Baseline 
Post injection 
assessment1 
Active 
Monitoring 
General disorders and 
administration site conditions 
Fatigue 
X 
 
X 
Immune system disorders 
Allergic reaction 
 
X 
 
Nervous system disorders 
Central nervous 
system necrosis 
 
 
X 
Nervous system disorders 
Vasovagal reaction 
 
X 
 
Injury, poisoning and procedural 
complications  
Bruising 
X 
X 
 
Skin and subcutaneous tissue 
disorders 
Rash maculo-
papular 
X 
X 
 
1. This assessment should occur approximately 15-20 minutes post injection (after scan is 
completed). 
 
10.61 Additional instructions:  
Submit via appropriate MCCC Case Report Forms (i.e., paper or electronic, as 
applicable) the following AEs experienced by a patient and not specified in 
Section 10.6: 
10.611 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
10.612 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
10.613 Grade 5 AEs (Deaths) (See Section 10.52) 


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10.62 Late Occurring Adverse Events: 
Refer to the instructions below and in the Forms Packet (or electronic data entry 
screens, as applicable) regarding the submission of late occurring AEs following 
completion of the Active Monitoring Phase (i.e., compliance with Test Schedule – 
see Section 4.0). 
Toxicity will be monitored continuously as each patient is accrued and follow-up 
data are accumulated. Acute radiation therapy and chemotherapy toxicities will 
be graded using Common Terminology Criteria for Adverse Events (CTCAE) 
v4.0 (available at http://ctep.cancer.gov). Late toxicities will be reported using 
the RTOG/EORTC late toxicity criteria [71]. 
11.0 
Evaluation Criteria 
11.1 
Measurement of Effect 
Tumor response will be assessed, using contrast and non-contrast brain magnetic 
resonance imaging (MRI) with assessment based on the RANO criteria, until progression 
of disease (up to 5 years). 
11.2 
Definitions 
Response and progression will be evaluated in this study using the international criteria 
proposed by the Response Assessment in Neuro-Oncology (RANO) Working Group 
[70]. Note: Lesions are either measurable or non-measurable using the criteria provided 
below. The term “evaluable” in reference to measurability will not be used because it 
does not provide additional meaning or accuracy. 
11.21 Measurable Disease 
Measurable disease is defined as bi-dimensionally contrast-enhancing lesions 
with clearly-defined margins by MRI, with two perpendicular diameters of at 
least 10 mm, visible on 2 or more axial slices which are preferably at most 5 mm 
apart with 0 mm skip. In the event the MRI is performed with thicker slices, the 
size of a measurable lesion at baseline should be two times the slice thickness.  In 
the event there are inter-slice gaps, this also needs to be considered in 
determining the size of measurable lesions at baseline. 
Measurement of tumor around a cyst or surgical cavity is problematic. In general, 
such lesions should be considered non-measurable unless there is a nodular 
component measuring at least 10 mm in diameter. The cystic or surgical cavity 
should not be measured in determining response. All tumor measurements must 
be recorded in millimeters (or decimal fractions of centimeters). 
11.22 Non-measurable Disease 
This is defined as either uni-dimensionally measurable lesions, masses with 
margins not clearly defined, or lesions with maximal perpendicular diameters 
<10 mm. 
11.23 Target Lesions 
All measurable lesions up to a maximum of five lesions should be identified as 
target lesions and recorded and measured (sum of the products of the 
perpendicular diameters) at baseline. Target lesions should be selected on the 
basis of their size (lesions with the longest diameters) and their suitability for 
accurate repeated measurements by imaging techniques. Occasionally, the largest 


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lesions may not be suitable for reproducible measurements and the next largest 
lesions which can be measured reproducibly should be selected. 
11.24 Non-target Lesions 
For patients with recurrent disease who have multiple lesions of which only one 
or two are increasing in size, the enlarging lesions should be considered the target 
lesions for evaluation of response. The other lesions will be considered non-
target lesions and should also be recorded. Rarely, unequivocal progression of a 
non-target lesion requiring discontinuation of therapy, or development of a new 
contrast-enhancing lesion may occur even in the setting of stable disease (SD) or 
partial response (PR) in the target lesions. These changes would qualify as 
progression. Non-target lesions also include measurable lesions that exceed the 
maximum number of 5. Measurements of these lesions are not required but the 
presence or absence of each should be noted throughout follow-up. 
11.3 
Guidelines for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers. Baseline evaluations should ideally be performed within 21 days before the 
beginning of treatment. These techniques should be performed with cuts of 4 mm or less 
in slice thickness contiguously. The MRIs will be evaluated both locally and centrally by 
a core lab. 
11.4 
Response Criteria 
11.41 Evaluation of Target Lesions 
11.411 
Complete Response (CR): Requires all of the following: 
• 
Complete disappearance of all enhancing measurable and non-
measurable disease sustained for at least 4 weeks 
• 
No new lesions 
• 
Stable or improved non-enhancing (T2/FLAIR) lesions 
• 
Patients must be off corticosteroids 
• 
Stable or improved clinically 
Patients with non-measurable disease cannot have a complete response. 
The best response possible is stable disease. 
11.412 
Partial Response (PR): Requires all of the following: 
• 
≥50% decrease compared to baseline in the sum of products 
 of perpendicular diameters of all measurable enhancing lesions 
sustained for at least 4 weeks 
• 
No progression of non-measurable disease 
• 
No new lesions 
• 
Stable or improved non-enhancing (T2/FLAIR) lesions on same or 
lower dose of corticosteroids compared to baseline scan 
• 
The corticosteroid dose at the time of the scan evaluation should be 
no greater than the dose at time of the baseline scan 
• 
Stable or improved clinically 
Patients with non-measurable disease cannot have a partial response. 
The best response possible is stable disease. 


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11.413 
Stable Disease (SD): Requires all of the following: 
• 
Does not qualify for complete response, partial response, or 
progression 
• 
Minimum 4 weeks duration 
• 
Stable non-enhancing (T2/FLAIR) lesions on same or lower dose 
of corticosteroids compared to baseline scan.  In the event that the 
corticosteroid dose has been increased, the last scan considered to 
show stable disease will be the scan obtained when the 
corticosteroid dose was equivalent to the baseline dose 
• 
Stable clinically 
11.414 
Progression: Defined by any of the following: 
• 
≥25% increase in the sum of products of perpendicular diameters 
of enhancing lesions compared to the smallest tumor measurement 
obtained either at baseline (if no decrease) or best response, on 
stable or increasing doses of corticosteroids 
• 
Significant increase in T2/FLAIR non-enhancing lesion on stable 
or increasing doses of corticosteroids compared to baseline scan or 
best response following initiation of therapy, not due to co-morbid 
events (e.g. radiation therapy, demyelination, ischemic injury, 
infection, seizures, post-operative changes, or other treatment 
effects) 
• 
Any new lesion 
• 
Clear clinical deterioration not attributable to other causes apart 
from the tumor (e.g. seizures, medication side effects, 
complications of therapy, cerebrovascular events, infection, etc.) or 
changes in corticosteroid dose. The definition of clinical 
deterioration is left to the discretion of the investigator but it is 
recommended that a decrease in 20% of KPS or from any baseline 
to 50% or less be considered, unless attributable to co-morbid 
events. 
• 
Failure to return for evaluation due to death or deteriorating 
condition 
• 
Clear progression of non-measurable disease 
11.415 
Pseudoprogression (PsP): All of the following must be true:  
• 
Progression of contrast enhancing lesions and or T2/FLAIR is 
restricted to the initial radiation therapy volume. 
• 
There are no new enhancing lesions outside of the initial radiation 
therapy volume. 
• 
Patients are stable or improved clinically. 
• 
PsP may be diagnosed at any time during therapy (beyond the 
typical 12 week window defined by RANO). 
 
 




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should be performed 4 weeks after the criteria for response are 
first met. 
11.4172 Duration of Overall Response 
The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first 
recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since 
the treatment started).  
The duration of overall CR is measured from the time 
measurement criteria are first met for CR until the first date 
that recurrent disease is objectively documented.  
11.4173 Duration of Stable Disease 
Stable disease is measured from the start of the treatment until 
the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started. 
12.0 
Descriptive Factors 
12.1 
Corticosteroid therapy at study entry: Yes (specify dose) vs. no 
12.2 
Histologic type of primary tumor:  Oligodendroglioma vs. oligoastrocytoma vs 
astrocytoma vs other, specify 
12.3 
Histologic grade of primary tumor: 3 vs. 4 
12.4 
ECOG PS (see Appendix I): 0 vs. 1 vs. 2 vs. 3 
12.5 
Neurologic deficit: Yes vs. no 
12.6 
History of seizures: Yes vs. no 
12.7 
Prior surgical resection or biopsy: Yes vs. no 
12.8 
Age ≤70 vs. >70 
12.9a 
MGMT: Methylated vs. Unmethylated vs. Not available 
12.9b Family history of brain tumor: Yes vs. no 
If yes, check all that apply: 
_____Father/Mother 
_____Brother/Sister 
_____Child 
_____Other (list: 
) 
 
13.0 
Follow–up Decision at Evaluation of Patient 
13.1 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry. 
The patient will go off study. 
• 
If the patient received MR and PET for radiotherapy planning, all data up until the 
point of confirmation of ineligibility must be submitted. 
• 
If the patient never received pre-RT PET, on-study material must be submitted. 
13.2 
On-study material and the End of Active Treatment/Cancel Notification Form must be 
submitted for patients who cancel participation prior to the start of pre-RT PET. These 


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materials must be provided to the MCCC Operations office. All data up to the point of 
going off study must be submitted to the MCCC Operations Office. No additional follow-
up will be necessary. 
13.3 
Those patients who will not receive 18F-DOPA PET image-guided dose escalation 
radiation treatment or who will receive radiation treatment elsewhere (other than 
specifically listed in section 6.4) will move to Event Monitoring phase. 
13.4 
Patients remain on study and continue to receive 18F-DOPA PET scans at each clinically 
indicated MR scan until all of the following are confirmed / complete (up to 5 years or 
patient refusal):  
• 
Radiological progression by central review per RANO criteria 
• 
Clinical progression identified by the treating oncologist 
o Because of the difficulty determining pseudoprogression from progression, and 
bevacizumab can be used to treat either progression or radiation-related treatment 
changes, treatment with bevacizumab alone does not qualify as progression.  
Clinical progression is determined by treating oncologist or initiation of systemic 
salvage regimens other than bevacizumab. 
• 
It is more than 3 months since radiation treatments have been completed, to ensure 
the radiological evidence is tumor progression versus treatment response 
• 
Note: the 18F-DOPA PET scan (study imaging) during the patient visit at the time the 
above three conditions are met is highly desired and the patient is to be encouraged to 
complete it even if it is scheduled after the patient has been informed they have 
progressive disease. 
13.5 
Patients who develop Confirmed PD (both clinical and radiologic progression) or 
withdraw from further 18F-DOPA PET scans will go to the event-monitoring phase per 
Section 18.0.  
 
14.0 
Body Fluid Biospecimens - None. 
 
15.0 
Drug Information 
The literature reports no deleterious effect was revealed in toxicity testing of 18F-DOPA-PET, 
and concludes the toxicological safety of the product is guaranteed given the toxicity data of the 
various potential impurities [72]. 18F-DOPA-PET is currently in production at this institution, and 
is used to image Parkinson’s patients to study the 18F-DOPA uptake in the caudate nucleus and 
putamen.  
 
 
 


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16.0 
Statistical Considerations and Methodology 
16.1 
Study Overview:  
This is a one-stage Simon’s Optimal Phase-II study [73] with an interim analysis that will 
compare confirmed-progression free survival at 6 months (CPFS6) for Grade IV MGMT 
un-methylated glioma patients after radiation therapy targeting volumes designed with 
both 18F-DOPA PET and conventional MR image information with historical controls from 
Mayo Clinic Rochester patients treated on NCCTG clinical trials.  To determine if the 
integration of 18F-DOPA imaging into a dose escalation strategy for RT/TMZ therapy 
significantly improves tumor control, we will analyze confirmed-progression free 
survival for patients treated with PET-guided dose escalation and will compare against 
historical controls for Grade IV MGMT un-methylated patients treated at Mayo Clinic 
either with standard of care RT+TMZ then TMZ-alone or on the NCCTG clinical trials 
N057K or N0874. These trials have completed accrual. These trials all use identical MRI-
based definitions of GTV1MR and GTV2MR, and the same CTV and PTV expansions as 
the proposed study (Section 7.0, Table 1). On all trials, PTV1 and PTV2 were treated to 
50 Gy and 60 Gy respectively, and radiation was delivered with concomitant TMZ (75 
mg/m2/day x 6 weeks) and subsequently adjuvant TMZ (150-200 mg/m2 days 1-5 x 6 
cycles). Progression-free survival was a secondary endpoint in all these trials, and each 
specified the same MR imaging follow-up regimen as the proposed study. Moreover, all 
patients had both acute and late toxicities recorded at each of their pre-defined follow-up 
and treatment visits. All of the treatment dosimetry and MR imaging is archived within 
the Mayo Clinic electronic medical record, which will facilitate greatly our planned 
analysis of patterns of failure. 
 
16.11 The primary endpoint of this trial is the proportion of Grade IV MGMT un-
methylated patients that experience confirmed-progression-free survival at 6 
months (CPFS6) based on our hypothesis that the combination of more accurate 
delineation of high density tumor by 18F-DOPA PET combined with dose 
escalation will improve overall tumor control. One of our neuro-radiologists, 
 or 
, will review all cases to define 
the date of radiographic progression, with analysis of historical controls falling 
under IRB #12-004263. With the close imaging follow-up mandated on all these 
clinical trials, we will be able to robustly evaluate progression. Both Grade III 
and IV glioma patients will be enrolled on this clinical trial, however Grade III 
astrocytomas are relatively rare and not commonly studied in NCCTG or Mayo 
Clinic trials. At the time of Addendum 8, there exists an Alliance clinical trial 
lead by a Mayo Clinic Principal Investigator enrolling Grade IV MGMT 
methylated patients.  Enrollment of Grade IV MGMT methylated patients has 
been reduced compared to the expected rate. Therefore, as of Addendum 8, only 
the Grade IV MGMT un-methylated patients will be included in the statistical 
analysis described below. All Grade IV MGMT un-methylated patients meeting 
eligibility criteria who have signed a consent form and who have begun treatment 
with 18F-DOPA PET image-guided dose escalation RT will be evaluable for the 
endpoint. 
 
 


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16.2 
Statistical Design 
16.21 Decision Rules 
An endpoint-evaluable patient is defined to be a patient that is treated with 18F-
DOPA PET image-guided dose escalation RT.  The primary endpoint is the 
proportion of grade-IV MGMT un-methylated patients treated with 18F-DOPA 
PET image-guided dose escalation RT who are alive and do not have confirmed -
progression within 6 months from the time of craniotomy. A success will be a 
patient who is alive and does not have confirmed-progression within 6 months 
from the time of craniotomy. At Mayo Clinic, the 81 Grade IV MGMT un-
methylated patients accrued to the two trials listed above, combined with the 14 
similar patients not treated on clinical trials had a combined rate of CPFS6 of 
59.3%. These patients were newly diagnosed grade-IV MGMT un-methylated 
patients treated with 3D-conformal or IMRT with TMZ. Therefore the largest 
success proportion where the proposed treatment regimen would be considered 
ineffective in this population is 60%, and the smallest success proportion that 
would warrant subsequent studies with the proposed regimen would be 72.5%. 
The following Simon’s Optimum design requires 45 grade-IV MGMT un-
methylated patients to test the null hypothesis that the proportion of successes is 
at most 60% with an overall significance level (alpha) of 0.20, and a power of 
80% to detect a true success proportion of 72.5%.  
16.211 
Stage 1: If 15 or fewer successes are observed in the first 25 grade-IV 
MGMT un-methylated evaluable patients that have been followed for 
at least 6 months, we will consider this regimen to be ineffective in this 
patient population. If 16 or more successes are observed in the first 25 
evaluable patients we will continue accrual and results will wait until 
the final analysis. 
16.212 
Stage 2: After 45 evaluable grade-IV MGMT un-methylated patients 
are accrued to this study and followed for at least 6 months, if 30 or 
more successes are observed in the first 45 evaluable patients, we may 
recommend further testing of this regimen in subsequent studies in this 
patient population. 
16.213 
Over Accrual: If more than the target number of Grade-IV MGMT un-
methylated patients are accrued, the additional patients will not be used 
to evaluate the stopping rule or used in any decision making process. 
16.214 
Note: We will not suspend accrual between stages to allow the first 25 
patients to become evaluable, unless undue toxicity is observed. 
16.22 Sample Size 
The two-stage design to be utilized is fully described in Section 16.21. A 
minimum of 25 and a maximum of 45 Grade-IV MGMT un-methylated 
evaluable patients will be accrued to this phase-II study unless undue toxicity is 
encountered. We anticipate accruing an additional 5 Grade-IV MGMT un-
methylated patients to account for ineligibility, cancellation, major treatment 
violation, or other reasons. We also anticipate accruing a total of 25 Grade-IV 
MGMT methylated, 12 Grade-IV patients with unknown MGMT status, and 6 
grade-III patients.  Maximum projected accrual is therefore 87 grade–IV patients 
and 6 grade-III patients. We anticipate pre-registering 150 patients to register 
these 93 patients necessary for the study design. 


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16.23 Accrual Time and Study Duration 
Based on institutional experience, we deliver RT on average to 48 Grade IV 
glioma patients annually, of which about 60% are MGMT un-methylated. Our 
plan to accrue 14 Grade IV MGMT un-methylated patients per year is based on 
including about 50% our Grade IV MGMT un-methylated glioma population, 
which is readily achievable. We plan to accrue patients for Years 1-5.5, leaving 
the last 6 months of Year 6 for remaining follow-up and analysis. Therefore, the 
overall study duration is expected to be 72 months.  
16.24 Power and Significance Levels 
Assuming the number of successes is binomially distributed, the significance 
level is 0.20 and the probability of declaring that this regimen warrants further 
studies (i.e. statistical power) under various success proportions and the 
probability of stopping accrual after the first stage can be tabulated as a function 
of the true success proportion as shown in the following table.  
 
If the true success proportion is ... 
0.55 0.60 0.65 0.70 0.725 0.75 
then the probability of declaring that the regimen 
warrants further studies is ... 
0.065 0.195 0.425 0.692 0.804 0.889 
and the probability of stopping at stage 1 is ... 
0.758 0.575 0.370 0.189 0.122 0.071 
 
16.25 Other Considerations 
Adverse events and patterns or failure observed in this study as well as scientific 
discoveries or changes in standard care will be taken into account in any decision 
to terminate the study. 
16.3 
Analysis Plan 
The analysis for this trial will commence at the planned timepoints (see 16.2) and at the 
time the patients have become evaluable for the primary endpoint. Such decision will be 
made by the Statistician and Study chair, in accord with the Cancer Center Statistics 
(CCS) Standard Operating procedures, availability of data for secondary endpoints, and 
the level of data maturity. It is anticipated that the earliest date in which the results will 
be made available via a manuscript, abstract, or presentation format is when 45 patients 
have either had confirmed-progression or been followed for at least 6 months. Subgroup 
analysis will be included for this primary endpoint to assess known prognostic factors 
such as performance status at baseline and age. Additionally, while no expected 
difference is anticipated, subset analysis will also be conducted for the primary endpoint 
to assess if there was any difference in patients treated via photons vs. protons. 
16.31 Primary Endpoint: 
16.311 Definition: The primary endpoint of this trial is the proportion of Grade-
IV MGMT un-methylated patients that experience confirmed-
progression-free survival at 6 months from the time of craniotomy. All 
Grade IV MGMT un-methylated patients meeting eligibility criteria who 
have signed a consent form and who have begun RT treatment will be 
evaluable for the endpoint. All eligible patients will be followed until 
death or a maximum of 5 years.  Time to confirmed-progression is 
defined as the time from initial surgery to the earliest date documenting 
confirmed-progression. If a patient dies without documentation of 
disease progression, the patient will be considered to have had tumor 


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progression at the time of death. If a patient is declared to be a major 
treatment violation, the patient will be censored on the date the treatment 
violation was declared to have occurred. In the case of a patient starting 
treatment and then never returning for any evaluation, the patient will be 
censored for progression on the last day of therapy. 
16.312 Estimation: The proportion of CPFS6 successes and associated 95% 
confidence intervals will be estimated using Kaplan-Meier analysis 
methods. 
16.313 Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used 
in any decision making processes; however, they will be included in final 
point estimates and confidence limits. 
 
16.32 Definitions and Analyses of Secondary Endpoints 
Subgroup analysis will be included as appropriate for these secondary endpoints 
to assess known prognostic factors such as performance status and age at 
baseline.  Additionally, subset analysis will also be conducted for the primary 
endpoint to assess whether there was any difference in patients treated via 
photons vs. protons. To control for multiple testing the false discovery rate 
(FDR) [75], which is the expected proportion of false discoveries amongst the 
rejected hypotheses, will be used at a 0.05 level. 
16.321 Compare progression free survival at 12 months for Grade III patients 
after radiation therapy targeting volumes designed with both 18F-DOPA 
PET and conventional MR image information with historical controls from 
Mayo Clinic Rochester patients, including those on clinical trials. 
While both Grade III and IV glioma patients will be enrolled on this 
clinical trial, Grade III astrocytomas are relatively rare and not 
commonly studied in NCCTG or Mayo Clinic trials. Grade III patients 
are included in our prospective dose-escalation trial given their overall 
poor prognosis and the often limited contrast enhancement observed in 
these tumors. The target definitions will be similar to those described in 
section 7.0, Table 1. The progression-free survival at 12 months will be 
compared to historical controls treated at Mayo Clinic. Given the small 
numbers of patients with Grade III glioma anticipated (4 endpoint-
evaluable patients as of 2/16/2017) on this prospective trial; this analysis 
will be hypothesis generating. The proportion of successes will be 
estimated by the number of successes divided by the total number of 
Grade-III evaluable patients. Confidence intervals for the true success 
proportion will be calculated according to the approach of Duffy and 
Santner (1987). 
16.322 Confirmed-Progression Free Survival 
We will analyze the confirmed-progression free survival time to event 
data combined with the confirmed-progression free survival data from 
the Mayo Clinic patients treated either with standard of care RT+TMZ 
then TMZ-alone or on studies N057K or N0874. These Mayo Clinic 
patients will be considered to be a control group. The distributions of 
confirmed-progression free survival times and comparisons between 
these two groups will be estimated using the method of Kaplan-Meier 


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[76].  Time to disease progression is defined as the time from initial 
surgery to the earliest date documenting confirmed-progression. If a 
patient dies without documentation of disease progression, the patient 
will be considered to have had tumor progression at the time of death. If 
a patient is declared to be a major treatment violation, the patient will be 
censored on the date the treatment violation was declared to have 
occurred. In the case of a patient starting treatment and then never 
returning for any evaluation, the patient will be censored for progression 
on the last day of therapy.  This analysis will be conducted split by 
MGMT-methylation status of the patients and historical control. 
16.323 Overall Survival 
Compare patient outcomes including overall survival after radiation 
therapy targeting volumes designed with both 18F-DOPA PET and 
conventional MR image information with historical controls from Mayo 
Clinic Rochester patients. As described above for confirmed-progression 
free survival, we will analyze both historical control patients and our 
prospective dose escalation patients for overall survival. Survival time is 
defined as the time from initial surgery to death due to any cause. The 
distributions of survival times and comparisons between these two 
groups will be estimated using the method of Kaplan-Meier [76]. 
16.324 Quality of Life 
Evaluate quality of life after radiotherapy treatment targeting dose escalated 
volumes defined to include high18F-DOPA PET uptake. Quality of life (QOL) 
will be compared to high-grade glioma patients treated on previous North 
Central Cancer Treatment Group protocols. QOL and cognitive function 
will be evaluated with the MD Anderson Symptom Inventory Brain 
Tumor Module (MDASI-BT) and Mini-Mental Status Exam (MMSE) 
questionnaires at baseline and at each MRI evaluation up to 6 evaluations 
to capture the quality of life profile and correlate findings with radiologic 
and clinical progression as well as time points used on prior studies to 
allow historical comparisons. The main QOL analysis will be the change 
from baseline to first subsequent MRI timepoint in the overall score from 
the MDASI-BT.  All other QOL analysis will be exploratory and may 
include change percent from baseline to all timepoints using t-tests and 
generalized linear models to test for changes at each time point and non-
zero slope respectfully. 
16.325 Adverse Events 
Determine acute and late effect toxicity after radiotherapy treatment 
targeting dose escalated volumes defined to include high18F-DOPA PET 
uptake. The rate of acute and late treatment-related toxicities for newly 
diagnosed high-grade glioma patients treated with 18F-DOPA PET 
image-guided dose escalation will be determined, with acute RT 
toxicities graded using Common Terminology Criteria for Adverse 
Events (CTCAE) v4.0 (available at http://ctep.cancer.gov), and late 
toxicities reported using the RTOG/EORTC late toxicity criteria [71]. 
Patients will be considered evaluable for adverse events if they receive 
18F-DOPA PET or  18F-DOPA PET image-guided dose escalation RT. 


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16.326 Compare confirmed-progression free survival at 12 months for Grade IV 
MGMT-methylated patients after radiation therapy targeting volumes 
designed with both 18F-DOPA PET and conventional MR image 
information with historical controls from Mayo Clinic Rochester patients, 
including those on clinical trials. 
 
 
16.33 Correlative Research 
In addition to the 45 evaluable Grade-IV MGMT Un-methylated patients, these 
correlative research endpoints will use the combined information from all of the 
evaluable grade-IV patients.  As of 2/16/2017 this sample size will include at 
least 22 endpoint-evaluable patients with Grade-IV MGMT methylated status 
and 5 endpoint-evaluable patients with unknown MGMT status. Therefore the 
minimum sample size for these correlative endpoints is 72 patients.  Subgroup 
analysis will be included as appropriate for these correlative endpoints to assess 
known prognostic factors such as MGMT and age.  To control for multiple 
testing the false discovery rate (FDR) [75], which is the expected proportion of 
false discoveries amongst the rejected hypotheses, will be used at a 0.05 level. 
16.331  Compare RT treatment volumes defined by MR only with RT treatment 
volumes defined with both PET and MR information for Grade IV 
glioma patients.  
To assess the impact of integrating PET on target definition, the treating 
radiation oncologists (Dr. N. Laack, 
) will 
first define the treatment volumes for GTV1MR and GTV2MR using the 
MR images while blinded to the PET study. Then the PET contours, 
using gold standard volumes generated by Drs. Hunt or Lowe for 
GTV1PET and T/N ratio of >2.0 for GTV2PET, will be reviewed by the 
treating radiation oncologist and expanded as described above. The 
volume of overlap and non-overlap between the GTV1 and 2 defined by 
MR and that defined by PET will be calculated. Similarly, the MR-only 
defined volumes will be compared against the volumes defined with the 
combination of MR and PET planning. Paired t-test statistical analysis 
will be performed to determine if any differences exist and the level of 
statistical significance between treatment volumes defined by MR only 
and treatment volumes defined with both PET and MR information. The 
analysis of volumes from the combined 72 Grade IV patients will have 
90% power to detect differences in volumes with an effect size of 0.39 
using a paired t-test with a 0.05 two-sided significance level. Alternate 
metrics for comparison will also be assessed, including spatial overlap, 
distance, correlations and 3D shape comparisons.  
16.332 Compare timing of accurate identification of progression defined by 18F- 
DOPA PET, pMRI and conventional MRI for Grade IV glioma patients. 
Both 18F-DOPA PET imaging [6, 9] and pMRI [54] have been shown to 
differentiate recurrence from pseudo-progression better than 
conventional MR imaging. There are several reasons why we anticipate 
18F-DOPA PET imaging will identify HGG progression earlier than 
pMRI, and may more accurately differentiate progression from pseudo-
progression. As pMRI is based on angiogenesis, it is possible that 18F-
DOPA may detect additional separate or complimentary tumor segments 


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that aren’t particularly angiogenic, and could therefore be missed with 
pMRI. Also, per our preliminary data, 18F-DOPA appears to successfully 
detect tumor in non-enhancing tissue.  pMRI has not been used to 
characterize tumor in the non-enhancing segment, so there is no 
historical data to compare 18F-DOPA and pMRI for this tumor segment. 
For each confirmed incidence of progression per conventional MRI we 
will review follow-up imaging acquired with PET and pMRI prior to the 
confirmed progression to determine which modality correctly identified 
progression earliest. We will compare 18F-DOPA PET with our recently 
published pMRI-Fractional Tumor Burden method to differentiate 
regional tumor progression from radiation necrosis and 
pseudoprogression [68]. To compare the progression identification 
timing we will calculate the percentage of time each modality was earlier 
than conventional MRI. With a sample size of 72, if the observed 
percentage earlier than conventional MRI is 30% for either modality, a 
two-sided 95.0% confidence interval for a single proportion using the 
large sample normal approximation will be ±10.6%. Progression 
identification timing will also be compared using Kaplan-Meier methods 
and paired t-tests to determine if differences exist between the 
modalities. 
16.333 Compare patterns of failure after radiation therapy targeting volumes 
defined with target volumes designed to with both 18F-DOPA PET and 
conventional MR image information with patterns of failure for historical 
controls from Mayo Clinic Rochester patients. As described above for 
confirmed-progression free survival, we will analyze both historical 
control patients and our prospective dose escalation patients. Imaging 
archived for the cohort of Mayo Clinic patients used as historical 
controls for confirmed-progression free survival will be assessed for 
patterns of failure, to compare with patterns of failure determined for 
patients treated with 18F-DOPA PET image-guided dose escalation. As 
noted above, one of our neuro-radiologists, 
 or 
, will review all cases to define the date of 
radiographic progression. The relevant image set will be fused with our 
treatment planning scan and then the radiologist will contour the region 
of progression blinded to the dose distribution contour. A volumetric 
analysis then can be performed to define the doses delivered to the 
absolute and relative volume of the region where the recurrence is 
defined. With the close imaging follow-up mandated on clinical trials 
and for our standard of care, we will be able to robustly evaluate the 
patterns of failure relative to dose delivered to those regions. Chi-square 
tests of proportions will be used to test for differences in the proportions 
of patients with central, in-field, marginal, or distant failures between the 
patients on this study and historical controls. 
16.334 Compare RT treatment volumes defined by MR only with RT treatment 
volumes defined with both PET and MR information for Grade III 
glioma patients. Paired t-test statistical analysis will be performed to 
determine if any differences exist and the level of statistical significance 
between treatment volumes defined by MR only and treatment volumes 
defined with both PET and MR information.  


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16.335 Evaluate intra- and inter-observer variability with vs. without the 
addition of 18F-DOPA PET uptake for radiotherapy target volume 
delineation. Potential for reduction in inter- and intra-observer variability 
for RT target delineation with the addition of PET in conjunction with 
biopsy-validated threshold guidance will be evaluated through volume 
comparisons of target volumes delineated with MR alone and MR in 
combination with PET information by our radiation oncologists (Drs. 
Laack, Sarkaria and Yan) as well as gold standard volumes generated by 
Drs. Morris or Kaufmann for MRI and Drs. Hunt or Lowe for PET. The 
concordance correlation coefficient will be used to measure agreement 
between volumes generated with each method, as well as to evaluate 
inter-observer variability, where variability associated with MR will serve 
as the standard for comparison. 
Several tools commercially available for semi-automated PET 
contouring will be investigated for consistency with the biopsy-validated 
thresholds, to standardize the method of 18F-DOPA PET integration into 
RT delineation, reducing operator error and subjectivity commonly 
associated with manual delineation of target volumes utilizing PET data. 
The variation of PET volumes defined with different segmentation 
techniques will be evaluated, including manual visual delineation, SUV-
based delineation using an isocontour of SUV = 2.5, fixed threshold 
techniques ranging from 40-80% of the maximum signal intensity in 
the primary tumor, adaptive threshold delineation using the source-to- 
background ration (SBR) technique, and the PET Edge gradient 
technique in the MIM software package. 
16.336 Compare timing of accurate identification of progression defined by 18F- 
DOPA PET, pMRI and conventional MRI for Grade III glioma patients. 
In addition to Grade IV patients analyzed above, progression 
identification will also be made for the Grade III patients and analysis 
will include determination of any differences between Grade IV and III 
patients. Progression identification timing will be compared using 
Kaplan-Meier methods and paired t-tests to determine if differences exist 
between the modalities. An exploratory analysis of DTI for detecting 
invasive non-enhancing tumor recurrence will also be performed.  
16.337 Compare predictive capabilities of 18F-DOPA PET, pMRI and DTI for 
localization of recurrences for patients treated with 18F-DOPA PET-
guided RT dose escalation. Predictive capabilities of 18F-DOPA PET, 
pMRI and DTI for localization of recurrences for patients treated with 
18F-DOPA PET-guided RT dose escalation will be compared by 
identifying the recurrence volume with each modality and correlating 
with identification of aggressive disease in the pre-RT planning images. 
16.4 
Data and Safety Monitoring Plan: 
16.41 The Study Chairs and the study statistician will review the study at least twice a 
year to identify accrual, adverse event, and any endpoint problems that might be 
developing. The Mayo Clinic Cancer Center (MCCC) Data Safety and 
Monitoring Board (DSMB) is responsible for reviewing the accrual and safety 
for this trial at least twice a year, based on reports provided by the MCCC 
Statistical Office. 


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16.42 Adverse Event Stopping Rules: 
As no reactions to 18F-DOPA have been reported within the institution, toxicity 
testing reported in the literature revealed no deleterious effects (section 
15.0), and there have been no allergic reactions in all patients accrued to date to 
the pilot study (MC1078), no reactions are anticipated. As such, at any point in 
the enrollment process after 10 or more patients have been enrolled, if more than 
10% of these patients enrolled are unable to complete PET scanning due to 
allergic reactions to the tracer, enrollment will be suspended so that details of 
each episode can be examined and a trial recommendation will be formulated and 
presented to the MCCC DMC. 
There have been no reports in the literature of the occurrence of NSF in patients 
with normal renal function [62, 69]. Additionally, we will use the contrast agent 
gadobenate dimeglumine, which has been shown to have a high safety profile 
(lower incidence of NSF in patients with renal failure/insufficiency) compared 
with many other available Gd-based contrast agents [62, 69]. Therefore no 
reactions are anticipated. As such, if at any time a patient develops NSF 
enrollment will be suspended so that details of the episode can be examined and a 
trial recommendation will be formulated and presented to the MCCC DMC. 
Using the dose escalation approach described in Section 7, previous studies have 
successfully dose escalated to 76 – 80 Gy without significant increases in acute 
or late adverse effects [51]. Nonetheless, both acute (available at 
http://ctep.cancer.gov) and late [71] toxicity will be monitored continuously as 
each patient is accrued and follow-up data are accumulated. As such, at any point 
in the enrollment process after 10 or more patients have been enrolled, if more 
than 10% of these patients enrolled experience any of the following adverse events 
considered to be at least possibly related to treatment, enrollment will be 
suspended so the details of each episode can be examined and a trial 
recommendation will be formulated and presented to the MCCC DMC, adjusting 
the PTV3 escalated dose level if necessary. 
• Grade 3 or 4 irreversible CNS toxicity 
• Grade 4 non-hematologic, non-CNS toxicity 
• Any Grade 5 toxicity 
16.5 
Results Reporting on ClinicalTrials.gov: 
16.51 Initial estimated Primary Completion Date:  At study activation, this study will 
have been registered within the www.ClinicTrials.gov (CT.gov) website. The 
Primary and Secondary endpoints along with other required information for this 
study will be reported on CT.gov. For purposes of timing of the CT.gov results 
reporting, the initial estimated completion date of the primary endpoint of this 
study is 60 months after the study opens to accrual. 
16.52 Definition of Primary-Endpoint Completion Date (PCD): The PCD is the date at 
which the last confirmed-progression free patient has been followed for 6 
months. 
 
 


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16.6 
Inclusion of Women and Minorities 
This study will be available to all eligible patients regardless of race, gender, or ethnic 
group. 
There is no information currently available regarding differential effects of this regimen 
in subsets defined by gender, race or ethnicity, and there is no reason to expect such 
differences to exist. Therefore, although the planned analyses will, as always, look for 
differences based on gender and racial groupings, the sample size is not increased in 
order to provide additional power for such subset analyses. Based on prior studies 
involving similar disease, we expect about 7% of patients will be classified as minorities 
by race and about 40% of patients to be women. Expected sizes of racial by gender 
subsets are shown in the following table: 
 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
3 
4 
7 
Not Hispanic or Latino 
35 
51 
86 
Ethnic Category: Total of all subjects 
38 
55 
93 
Racial Category 
American Indian or Alaskan Native 
1 
1 
2 
Asian 
1 
1 
2 
Black or African American 
1 
1 
2 
Native Hawaiian or other Pacific Islander 
0 
1 
1 
White 
35 
51 
86 
Racial Category: Total of all subjects 
38 
55 
93 
 
17.0 
Pathology Considerations/Tissue Biospecimens: N/A 
 
 
 


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18.0 
Records and Data Collection Procedures 
 
18.1 
Submission Timetables 
 
18.11 Initial Material(s) 
CRF 
Active-Monitoring 
Phase 
(Compliance with Test Schedule 
Section 4.0) 
On-Study Form 
≤2 weeks after registration 
Baseline Adverse Event Form 
MMSE Form 
Patient Questionnaire Booklet3  
Patient Questionnaire Booklet Compliance Form2 
End of Active Treatment/Cancel Notification 
Form1 
Submit ≤2 weeks after registration if 
withdrawal/refusal occurs prior to beginning 
protocol therapy 
Concurrent Steroid and Anticonvulsant Treatment 
Form 
≤4 weeks after start of RT 
1 
Submit if withdrawal/refusal prior to radiotherapy treatment occurs. 
2 
This form must be completed only if the QOL booklet contains absolutely NO patient 
provided assessment information. 
3 
Patient questionnaire booklet must be used; copies are not acceptable for this submission. 
 
 


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18.12 Test Schedule Material(s) 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
≤4 weeks 
after each 
evaluation 
during RT 
treatment 
≤1 week 
after each 
18F-DOPA- 
PET scan 
≤6 months 
after end 
of RT 
treatment5 
≤6 months after 
every clinically 
indicated MR 
scan5 
Pre-RT Measurement Form 
 
 
X 
 
Imaging Form 
 
X 
 
X 
End of Active Treatment/Cancel 
Notification Form 
 
 
X 
 
Adverse Event Form (Post 
Injection of 18F-DOPA) 
 
X7 
 
 
Radiation Therapy Adverse 
Event Form (Toxicity) 
X1 
 
 
X2 
Concurrent Steroid and 
Anticonvulsant Treatment 
 
 
X 
X 
Radiation Therapy Reporting  
 
 
X3 
 
Active Monitoring Measurement 
 
 
X 
X6 
Patient Questionnaire Booklet9 
 
 
X4 
X4 
MMSE 
 
 
X4 
X4 
Patient Questionnaire Booklet 
Compliance Form8 
 
 
 
 
ADR/AER (see Section 10.0) 
At each occurrence 
 
1 Acute toxicity will be assessed during standard of care monitoring by the radiotherapy 
team during the course of treatment. 
2 Late toxicity will be assessed during standard of care appointments. To be submitted 
≤2 weeks after each clinically indicated MR scan. 
3 This form should be completed after the radiation is completed. 
4 Patient will complete a maximum of 6 post-RT QOL evaluations 
5 Timeframes for submission purposefully large as they do not affect patient care i.e. the 
data being collected is for investigational use only and no patient decisions will be made 
with it, which allows us to batch the data for analysis by the study team (e.g. for 
Radiation Oncologist and Radiologists to contour volumes on image data). 
6 See Section 4 for time of assessments. 
7 Done approximately 15-20 minutes post injection of 18F-DOPA after scan is completed 
and if AE observed a second AE assessment is required <24 hours post injection. 
8 This form must be completed only if the QOL booklet contains absolutely NO patient 
provided assessment information. 
9 Patient questionnaire booklet must be used; copies are not acceptable for this submission. 


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18.13 Follow-up Material(s) 
CRF 
Event Monitoring Phase1 
q. yearly  
for 5 years 
At PD 
Death 
Event Monitoring Form 
X 
X 
X 
CD/DVD Radiology Imaging 
 
X2 
 
1. If a patient is still alive 5 years after registration, no further follow-up is required. 
2. If patient leaves Mayo Clinic, please obtain imaging in DICOM format from local MD. The 
study will pay for costs associated with providing copies of the imaging to Mayo Clinic. 
See Appendix VI for details. Imaging CDs (MRI) must be de-identified. The surface of the 
CD should be labeled with MC1374, the patient’s Mayo Clinic identification number (or 
initials (L, F, M) and birth date) and the scan date only. 
Mail CDs to: Mayo Clinic, Attn: QAS Study MC1374, 
 
 Rochester, MN  
. 
 
19.0 
Budget 
19.1 
Costs charged to patient: routine clinical care 
19.2 
Tests to be research funded:  
Pregnancy test for women of childbearing potential only, FDOPA, PET scan, additional 
limited 3T MR scan for advanced imaging prior to radiotherapy when not clinically 
indicated (i.e. for patients who have had a post-operative 3T glioma MR scan at this 
institution); and costs incurred for providing copies of imaging from local MD. 
19.3 
Other budget concerns: None. 
 
 


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20.0 
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36. 
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37. 
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volumes using a combined multiscale and statistical model. Medical physics, 2007. 34(2): p. 722-
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38. 
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39. 
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40. 
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cancer. International journal of radiation oncology, biology, physics, 2005. 62(3): p. 893-900. 
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45. 
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47. 
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48. 
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grade gliomas. Journal of neuro-oncology, 2009. 93(3): p. 343-8. 
50. 
Lee, I.H., et al., Association of 11C-methionine PET uptake with site of failure after concurrent 
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56. 
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Technology, 2007. 50: p. 77-90. 


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Appendix I ECOG PERFORMANCE STATUS 
 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair. 
5 
Dead 
*As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity 
And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. 
The ECOG Performance Status is in the public domain therefore available for public use. To duplicate the 
scale, please cite the reference above and credit the Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
From http://www.ecog.org/general/perf stat.html 
 
 


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Appendix II Folstein Mini Mental State Examination (MMSE) 
 
INTRODUCTION 
 
The Mini-Mental Status Exam could be administered by the physician, a nurse or an assistant trained in 
the administration of such tools.  The person administering the Mini-Mental Status Exam needs to be 
sensitive when the patient shows embarrassment about their inability to answer these questions.  Patients 
should be assured by telling them that this is another way of telling how the treatment is affecting their 
brain tumor.  It also needs to be made clear to the patient that it is very important to get this type of 
information directly from them.  The person administering the test needs to understand that either the 
correct answer is given or not.  There should be no partial credit for answers short of the mark. 
 
The MMSE begins with a graded assessment of orientation to place and time, for which a maximum of 10 
points is possible.  This is followed by testing two aspects of memory.  The first is the immediate recall 
for three objects presented orally, followed by a serial sevens task which is interposed to assess attention, 
concentration, and calculation, and also to prevent the individual from rehearsing the three objects 
previously learned.  A maximum of 21 points may be obtained on this section of the test. 
 
The final section surveys aphasia and apraxia by testing functions of naming, repetition, understanding a 
three-stage command, reading, writing and copying a drawing.  There are a maximum of 9 points which 
may be obtained on this section, for a total possible MMSE score of 30 points. 
 
MMSE SECTIONS 
 
Detailed instructions are included here.  A brief form for recording and scoring MMSE answers follows. 
 
Orientation.  Ask the patient for the date.  Then ask for parts omitted (e.g., “Can you also tell me what 
season it is?”).  Give one point for each correct response. 
 
Ask in turn, “Can you tell me the name of this hospital? town? count? (and so on)”.  Give one point for 
each correct response. 
 
Registration.  Ask the patient if you may test his/her memory.  Then name three unrelated objects, 
clearly and slowly, about a second for each.  After you have said all three, ask the patient to repeat them.  
This first repetition determines the score.  Score one point for each repeated object (0 – 3).  If the patient 
does not repeat all three objects, the tester should repeat the objects (up to a maximum of six times) until 
the patient can say all three.  In cases where a patient cannot learn all three objects in six trials, recall (see 
below) cannot be meaningfully tested. 
 
When registration is complete, tell the patient, “Try to remember them because I will ask for them in a 
little while.” 
 
Attention and Calculation.  Ask the patient to begin with 100 and count backwards by seven.  Stop after 
five subtractions (93, 86, 79,72, 65).  Score the total number of correct answers.  If the patient will not 
perform this task, ask him or her to spell the word “WORLD” backwards.  The score is the number of 
letters in correct order (e.g., DLROW – five, DLORW – three). 
 
Recall.  Ask the patient if he/she can remember the names of the three objects learned in the Registration 
section.  Give one point for each correct answer. 
 


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Language.  There are six operations in this section. 
 
Naming.  Show the patient a wrist watch and ask him/her what it is.  Repeat for a pencil.  Give one point 
for each correct naming (0 – 2). 
 
Repetition.  Have the patient repeat, “No, ifs, ands, or buts”.  All only one trial.  Given one point for a 
completely correct repetition. 
 
Three-Stage Command.  Place a piece of blank paper in front of the patient and say; “Take this paper in 
your right hand.  Fold the paper in half.  Put the paper on the floor”.  Give one point for each correctly 
performed command. 
 
Reading.  Show the patient the page with the sentence “Close your eyes” (page 2).  Ask the patient to 
read it and do what it says.  Since this is not a memory task, the tester may prompt the reader to “do what 
it says” after the reader reads the sentence.  Score one point if the patient actually closes his or her eyes. 
 
Writing.  Give the patient the page with the word sentence (page 3) and ask him/her to write a sentence 
for you.  Do not dictate a sentence; it is to be written spontaneously.  The sentence should contain a 
subject and a verb, and should make sense.  Ignore minor spelling or minor grammatical errors when 
scoring.  Score one point for a correct sentence. 
 
Copying.  Show the patient the page with the intersecting pentagons (page 4).  Ask the patient to copy it 
exactly as it is.  Give one point if all sides are preserved and if the intersecting sides from a four sided 
figure (i.e., ten sides and ten angles). 
 
SPECIAL CONSIDERATIONS 
 
The examination is conducted so as to minimize stress for the patient.  Errors are not indicated to the 
subjects and, in general, mistakes are not corrected.  Refusals are considered to be errors after a minimum 
of encouragement.  Individuals with peripheral impairment such as blindness or restriction of the hands 
due to arthritis or other peripheral disorders are scored the number correct out of the possible items they 
could answer given their other non cognitive impairments.  Please note these exceptions on the MMSE 
and the cover sheet.  It is important not to allow your administration of this test to be affected by your 
perception of why the patient may have responded incorrectly or not at all.  That is, the examination 
should be conducted without the examiner modifying the scoring by assumptions of whether or not the 
individual was motivated, paying attention, or could understand.  For the purpose of the exam, the score 
indicates a failed performance, not necessarily a failed performance under all conceivable circumstances. 
 
Spencer MP and Folstein MF.  The Mini-Mental State Examination.  In:  PA Keller and LG Ritt (Eds), 
Innovations in Clinical Practice:  A Source Book. 
 
Vol. 4. Sarasota, FL:  Professional Resource Exchange, Inc., 1985, 307-308. 
 
 


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Folstein Mini Mental State Examination (MMSE) 
 
 
Place Label Here 
Protocol Number ____________________ 
Patient ID # ________________________ 
Patient Initials ______________________ 
Date (mm/dd/yyyy) _________________________ 
 
 
 
_____/5 
What is the: (year) (season) (date) (day) (month)? 
 
_____/5 
Where are we:  (state) (county) (town) (building) (floor)? 
 
_____/3 
Learn: “apple, table, penny.”    _____ # of trials 
 
_____/5 
Subtract serial 7’s: (100, 93, 86, 79, 72); or spell “WORLD” backwards 
 
_____/3 
Recall: “apple, table, penny.” 
 
_____/2 
Name: “pencil and watch.” 
 
_____/1 
Repeat: “no ifs, ands or buts.” 
 
_____/3 
“Take this paper in your right hand, fold it in half, and put it on the floor.” 
 
_____/1 
Read and obey: “Close your eyes.” 
 
_____/1 
Write a sentence on the back of this card. 
 
_____/1 
Copy the design on the back of this card 
 
 
_____/30 
Total (abnormal if <24; if <8th grade, then <21 is considered abnormal.) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix III PATIENT INFORMATION SHEET 
 
 
Patient Completed Quality of Life Booklet 
________________________________________________________________________ 
 
You have been given a booklet to complete for this study.  The booklet contains some 
questions about your ‘quality of life’ as a patient receiving treatment for cancer.  Your 
answers will help us to better understand how the treatment you are receiving is affecting 
the way you feel. 
 
1. This booklet contains questions for the MD Anderson Symptom Inventory Brain Tumor 
Module (MDASI-BT): 
 
2. Directions on how to complete the questions are written on the top of the first set of 
questions. 
 
3. Please complete the booklet during your scheduled clinical visit and return it to your 
nurse or your physician. 
 
 
Thank you for taking the time to help us. 
 
 


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Appendix IV MDASI - BT 
 


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Appendix V Contouring CNS and H/N 
ARIA Atlas Patient is Contours, Head (000-11-19-2013)  
1) Brain: For patients receiving craniospinal or otherwise requiring treatment of CSF, window-level 
should be adjusted to bone windows to ensure brain contour includes entire CSF space/meninges 
as well as cribiform plate. For intraparenchymal tumors, it may be appropriate to use window-
level on CT or MRI that allows visualization of brain parenchyma and contour actual brain 
parenchyma which may allow greater skin sparing for superficial targets.   
2) Brain stem: (based on QUANTEC definition) Use CT/MRI sagittal image to define axial slice for 
the foramen magnum (usually one slice above dens) and cranially to include midbrain (ending 
inferior to the optic tracts/thalami).   
3) Cochlea: Use CT bone window for contouring.  Use a 6mm brush and deposit circular structure in 
the bone anterior to the internal auditory canal including the apical and basal turns of the cochlea.  
Usually on 2-3 axial slices.  Alternatively, contour this volume using the free hand tool. 
4) Cord: rostral; start on the slice inferior to brain stem and continue caudally to the end of the data 
set or to the end of the “region of interest depending on whether the full cord visualized on CT 
being in the denominator will impact your dvh evaluation. The standard should be to contour the 
cord 2 cm distal or proximal to the PTV whichever applies. In this case contouring was stopped at 
the upper chest for no particular reason as this study goes down through the thorax.  
5) External auditory canal (middle ear and eustachian tube): Use CT bone window to contour boney 
portion of external auditory canal, middle ear (malleus, incus and stapes) and eustachian tube.  
Use Acquisition W/L to contour fleshy portion of external auditory canal from the inferior to the 
superior aspect of tragus. 
6) Eyes: This is most easily done in GE prior to exporting to Eclipse where an automated tool 
contours the Eyes and the lenses. In Eclipse contour the globe on the CT data set and check on 
any MR data set. IF discordant use CT data set. 
7) Hippocampus: Based on RTOG guidelines, contour the subgranular zone on T1-weighted SPGR 
MRI.  Begin contouring at the most caudal (inferior) extent of the crescentic-shaped floor of the 
temporal horn of the lateral ventricle and contour the hypointense grey matter located medial to 
the CSF hypointensity, not the white, bright white matter. The emergence of the uncal recess of 
the temporal horn defines the anterior boundary of the hippocampus.  The medial boundary of the 
hippocampus becomes defined by the medial edge of the uncal recess. Postero-cranially, the 
medial boundary of the hippocampus is defined by the lateral edge of the quadrageminal cistern 
which is the CSF containing space lateral to the pons. The hippocampal tail remains posterior to 
the thalamus as it curves medially toward the splenium of the corpus callosum and is still 
medially located relative to the lateral ventricle.   Terminate hippocampal contours at the point 
where the T1-hypointense structure no longer borders the atrium of the lateral ventricle.  At this 
point, the crux of the fornix emerges anteriorly and the splenium of the corpus callosum can be 
visualized posteriorly.  If MRI is not available, a reasonable approximation can be drawn using an 
8mm brush and contouring along the medial edge of the lateral ventricles from the temporal horn 
to posterior splenium of corpus callosum. 
8) Hippocampus PRV: 3mm expansion of hippocampus contour 
9) Hypothalamus. Follow pituitary stalk as it travels posterior to the chiasm.  Posteromedial to the 
optic radiations are the mammillary bodies.  Beginning one slice rostral to mammillary bodies, 
contour a cuboidal shaped structure that forms the walls of the third ventricle.  Hypothalamus 
terminates antero-rostrally at the fornix 


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10) Lacrimal gland: the lacrimal gland is located between the lateral orbital rim and the globe, 
beginning at the most superior and lateral aspect of the globe and extending inferiorly to the level 
of the lens or lateral rectus muscle. 
11) Lens: contour on CT data set (or use auto contour in GE prior to exporting to Eclipse). 
12) Mastoid: Use CT bone window for contouring.  Include all of the visible air cells. 
13) Midbrain: begin contouring just above the pons structure (see above) and contour cephalad until 
the level of the ventricular system is reached. Check this on the CT so that partial volume 
averaging on the MRI doesn’t have contour extending to where the ventricular space exists on the 
CT data but not quite present on the MR data set. 
14) Nasal cavity: Inferiorly, start at the most inferior portion of the maxillary sinuses and first image 
of the boney hard palate, just above the alveolar ridge of the maxilla and mucosa of the hard 
palate.  Going superiorly, include the nasal tip, ala, vestibule and columella anteriorly, the 
maxillary sinuses laterally and the septum and sphenoid sinuses posteriorly.  Continue superiorly 
to include the ethmoid sinuses and stop at the opening to the frontal sinuses.  You can include the 
frontal sinuses in nasal cavity/paranasal sinus cases in which it would be appropriate to spare it.  
In most head and neck cases, the frontal sinuses will be out of the treatment volume. 
15) Optic Radiations: Approximately 1 cm long just posterolateral to the chiasm. Best seen on a 
FLAIR or T2 MR data set. Check against CT to ensure fusion there is accurate. Adjust on CT 
data set if needed. 
16) Optic chiasm. A stubby chromosome shape using a 0.3 or 0.4 mm drawing sphere. It can be 
located behind or anterior to the stalk. Coronal view of CT/MR is helpful as the typical MR fused 
for H/N brain is not sliced thin enough to pick it up accurately and it exists on multiple axial 
images due to its oblique course. This can be minimized when needed by simulating the patient 
with 17-20 degrees of chin extension (that rotates the plane of imaging into the plane of the 
course of the ON to the chiasm. 
17) Optic nerve: using a 0.3 or 0.4 mm sphere tool, contour from back of eye to chiasm. It is helpful 
to do chiasm first. The nerve should transit the optic canal seen on the CT data set. (see chiasm 
for optimizing this structure re head position for simulation). Double check the Orbital portion on 
the CT as this portion can move a great deal. When critical, instruct the patient to look straight 
ahead during simulation and MR and treatment. 
18) Pituitary: using the FLAIR (to avoid contouring CSF) and the T1con fused data sets. Contour the 
gland just distal to the stalk. Do not contour the stalk itself. Check by moving to CT data set to 
see that structure lies in the fossa between the post clinoids and the medial edge of the sphenoid 
bone. 
19) Retina: use a 3 mm static sphere contour the back of the eye. To determine ant extent draw a line 
in the long axis of the eye, then draw a perpendicular line that bisects the posterior edge of lens. 
That can serve as a surrogate for the ora serrata (which can be visualized on MRI if more 
accuracy is needed).  
20) Semi-circular canals: Use CT bone widow for contouring. If you include the entire bone posterior 
to the internal auditory canal you will include the vestibule, superior semi-circular canal, 
lateral/horizontal semi-circular canal, posterior semi-circular canal and vestibular aqueduct. 
21) Skin: standard skin definition is 5mm rind on body. However, in the head, deep skin border is 
limited by skull.  3mm is often a closer approximation of skin in the scalp. If 5mm is used, bones 
should be removed from skin volume. 
 


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Appendix VI IMAGING GUIDELINES 
 
 
 
Coil
SERIES 1 3 plane localizer
SERIES 2 T1 Flair
Pulse Sequence Spin Echo
TE 9.3
TI 890-930
Orientation Sag Oblique
TR (ms) 2200 - 2950
Averages 1
FOV Read (mm) 240
Dimension 2D
FOV Phase (mm) 240
Matrix 384/256
Slice Thickness (mm) 5.0
Slice Gap (mm) 1
Phase Enc. Dir. A>>P
Comments Cover Brain scanning Left to Right
Angle slices to the patient's anatomy
 
SERIES 3 DTI (Diffusion Tensor)
Pulse Sequence Spin Echo EPI
TE1 109
Number of b-values 2
b-value 1 0
Orientation Axial Obl
b-value 2 1000
TR 5600-8000
Fat Suppr. Fat sat
Diff. Directions 25-30
Averages 2
FOV Read (mm) 230
FOV Phase (mm) 230
Slice Thickness (mm) 4.0
Matrix 128/128
slice Gap (mm) 0
Phase Enc. Dir. A>>P
Comments Cover Brain scanning Inferior to Superior.
Scan parallel to the inferior tips of the Corpus Callosum as seen on the Sagittal
Angle slices to the patient's anatomy as seen on all 3 planes.
SERIES 4 T2 Flair
Pulse Sequence Spin Echo
TE 145-147
TI 2250-2600
Orientation Axial
Fat Suppr. Fat sat.
TR 9200-11000
Averages 1
FOV Read (mm) 220
FOV Phase (mm) 220
Dimension 2D
Matrix 256/192
Slice Thickness (mm) 4.0
Slice Gap (mm) 0
Phase Enc. Dir. R>>L
Comments Cover Brain scanning inferior to superior
Scan parallel to the inferior tips of the corpus callosum as seen on the sagittal.
Angle slices to the patient's anatomy
Multi channel head coil (receive-only)
3.0 T Generic Protocol


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SERIES 5 MPRAGE (or equivalent)
Pulse Sequence Gradient Echo
TE 3.2-3.34
TI 900
Orientation Axial
Slices per Slab 176-200
TR 2200
Averages 1
FOV Read (mm) 220
Dimension 3D
FOV Phase (mm) 220
Matrix 256/256
Slice Thickness (mm) 1.0
Phase Enc. Dir. R>>L
Comments Cover Brain scanning inferior to superior
Scan parallel to the inferior tips of the corpus callosum as seen on the sagittal.
Angle slices to the patient's anatomy
SERIES 6 Perfusion
Flip Angle 60
Pulse Sequence Gradient Echo
TE 20-25
Orientation Axial
Fat Suppr. Fat sat.
TR 1500
Averages 1
FOV Read (mm) 230
FOV Phase (mm) 230
Matrix 96/128
Slice Thickness (mm) 5
Slice Gap (mm) 0
Phase Enc. Dir. A>>P
Comments
Inject contrast 1 minute after administration of contrast
 
SERIES 7 T2-weighted
Pulse Sequence Spin Echo
TE 102
Orientation Axial
Fat Suppr. Fat sat.
TR 3000-6000
Averages 2
FOV Read (mm) 220
Dimension 2D
FOV Phase (mm) 220
Matrix 256/256
Slice Thickness (mm) 4.0
slice Gap (mm) 0
Phase Enc. Dir. R>>L
Comments Cover Brain scanning inferior to superior
Scan parallel to the inferior tips of the corpus callosum as seen on the sagittal.
Angle slices to the patient's anatomy
Administration of Gadolinium Contrast


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SERIES 8 T1 Volumetric
Pulse Sequence Spin Echo
TE minimum (full echo)
Orientation Sagittal
Fat Suppr. Fat sat.
Slices per Slab 200-224
TR 600
Averages 0.5-1.0
Dimension 3D
FOV Read (mm) 220
Matrix 256/256
FOV Phase (mm) 100%
Slice Thickness (mm) 0.75-1.0
Phase Enc. Dir. A>>P
Comments Cover Brain scanning Left to Right
Angle slices to the patient's anatomy as seen on all 3 planes.
Reformat Straight Cor & Ax Obl


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Coil:
SERIES 1 3 plane localizer
SERIES 2 T1
Pulse Sequence Spin Echo
TE (ms) 9.5
Orientation Sag Oblique
TR (ms) 400 - 700
Averages 1
FOV Read (mm) 220
Dimension 2D
FOV Phase (mm) 220
Matrix 256/192
Slice Thickness (mm) 5 0
Slice Gap (mm) 1
Phase Enc. Dir. A>>P
Comments Cover Brain scanning Left to Right
Angle slices to the patient's anatomy
 
SERIES 3 DWI
Pulse Sequence Spin Echo EPI
TE 82
Orientation Axial Obl
TR 5500
Fat Suppr. Yes
Averages 4
FOV Read (mm) 260
Diffusion B Value=1000
FOV Phase (mm) 260
Diff Dir=All
Slice Thickness 4 0
Matrix 128/128
Slice Gap (mm) 0
Phase Enc. Dir. A>>P
Comments Cover Brain scanning Inferior to Superior.
SERIES 4 T2 Flair
Pulse Sequence Spin Echo
TE 147
TI 2250
Orientation Axial
TR 9500-11000
Averages 1
FOV Read (mm) 220
FOV Phase (mm) 220
Dimension 2D
Matrix 256/192
Slice Thickness 4 0
Slice Gap (mm) 0
Phase Enc. Dir. R>>L
Comments Cover Brain scanning inferior to superior
Scan parallel to the inferior tips of the corpus callosum as seen on the sagittal.
Angle slices to the patient's anatomy
1.5 T  Generic protocols
Multi channel head coil (receive-only)


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SERIES 5 Perfusion
Pulse Sequence Gradient Echo
TE 25-50
Orientation Axial
Fat Suppr. Fat sat.
Groups 1
TR 1700-2000
Averages 1
FOV Read (mm) 220
Dimension 2D
FOV Phase (mm) 220
Matrix 96/128
Slice Thickness 5
slice Gap (mm) 0
Phase Enc. Dir. A>>P
Comments
Inject contrast 1 minute after administra ion of contrast
 
SERIES 6 T2-weighted
Pulse Sequence Spin Echo
TE 103
Orientation Axial
TR 4000
Averages 1
FOV Read (mm) 220
Dimension 2D
FOV Phase (mm) 220
Matrix 256/256
Slice Thickness 4 0
Slice Gap (mm) 0
Phase Enc. Dir. R>>L
Comments Cover Brain scanning inferior to superior
Scan parallel to the inferior tips of the corpus callosum as seen on the sagittal.
Angle slices to the patient's anatomy
SERIES 7 T1
Pulse Sequence Spin Echo
TE Minimum (full echo)
Orientation Axial
TR 400-700
Averages 2
Dimension 2D
FOV Read (mm) 220
Bandwidth (Hz/pixel) 630
FOV Phase (mm) 220
Slice Thickness 4
slice Gap (mm) 0
Phase Enc. Dir. R>>L
Comments Cover Brain scanning Left to Right
Angle slices to the patient's anatomy as seen on all 3 planes.
Reformat Straight Cor & Ax Obl
Administration of Gadolinium Contrast


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SERIES 8 T1
Pulse Sequence Spin Echo
TE 7.6
Orientation Coronal
TR 400-700
Averages 2
FOV Read (mm) 180
Dimension 2D
FOV Phase (mm) 180
Matrix 320/224
Slice Thickness 4 0
Slice Gap (mm) 1 0
Phase Enc. Dir. R>>L
Comments Cover Brain scanning inferior to superior
Scan parallel to the inferior tips of the corpus callosum as seen on the sagittal.
Angle slices to the patient's anatomy