Clinical trial NCT03778294
Conditions: Glioblastoma Malignant Glioma
Sponsor: Mayo Clinic
Start date: 2019-03-28; Completion date: 2023-11-26
Enrollment: 43 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well fluorodopa F 18-positron emission tomography/magnetic resonance imaging scan (18F-DOPA-PET/MRI) works in imaging elderly patients with newly diagnosed grade IV malignant glioma or glioblastoma during planning for a short course of proton beam radiation therapy. 18F-DOPA is a chemical tracer that highlights certain cells during imaging. PET scan, is a metabolic imaging technique which takes advantage of how tumor cells take up nutrients differently than normal tissue. MRI scans are used to guide radiation therapy for most brain tumors. Hypofractionated proton beam therapy delivers higher doses of radiation therapy over a shorter period of time and may kill more tumor cells and have fewer side effects. Using 18FDOPA-PET scans along with MRI scans may be able to provide the radiation doctor with information on tumor tissue versus normal, healthy tissue and may help the doctor more accurately plan the radiation treatment.

Detailed description:
PRIMARY OBJECTIVE:

I. Compare overall survival at 12 months for grade IV glioma patients after radiation therapy targeting volumes designed with both 18F-DOPA-PET and conventional magnetic resonance (MR) image (or PET/computed tomography \[CT\]) information with historical controls.

SECONDARY OBJECTIVES:

I. Compare progression free survival at 12 months after radiation therapy targeting volumes designed with both 18F-DOPA-PET and conventional MR image information with historical controls.

II. Determine acute and late effect toxicity after hypofractionated proton beam radiotherapy treatment including areas of high 18F-DOPA-PET uptake (T/N \> 2.0).

CORRELATIVE RESEARCH OBJECTIVES:

I. Compare radiotherapy (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 differences in RT volumes identified using biopsy-validated thresholds as highly aggressive disease comparing 18F-DOPA uptake and relative cerebral blood volume (relCBV) from perfusion MRI (pMRI) as well as differences in RT volumes identified using biopsy-validated thresholds as tumor extent comparing 18F-DOPA uptake and diffusion maps from diffusion tensor imaging (DTI) will be evaluated.

III. Evaluate quality of life after radiotherapy using European Organization for Research and Treatment of Cancer (EORTC) questionnaires compared with historical controls from Keim-Guibert et al.

IV. Compare differences in proton radiation planning utilizing radiobiologic modeling/evaluation techniques performed at Mayo Clinic Rochester to linear energy transfer distribution evaluation at Mayo Clinic Arizona.

OUTLINE:

Patients receive 18F-DOPA intravenously (IV) and undergo PET/MRI or PET/CT imaging scan. Patients then receive proton beam radiotherapy over 5 or 10 consecutive days excluding weekend and standard of care temozolomide on days 1-7 or 1-14. Beginning cycles 2, patients receive standard of care temozolomide on days 1-5. Cycles with temozolomide repeat every 28 days for up to 7 cycles in the in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 2 months for 1 year, and then periodically for up to 5 years.

Arms: arm 1: Patients receive 18F-DOPA IV and undergo PET/MRI or PET/CT imaging scan. Patients then receive proton beam radiotherapy over 5 or 10 consecutive days excluding weekend and standard of care temozolomide on days 1-7 or 1-14. Beginning cycles 2, patients receive standard of care temozolomide on days 1-5. Cycles with temozolomide repeat every 28 days for up to 7 cycles in the in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Computed Tomography intervention 2: Fluorodopa F 18 intervention 3: Magnetic Resonance Imaging intervention 4: Positron Emission Tomography intervention 5: Proton Beam Radiation Therapy intervention 6: Quality-of-Life Assessment intervention 7: Questionnaire Administration intervention 8: Temozolomide
Intervention descriptions: intervention 1: Undergo PET/CT intervention 2: Given IV intervention 3: Undergo PET/MRI intervention 4: Undergo PET/CT or PET/MRI intervention 5: Receive proton beam RT intervention 6: Ancillary studies intervention 7: Ancillary studies intervention 8: Drug

Protocol documents:
Prot_SAP_000.pdf: 
MC1774 
Protocol Version Date: v.6.0, 14APR2020 
 
 
 Mayo Clinic Cancer Center 
 
Phase II Study of Short Course Hypofractionated Proton Beam Therapy incorporating 18F-DOPA-
PET/MRI for Elderly Patients with Newly Diagnosed Glioblastoma 
 
Study Chairs: 
  
Mayo Clinic Arizona 
 
 
 
 
 
 
Study Co-chairs: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statistician: 
√
 
 
 
 
 
 
 
 
 
 
1Department of Radiation Oncology, Mayo Clinic Arizona  
2Department of Radiation Oncology, Mayo Clinic Rochester 
3Department of Neurology, Mayo Clinic Arizona  
4Department of Neurosurgery, Mayo Clinic Arizona 
5Department of Radiology, Mayo Clinic Arizona 
6Department of Health Sciences Research, Section of Biostatistics, Mayo Clinic Arizona 
7Department of Radiology, Mayo Clinic Rochester  
 
√Study contributor(s) not responsible for patient care. 
 
   
   
   
  
 
 
 
Document History 
(Effective Date) 
Activation 
Modification 1.0 
Modification 2.0 
11/6/2018 
4/9/2019 
6/5/2019 


MC1774 
Protocol Version Date: v.6.0, 14APR2020 
 
 
Modification 3.0 
Modification 4.0 
Modification 5.0 
8/20/2019 
1/31/2020 
5/8/2020 
 
 
 
  
Drug Availability  
Supplied Investigational Agents:  
Arizona 18F-DOPA IND#: 140882 
Rochester 18F-DOPA IND#:  61300 
 
 
Protocol Resources 
Questions: 
Contact Name: 
Patient eligibility*, test schedule, 
treatment delays/interruptions/adjustments, 
dose modifications, adverse events, 
forms completion and submission 
Rad Onc Study Coordinator 
 
 
Protocol document, consent form, 
regulatory issues 
See Protocol Catalog for current Research Protocol Specialist 
Assigned: 
 
Arizona 18F-DOPA IND 
 
 
 
 
Serious Adverse Event Reporting 
 
 
 
  
*No waivers of eligibility allowed 
 
 


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Protocol Version Date: v.6.0, 14APR2020 
 
 
Table of Contents 
Title of Protocol 
1 
Protocol Resources 
2 
Table of Contents 
3 
Schema 
4 
1.0    Background 
5 
2.0    Goals 
9 
3.0    Patient Eligibility 
10 
4.0    Test Schedule 
11 
5.0    Stratification Factors OR Grouping Factor 
11 
6.0    Registration Procedures 
12 
7.0    Protocol Treatment 
12 
8.0    Dosage Modification Based on Adverse Events 
19 
9.0    Ancillary Treatment/Supportive Care 
19 
10.0  Adverse Event (AE) Monitoring and Reporting 
19 
11.0  Treatment Evaluation  
25 
12.0  Descriptive Factors 
30 
13.0  Follow–up Decision at Evaluation of Patient 
30 
14.0  Body Fluid Biospecimens 
30 
15.0  Drug Information 
31 
16.0  Statistical Considerations and Methodology 
31 
17.0  Pathology Considerations/Tissue Biospecimens 
36 
18.0  Records and Data Collection Procedures 
36 
19.0  Study Finances 
39 
20.0  References 
40 
 
 
Appendix I        ECOG Performance Status 
42 
Appendix II 
EORTC QLQ-Q30 
43 
Appendix III 
EORTC QLQ-BN20 
45 
Appendix IV     Mini Mental State Exam (MMSE) 
48 
Appendix V 
Contouring Guidelines 
Appendix VI     Imaging Form  
50 
52 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol Version Date: v.6.0, 14APR2020 
 
 
Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Registration 
Standard of care CT simulation 
Treatment planning imaging 
18FDOPA (Research)  
Treatment: Proton Beam Therapy (5 or 
10 fractions) + Concurrent/Adjuvant 
Temozolomide x7 cycles  
Active Monitoring: MRI, 
toxicity, QOL, and MMSE 
during Cycles 2-7 
Observation: Routine clinical 
follow-up until 2 years post-RT  
Event Monitoring: Follow for 
survival until 5 years after 
registration 


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1.0 
Background  
 
Glioblastoma Multiforme (GBM) is the most common primary malignant brain tumor with approximately 
11000 cases yearly. From this group, approximately 50% of all newly diagnosed patients are older than 
65 with the highest rate between ages 75-84.1 The overall survival in the elderly is significantly worse 
with a median of 6 months.2 Despite this poor overall survival rate, the majority of elderly patients are 
still treated with the "Stupp regimen", a 6 week course of concurrent radiation therapy with temozolomide 
(TMZ) followed by adjuvant temozolomide.3 
 
Due to limited survival, there has been interest in developing shorter courses of radiation therapy which 
are more convenient for the patient and families. Three prospective randomized studies have examined 
this question in the elderly population.  Roa et al. prospectively compared standard radiation therapy (RT) 
with an abbreviated course of RT in patients >60 years in a phase III trial. One hundred patients with 
GBM were randomly assigned after surgery to receive either standard RT (60 Gy in 30 fractions over 6 
weeks) or a shorter course of RT (40 Gy in 15 fractions over 3 weeks). The primary end point was overall 
survival. Health related quality of life (HRQoL) was assessed using the Karnofsky performance status 
(KPS) and Functional Assessment of Cancer Therapy-Brain (FACT-Br). No difference in overall survival 
or HRQoL was noted with a median overall survival of 5.1-5.6 months.4 The International Atomic Energy 
Agency randomized elderly and/or frail patients to 40 Gy/15 fractions or 25 Gy/5 fractions. The median 
overall survival was not statistically different between the groups, 7.9 months in 25 Gy/1 week and 6.4 
months in 40 Gy/3 weeks cohorts, respectively  (p = 0.988). Median progression-free survival time was 
4.2 months in both treatment arms (p = 0.716). With a median follow-up of 6.3 months, the quality of life 
between both arms at 4 weeks after treatment and 8 weeks after treatment was not different.5 Perry et al.6 
reported a phase III randomized trial of 40 Gy in 15 treatments with or without temozolomide for patients 
>65. Overall survival was improved with the addition of temozolomide 9.3 mos. vs. 7.6 months. 
(p<0.0001). Quality of life showed no differences in functional domains per EORTC QLQC30 and BN20 
between the two treatment arms. Therefore, from these trials, it appears that hypofractionated radiation 
therapy with temozolomide may be a preferable approach in the elderly given the poor overall survival.  
 
1.1 Hypofractionated Radiation Regimens using IMRT 
With intensity modulated radiation therapy (IMRT), this photon based technology allows for “dose 
painting” or the ability to preferentially deliver higher doses of radiation to MRI contrast enhanced (MRI 
CE) regions and lower doses to less suspicious areas at the same time. There have been a few studies that 
have looked into this treatment option.  Omuro et al.7 reported a phase II trial of hypofractionated IMRT 
delivering 36 Gy to the MRI CE tumor and 24 Gy to the FLAIR hyperintensity over 6 treatments with 
temozolomide and bevacizumab. With a median age of 55 years, median OS compared favorably to 
historical controls at 19.3 months. Quality of life was stable over time. Ney et al.8 reported a phase II trial 
of hypofractionated IMRT delivering 60 Gy to the MRI CE tumor and 30 Gy to the flair hyperintensity 
over 10 treatments with temozolomide and bevacizumab. It was noted that treatment volumes were 
sizable with median volume of MRI CE tumor and FLAIR changes with margin of 131 cm3 and 342.6 
cm3 respectfully.  Median OS of 16.3 months was favorable to historical controls. However, they did 
observe significant symptomatic radiation necrosis of 50%. Iuchi et al.9 reported a Japanese phase II trial 
of hypofractionated IMRT with concurrent and adjuvant temozolomide delivering 68 Gy to the MRI CE 
tumor and 32 Gy to the FLAIR hyperintensity over 8 treatments.  The majority of progression occurred 
outside of the radiation field. Median survival was 20 months. However, 20/46 patients developed 
radiation necrosis.  
 
Thus, these shorter fractionation regimens do provide similar overall survival compared to historical 
controls with higher incidence of symptomatic radiation necrosis.  Proton beam therapy has the potential 


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to provide an improved method of balancing maximizing tumor control with greater sparing of normal 
tissue, possibly leading to a lower incidence of symptomatic radiation necrosis.  
 
1.2 Use of proton beam therapy for glioma 
 
Proton beam therapy delivers a radiation dose with positively charged atomic particles (protons), while 
conventional external beam RT does with photons. Unlike photons, protons have a physical property to 
deposit most of their energy only when they reach their target. This allows protons to deliver a radiation 
dose to a target more preferentially, while minimizing radiation exposure to the healthy brain, brainstem 
and other normal tissues. There have been several studies that have performed comparative planning to 
study these differences. Adeberg et al.10 compared intensity-modulated proton therapy, volumetric-
modulated arc photon therapy, and 3D conformal photon radiotherapy in anaplastic astrocytoma and 
glioblastoma. They found essential dose reduction to normal tissues while maintaining equal target 
volume coverage using proton beam therapy, particularly in reducing dose to contralaterally located 
critical neuronal structures, areas of neurogenesis, and structures of neurocognitive functions.  Munck Af 
Rosenshold et al11 compared (IMRT), inversely optimized arc therapy and spot-scanned intensity 
modulated proton therapy (IMPT) for high grade glioma. The IMPT technique produced the most 
conformal plans.  In addition, IMPT offered the largest sparing of the brain and fiber tracts.  Aside from 
normal tissue sparing, proton beam therapy has a higher relative biologic effect (RBE) as compared to 
conventional x-rays with a higher linear energy transfer (LET). Hirota et al.12 demonstrated in vitro that 
high-LET proton particles caused greater DNA double strand breaks in glioma stem-like cells as 
compared to gamma rays. For all these reasons, the use of proton beam therapy may provide an 
improvement in local control with significantly more normal brain/structure sparing, possibly reducing 
the risk for symptomatic radiation necrosis.  
 
 
 
 
Arrows demonstrate excess normal tissue radiation exposure 
 
 
 
 
 


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Sample plans: IMRT (photons) vs. Protons  
  
 
         IMRT (photons)  
 
 
Protons 
 
 
Figure 1. Illustration of differences in low-dose radiation between IMRT and protons. 
 
 
1.3 Conventional imaging is inadequate to differentiate high 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, 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. Contrast enhancement 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.13 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 nontumoral vasogenic edema 
and non-uniform tumor infiltration14,15. 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 infiltration14. Furthermore, tumor infiltration has been found to extend beyond 
areas that demonstrate abnormal T2/FLAIR or enhancement15. There is a critical need to incorporate 
imaging-based techniques to guide therapy that address these deficiencies of MRI imaging. Molecular 
imaging techniques provide visual information about biological processes and have the potential to 
improve the accuracy of RT tumor delineation, which impact the overall course of treatment and 
prognosis for brain tumor patients. 
  
1.4 Amino acid PET tracer 18F-DOPA PET appears promising for gliomas: 
  
 
Various PET tracers have been studied for gliomas including 18F-flurodeoxyglucose (18-FDG), 18F-
fluorodopa (18F-DOPA), and 11C-methionine (11C-MET).  18F-DOPA transport is independent of the 
blood-brain barrier breakdown, allowing uptake to occur in both enhancing and nonenhancing 


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tumor with MRI CE . 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-FDG16,17. The most studied amino acid tracer is 11C-MET.18  Discrepancies of high 11C-MET PET 
uptake extending up to 4.5 cm beyond the CE region on MRI imaging for glioma patients have been 
reported19, with high MET uptake also reported extending beyond the abnormal T2 signal area19. Several 
studies have indicated 11C- MET altered resection planning for a majority of both low- and high-grade 
gliomas20,21. 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 lesions22. The short 
physical half-life of 11C-MET limits the ability to image patients at a facility without a cyclotron. 
Therefore, labeling an amino acid tracer with 18F-DOPA would increase the physical half-life and 
increase the feasibility of multi-institutional use. Unfortunately, labeling methionine with 18F-DOPA 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 MRI, 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. 
 
1.5 18F-DOPA correlation with pathologic tissue 
 
18F-DOPA-PET has been in production at Mayo Clinic Rochester since 2001, used to image Parkinson’s 
patients to study the 18F-DOPA uptake in the caudate nucleus and putamen.   Due to the imaging potential 
of 18F-DOPA-PET for gliomas, an initial study by Pafundi et al.23 correlated 18F-DOPA-PET against 
conventional MRI for neurosurgical biopsy targeting, resection planning and radiotherapy target volume 
delineation. Pathologic review confirmed glioma in 22 of 23 biopsy specimens. Thirteen of 16 high-grade 
biopsy specimens were obtained from regions of elevated 18F-DOPA uptake, while T1-CE was present in 
only 6 of those 16 samples. Optimal 18F-DOPA-PET thresholds corresponding to high-grade disease 
based on histopathology were calculated as Tumor uptake/Normal tissue uptake (T/N) > 2.0. In every 
patient, 18F-DOPA uptake regions with T/N > 2.0 extended beyond T1-CE up to a maximum of 3.5 cm. 
SUV was found to correlate with grade and cellularity. 
 
 
 
 
Pafundi et al. Neuro Oncol 2013 Aug: 15(8), 1058-106723 
 
 


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1.6 Preliminary data incorporating 18F-DOPA for radiation treatment planning  
 
MC1374 is a currently active study incorporating 18F-DOPA-PET to delineate areas of disease within the 
"boost" volume for radiation dose escalation in patients with high grade glioma. Thus far, it has been 
observed that 36% of patients have >30% high-density disease outside CE-MRI. From chemoradiation, 
dose escalating 18F-DOPA areas of T/N >2.0 to 76 Gy, a change in patterns of failure has been noted with 
fewer in field failures.  The findings were more pronounced in patients who were MGMT methylated than 
in patients who were unmethylated. (Unpublished, update provided by Dr. Laack) 
  
1.7 Advanced MRI techniques 
 
Advanced techniques using perfusion MRI(pMRI) and diffusion tensor imaging (DTI) also show promise 
for better differentiation of high density tumor and post-treatment radiation effect from true tumor 
progression compared to CE-MRI. No reported studies have performed a head-to-head comparison of 18F-
DOPA-PET with pMRI and DTI. Dr. L. Hu has extensive experience with the use of state-of-the-art MR 
for gliomas, and has demonstrated the direct impact of both acquisition and post-processing on 
determining relative cerebral blood volume (relCBV) threshold values for distinguishing tumor from 
post-treatment radiation effect24. Differences in RT volumes identified using biopsy-validated thresholds 
as highly aggressive disease comparing 18F-DOPA uptake and relCBV from pMRI as well as differences 
in RT volumes identified using biopsy-validated thresholds as tumor extent comparing 18F-DOPA uptake 
and diffusion maps from DTI will be evaluated. 
 
In summary, 18F-DOPA-PET metabolic imaging demonstrates significant correlation with histopathologic 
markers of grade and cellularity. MC1374 suggests that biopsy-validated 18F-DOPA-PET thresholds may 
reliably delineate areas of high-grade glioma not otherwise recognized with standard MRI. MC1374 
suggest that 18F-DOPA-PET may more accurately identify regions of higher grade disease in patients with 
glioma and will have utility in guiding radiotherapy targeting. Future incorporation of 18F-DOPA-PET 
into clinical practice for radiation therapy planning will evaluate the influence of 18F-DOPA-PET on local 
control and survival outcomes.  
 
2.0 
Goals  
2.1 Primary  
 
2.1.1 Compare overall survival at 12 months for Grade IV glioma patients after radiation therapy 
targeting volumes designed with both 18F-DOPA-PET and conventional MR image (or PET/CT) 
information with historical controls.  
2.2 Secondary 
 
 2.2.1 Compare progression free survival at 12 months after radiation therapy targeting volumes 
designed with both 18F-DOPA-PET and conventional MR image information with historical 
controls.  
 
2.2.2 Determine acute and late effect toxicity after hypofractionated proton beam radiotherapy 
treatment including areas of high 18F-DOPA-PET uptake (T/N>2.0) 
 2.3 Correlative Research  
 
2.3.1 Compare RT treatment volumes defined by MR only with RT treatment volumes defined 
with both PET and MR information for Grade IV glioma patients. 
  
2.3.2 Compare differences in RT volumes identified using biopsy-validated thresholds as highly 
aggressive disease comparing 18F-DOPA uptake and relCBV from pMRI as well as differences 


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in RT volumes identified using biopsy-validated thresholds as tumor extent comparing 18F-DOPA 
uptake and diffusion maps from DTI will be evaluated. 
 
2.3.3 Evaluate quality of life after radiotherapy using EORTC questionnaires compared with 
historical controls from Keim-Guibert et al.27 
2.3.4 Compare differences in proton radiation planning utilizing radiobiologic 
modeling/evaluation techniques performed at Mayo Clinic Rochester to Linear Energy Transfer 
distribution evaluation at Mayo Clinic Arizona  
3.0 Patient Eligibility 
 
 3.1 Inclusion Criteria  
 
 
3.1.1 Age ≥65  years.  
 
 
3.1.2 Histologically confirmed newly diagnosed Grade IV malignant glioma.  
 
 
3.1.3 Planned radiation treatments at Mayo Clinic Arizona or Mayo Clinic Rochester 
  
 
3.1.4 Willing to sign release of information for any radiation and/or follow-up records. 
 
 
3.1.5 Provide informed written consent.  
 
 
3.1.6 Patients with eGFR ≥ 60 mg/min/1.72m2  
 
 
3.1.7 Ability to complete questionnaire(s) by themselves or with assistance.  
 
 
3.1.8 ECOG performance status 0, 1, 2 
 
3.2 Exclusion Criteria  
3.2.1 Patients diagnosed with Grades I-III glioma 
3.2.2 Currently on Avastin at time of treatment  
3.2.3 Unable to undergo MRI scans with contrast (e.g. cardiac pacemaker, defibrillator, 
kidney failure).  
3.2.4 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, 
paroxetine, citalopram, and sertraline. If a patient is on any of these drugs, list 
which ones on the On-Study form. 
 
3.2.5 Pregnant women, nursing women, or men or women of childbearing potential who  
are unwilling to employ adequate contraception. 
NOTE: All women enrolled in this study will be age 65  or over, and at the 
determination of the PI, will not be of childbearing potential.  If the radiology 
department requires a pregnancy test before administering the 18FDOPA 
injection, they may perform one per their standard of care. 
 
 
 
 
 


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4.0  
Test Schedule 
 
 
Pre-
Treatment 
Treatment Phase 
and Active Monitoring 
Observation/
Follow-up 
Tests and procedures 
≤21 days 
prior to 
registration Prior to RT 
Cycle 1 RT 
and Chemo 
Cycle 2-7 
Chemo7 
At every 
clinically 
indicated 
follow-up1 
Physical exam, wt, ECOG PS  
X 
 
 
X 
X 
Neuro history and exam 
X 
 
 
X 
X 
CBC with differential 
X 
 
 
X 
X 
18F-DOPA adverse event 
assessment2 
 
X 
 
 
 
18F-DOPA PET/MRI8   
 
X 
 
 
 
Assessment of Concurrent 
steroids and anticonvulsants 
 
X6 
 
X 
X 
CT simulation3  
 
X 
 
 
 
Toxicity assessment4 
X 
 
X 
X 
X 
EORTC QLQ-C305
 
 
X 
 
X 
X 
EORTC QLQ-BN205
 
 
X 
 
X 
X 
MMSE5
 
 
X 
 
X 
X 
Advanced MRI 9 
 
X 
 
X 
X 
Proton Beam RT 
 
 
X 
 
 
Temozolomide 
 
 
X 
X 
 
1. The timing of follow-up visits for each patient will be per the clinician’s discretion from the end of 
Cycle 7 until death or 2 years post-RT.   
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. CT simulation can be done prior to or after registration, but before RT start. 
4. Baseline and cycle 1 toxicities to be assessed by Radiation Oncologist, cycles 2-7 to be assessed by 
Neuro-oncologist.  Toxicity assessment completion window during RT and chemotherapy is +/- 1 week. 
5. May be done any time before registration, but must be completed prior to start of RT.  Patients will 
complete a maximum of 6 post-baseline QOL/MMSE evaluations  
6. Must be completed prior to first 18F-DOPA injection. 
7. Post-RT scans during Cycles 2-7 must be completed every 2 months (+/-2 weeks).  All other tests and 
procedures in Cycles 2-7 will be completed when the patient is seen at the clinician’s discretion. 
8. 18F-DOPA PET/CT + diagnostic MRI is an acceptable alternative to 18F-DOPA PET/MRI 
9. Advanced MRI is performed per standard clinical care in Arizona.  Rochester will perform either MRI 
or advanced MRI at the physician’s discretion.   
 
 
5.0 
Stratification Factors: None 
 
6.0  
Registration Procedures  
 


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 6.1 
Patients will be registered to the study when they have consented, met eligibility criteria, 
and have been logged into the Research Participant Tracking (Ptrax) system. 
 
6.2 
Treatment on this protocol must commence at Mayo Clinic Arizona or Mayo Clinic 
Rochester under the supervision of a radiation oncologist. 
 
6.3 
Radiation oncologist has seen the patient and confirms the patient is a suitable candidate 
for this study.  
 
6.4 
Patient questionnaires are available on site.  
 
 
7.0 
Protocol Treatment 
 
 
7.1 
Radiation Therapy 
 
 
Doses throughout will be prescribed in Gy(RBE)/Gy or Gy. One Gy will be the equivalent of 
one Gy (RBE)/Gy for proton therapy for the purposes of the descriptions below. Radiation therapy 
must begin within 8 weeks of the biopsy or surgical resection. The dose and fractionation will be 
dependent on the combined volume of the CTV of the PET(T/N>2.0) and MRI (T1 cavity+T1 
contrast enhancement)-see section 7.1.9. Radiation will be delivered one fraction/day on consecutive 
days excluding weekends.  
 
 
 
7.1.1 
Immobilization and CT simulation: performed based on the standard of each 
institution.  
 
7.1.2 
Treatment planning utilizing image fusion with 18F-Dopa-PET and MRI imaging. 
Currently, 18F-DOPA is an investigational diagnostic PET radiopharmaceutical. 
Investigational new drug (IND) application of 18F-DOPA will be submitted to 
FDA by Nuclear Medicine of Department of Radiology. The on-site cyclotron 
facilities will be able to produce 18F-DOPA PET tracer for this clinical research 
project.    
 
 
 
 
7.1.21 Timing of PET scanning 
 
The PET scan to be used for radiation treatment planning should be 
acquired no more than 14 days prior to beginning radiation treatments.  
 
 
 
 
7.1.22 Patient preparation for PET scan 
 
7.1.23 A negative pregnancy test must be done ≤48 hours prior to 18F-DOPA 
injection for women of child-bearing potential only.  
 
7.1.24 Patients will be instructed to follow a low-protein diet after the previous 
evening meal. 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. 
 
 
 
 
 
 
7.1.3 Simultaneous PET/MRI is preferred for this protocol. PET/CT + diagnostic MRI is 
also acceptable.  


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7.1.4 PET/CT  
 
7.1.41 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 20 minute 3D PET acquisition will 
be acquired. 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.  
  
 
7.1.5 PET/MRI  
  
7.1.51 The subject will undergo MRI screening for contraindications to scanning 
and contrast agent administration as per routine clinical protocol at Mayo Clinic. MRI 
will be acquired on a PET/MR scanner simultaneously during the 20 minute PET 
acquisition phase.  
 
7.1.52 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. MR images will be obtained and used for attenuation correction of the PET 
data and, at 10 minutes after injection of 18F-DOPA, a 20 minute 3D PET acquisition will 
be acquired. 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 time-of-flight algorithm into a 300 mm field of view with a pixel 
size of 1.17mm and slice thickness of 2.78mm. All images will be transferred to a 
Radiation Oncology workstation, MIM workstation, and PACS system.  Areas of high 
metabolic activity (defined as T/N ratio of 2.0 or greater) will be defined by Brinkman, 
Pafundi (MCR) or Yang (MCA).   
 
7.1.6 Diagnostic MRI 
 
The following MRI sequences should be obtained if possible: Sagittal T1 FLAIR, Axial 
DWI, Axial T2 FLAIR, Axial BRAVO ARC, Gad Axial T2, Gad Sagittal Cube T1. 
Advanced MRI protocols including perfusion MRI (pMRI) and diffusion tensor imaging 
(DTI) will be applied to this study.  The estimated additional time of these two advanced 
MRI protocols will be approximately 10 minutes total. The pMRI DSC acquisition will 
be acquired as per standard perfusion DSC clinical protocol of the Radiology Department 
at Mayo Clinic. A dose of Gd-based contrast agent gadobutrol (Gadavist) (0.10 mmol/kg) 
administered before, and then another dose administered during the perfusion scan for 
each MRI exam is the current standard of care for the Radiology Department at Mayo 
Clinic. The DSC acquisition time is approximately 3 minutes. DTI data will be acquired 
as per standard DTI clinical protocol of the Radiology Department at Mayo Clinic.  Mayo 
Clinic Rochester will perform advanced MRI at the physician’s discretion.   
 
7.1.62 The first post-RT MRI scan should be acquired 3-6 weeks after 
completing radiation treatments, to correspond with the first follow-up 


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appointment. Follow-up MRI scans will also be acquired at each clinically 
indicated appointment per the standard of care follow-up regimen.  
 
 
 
7.1.9 Contouring and Target Definition (please refer to diagram below) 
 
1. Co-registration with CT scans, MRI scans, and PET scans will be used in identifying the 
CTV volumes 
 
2. The doses prescribed will be based on the boolean(combined) volume of CTV defined by the 
PET(T/N≥2.0) and the MRI areas of contrast enhancement including the surgical cavity. 
 
a.  For patients with a combined volume ≤ 65 cc, over five treatment days, patients will 
receive 35 Gy to CTV3500_PET, 30 Gy to CTV3000_MR and 25 Gy(CTV2500) to 
boolean(combined) volume of CTV3500_PET+CTV3000_MR+1cm.  
b. For patients with a combined volume > 65 cc, over ten treatment days, patients will 
receive 40 Gy to CTV4000_PET, 35 Gy to CTV3500_MR and 30 Gy(CTV3000) to 
boolean(combined) volume of CTV4000_PET+CTV3500_MR+1cm. 
 
3. The optimization target volume (OTV) is defined as a margin of 2 mm isotropic expansion of 
the CTV and edited clinically based on patterns of tumor spreading and anatomic boundaries 
such as skulls and nasal cavity. 
 
4. All normal structures will be contoured on the standard of each institution.  
 


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7.1.10 Image Guidance 
 
The Hitachi Patient Image Alignment System (PIAS) (2D) and/or CT on rails (3D) will be 
used for image guidance. Both are allowed under this protocol.  
 
 
7.1.11 Treatment Planning 
 
i. 
The prescription isodose line definition is up to the treating physician. However, we 
recommend that in the worst-case scenario the CTV D95% is at least 95% of the prescription 
dose.  
 
ii. 
The optimization method can be either multi-field optimization (MFO) or single-field 
optimization (SFO) also known as single-field uniform dose (SFUD).  SFO optimizes the 
spots of each proton field individually and creates a more uniform dose distribution from 
each beam than MFO. MFO is usually referred to as intensity-modulated proton therapy 
(IMPT). In MFO, spots from all the proton fields are optimized together. The inhomogeneous 
dose from each field is summed up to create homogeneous target coverage. 
 
iii. 
Beam angles will be selected to spare normal tissues and improve plan robustness.   
 
iv. 
If possible patients will be planned using SFO technique. If SFO cannot meet the dose 
volume constraints and plan robustness requirement, robustly optimized MFO will be used.  
 
v. 
Robustness quantification to evaluate the impact of patient setup and proton beam range 
uncertainties will be performed. The inter-fractional setup uncertainty is assumed to be a 
minimum of 2 mm and proton beam range uncertainty is assumed to be a minimum of 2%. 
For all patients, the plan robustness will be reviewed by a physicist co-chair. We recommend 
that in the worst-case scenario the CTV D95% is at least 95% of the prescription dose  
 
vi. 
Linear energy transfer (LET) distribution, which is calculated by an in-house developed 
system, will be reviewed by a physics co-chair to make sure that no high LET spots exist in 
the critical organs like optic chiasm and brainstem. Otherwise a new plan would be generated 
at the discretion of the physicist. Alternatively biologic dose distributions may be evaluated 
based on the RBE model developed at Mayo Clinic in Rochester and critical organs may be 
protected from excessive biologic dose. A new plan may be generated at the discretion of the 
physicist. 
  
vii. 
Calculated dose distributions will be verified by comparison to a Monte Carlo/semi-analytic 
calculation.  In cases where the CTV mean dose differs by more than 3% a new plan would 
be generated at the discretion of the physician.  
 
viii. 
The radiobiological effects evaluation is performed based on the standard of each institution. 
Linear energy transfer (LET) distribution and/or biologic dose will be reviewed by the 
clinical team (radiation oncologist, dosimetrist, and physicist).   Plans may be modified, 
within the protocol-specified dose-constraints, as per standard clinical practice to minimize 
high LET spots and/or biologically enhanced dose in the critical organs like optic chiasm and 
brainstem. 
 
 
7.1.12 Treatment Delivery 


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The corresponding treatment delivery techniques as employed in the treatment planning will be 
used to deliver the plan.  
 
Prescription Deviations and Goals 
 
 
Goal 
Min deviation (2) 
Major deviation (1) 
 
 
 
 
CTV 
D95% = 95% 
D95% = 85% - 120% 
<85% or >120% 
 
 
Prescription Dose: we recommend that in the worst-case scenario the 
CTV D95% is at least 95% of the prescription dose and the CTV D5% is 
at most 120% of the prescription dose.  
 
Minor deviation: CTV D95%: 85-95% of the prescription dose, CTV 
D5%: 110-120% of the prescription dose in the worst-case scenario. 
 
Major deviation: CTV 95% : <85% of the prescription dose, CTV D5%: 
>120% of the prescription dose in the worst-case scenario. 
 
Volume: The CTV must be specified on any plans with dose –volume 
histograms for these and all critical organs  
 
Critical structures in Table 7.1 with the dose volume indices up to 110% 
of the limit will be considered a minor deviation.  Critical structures in 
Table 7.1 with the dose volume indices more than 120% of the limit will 
be considered a major deviation. 
 
 
7.1.13 Critical Structures  
Table 7.1 Dose volume constraints for critical structures in the nominal scenario. 
Minor deviation (110% of the limit) is allowed in the worst-case scenario 
 
FIVE FRACTION 
Volume 
Volume Max 
Gy[RBE] 
Max Point Dose 
Gy[RBE] 
  Optic Pathway  
<0.2 cc 
23 Gy[RBE] 
25 Gy[RBE] 
  Brainstem  
<0.5 cc 
23 Gy[RBE] 
31 Gy[RBE] 
  Skin 
<10 cc 
36.5 Gy[RBE] 
38 Gy[RBE] 
 
TEN FRACTION 
Volume 
Volume Max  
Max Point Dose 
Optic Pathway  
<0.5cc 
32 Gy[RBE] 
37.5 Gy[RBE] 
Brainstem  
<0.5 cc 
33 Gy[RBE] 
40 Gy[RBE] 
Skin 
<10 cc 
43.2 Gy[RBE] 
45.6 Gy[RBE] 
 
7.1.14 Quality Assurance Documentation  
 
All plans will be reviewed by the PI and/or the co-PIs and rated as within guidelines 
(no deviations), minor deviation (any number of minor deviations mentioned 
above), or major deviation (1 or more major deviations present) 
 
 
7.2 
Patient Outcomes Quality of Life Assessment [Database] 
 
 
7.2.1 The EORTC QLQ-C30 and QLQ-BN20 will be completed, and a MMSE will be 
performed per the scheduled test timepoints. 


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7.3 
Adjuvant therapy  
 
 
Patients will receive concurrent chemotherapy, temozolomide (75 mg/m2 daily, d1-7 (5 
day RT regimen) or d1-14(10 day RT regimen) during radiation followed by 6 cycles of 
temozolomide (150-200 mg/m2) starting one month post radiation (d1-5 cycle q 28 days). 
This will be given and administered in standard doses as per institutional and standard 
regimen guidelines. Dose modifications will be done as per standard institutional 
guidelines.  Alternating electric field therapy will be allowed during the adjuvant 
temozolomide phase of treatment.  
 
7.4       Follow-up protocol  
 
Post-treatment tumor recurrence will be monitored through follow-up imaging, using 
standard of care MRI (including pMRI and DTI sequences) per protocol and then when 
recommended by treating physician during the event monitoring phase to assess tumor 
response based on the Response Assessment in Neuro-Oncology (RANO) Working 
Group criteria until progression of disease (up to 5 years)25. Central review will be 
required to verify progression (Dr. L. Hu, neuroradiology to review). 
 
7.5  
Patterns of Failure  
 
For those who recur, follow-up imaging at progression will be co-registered with pre-
treatment imaging in the Eclipse treatment planning software (Varian Medical Systems, 
Palo Alto, CA) , and patterns of failure will be analyzed by determining the portion of the 
recurrence volume (RecVol) that falls within the delivered RT plan and classifying each 
recurrence as either ‘central’ (>95% isodose line(IDL), ‘in field’ (80 - 95% IDL), 
‘marginal’ (20 - <80% IDL), or ‘distant’ (<20% IDL).  
 
 
 
7.6  
Outcomes  
 
Outcomes for patients treated prospectively with the addition of 18F-DOPA-PET will be 
determined and compared against historical controls from patients treated on NCCTG 
clinical trials.  
 
7.7  
Quality of life – patient reported outcomes  
QOLs will be compared to high-grade glioma patients treated on Keime-Guibert et al.27 
that examined a similar group. QOL and cognitive function will be evaluated with the 
EORTC QLQ-C30 and QLQ-BN20 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. 
 
 
 
8.0 
Dosage Modification Based on Adverse Events  


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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) Monitoring and Reporting  
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/protocolDevelopment/electronic_applications/ctc.htm) 
a. Identify the grade and severity of the event using the CTCAE version 4.0. 
b. Determine whether the event is expected or unexpected (see Section 10.2). 
c. Determine if the adverse event is related to the study intervention (agent, treatment or 
procedure) (see Section 10.3). 
d. Determine whether the event must be reported as an expedited report. If yes, 
determine the timeframe/mechanism (see Section 10.4).  
e. Determine if other reporting is required (see Section 10.5). 
f. Note: 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). 
NOTE: A severe AE is NOT the same as a serious AE, which is defined in Section 10.4. 
10.2 
Expected vs. Unexpected Events  
Expected events are those described within the study specific consent form, package 
insert (if applicable), and/or the investigator brochure, (if an investigator brochure is not 
required, otherwise described in the general investigational plan).  
Unexpected adverse events or suspected adverse reactions are those not listed in Section 
15.0 of the protocol, the study specific consent form, package insert (if applicable), or in 
the investigator brochure (or are not listed at the specificity or severity that has been 
observed); if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan. 
Unexpected also refers to adverse events or suspected adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of drugs but have not 
been observed with the drug under investigation. 
An investigational agent/intervention might exacerbate the expected AEs associated with a 
commercial agent. Therefore, if an expected AE (for the commercial agent) occurs with a 
higher degree of severity or specificity, expedited reporting is required. 
 
NOTE: The consent form may contain study specific information at the discretion of the 
Principal Investigator; it is possible that this information may NOT be included in the 
protocol or the investigator brochure. Refer to protocol or IB for reporting needs. 
10.3 
Attribution to agent(s) or procedure 


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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.  
 
  
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:  
 
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 hypofractionated proton beam therapy.   
Probable - The adverse event is likely related to hypofractionated proton beam therapy.  
Possible - The adverse event may be related to hypofractionated proton beam therapy. 
Unlikely - The adverse event is doubtfully related to hypofractionated proton beam 
therapy. 
Unrelated - The adverse event is clearly NOT related to hypofractionated proton beam 
therapy. 
 
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. 
 
10.3.1 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.  
 
10.3.2 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.  
 
10.3.3 Expedited Reporting  


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• 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. 
 
• An investigational agent/intervention might exacerbate the expected AEs associated 
with a commercial agent. Therefore, if an expected AE (for the commercial agent) occurs 
with a higher degree of severity, expedited reporting is required. The clinical investigator 
must determine severity.  
10.4 
Expedited Reporting Requirements for IND/IDE Agents  
10.4.1 Phase 1 and Early Phase 2 Studies: Expedited Reporting Requirements for 
Adverse Events that Occur on Studies under an IND/IDE within 30 Days of the 
Last Administration of the Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:  
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 
21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the sponsor within 
the timeframes detailed in the table below.  
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization 
≥24 hrs 
7 Calendar Days 
24-Hour 3 Calendar 
Days 
Not resulting in 
Hospitalization 
≥24 hrs 
Not required 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 3 Calendar Days” - The AE must initially be reported within 24 hours of learning of the AE, 
followed by a complete expedited report within 3 calendar days of the initial 24-hour report. 
o “7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days 
of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
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Expedited 24-hour notification followed by complete report within 3 calendar days for: 
 All Grade 3, 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
 Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered. Footnote “1” above 
applies after this reporting period. 
Effective Date: May 5, 2011 
 
NOTE: Refer to Section 10.3.3 for exceptions to Expedited Reporting  
 
10.4.2 Special situations to Expedited Reporting 
 
Exceptions to Expedited Reporting: EXPECTED Serious Adverse Events  
 
An expedited report may not be required for specific Grade 1, 2 and 3 Serious Adverse Events 
where the AE is EXPECTED. Any protocol specific reporting procedures MUST BE SPECIFIED 
BELOW and will supersede the standard Expedited Adverse Event Reporting Requirements: 
Hospitalizations for reasons deemed to be disease related will not be reported.  
 
PET scanning and PET tracer injection are the only procedures unique to this study.  The use of 
hypofractionated radiation therapy is an acceptable form of treatment per National 
Comprehensive Cancer Network (NCCN) guidelines. All other aspects of radiation therapy and 
follow-up are part of standard brain cancer treatment. Consequently, only adverse events 
possibly, probably, or definitely related to 18F-DOPA-PET administration or radiotherapy will be 
graded and reported in this protocol. All other toxicities associated with other components of 
conventional brain cancer treatment (e.g. hematological events resulting from chemotherapy) will 
not be graded or reported as part of this protocol 
 
 
 
 


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10.4.3 General reporting instructions 
The Mayo IND Coordinator will assist the sponsor-investigator in the processing 
of expedited adverse events and forwarding of suspected unexpected serious 
adverse reactions (SUSARs) to the FDA and IRB. 
Use Mayo Expedited Event Report form 
for investigational agents or 
commercial/investigational agents on the same arm.  
10.4.4 Reporting of re-occurring SAEs 
ALL SERIOUS adverse events that meet the criteria outlined in table10.41 
MUST be immediately reported to the sponsor within the timeframes detailed in 
the corresponding table. This reporting includes, but is not limited to SAEs that 
re-occur again after resolution. 
10.5 
Other Required Reporting  
 
10.5.1 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).  
 
10.5.2 Death  
 
The reporting period for 18F-DOPA for this study is 1 day.  
The reporting period for radiation-related toxicity 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.  


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10.5.3 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: 
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. 
10.5.4 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 unless otherwise specified. 
10.6 
Required Routine Reporting  
10.6.1 Baseline and Adverse Events Evaluations 
 
CTCAE  
System/Organ/Class 
(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 
 
Skin and subcutaneous 
tissue disorders 
Alopecia 
x 
 
x 
Investigations 
Lymphocyte count 
decreased 
x 
 
x 
Investigations 
Platelet count decreased 
x 
 
x 
Investigations 
Weight loss 
x 
 
x 
Metabolism 
Anorexia 
x 
 
x 


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CTCAE  
System/Organ/Class 
(SOC) 
Adverse 
event/Symptoms 
Baseline 
Post 
Injection 
assessment1 
Active 
Monitoring 
Nervous system disorders Enephalopathy 
x 
 
x 
Nervous system disorders Headache 
x 
 
x 
Nervous system disorders Seizure 
x 
 
x 
Psychiatric disorders 
Confusion 
x 
 
x 
1. This assessment should occur approximately 15-20 minutes post injection (after scan is 
completed) 
10.6.2 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. 
  
10.6.2.1 Grade 2 AEs deemed possibly, probably, or definitely related to the 
study treatment or procedure.  
10.6.2.2 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure.  
10.6.2.3 Grade 5 AEs (Deaths) (See Section 10.5.2)  
 
10.6.3 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.  
 
11.0 
Treatment Evaluation/Measurement of Effect  
 
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 25. 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.  
 
11.2.1 Measurable Disease 
  


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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).  
 
11.2.2 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.  
 
11.2.3 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 
 
lesions may not be suitable for reproducible measurements and the next largest lesions which can 
 
be measured reproducibly should be selected.  
 
11.2.4 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. Any evidence of progression will be also 
 
reviewed centrally by Dr. Leland Hu.  
 
11.4 Response Criteria  
 
11.4.1 Evaluation of Target Lesions  
11.4.1.1 Complete Response (CR): Requires all of the following:  


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• 
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.  
 
11.4.1.2 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 
 


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Patients with non-measurable disease cannot have a partial response. The best response possible 
is stable disease.  
 
11.4.1.3 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  
 
11.4.1.4 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  
 
11.4.1.5 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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1. RANO25 Progression occurs when any of the criteria with * are present.  
2. Confirmed PD requires all of the following if not all criteria are met then Preliminary PD  
• More than 3 months post RT  
• Radiologic progression by central review 
 by RANO criteria  
• Clinical progression as determined by treating Oncologist  
• Cannot be considered Pseudoprogression  
3. Patients with possible PsP should initially be given the Objective Status of Preliminary Progression. 
Once PsP or Progression is confirmed, the Objective Status can be changed accordingly.  
 
11.4.1.6 Confirmatory Measurement/Duration of Response  
 
11.4.1.6.1 Confirmation  
To be assigned a status of PR or CR, changes in tumor measurements must be 
confirmed by repeat assessments that should be performed 4 weeks after the 
criteria for response are first met.  
 
11.4.1.6.2 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.  
 
11.4.1.6.3 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.  


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12.0 
Descriptive Factors  
12.1 Corticosteroid therapy at study entry: Yes (specify dose) vs. no  
12.2 IDH1 mutant or wildtype or not available 
12.3 ECOG PS (see Appendix I): 0 vs. 1 vs. 2  
12.4 Neurologic deficit: Yes vs. no  
12.5 History of seizures: Yes vs. no  
12.6 Gross total resection vs. Subtotal resection vs. biopsy  
12.7 MGMT: Methylated vs. Unmethylated vs. not available  
12.8 Family history of brain tumor: Yes vs. no  
If yes, check all that apply:  
_____Father/Mother  
_____Brother/Sister  
_____Child  
_____Other (list: )  
12.9 Use of alternating electric therapy: yes vs. no 
 
 
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 18F-DOPA-PET for radiotherapy planning, all data up until the 
point of confirmation of ineligibility must be submitted.  
• If the patient never received pre-RT 18F-DOPA-PET, on-study material must be submitted.  
 
13.2 Those patients who will not receive any radiation treatment or who will receive radiation 
treatment elsewhere will move to Event Monitoring phase and be monitored for survival until 5 
years after registration. 
 
13.3 Patients who are CR, PR, REGR, or SD will continue to obtain clinically indicated MRI 
scans for up to 5 years from registration.  
 
13.4 Patients remain on study until all of the following are confirmed / complete (up to 2 years or 
patient refusal): 
 
Radiological progression by central review per RANO criteria 
 
Clinical progression identified by the treating oncologist 
 
It is more than 3 months since radiation treatments have been completed, to ensure 
the radiological evidence is tumor progression versus treatment response 
 
All follow-up study imaging during the patient visit at the time the above three 
conditions are met is complete 
13.5 Patients who develop PD will go to the event-monitoring phase. 
 
 
14.0 
Body Fluid Biospecimens: None 
 
 


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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 impurities26. 18F-DOPA-PET is currently in production at these institutions, and is used to image 
Parkinson’s patients to study the 18F-DOPA uptake in the caudate nucleus and putamen. 
 
16.0  
Statistical Considerations and Methodology  
 
16.1 Study Overview   
This protocol will assess the overall survival of newly diagnosed elderly glioblastoma patients 
using a one-stage phase II study design. 
 
16.1.1 Primary endpoint:  The primary endpoint of this trial is the proportion of patients 
alive (overall survival) at 12 months based on our hypothesis that the combination of 
more accurate delineation of high density tumor by 18F-DOPA-PET combined with 
hypofractionated proton therapy will improve overall tumor control.  All patients meeting 
eligibility criteria who have signed a consent form and who have begun treatment will be 
evaluable for the endpoint. 
 
16.2 Statistical Design  
A patients will be considered a success if they are alive at 12 months.  Previous studies and 
institutional data indicate a median overall survival between 6 and 9 months, therefore we 
estimate median overall survival (OS) to be 7.5 months2,4,5, which corresponds to 33% of patients 
surviving at 12 months.  Therefore the largest success proportion where the proposed treatment 
regimen would be considered ineffective in this population is 33%, and the smallest success 
proportion that would warrant subsequent studies with the proposed regimen would be 50% 
(corresponding to a median OS of 12 months). The following single stage one-sided Exact test for 
proportions design uses 39 evaluable patients to test the null hypothesis that the proportion of 
successes is at most 33% with an overall significance level (alpha) of 0.1, and a power of 82% to 
detect a true success proportion of 50%.  
 
16.2.1 Decision Rules  
 
16.2.1.1 If 17 or fewer successes are observed in the first 39 evaluable patients 
that have been followed for at least 12 months, we will consider this regimen to 
be ineffective in this patient population.  If 18 or more successes are observed in 
the first 39 evaluable patients, we may recommend further testing of this regimen 
in subsequent studies in this patient population.  
 
16.2.1.2 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 process.  
 
16.2.2 Sample Size  
The one-stage design to be utilized is fully described in Section 16.22. A minimum of 39 
evaluable patients will be accrued to this phase-II study unless undue toxicity is 
encountered. We anticipate accruing an additional 4 patients to account for ineligibility, 
cancellation, major treatment violation, or other reasons. Maximum projected accrual is 
therefore 43 patients.  


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16.2.3 Accrual Time and Study Duration  
We anticipate enrolling 15-20 patients per year and thus plan to finish accrual of patients 
by year 2, leaving year 3 for follow-up and analysis. Therefore, the overall study duration 
is expected to be 36 months.  
 
16.2.4 Power and Significance Levels  
Assuming the number of successes is binomially distributed, the significance level is 
0.075 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 can be tabulated as a function of the true success proportion as shown in the 
following table. 
 
If the true success 
proportion is … 
0.35 
0.40 
0.45 
0.50 
If the true 
success 
proportion 
is … 
Then the probability of 
declaring that the 
regimen warrants further 
studies is… 
0.16 
0.37 
0.62 
0.82 
Then the 
probability 
of 
declaring 
that the 
regimen 
warrants 
further 
studies 
is… 
 
16.2.5 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 time the patients have become evaluable for the 
primary endpoint (see 16.2). 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 make available via a manuscript, abstract, or presentation format is 
when 39 patients have been followed for at least 12 months.  
 
16.3.1 Primary Endpoint:  
 
16.3.1.1 Definition: The primary endpoint of this trial is the proportion of alive (overall 
survival) at 12 months.  Survival time is defined as the time from registration to death 
due to any cause.  All patients meeting eligibility criteria who have signed a consent form 
and who have begun treatment will be evaluable for the endpoint. All eligible patients 
will be followed until death or a maximum of 5 years.   
 
16.3.1.2 Estimation: The proportion of successes will be estimated by the number of 
successes divided by the total number of evaluable patients. Confidence intervals for the 


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true success proportion will be calculated utilizing Exact Binomial methodology.  The 
distribution of survival time will be estimated using the method of Kaplan-Meier (1958).  
 
16.3.1.3 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.  
 
16.3.2 Definitions and Analyses of Secondary Endpoints  
 
16.3.2.1 Progression free survival at 12 months after radiation therapy targeting volumes 
designed with both 18F-DOPA-PET and conventional MRI information with historical 
controls.  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. The 
proportion of successes will be estimated by the number of successes divided by the total 
number of evaluable patients.  Confidence intervals for the true success proportion will 
be calculated utilizing Exact Binomial methodology.  
 
16.3.2.2 Progression Free Survival  
The distribution of progression free survival times groups will be estimated using the 
method of Kaplan-Meier (1958). Time to disease progression is defined as the time from 
registration to the earliest date documenting disease progression. If a patient dies without 
documentation of disease progression, the patient will be censored on the last date the 
tumor was evaluated. 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.  
 
16.3.2.3 Adverse Events  
Determine acute and late effect toxicity after radiotherapy treatment targeting dose 
escalated volumes defined to include high 18F-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 hypofractionated proton beam therapy will be 
determined, with acute RT toxicities graded using Common Terminology Criteria for 
Adverse Events (CTCAE) v4.0 (available at http://ctep.cancer.gov). 
 
16.4 Correlative Research  
 
16.4.1 Compare RT treatment volumes defined by MR only with RT treatment volumes 
defined with both PET and MR information.  To assess the impact of integrating PET on 
target definition, the treating radiation oncologists will first define the treatment volumes 
for CTVMR and using the MR images while blinded to the PET study. Then the PET 
study will be reviewed with the planning CT and MRI studies to allow contouring of the 
CTVPET defined by the T/N ratio of  >2.0, respectively. The contours will be combined by 
the treating radiation oncologist and then expanded as described above. The volume of 
overlap and non-overlap between the CTV 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 


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defined with both PET and MR information. Alternate metrics for comparison will also 
be assessed, including spatial overlap, distance, correlations and 3D shape comparisons. 
  
16.4.2 Compare differences in RT volumes identified using biopsy-validated thresholds 
as highly aggressive disease comparing 18F-DOPA uptake and relCBV from pMRI as 
well as differences in RT volumes identified using biopsy-validated thresholds as tumor 
extent comparing 18F-DOPA uptake and diffusion maps from DTI will be evaluated. 
Paired t-test statistical analysis will be performed to determine if any differences exist 
and the level of statistical significance between RT volumes based on 18F-DOPA uptake 
and the measures mentioned above.  
 
16.4.3 Quality of Life  
Evaluate quality of life after radiotherapy treatment targeting dose escalated volumes 
defined to include high 18F-DOPA-PET uptake. QOL surveys will be compared to data 
from historical controls27.  Quality of life will be assessed at baseline and at each MRI 
evaluation (up to 6 evaluations).  QOL will be measured using the EORTC QLQ-C30, a 
30-item patient-reported questionnaire about patient ability to function, symptoms related 
to the cancer and its treatment, overall health and quality of life, and perceived financial 
impact of the cancer and its treatment.  28 of the 30 items are measured on a 1-4 scale 
(1=not at all; 4=very much) with the remaining two items (overall health and overall 
quality of life) scored on a 1-7 numeric analogue scale (1=very poor; 7=excellent).  The 
recall period for the EORTC QLQ-C30 is one week.  The EORTC QLQ-C30 is the 
product of more than a decade of collaborative research and to date, more than 2200 
studies using the EORTC QLQ-C30 have been registered with the EORTC (Fayers et al, 
2001 [EORTC Scoring Manual]). Of the 30 items, 24 aggregate into nine multi-item 
scales representing various HRQoL dimensions: five functioning scales (physical, role, 
emotional, cognitive and social), three symptom scales (fatigue, pain and nausea), and 
one global measure of health status. The remaining six single-item scales assess 
symptoms: dyspnea, appetite loss, sleep disturbance, constipation and diarrhea, and the 
perceived financial impact of the disease treatment. High scores indicate better QoL for 
the global health status and functioning scales, and worse QoL for the symptom scales. 
The QLQ-BN20 contains 20 items, 13 of which aggregate into four scales assessing 
future uncertainty, visual disorder, motor dysfunction, and communication deficit. The 
remaining single items assess other disease symptoms (e.g. headaches and seizures) and 
treatment toxic effects (e.g. hair loss) For all these scales, a higher score represents worse 
QOL. 
 
The patient-completed questionnaires will be administered to all willing patients via 
paper or electronic format in clinic at baseline and at each evaluation.  Questionnaires 
will be scored according to the published scoring algorithms.   
 
Scale score trajectories over time will be examined using stream plots and mean plots 
with standard deviation error bars overall. Analysis will include change from baseline 
using t-tests and mixed linear models to test for changes at each time point and non-zero 
slope respectfully.  
 
16.4.4 Compare differences in proton radiation planning utilizing radiobiologic 
modeling/evaluation techniques performed at Mayo Clinic Rochester to Linear Energy 
Transfer (LET) distribution evaluation at Mayo Clinic Arizona.  Paired t-test statistical 
analysis will be performed to determine if any differences exist and the level of statistical 


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significance between proton plan metrics based off the two modeling/evaluation 
techniques.  
 
16.5 Data and Safety Monitoring Plan 
 
16.5.1 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.  
 
16.5.2 Adverse Event Stopping Rules:  
As no reactions to 18F-DOPA have been reported within Mayo Clinic Rochester, toxicity 
testing reported in the literature revealed no deleterious effects (section 15.0), 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 DSMB.  There have been no reports in 
the literature of the occurrence of NSF in patients with normal renal function28,29 . 
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 agents28,29. 
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 DSMB. 
 
Using the hypofractionation approach described in Section 7, previous studies have 
successfully used hypofractionation without significant increases in acute or late adverse 
effects4,5. However, some studies with more aggressive, higher daily doses of 
hypofractionation have reported increased toxicity. Nonetheless, both acute (available at 
http://ctep.cancer.gov) and late30 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 DSMB 
• Grade 3 or 4 irreversible CNS toxicity  
 
• Grade 4 non-hematologic, non-CNS toxicity  
 
• Any Grade 5 toxicity  
 
16.6 Results Reporting on ClinicalTrials.gov  
 
16.6.1 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 36 months after the 
study opens to accrual.  


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16.6.2 Definition of Primary-Endpoint Completion Date (PCD): The PCD is the date at 
which the last patient has been followed for 12 months.  
 
16.7 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 and gender subsets are shown in the following table: 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
1 
2 
3 
Not Hispanic or Latino 
16 
24 
40 
Ethnic Category: Total of all subjects 
17 
26 
43 
Racial Category 
American Indian or Alaskan Native 
1 
0 
1 
Asian 
0 
1 
1 
Black or African American 
1 
2 
3 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
15 
23 
38 
Racial Category: Total of all subjects 
17 
26 
43 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 
 


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17.0  
Pathology Considerations/Tissue Biospecimens  
N/A 
18.0 
Records and Data Collection Procedures  
 
18.1 Submission Timetables  
 
Initial Material(s) 
 
CRF 
Pre-Treatment 
(Compliance with Test Schedule Section 4.0) 
 
Patient Eligibility 
 
 
 
2 weeks after registration 
 
 
 
 
 
Demographics 
On-Study 
Adverse Events: Baseline 
Patient Status: Baseline 
Patient Assessments 
MMSE Form 
Patient Questionnaire Booklet 
Concurrent Steroid and Anticonvulsant 
Treatment Form 
Off Treatment 
Submit 2 weeks after registration if 
withdrawal/refusal occurs prior to beginning protocol 
therapy 
 
Test Schedule Material(s) 
 
 
 
CRF 
Treatment Phase and Active Monitoring 
(Compliance with Test Schedule Section 4.0) 
 
Event Monitoring7 / 
Follow-up 
(Compliance with Test 
Schedule Section 4.0) 
 
<4 weeks 
after each 
evaluation 
during RT  
<1 week 
after 18F-
DOPA-
PET scan 
End of 
Treatment  
Radiation Therapy 
X 
 
X 
 
Adverse Event Form 
(Post Injection of 18F-
DOPA) 
 
X4 
 
 
Radiation Therapy 
Adverse Event Form 
(Toxicity) 
 
 
X5 
X5 
Off Treatment2 
X 
 
X 
X 
Patient Status Form 
X 
 
X 
X 
Consent Withdrawal2  
X 
X 
X 
X 


38 
 
Protocol Version Date: v.6.0, 14APR2020 
 
 
 
 
CRF 
Treatment Phase and Active Monitoring 
(Compliance with Test Schedule Section 4.0) 
 
Event Monitoring7 / 
Follow-up 
(Compliance with Test 
Schedule Section 4.0) 
 
<4 weeks 
after each 
evaluation 
during RT  
<1 week 
after 18F-
DOPA-
PET scan 
End of 
Treatment  
Lost to Follow-up2 
X 
 
X 
X 
Patient Questionnaire 
Booklet3 
 
 
X6 
X6 
Concurrent Steroid and 
Anticonvulsant 
Treatment Form 
 
 
X 
X 
MMSE 
 
 
X6 
X6 
Imaging Form8 
 
X 
 
X 
1. Acute toxicity will be assessed during standard of care monitoring by the radiotherapy team during 
the course of treatment. 
2. When applicable. 
3. Survey will need to be entered manually if it is not completed electronically 
4. 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. 
5. Late toxicity will be assessed during standard of care appointments. To be submitted ≤2 weeks after 
each clinically indicated MR scan. 
6. Patient will complete a maximum of 6 post-RT QOL evaluations 
7. Follow-up is until death or a maximum of 5 years from the time of registration. 
8. See Appendix VI. 
 
 
18.2 Data Handling and Record Keeping 
 
 
 
18.2.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 
(HIPAA).  Those regulations require a signed subject authorization informing the subject 
of the following:  
• 
What protected health information (PHI) will be collected from subjects in 
this study 
• 
Who will have access to that information and why 
• 
Who will use or disclose that information 
• 
The rights of a research subject to revoke their authorization for use of their 
PHI.  
(This information is contained within the Mayo IRB Informed Consent Template 
Section 14) 
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of 
subject authorization.  For subjects that have revoked authorization to collect or use PHI, 
attempts should be made to obtain permission to collect at least vital status (long term 
survival status that the subject is alive) at the end of their scheduled study period. 
 
18.2.2 Source Documents 


39 
 
Protocol Version Date: v.6.0, 14APR2020 
 
 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  
Source data are contained in source documents.  Examples of these original documents, 
and data records include: hospital records, clinical and office charts, laboratory notes, 
memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate and complete, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at 
the laboratories, and at medico-technical departments involved in the clinical trial. Source 
documents are kept in a secure location that is locked and requires approved access. 
 
18.2.3 Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study.  
All data requested on the CRF must be recorded.  All missing data must be explained.  If 
a space on the CRF is left blank because the procedure was not done or the question was 
not asked, write “N/D”.  If the item is not applicable to the individual case, write “N/A”.  
All entries should be printed legibly in black ink.  If any entry error has been made, to 
correct such an error, draw a single straight line through the incorrect entry and enter the 
correct data above it.  All such changes must be initialed and dated.  Do not erase or use 
“white-out” for errors.  For clarification of illegible or uncertain entries, print the 
clarification above the item, then initial and date it.  If the reason for the correction is not 
clear or needs additional explanation, neatly include the details to justify the correction. 
 
18.2.4 Records Retention 
The investigator will maintain records and essential documents related to the conduct of 
the study.  These will include subject case histories and regulatory documents. 
 
The investigator will retain the specified records and reports for; 
1. As outlined in the Mayo Clinic Research Policy Manual –“Retention of and Access 
to Research Data Policy” 
   
 
 
19.0 Study Finances  
 
19.1 Costs charged to patient: Routine clinical care  
 
19.2 Tests to be research funded: 18F-DOPA-PET scan and costs incurred for providing copies 
of imaging from local MD.  
 
19.3 Other budget concerns: None. 
 


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Protocol Version Date: v.6.0, 14APR2020 
 
 
20.0 References 
 
 
1. 
Zhang AS, Ostrom QT, Kruchko C, et al: Complete prevalence of malignant primary 
brain tumors registry data in the United States compared with other common cancers, 2010. Neuro Oncol, 
2016 
 
2. 
Burton E, Ugiliweneza B, Woo S, et al: A Surveillance, Epidemiology and End Results-
Medicare data analysis of elderly patients with glioblastoma multiforme: Treatment patterns, outcomes 
and cost. Mol Clin Oncol 3:971-978, 2015 
 
3. 
Stupp R, Hegi ME, Mason WP, et al: Effects of radiotherapy with concomitant and 
adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III 
study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10:459-66, 2009 
 
4. 
Roa W, Brasher PM, Bauman G, et al: Abbreviated course of radiation therapy in older 
patients with glioblastoma multiforme: a prospective randomized clinical trial. J Clin Oncol 22:1583-8, 
2004 
 
5. 
Roa W, Kepka L, Kumar N, et al: International Atomic Energy Agency Randomized 
Phase III Study of Radiation Therapy in Elderly and/or Frail Patients With Newly Diagnosed 
Glioblastoma Multiforme. J Clin Oncol 33:4145-50, 2015 
 
6. 
Perry JR, Laperriere N, O'Callaghan CJ, et al: Short-Course Radiation plus 
Temozolomide in Elderly Patients with Glioblastoma. N Engl J Med 376:1027-1037, 2017 
 
7. 
Omuro A, Beal K, Gutin P, et al: Phase II study of bevacizumab, temozolomide, and 
hypofractionated stereotactic radiotherapy for newly diagnosed glioblastoma. Clin Cancer Res 20:5023-
31, 2014 
 
8. 
Ney DE, Carlson JA, Damek DM, et al: Phase II trial of hypofractionated intensity-
modulated radiation therapy combined with temozolomide and bevacizumab for patients with newly 
diagnosed glioblastoma. J Neurooncol 122:135-43, 2015 
 
9. 
Iuchi T, Hatano K, Kodama T, et al: Phase 2 trial of hypofractionated high-dose intensity 
modulated radiation therapy with concurrent and adjuvant temozolomide for newly diagnosed 
glioblastoma. Int J Radiat Oncol Biol Phys 88:793-800, 2014 
 
10. 
Adeberg S, Harrabi SB, Bougatf N, et al: Intensity-modulated proton therapy, 
volumetric-modulated arc therapy, and 3D conformal radiotherapy in anaplastic astrocytoma and 
glioblastoma : A dosimetric comparison. Strahlenther Onkol 192:770-779, 2016 
 
11. 
Munck Af Rosenschold P, Engelholm S, Ohlhues L, et al: Photon and proton therapy 
planning comparison for malignant glioma based on CT, FDG-PET, DTI-MRI and fiber tracking. Acta 
Oncol 50:777-83, 2011 
 
12. 
Hirota Y, Masunaga S, Kondo N, et al: High linear-energy-transfer radiation can 
overcome radioresistance of glioma stem-like cells to low linear-energy-transfer radiation. J Radiat Res 
55:75-83, 2014 
 
13. 
Mihara F, Numaguchi Y, Rothman M, et al: Non-enhancing supratentorial malignant 
astrocytomas: MR features and possible mechanisms. Radiat Med 13:11-7, 1995 
 
14. 
Grosu AL, Feldmann H, Dick S, et al: Implications of IMT-SPECT for postoperative 
radiotherapy planning in patients with gliomas. Int J Radiat Oncol Biol Phys 54:842-54, 2002 
 
15. 
Schomas DA, Laack NN, Brown PD: Low-grade gliomas in older patients: long-term 
follow-up from Mayo Clinic. Cancer 115:3969-78, 2009 
 
16. 
Chen W, Silverman DH, Delaloye S, et al: 18F-FDOPA PET imaging of brain tumors: 
comparison study with 18F-FDG PET and evaluation of diagnostic accuracy. J Nucl Med 47:904-11, 
2006 
 
17. 
Hustinx R, Smith RJ, Benard F, et al: Can the standardized uptake value characterize 
primary brain tumors on FDG-PET? Eur J Nucl Med 26:1501-9, 1999 
 
18. 
Chen W: Clinical applications of PET in brain tumors. J Nucl Med 48:1468-81, 2007 


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Protocol Version Date: v.6.0, 14APR2020 
 
 
 
19. 
Grosu AL, Weber WA, Riedel E, et al: L-(methyl-11C) methionine positron emission 
tomography for target delineation in resected high-grade gliomas before radiotherapy. Int J Radiat Oncol 
Biol Phys 63:64-74, 2005 
 
20. 
Pirotte B, Goldman S, Dewitte O, et al: Integrated positron emission tomography and 
magnetic resonance imaging-guided resection of brain tumors: a report of 103 consecutive procedures. J 
Neurosurg 104:238-53, 2006 
 
21. 
Pirotte B, Goldman S, Van Bogaert P, et al: Integration of [11C]methionine-positron 
emission tomographic and magnetic resonance imaging for image-guided surgical resection of infiltrative 
low-grade brain tumors in children. Neurosurgery 57:128-39; discussion 128-39, 2005 
 
22. 
Becherer A, Karanikas G, Szabo M, et al: Brain tumour imaging with PET: a comparison 
between [18F]fluorodopa and [11C]methionine. Eur J Nucl Med Mol Imaging 30:1561-7, 2003 
 
23. 
Pafundi DH, Laack NN, Youland RS, et al: Biopsy validation of 18F-DOPA PET and 
biodistribution in gliomas for neurosurgical planning and radiotherapy target delineation: results of a 
prospective pilot study. Neuro Oncol 15:1058-67, 2013 
 
24. 
Hu LS, Eschbacher JM, Heiserman JE, et al: Reevaluating the imaging definition of 
tumor progression: perfusion MRI quantifies recurrent glioblastoma tumor fraction, pseudoprogression, 
and radiation necrosis to predict survival. Neuro Oncol 14:919-30, 2012 
 
25. 
Wen PY, Macdonald DR, Reardon DA, et al: Updated response assessment criteria for 
high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 28:1963-72, 
2010 
 
26. 
Talbot JN, Kerrou K, Montravers F, et al: FDOPA PET has clinical utility in brain 
tumour imaging: a proposal for a revision of the recent EANM guidelines. Eur J Nucl Med Mol Imaging 
34:1131-2; author reply 1133-4, 2007 
 
27. 
Keime-Guibert F, Chinot O, Taillandier L, et al: Radiotherapy for glioblastoma in the 
elderly. N Engl J Med 356:1527-35, 2007 
 
28. 
Altun E, Martin DR, Wertman R, et al: Nephrogenic systemic fibrosis: change in 
incidence following a switch in gadolinium agents and adoption of a gadolinium policy--report from two 
U.S. universities. Radiology 253:689-96, 2009 
 
29. 
Wang Y, Alkasab TK, Narin O, et al: Incidence of nephrogenic systemic fibrosis after 
adoption of restrictive gadolinium-based contrast agent guidelines. Radiology 260:105-11, 2011 
 
30. 
Cox JD, Stetz J, Pajak TF: Toxicity criteria of the Radiation Therapy Oncology Group 
(RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat 
Oncol Biol Phys 31:1341-6, 1995 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol Version Date: v.6.0, 14APR2020 
 
 
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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Protocol Version Date: v.6.0, 14APR2020 
 
 
Appendix II 
The European Organization for Research and Treatment of Cancer quality of life questionnaire 
(EORTC QLQ-C30) 
 
EORTC QLQ-C30 (version 3) 
We are interested in some things about you and your health. Please answer all of the questions 
yourself by circling the number that best applies to you. There are no "right" or "wrong" answers. 
The information that you provide will remain strictly confidential. 
Please fill in your initials: 
bbbb 
Your birthdate (Day, Month, Year): 
cececdde 
Today's date (Day, Month, Year): 
31     cececdde 
1. 
Do you have any trouble doing strenuous activities, 
Not at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much 
like carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
2. 
Do you have any trouble taking a long walk? 
1 
2 
3 
4 
3. 
Do you have any trouble taking a short walk outside of the house? 
1 
2 
3 
4 
4. 
Do you need to stay in bed or a chair during the day? 
1 
2 
3 
4 
5. 
Do you need help with eating, dressing, washing 
yourself or using the toilet? 
1 
2 
3 
4 
During the past week: 
Not at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much 
6. 
Were you limited in doing either your work or other daily activities? 
1 
2 
3 
4 
7. 
Were you limited in pursuing your hobbies or other 
leisure time activities? 
1 
2 
3 
4 
8. 
Were you short of breath? 
1 
2 
3 
4 
9. 
Have you had pain? 
1 
2 
3 
4 
10.  Did you need to rest? 
1 
2 
3 
4 
11.  Have you had trouble sleeping? 
1 
2 
3 
4 
12.   Have you felt weak? 
1 
2 
3 
4 
13.   Have you lacked appetite? 
1 
2 
3 
4 
14.   Have you felt nauseated? 
1 
2 
3 
4 


44 
 
Protocol Version Date: v.6.0, 14APR2020 
 
 
15.   Have you vomited? 
1 
2 
3 
4 
16.   Have you been constipated? 
1 
2 
3 
4 
 
During the past week: 
Not at 
A 
Quite 
Very 
All 
Little 
a Bit 
Much 
17.   Have you had diarrhea? 
1 
2 
3 
4 
18.  Were you tired? 
1 
2 
3 
4 
19.  Did pain interfere with your daily activities? 
1 
2 
3 
4 
20. Have you had difficulty in concentrating on things, 
like reading a newspaper or watching television? 
1 
2 
3 
4 
21.  Did you feel tense? 
1 
2 
3 
4 
22.   Did you worry? 
1 
2 
3 
4 
23.  Did you feel irritable? 
1 
2 
3 
4 
24.  Did you feel depressed? 
1 
2 
3 
4 
25.  Have you had difficulty remembering things? 
1 
2 
3 
4 
26. Has your physical condition or medical treatment 
interfered with your family life? 
1 
2 
3 
4 
27. Has your physical condition or medical treatment 
interfered with your social activities? 
1 
2 
3 
4 
28. Has your physical condition or medical treatment 
caused you financial difficulties? 
1 
2 
3 
4 
 
For  the  following  questions  please  circle  the  number   between  1  and  7   
that   best applies to you 
29. 
How would you rate your overall health during the past week? 
 
1 
2 
3 
4 
5 
6 
7 
 
Very poor 
Excellent 
 
30. 
How would you rate your overall quality of life during the past week? 
 
1 
2 
3 
4 
5 
6 
7 
 
Very poor 
Excellent 
 
©  Copyright 1995 EORTC Quality of Life Group. All rights reserved. Version 3.0 


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Protocol Version Date: v.6.0, 14APR2020 
 
 
Appendix III 
 The European Organization for Research and Treatment of Cancer (EORTC) QLQ-BN20 
 
 
EORTC  QLQ - BN20 
 
 
Patients sometimes report that they have the following symptoms.  Please indicate the extent to 
which you have experienced these symptoms or problems during the past week. 
 
 
During the past week: 
Not at 
A 
Quite 
Very 
All 
Little 
a Bit 
Much 
31. 
Did you feel uncertain about the future? 
1 
2 
3 
4 
32. 
Did you feel you had setbacks in your condition? 
1 
2 
3 
4 
33. 
Were you concerned about disruption of family life? 
1 
2 
3 
4 
34. 
Did you have headaches? 
1 
2 
3 
4 
35. 
Did your outlook on the future worsen? 
1 
2 
3 
4 
36. 
Did you have double vision? 
1 
2 
3 
4 
37. 
Was your vision blurred? 
1 
2 
3 
4 
38. 
Did you have difficulty reading because of your vision? 
1 
2 
3 
4 
39. 
Did you have seizures? 
1 
2 
3 
4 
40. 
Did you have weakness on one side of your body? 
1 
2 
3 
4 
41. 
Did you have trouble finding the right words to 
express yourself? 
1 
2 
3 
4 
42. 
Did you have difficulty speaking? 
1 
2 
3 
4 
43. 
Did you have trouble communicating your thoughts? 
1 
2 
3 
4 
44. 
Did you feel drowsy during the daytime? 
1 
2 
3 
4 
45. 
Did you have trouble with your coordination? 
1 
2 
3 
4 
46. 
Did hair loss bother you? 
1 
2 
3 
4 
47. 
Did itching of your skin bother you? 
1 
2 
3 
4 


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Protocol Version Date: v.6.0, 14APR2020 
 
 
48. 
Did you have weakness of both legs? 
1 
2 
3 
4 
49. 
Did you feel unsteady on your feet? 
1 
2 
3 
4 
50. 
Did you have trouble controlling your bladder? 
1 
2 
3 
4 
 
 
 
© Copyright 1994 EORTC Study Group on Quality of Life.  (phase III module) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


47 
 
Protocol Version Date: v.6.0, 14APR2020 
 
 
 
 
 
 
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.) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix IV 
Mini Mental State Exam (MMSE) 


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Protocol Version Date: v.6.0, 14APR2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix V  
Contouring CNS 
 
1) Brain: 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 (typically 
ending inferior to the thalami, i.e. where the brainstem “splits”).   
3) Brainstem PRV: add 3 mm expansion of brainstem contour 
4) 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. 
5) Eyes: In Eclipse contour the globe on the CT data set and check on any MR data set. IF 
discordant use CT data set. 
6) Hippocampus: Based on RTOG guidelines (please see NRG/RTOG contouring atlas for 
reference), 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. 
7) Hippocampus PRV: 5mm expansion of hippocampus contour 


49 
 
Protocol Version Date: v.6.0, 14APR2020 
 
 
8) 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.  It is bounded 
laterally by the optic radiations and posteriorly by the interpeduncular fossa and posterior 
commissure.  Continue the contours until the hypothalamus terminates antero-rostrally at the 
fornix and anterior commissure. 
9) 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. 
10) Lens: contour on CT data set (or use auto contour in GE prior to exporting to Eclipse). 
11) 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. Remember the MR should only be a guide and the CT truly 
defines the optic chiasm.  Also do not include the carotid arteries as part of the optic chiasm 
contour. 
12) 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. 
13) Optic structures PRV: 3 mm expansion of the optic nerve and chiasm contours 
14) 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 clinoids and the medial edge of the sphenoid bone. 
15) 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).  
16) 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. 
17) Skin: standard skin definition is 5mm rind on body.  However, in the head, deep skin border is 
limited by skull.  If 5mm is used, bones should be removed from skin volume.  3mm is often a 
closer approximation of skin in the scalp. 
 
 
 
 
 
 
 
 


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Appendix VI  
 


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