Enhancing Brain Lesions After Radiation Therapy: A Comparison of MRI Perfusion and FDG PET/CT to Distinguish Between Radiation Injury and Tumor Progression
Phase: NA
Conditions: Brain Cancer
Sponsor: Memorial Sloan Kettering Cancer Center

 
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MSK PROTOCOL COVER SHEET 
Enhancing Brain Lesions after Radiation Therapy: A Comparison of MRI Perfusion 
and FDG PET/CT to Distinguish Between Radiation Injury and Tumor Progression 
Principal Investigator/Department: Robert Young, MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Memorial Sloan Kettering Cancer Center
IRB Number: 12-067 A(25)
Approval date: 02-Feb-2023

 
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Table of Contents
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA..................................................................... 3 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .............................................................................. 3 
3.0 
BACKGROUND AND RATIONALE ................................................................................... 4 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ........................................................... 9 
4.1 
Design ............................................................................................................................ 9 
4.2 
Intervention ................................................................................................................... 10 
5.0 
CRITERIA FOR SUBJECT ELIGIBILITY ......................................................................... 13 
5.1 
Subject Inclusion Criteria .............................................................................................. 13 
5.2 
Subject Exclusion Criteria ............................................................................................. 13 
6.0 
RECRUITMENT PLAN ..................................................................................................... 13 
7.0 
ASSESSMENT/EVALUATION PLAN .............................................................................. 13 
8.0 
TOXICITIES/SIDE EFFECTS ........................................................................................... 17 
9.0 
PRIMARY OUTCOMES ................................................................................................... 19 
10.0 CRITERIA FOR REMOVAL FROM STUDY ..................................................................... 19 
11.0 BIOSTATISTICS .............................................................................................................. 19 
12.0 RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 21 
12.1 Research Participant Registration ................................................................................. 21 
12.2 Randomization .............................................................................................................. 22 
13.0 DATA MANAGEMENT ISSUES....................................................................................... 22 
13.1 Quality Assurance ......................................................................................................... 22 
13.2 Data and Safety Monitoring ........................................................................................... 22 
14.0 PROTECTION OF HUMAN SUBJECTS .......................................................................... 23 
14.1 Privacy .......................................................................................................................... 23 
15.0 INFORMED CONSENT PROCEDURES .......................................................................... 25 
16.0 REFERENCES ................................................................................................................. 25 
17.0 APPENDICES .................................................................................................................. 28 
 
 
 
 
 
 
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Approval date: 02-Feb-2023

 
Page 3 of 29 
1.0
PROTOCOL SUMMARY AND/OR SCHEMA
Some patients treated with brain radiation therapy for tumors located in the head may 
develop new or increased enhancing mass lesions. These worsening lesions may 
represent radiation injury/necrosis or tumor progression. This study will examine the utility 
of MRI perfusion and FDG PET/CT to determine if the enhancing lesions represent 
radiation injury or tumor progression. Both MRI perfusion and FDG PET/CT scans are part 
of the standard of care for patients with indeterminate lesions after treatment. The purpose 
of this study is to prospectively enroll these patients in order to determine if MRI perfusion 
or FDG PET/CT performs better in predicting if a worsening enhancing brain lesion 
represents radiation injury or tumor progression. In addition the entire cohort analyses, 
subcohort analyses will be performed for patients belong to specific clinical scenarios and 
compared using an interaction test.  
Prior to enrolling in the study, each patient  will have a CT or MRI scan that shows an 
increasing indeterminate mass lesion. If the screening scan is a brain MRI perfusion, it can 
also function as the protocol intervention. 
Screening (within 12 weeks of enrollment): Neurological and/or physical examination  
Intervention: Brain MRI perfusion and PET/CT performed within 12 weeks of each other. 
Either MRI perfusion or PET/CT may be performed first. The first of the two scans should 
be performed within 12 weeks after the screening scan showing an increasing 
indeterminate mass lesion. If the screening scan is a brain MRI perfusion, it can also 
function as the protocol intervention. Imaging based diagnosis of radiation injury vs. 
worsening tumor will be rendered by a study neuroradiologist and by a nuclear medicine 
radiologist and entered into a secure database.  
*Note that clinical reads of the MRI perfusion and PET/CT will be rendered as per the 
standard of care, usually within 24-48 hours after completion of the study. These reports 
get dictated in Powerscribe and then become part of t
record. 
Off study: Patients will remain on study until the completion of either the MRI perfusion or 
PET/CT that are within 12 weeks of each other. After one of these scans, the patient will 
have no active interventions and will be off study. Patients will obtain a standard of care 
brain MRI scan about every 2-3 months. These MRI scans will be used to track disease 
progression. 
Follow up: Neurological/physical examination and brain MRI approximately every 2-3 
months  until death or 1 year after last MRI if lost to follow up. If clinical and radiological 
follow up is required, determination of the outcome (tumor progression vs. radiation injury) 
may require 6 months or more from the time of the intervention MRI perfusion and PET/CT 
scans.   
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
The primary goal of the proposed study is to directly compare PET/CT with MRI perfusion 
in distinguishing between radiation injury and tumor progression. These are the two most 
commonly performed tests for possible radiation injury cases (MRI spectroscopy, diffusion 
imaging, and experimental PET/CT tracers trail far behind). There has been very little 
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comparative effectiveness research to determine an optimal imaging strategy, whether 
both are complementary and necessary, or whether one outperforms the other. This 
protocol will help us answer those questions, and may lead to dramatic changes in the 
way we and other institutions manage these diagnostic dilemmas. After the completion of 
radiation therapy and a follow-up MRI exam demonstrating a worsening enhancing brain 
lesion, patients will undergo both MRI perfusion and PET/CT exams. If the follow up MRI 
is a brain MRI perfusion, it will serve as both the screening scan and protocol intervention. 
In this case, patients will undergo only a PET/CT exam.The findings from each of these 
imaging studies will be used to predict whether the lesion represents tumor progression or 
radiation necrosis based on clinical follow-up and/or pathologic tissue sampling. 
Primary Endpoint:  
1. To assess the utility of PET/CT and MRI perfusion studies in predicting whether 
worsening enhancing brain lesions seen after radiation therapy represent radiation injury 
or tumor progression. This study will examine the role of these two imaging techniques in 
predicting diagnosis and treatment planning.  
Exploratory Endpoint:  
1. To assess the utility of PET and MRI perfusion studies in predicting tumor progression 
in patients with tumors with a history of brain radiation therapy receiving anti-angiogenic 
therapy (such as bevacizumab). Due to direct drug effects upon the vasculature, these 
tumors often show little or no enhancement despite clinical worsening and increasing non-
enhancing abnormalities. The role of advanced imaging in determining progression in 
lesions that do not show increased enhancement has not been defined. In an exploratory 
fashion, we will enroll patients with tumors with a history of brain radiation therapy 
receiving anti-angiogenic therapy with suspected progression and increased 
nonenhancing lesions.  
2. To assess the utility of MR diffusion imaging in predicting radiation injury or tumor 
progression. Water diffusion occurs independent of tumor blood flow (MRI perfusion) or 
glucose uptake (FDG PET/CT), and may also be a useful technique to evaluate worsening 
enhancing brain lesions. 
3.0 
BACKGROUND AND RATIONALE 
Patients with tumors treated by brain radiation therapy may develop new and/or increased 
enhancing mass lesions within the spectrum of radiation injury. This frequently poses a 
diagnostic dilemma, as both radiation injury and worsening tumor may fulfill requirements 
for worsening disease when applying standard response criteria.1 These criteria usually 
rely on changes in size of the enhancing lesion on contrast brain MRI scans, which is the 
current imaging standard for the evaluation and follow up of patients with a history of brain 
radiation therapy.  
 
Radiation therapy plays an important role in prolonging the survival of patients with 
primary (malignant gliomas) and secondary (metastases) malignancies of the head. 
Treatment protocols include administration of whole and/or partial brain radiation therapy 
as well as stereotactic radiosurgery. Toxicity of radiation therapy on the brain includes 
radiation-induced injury of healthy brain occurring months to years after treatment. 1 Brain 
tolerance is related to the prescribed volume, dose, fraction and interval of radiation. Focal 
radiation injury may manifest with increased or new enhancing mass lesions that mimic 
worsening tumor. The term focal radiation injury is used here to include 
pseudoprogression in gliomas and radiation necrosis in both gliomas and metastases  
these are related but distinct enhancing entities along a common continuum. 
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Pseudoprogression is the transient worsening of enhancing disease that occurs soon after 
completion of radiation therapy in patients with malignant gliomas. This occurs in 
approximately 31% of treated patients, and in 58% of patients with methylated O6-
methylguanine-methyltransferase enzyme (MGMT) promoter status.2-5 The increased 
and/or new enhancing mass lesions are due to early subacute potentiated radiation-
induced tissue injury with inflammatory changes and necrosis. This is most common 1-3 
months after radiation therapy, with lesions usually spontaneously stabilizing or improving 
by 6 months. In contrast to tumor progression, pseudoprogression has been associated 
with prolonged survival.6, 7  
In contrast, radiation necrosis is an often irreversible process that develops many months 
to years after completion of radiation therapy. Patients develop increased or new 
enhancing mass lesions due to late subacute radiation-induced tissue necrosis, 
inflammatory changes and blood-brain barrier disruption. The lesions are also 
characterized by marked adjacent brain edema. Surgical resection is the most efficacious 
treatment. Patients may become dependent on steroids to control the enhancement and 
edema.  
Enhancement is the combined result of tissue vascularity and accumulation of contrast in 
the extracellular extravascular space secondary to transendothelial diffusion or 
permeability. Tumors are characterized by neovascularization and angiogenesis with the 
formation of many new immature and leaky intratumoral blood vessels. While 
enhancement is usually interpreted to represent tumor, enhancement may also occur due 
to radiation injury from blood-brain barrier disruption without neovascularization. Rather 
than relying on contrast enhancement, we propose using two physiological imaging 
techniques to investigate the biology of the enhancing lesion(s): MRI perfusion and 
PET/CT.  
 
No study has directly compared MRI perfusion with FDG PET/CT for the diagnosis of focal 
radiation injury. Although both are commonly performed, their comparative predictive 
value, sensitivity, specificity and indications remain uncertain. Many studies were 
performed using small patient cohorts and retrospective designs. We believe that the large 
numbers of neuro-oncology patients at MSKCC, and the large numbers of scans we 
(already) perform, leveraged with the benefits of a prospective protocol, will help 
overcome many of the limitations in the current literature. We hypothesize that MRI 
perfusion and PET/CT can prospectively predict radiation necrosis from tumor 
progression. Our goal is to directly compare the two techniques and determine if any 
particular clinical scenario (such as hemorrhagic lesions) would favor one over the other. 
Early diagnosis would help clinical decision-making, as the treatments for these two 
entities are very different.  
 
The gold standard for the diagnosis of radiation injury is histopathology. This is an invasive 
technique, however, which may be limited by sampling error or may not be possible for 
inaccessible lesions in eloquent brain. A safe, noninvasive imaging biomarker to 
determine radiation injury is therefore desirable.  
 
3.1 MRI 
 
Conventional MRI provides exquisite high resolution images and detailed structural 
information about the size, location and effects of a tumor on the surrounding brain. When 
evaluating patients who have undergone radiation therapy, however, lesion size and 
enhancement characteristics are of relatively limited utility in distinguishing tumor 
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progression from radiation necrosis8, both of which can present as enhancing mass 
lesions on conventional MRI.9, 10  Enhancement in these cases reflects disruption or 
absence of the normal blood-brain barrier,9, 10 and does not necessarily correlate with 
residual or progressive tumor. Furthermore, contrast enhancement alone will likely 
become a less reliable marker with the increasing use of anti-angiogenesis agents such as 
Avastin (bevacizumab) that directly induce rapid and profound decreases in tumor 
enhancement.  
 
3.1.2 Rational for the use of MRI Perfusion  
 
MRI perfusion provides physiologic information about brain tissue biology, allowing the in 
vivo measurement of increased microvascularity and permeability to suggest tumor.11, 12 
There is growing evidence that MRI perfusion can improve the diagnosis and prognosis of 
patients with brain tumors over conventional imaging alone.13-15 MRI perfusion correlates 
with microvessel density and vascular endothelial growth factor (VEGF) expression at 
histopathology and catheter based angiography.16, 17  Two main methods of MR perfusion 
are currently being utilized to evaluate brain tumors  dynamic susceptibility contrast 
(DSC) perfusion imaging and dynamic contrast enhanced (DCE) perfusion imaging.  DSC 
MRI perfusion is a T2* technique that relies on signal changes detected during the rapid 
bolus of contrast through brain tissues. Although small retrospective studies have 
suggested a role for MRI perfusion,18-21 no prospective trial has been designed to 
distinguish between radiation injury and tumor progression. 
 
DCE MRI perfusion is a T1 technique with superior spatial resolution that is beneficial in 
regions where hemorrhage or bone/air interfaces may otherwise limit DSC imaging. In 
addition, DCE provides potentially more robust absolute measurements of cerebral 
perfusion, flow and permeability  as opposed to the only relative measurements obtained 
by DSC. We propose studying the role of DCE MRI perfusion in distinguishing between 
focal radiation injury and tumor progression.  
 
3.1.2 Rationale for the use of PET/CT 
 
PET/CT is a commonly used technique in oncologic imaging that relies on combining the 
functional/physiologic information provided by PET imaging with the anatomic information 
provided by the concurrently acquired CT scan. As a proxy for cellular glucose uptake, 
FDG PET/CT can identify hypermetabolic lesions to suggest tumor. After the 
administration of a radiolabeled glucose analogue (F-18 FDG), relative metabolic activity 
in the brain can be imaged with tracer uptake directly correlated to the level of cellular 
glucose metabolism. In the brain, abnormal uptake can be determined by visual inspection 
and comparison to uptake in normal cortex or via quantification by measurement of 
standardized uptake values (SUV). No consensus SUV cut-off values for tumor detection 
have been established in the literature.22  Quantification of abnormal FDG uptake may 
also be performed by textural and topographc analysis using feature-based image 
analysis tools. Although retrospective reports23-29 suggest that PET imaging may play a 
role in distinguishing radionecrosis from tumor progression, this role has yet to be well 
defined in a prospective trial.  
 
3.2 Preliminary Data 
 
MRI perfusion and PET/CT are already routinely performed for patients with tumors with a 
history of brain radiation at MSKCC. In 2010, we performed 1,474 MRI perfusion scans 
and 212 PET/CT scans, for determining radiation injury as well as a variety of other 
reasons that include for staging, preoperative planning, preradiation therapy planning, and 
treatment follow up. The vast majority of the MRI perfusion scans were performed using 
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the DSC technique, with very few (<50) performed using the potentially more robust DCE 
technique.  
 
In a preliminary retrospective analysis, we identified 12 consecutive patients over a one 
year period with indeterminate enhancing lesions after radiation therapy who underwent 
DSC MRI perfusion, FDG PET/CT, and subsequent surgical resection with pathologic 
diagnosis (Hatzoglou V, Ulaner G, Beal K, Zhigang Z, Young RJ; Abstract 9012072, 
Radiological Society of North America, Chicago, IL, December 2010). Both primary (n=3) 
and secondary (n=9) brain neoplasms were included. Seven patients received stereotactic 
radiosurgery (SRS, 18-21 Gy), 2 patients whole brain radiation (35-52.5 Gy) and 3 
patients partial brain radiation therapy (59.4-60 Gy). From the PET/CT scans, 
standardized uptake values (SUV) of the lesion and background were measured by a 
board-certified nuclear medicine radiologist and ratios (SUVratio) calculated. From the DSC 
MRI perfusion images, maximal relative cerebral blood volume (rCBVmax) values were 
measured by a board-certified neuroradiologist. P-values were obtained using bootstrap or 
permutation tests, and receiver operating characteristic (ROC) analyses and areas under 
curve (AUC) were calculated. 
 
We found that the SUVratio had the highest predictive value (AUC=0.943) for tumor 
progression, although this was not statistically better than any perfusion metric 
(AUC=0.757-0.829). After excluding two patients with hemorrhagic lesions, the AUC of the 
perfusion metrics improved slightly to 0.917-0.938.  
 
This preliminary study found similar accuracy for PET/CT and MRI perfusion in 
distinguishing recurrent tumor from treatment necrosis. MRI perfusion performed better 
when patients with hemorrhagic lesions were excluded. These results have compelled us 
to develop a prospective trial, which will allow us to determine the optimal roles for 
PET/CT and MRI perfusion in the evaluation of patients with worsening enhancing lesions 
after treatment. We plan to perform DCE T1 perfusion instead of DSC T2* perfusion, as 
the DCE technique provides absolute measures of perfusion and permeability and is not 
limited by hemorrhage.  
 
A systemic feature- or texture-based approach has been applied to PET scans in 
gynecological and head and neck cancers. This is similar to increasingly popular 
histogram analyses for other imaging data,30 and has shown promise in treatment 
response analyses using multiparameter predictive models over single metrics such as 
simple SUV descriptive statistics. In a pilot study, correlation between feature-based 
predictive models and outcome improved by 14% in gynecological and 12% in head and 
neck cancers over SUV statistics.31 
 
3.3 Exploratory use in patients treated with anti-angiogenic therapy 
 
Bevacizumab is an anti-angiogenic therapy that is commonly used to treat patients with 
malignant gliomas (usually recurrent) as well as some systemic tumors (e.g., breast). In 
these cases, the use of contrast enhancement to determine response as performed in 
daily clinical practice and as defined by many clinical protocols, is less reliable.32 This is 
because bevacizumab may induce rapid decreases in contrast enhancement at imaging 
not accompanied by actual reductions in tumor. An alternative imaging marker to 
determine tumor progression in these patients is necessary. 
 
Several studies have described decreased perfusion and decreased enhancement after 
anti-angiogenic therapy.33-35 This has been postulated to be due to normalization of the 
blood-brain barrier rather than decreased tumor burden. The exploratory endpoint 
concerns the growing use of anti-angiogenesis therapy (such as bevacizumab) in brain 
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tumor patients. Although direct effects on the vasculature may also affect perfusion, the 
precise effects involved remain poorly understood. The effects upon FDG uptake are 
similarly poorly understood, although the effects on glucose metabolism may be less 
dramatic than the effects on the vasculature. We believe that adding these patients to an 
exploratory endpoint will help us improve our understanding of the imaging effects of anti-
angiogenic therapy and develop better imaging tools to determine tumor progression.   
 
Exploratory Endpoint:  
1. To assess the utility of PET and MRI perfusion studies in predicting tumor progression 
in patients with malignant gliomas receiving anti-angiogenic therapy (such as 
bevacizumab). Due to direct drug effects upon the vasculature, these tumors often 
show little or no enhancement despite clinical worsening and increasing non-
enhancing abnormalities. Therefore, we often cannot rely on changes in size of the 
contrast enhancing mass lesion as usual. The role of advanced imaging in determining 
progression in lesions that do not show increased enhancement has not been defined. 
In an exploratory fashion, we will enroll patients with malignant gliomas receiving anti-
angiogenic therapy with suspected progression and increased nonenhancing lesions. 
Analysis will be similar to that for patients under the Primary Endpoint.  
3.3.1 Exploratory use of advanced diffusion imaging  
Restriction spectrum imaging (RSI) is an advanced diffusion technique that models 
diffusion signal by incorporating tissue parameters such as the size, shape and orientation 
fo water diffusion. RSI offers the ability to separate the diffusion components according to 
the different tissue types, potentially improving tumor margin conspicuity. By maximizing 
the diffusion signal from within tumor cells while minimizing diffusion signal from edema, 
RSI may be useful in evaluating tumor progression and in particular patients treated with 
anti-angiogenic agents such as bevacizumab56. 
3.4 Benefits 
The proposed study will make a significant contribution to our understanding of the optimal 
imaging evaluation of neoplasms treated with brain radiation therapy.  Determining the 
presence of tumor progression can directly impact patient therapy. If the data indicates 
that MRI perfusion and/or PET/CT (alone or in combination) can accurately predict the 
presence of radiation injury or tumor progression, then potential treatment options could 
patient survival. This information will likely also be very useful for neurosurgical planning to 
maximize the timing and resection of lesions that require surgical management. The 
nonsurgical treatments for these two entities are different, as tumors may benefit from 
additional chemotherapy and radiation therapy, whereas radiation injury will be worsened 
by additional radiation therapy and likely not helped by chemotherapy. 
In addition, if the results indicate that MRI perfusion is comparable to or superior to 
PET/CT, several patient and systemic advantages may emerge. First, nearly all patients 
with a history of radiation therapy to the brain undergo MRI scans for surveillance after 
treatment, whereas PET/CT is reserved as a problem-solving tool. Therefore, MRI 
perfusion is more convenient for patients, as it may be obtained at the time of their routine 
MRI scan, and does not require a separate appointment. MRI perfusion requires 5 minutes 
to acquire, but does not require any additional intravenous contrast. The 3D workstation 
charge associated with MRI perfusion is much less than the charges associated with 
PET/CT. In addition, MRI has no radiation risk, in contrast to the very small but present 
risk with PET/CT.  
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By designing this as a prospective study, we will minimize the potential biases and 
variability of a retrospective analysis. Both MRI perfusion and FDG PET/CT scans are part 
of the standard of care for patients with indeterminate lesions after treatment. The purpose 
of this study is to prospectively enroll these patients in order to standardize the scanning 
intervals and formalize the imaging, evaluation and follow up of these patients. What we 
learn may improve our understanding of radiation injury and thus benefit society and future 
brain tumor patients. 
This research project will help develop the career of the P.I., who has published several 
papers in peer-reviewed journals about the advanced MRI technique in evaluating 
malignant gliomas. MRI perfusion is regarded as a very important tool in the diagnosis, 
prognosis and management of brain tumors and treatment complications. Although the 
older T2* technique has been used for >10 years, there is still avid interest and research 
into the optimal imaging parameters, reconstruction algorithms, processing techniques 
and clinical relevance. This is particularly true for the newer T1 perfusion technique 
proposed in this protocol. The P.I. has given invited talks at national meetings and built a 
reputation as an innovative clinical investigator with abundant experience in advanced 
MRI techniques. The P.I. anticipates that the data collected from this project will be an 
essential part of a subsequent R21 quick trial or similar grant to the NIH.  
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1 
Design 
Accrual: In 2011, a total of 825 patients were treated at MSKCC for a brain tumor with 
surgery, radiation therapy (n=286+) and/or chemotherapy (Caisis database, accessed 
3/1/2012). In 2010 and 2011, a total of 86 patients had suspected radiation injury and 
underwent surgical resection of their lesions (outcomes consisted o
-
 The ratio of 
nonsurgical vs. surgical treatment for patients with suspected radiation necrosis at 
MSKCC is estimated at 2-3:1, based on our recent study  on suspected 
pseudoprogression (early radiation injury in high grade glioma patients) and observed 
patterns from imaging studies and multidisciplinary tumor board discussions. Extrapolating 
from the 86 patients with suspected radiation injury and subsequent histopathology, we 
estimate that approximately 258-344 patients over 2 years undergoing brain tumor 
treatment at MSKCC may have a concern of radiation injury. Based on accrual rates for 
similar protocols at MSKCC, and our accrual rate thus far (75 patients over 2 years), the 
estimated accrual for this study is 2-4 patients per month. We plan to enroll approximately 
35 patients per year, for a total of 150 patients over a 4 year period. We will continue to 
 
 
The study will prospectively enroll patients who have increasing size and/or enhancement 
of brain lesion(s) after brain radiation therapy for a neoplasm (either primary or 
metastatic), where it is unclear if a lesion represents radiation injury or progressive tumor. 
The procedures and the minimal risks of MRI perfusion and PET/CT are the same 
regardless of the situation (tumor type or radiation plan) in which they are applied. We 
apply identical processing procedures to analyze the data regardless of the original tumor 
type or radiation therapy regimen, and when applicable apply identical imaging metric 
thresholds. Radiation injury may occur after stereotactic radiosurgery, partial brain 
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radiation, or less commonly after whole brain radiation therapy. The most important factors 
for developing radiation injury are radiation dose, schedule and fractionation. We will for 
the purposes of this protocol assume that the subject population is homogeneous (given a 
common radiation injury mechanism and imaging manifestations) and recruit to a single 
subject cohort.  
In addition to studying all enrolled patients as a single cohort, we will at the end of the 
study examine specific subcohorts as described in the following specific clinical scenarios. 
This will help us to determine if there are any differences in our techniques and 
measurements between groups.  
Specific clinical scenarios when PET/CT and MRI perfusion may be clinically necessary to 
examine indeterminate lesions: 
1) Gliomas after radiation therapy with increased or new enhancing lesions 
 
2) Gliomas after radiation therapy in patients receiving bevacizumab or other anti-
angiogenic chemotherapy with increased or new enhancing and/or non-enhancing lesions 
 
3) Metastases after radiation therapy with increased or new enhancing lesions  
 
4) Metastases after radiation therapy who may be receiving bevacizumab or other anti-
angiogenic chemotherapy for systemic or brain disease 
This is a nonrandomized study in which each patient will receive the standard clinical care 
(in the form of surgery, radiation treatment and/or chemotherapy) as per the treating 
physician(s). Upon enrollment, the patients will undergo both MRI perfusion and PET/CT 
imaging, preferably on the same day to maximize patient convenience and reduce 
potential changes between scans, but at most within 12 weeks of one another. The two 
scans will be performed within 12 weeks after the indeterminate lesion is initially identified 
(unless the screening scan is a DCE MRI perfusion, in which case it will serve as the 
protocol MRI intervention as well). The neuroradiologist reading the MRI and nuclear 
medicine physician reading the P
and existing guidelines in the literature, the nuclear medicine physician and 
neuroradiologist will independently predict the most likely outcome for each lesion: 
radiation injury vs. tumor progression. Only the results of the first MRI perfusion and FDG 
PET/CT will be used for data analysis (some patients may require repeat scans as part of 
their standard of care, as per their treating physician). 
Patient outcome will be determined by a neuro-oncologist using standard histopathologic 
or clinical and imaging follow-up criteria (excluding any subsequent MRI perfusion or FDG 
PET/CT data). Unless the patient requires surgery as part of the standard of care for their 
brain tumor, the diagnosis will be established by follow up. Patients will remain on study 
until the completion of either the MRI perfusion or PET/CT that are within 12 weeks of 
each other. After one of these scans, the patient will have no active interventions and will 
be off study. Follow up will occur approximately every 2-3 months as per the treating 
physician and the standard of care (most gliomas are followed every 2 months, most 
metastases every 3 months). Follow up is expected to take 6 months or less in most 
patients, although some patients with slowly growing or otherwise confusing lesions may 
require longer follow up.  
4.2 
Intervention 
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The MRI perfusion and PET/CT scans will be obtained within 12 weeks of each other. 
These scans are part of the standard of care for patients with brain tumors and uncertain 
tumor response or progression after treatment. Although every effort will be made to 
perform both MRI perfusion and PET/CT on the same day or during the same week, some 
patients may experience longer intervals between scans due to scheduling conflicts. The 
disease in question (radiation injury vs. tumor progression) may change slightly during this 
interval (e.g., the lesion may grow or shrink slightly), but no large changes are expected 
between the two scans. The patients may continue existing treatments in the interval 
between scans (e.g., steroids, chemotherapy), but the two scans must be performed 
before any change or new treatment occurs.  Fusion images of MRI and PET/CT will not 
be reviewed by the neuroradiologist interpreting the MRI perfusion nor the nuclear 
medicine radiologist interpreting the PET/CT.  
4.2.1 MRI perfusion:  
Dynamic contrast enhanced (DCE) T1 perfusion will be performed per standard of care 
using (1) an axial 3D spoiled gradient-recalled acquisition in the steady state (SPGR) 
sequence with these or similar parameters: TR/TE=8.3/1.5; flip angle 25°; matrix 
256x128x128; slice thickness 5 mm; field-of-view 24 cm; acquisition time 10 seconds 
per volume of 12-18 slices; acquired 40 times, once before and 39 times immediately 
after intravenous bolus administration of a single dose of contrast material; - or - (2) an 
axial 3D differential subsampling with Cartesian ordering (DISCO) sequence with these 
or similar parameters: TR/TE=4.5/1.8; matrix 288x160; slice thickness 4 mm; field-of-
view 24 cm; acquisition time 10 seconds per volume of 35-40 slices; acquired 40 times, 
once before and 39 times immediately after intravenous bolus administration of a single 
dose of contrast material. Both sequences will require approximately 5 minutes of 
scanning time. SPGR MRI perfusion does not allow whole brain coverage due the 
dynamic nature of the contrast injection. If multiple lesions exist, then the lesion(s) of 
clinical concern (e.g., the lesion(s) that is growing) or the largest lesion(s) will be 
interrogated and as many other lesions as possible will be included in the perfusion 
volume. Although patients commonly receive treatment for multiple lesions, in our 
experience most (>90%) patients only have growth of one lesion whereas the other 
lesions remain stable. Only existing previously irradiated lesions at the time of 
enrollment will be considered target lesions for this study. The DISCO sequence is the 
updated, FDA approved sequence from GE Healthcare that is capable of whole brain 
coverage. DISCO has been adopted as the standard of care for MRI perfusion, where 
available on selected MRI scanners. Patients will receive DISCO perfusion if it is available, 
or the standard SPGR perfusion.  
The data will be transferred to an off-line workstation running Windows platform for 
analysis using commercially available or research perfusion software packages, such 
as: NordicICE by NordicNeuroLab, which is a commercially available, FDA approved 
product. The software package performs pharmacokinetic modeling to analyze DCE T1 
perfusion data.  
The methods of analysis will include: region-of-interest (ROI) measurements of the 
lesion and normal brain will be performed. ROIs will be placed in the lesion while 
avoiding areas of hemorrhage, calcification, and cystic/necrotic change. This is the 
standard way of measuring lesions in clinical practice. Multiple small ROIs will be 
placed, and the maximum recorded, a technique that has been described as providing 
the best reproducibility.37, 38 Recorded metrics will include: plasma volume (Vp) and 
volume transfer coefficient between plasma and extravascular extracellular space 
(Ktrans). We may also use volume of interest (VOI) measurements of the entire lesion.  
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Additional postprocessing: Feature-based analyses will be performed on an 
investigational basis. These are not routinely performed as part of the standard of care, 
and therefore the results will be only for research and not included in the MRI report. 
The DCE maps will be processed using in-house routines developed in C++ and Matlab 
for extracting image-based textures and Gabor edge features to characterize each 
lesion in terms of topological and textural factors. In-house developed machine learning 
techniques may be applied to automatically find correlations between image features 
and lesion outcomes. 
4.2.2. PET/CT:  Patients will fast except for water ± medications (as per their clinical 
physician) for at least 6 hrs prior to this study.  The patient is seated comfortably in the 
injection room and venous access is established.  The patency of the venous access is 
checked with normal saline prior to the administration of the FDG.  
Blood glucose is checked by finger stick.  If blood glucose is >60 and <200mg/dL the 
study continues as planned.  If the blood sugar is between 200 and 300mg/dL, then a 
standard insulin administration protocol is used to bring the blood glucose below 200.  If 
blood glucose is > 300mg/dL, the study is rescheduled.  If the blood glucose is <60, juice 
is given orally and the study is rescheduled. 
10 mCi of Fluorine-18 fluorodeoxyglucose (FDG) is injected IV.  The patient remains 
seated quietly in the injection room for 60 minutes. The patient is then positioned on a GE 
Discovery STE PET/CT.  A scout view of the head is acquired at 30 mA, 120 kVp.  Once 
the scanning field is determined from the scout, a spiral CT is acquired using a full helical 
acquisition at 1 sec/rotation, 30 mA, 140 kV, 5.0 mm slice thickness, 4.5 mm interval.  
Immediately upon completion of the CT, acquisition of a 10-minute 3D brain PET scan is 
performed.  CT and PET data are re-reconstructed using a 30 cm FOV.  CT, PET, and 
hybrid images are evaluated in transaxial, coronal, and sagittal planes. The standardized 
uptake value (SUV) of the lesion (SUVlesion), normal brain (SUVnormal) and SUVratio 
(SUVlesion/SUVnormal) will be calculated using standard ROI tools. PET/CT allows whole 
brain coverage. Measurements of each lesion will be performed and each lesion 
evaluated independently for radiation injury vs. tumor progression.  
Additional postprocessing: Feature-based analyses will be performed on an 
investigational basis. These are not routinely performed as part of the standard of care, 
and therefore the results will be only for research and not included in the PET report (as 
compared to SUV, which are standard of care and reported to the clinician). The PET 
scans will be processed using CERR (Computational Environment for Radiotherapy 
Research) and/or in-house routines developed in C++ and Matlab for extracting image-
based textures and Gabor edge features to characterize each lesion in terms of 
topological and textural factors. In-house developed machine learning techniques may 
be applied to automatically find correlations between image features and lesion 
outcomes. We may also investigate novel analysis methods in addition to SUV by using 
other correction factors for normal tissue selection and ratio calculations. 
4.2.3 Advanced diffusion imaging (Optional): RSI acquisition will require 
approximately 4-5 min, similar to the time required for the standard of care DTI 
acquisition. The only thing noticeable by the patient will be the extra scan time required 
to acquire DSI. The patient will be requested to remain motionless during this scan.  
RSI will be acquired using a single-shot gradient spin-echo echo-planar sequence with 
these or similar parameters: 6-15 directions, TR=96 msec, TE=17 msec, matrix 
128x128, slice thickness 3 mm, b-values 0-4000 s/mm2. Total of 40-45 direct axial 
slices with no interslice gap will be obtained to cover the entire brain. The sequence will 
require 4-5 min.  
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Post-processing will be performed using software that will be provided to MSKCC by 
GE Global Research. The acquired data will be analyzed on an offline workstation, after 
the RSI data have been acquired and after the patient has left the MRI suite.  
At the discretion of PI the RSI sequence may be repeated at SOC FDG or other 
radiotracer imaging carried out while the patient is still on study, if deemed clinically 
necessary.  
5.0 
CRITERIA FOR SUBJECT ELIGIBILITY. 
5.1 
Subject Inclusion Criteria 
 Pathological or clinical/radiological diagnosis of a neoplasm, either primary (e.g., 
malignant glioma) or secondary (metastasis from systemic malignancy) with a history of 
brain radiation therapy 
 Completed fractionated radiation therapy (to 60 Gy for high grade gliomas) or 
stereotactic radiosurgery or hypofractionated radiation therapy (e.g. for brain 
metastases, anaplastic meningiomas), without or with concurrent chemotherapy 
 New or increased enhancing brain lesion(s) OR nonenhancing brain lesion(s) if 
receiving anti-angiogenic therapy, which is considered indeterminate for tumor 
progression vs. radiation injury by the neuroradiologist or clinician 
 Patient and/or guardian is able to provide written informed consent prior to study 
registration 
 Age 18 years old 
 
5.2 
Subject Exclusion Criteria 
 Claustrophobia 
 Known allergic reaction to Gd-DTPA 
 Any contraindication to gadolinium intravenous contrast as per standard Department of 
Radiology contrast guidelines  
 Any contraindication to MRI (e.g., pacemaker, aneurysm clip, tissue expander). 
 Pregnant or nursing female 
 Unable to cooperate for MRI and/or PET/CT 
 
 
6.0 
RECRUITMENT PLAN 
Patients for this study will be referred by members from the Departments of Radiation 
Oncology and Neurology. Patients will typically have a CT or MRI scan showing an 
18 years are eligible for participation 
regardless of sex or race. Every effort will be made to encourage eligible women and 
minorities to enroll in this study. Prior to study entry, the study staff will explain to each 
potential subject the research objectives, risks and benefits of study participation, 
agrees to participate in the study, informed consent will be obtained by a consenting 
individual on the study. All patients must sign written informed consent prior to being 
registered on this protocol.  
 
7.0 
ASSESSMENT/EVALUATION PLAN 
7.1 Imaging evaluation 
 
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The maximal abnormalities on the MRI perfusion scans and PET/CT scans will be 
recorded according to standard ROI and volume of interest (VOI) measurements:  
 
FDG PET/CT:  
1. SUVlesion (SUV=standardized uptake value) 
2. SUVnormal 
3. SUVratio = SUVlesion/SUVnormal 
4. PET texture factors: contrast, homogeneity, entropy, skewness, kurtosis 
5. PET topological factors: eccentricity, solidity, and extent 
 
 
(SUV=standardized uptake value) 
 
MRI Perfusion:  
1. VP (plasma volume) 
2. Ktrans (volume transfer coefficient between plasma and extravascular extracellular 
space) 
 
RSI Diffusion: 
1. RSI Celluarity  
 
Either PET/CT or MRI perfusion may be performed first, but both studies should be 
completed within 12 weeks of each other. The PET/CT will be interpreted by a study 
nuclear medicine radiologist while blinded to the MRI perfusion results. The MRI 
perfusion will be interpreted by a study neuroradiologist while blinded to the PET/CT 
results. Each MRI perfusion metric and each FDG PET/CT metric will be independently 
tested to predict the diagnosis of radiation injury vs. tumor progression. In addition to 
independently testing the utility of MRI perfusion and PET/CT in determining radiation 
injury, we will also examine if combining both techniques will perform better than either 
one alone.  
 
The protocol proposes using the current standard of practice for diagnosing radiation 
injury vs. worsening tumor, in terms of histopathology (when available) or clinical and 
radiological follow up. We will also perform a subcohort analysis to determine if there is 
any difference between patients diagnosed by histopathology (anticipated at 
approximately 15-25%) vs. patients diagnosed by follow up.  
 
Clinical and radiological follow up constitute the current standard of practice when 
histopathology is not available, either due to lesion location (e.g., deep in brain, in 
brainstem, or in eloquent motor or language areas) or due to patient comorbidities. The 
table below summarizes several recent papers from the Radiology and Neuro-oncology 
literature examining the issue of radiation injury. Of the seven cited papers, only one 
included only pathology proven patients. The other six papers used follow up for diagnosis 
in 26.7-92.6% of all patients. Our previous paper36 was near the middle of this range, with 
follow up implemented in 69.9% and using a 6 month minimum follow up time. Although 
there is no clearly defined clinical and radiological criteria to determine radiation injury, the 
6 month minimum follow up approach is more conservative than the 3 months minimum 
follow up time used by other authors.20, 47, 48  
 
 
Table. Representative imaging papers studying radiation injury.  
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7.2 Histopathologic Diagnosis  
 
The diagnosis of radiation injury versus tumor progression will be made using 
histopathologic findings if resection is determined to be clinically necessary by the treating 
physician. If pathology indicates a mixed population of tumor cells and treatment effects, 
then the predominant cell population will be used to determine the patient outcome. If the 
diagnosis remains unclear based on pathology, then the lesion will be placed in a third 
category of uncertain, and excluded from statistical analysis. Based on the retrospective 
results presented in Section 3.2, we anticipate 15-25% (n=13-21) of the patients will 
undergo surgical resection or biopsy of their increasing lesions.  
 
Based on clinical experience, we anticipate that <10% of these 13-21 patients will have 
indeterminate pathology results. Resection of the indeterminate lesion in itself may have 
therapeutic value for both radiation injury and tumor progression. Therefore, we not 
anticipate that we will be able to use clinical and radiological follow up for these patients 
with uncertain diagnosis after indeterminate pathology. 
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7.3 Clinical and Radiological Diagnosis 
 
If tissue sampling is clinically not warranted, then the lesion outcome will be determined 
after clinical and imaging follow up by the neuro-oncologist and/or radiation oncologist, 
while blinded to the MRI perfusion and PET/CT results. The accuracy of these non-
pathologic diagnoses is expected to be maximized by the follow up process, in which 
determinations may be made up to 6 months (or more) after presentation of the lesion(s). 
In many cases, following lesions to determine their natural history is expected to provide 
the best characterization of the underlying biology. These assessments to determine 
lesion(s) outcome will be performed approximately every 2 months during the study.  
Blinding will be performed by a third party (e.g., research study assistant). The results of 
both MRI perfusion and PET/CT are available in the electronic medical record as 
individual Radiology reports, and may be mentioned in the clinical notes of the treating 
physician. The chart records and official radiology reports will be saved and/or printed with 
redaction of these results, by deleting and/or blacking-out the relevant sentences. The 
MRI perfusion images and without the PET/CT images. Only the regular MRI images 
would be reviewed to examine changes in size of the lesion(s).  
We will adopt the updated response criteria proposed by the Response Assessment in 
Neuro-Oncology Working Group52 shown in the table, with some modifications as below.  
 
 
 
Specifically, to be classified as radiation injury, the lesion must spontaneously stabilize 
(stable disease) or decrease (partial response or complete response) on subsequent 
scans over a minimum of 6 months without new chemotherapy. Lesions that continue to 
increase (fulfilling criteria for progressive disease) will be considered tumor. If the lesion is 
stable for <6 months and therefore does not meet above criteria for radiation injury, it will 
be placed in a third category of uncertain and may be excluded from statistical analysis, 
unless additional follow up beyond the 6 months shows stability (radiation injury) or 
enlargement (worsening tumor). Therefore, the designation of uncertain may be only 
temporary, as we will continue to follow the lesion and the patient whenever possible. If a 
lesion has an uncertain diagnosis despite continued follow up at the end of the study, it will 
also be placed in the uncertain category and may be excluded from statistical analysis.  
 
Patients with metastatic disease who have enhancing lesions and receive chemotherapy 
for systemic disease may be determined to have radiation necrosis if: 1) the systemic 
chemotherapy does not change during the 6 month follow up period to establish radiation 
necrosis; and 2) the systemic chemotherapy has no known efficacy for CNS disease. If the 
lesion diagnosis is uncertain after follow up for reason, including interval changes in 
systemic chemotherapy or additional radiation therapy for new lesions (unrelated to the 
initially treated lesion that is being followed) as per their treating physician and the 
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standard of care, then the treated lesion will be placed in the third category of uncertain
and excluded from statistical analysis.  
 
7.4 Multiple lesions 
 
If a patient has multiple lesions, only the enlarging or otherwise worrisome lesion(s) will be 
evaluated. MRI perfusion (that has incomplete brain coverage) will be performed through 
this dominant lesion and as many of the other lesions of interest as feasible. Only a 
minority of patients are expected to have multiple lesions of concern, as supported by 
published papers summarized in the Table shown in Section 7.1.     
 
Patients may get a variety of radiation therapy doses. Sometimes patients receive whole 
brain radiation therapy followed by a boost or stereotactic radiosurgery to one dominant 
lesion or postoperative cavity. Therefore, we cannot assume that all lesions in a single 
patient will behave in a similar fashion and represent a single process. In patients with 
multiple irradiated lesions, usually the lesions respond in unison (ideally, they all decrease 
in size and indicate a positive treatment response). Sometimes, one or two or more 
lesions may increase in size and become concerning for radiation injury vs. tumor 
progression. This presents several possible scenarios in a single patient: one or more 
lesions may be due to radiation injury and the others due to worsening tumor; or they are 
all due to radiation injury; or they are all due to worsening tumor. Although clinically a 
bottom line result may be concluded as progression vs. no progression, for the purpose of 
possibly initiating systemic chemotherapy or whole brain radiation therapy, this 
oversimplifies a problem in which each lesion represents an unknown that is not 
necessarily related to the other. If there are only two lesions, and they both increase, it is 
possible that they represent the same or different process. The outcome for multiple 
lesions within a single patient may be dependent and statistical analyses based on 
dependent samples will be employed. There is no plan to aggregate imaging metrics of 
multiple lesions into a single metric for an entire patient. 
 
If several lesions all increase in size, then that would suggest treatment failure and tumor 
progression (especially if new lesions also appear). This patient would not be enrolled into 
this protocol because there is no or little doubt about the diagnosis of the worsening 
lesion(s). Note that patients with >3 lesions from metastatic disease usually receive whole 
brain radiation therapy, which is less likely to cause radiation injury than the higher dose 
partial brain and stereotactic radiosurgery techniques. 
The potential problem of multiple lesions will be avoided with the new DISCO sequence.  
 
8.0 
TOXICITIES/SIDE EFFECTS 
PET/CT of the Brain:  FDG PET/CT is a routine medical imaging procedure proven to be 
safe and noninvasive.  Risks and side effects related to the IV catheter may include 
discomforting pain at the site of injection, bleeding, and bruising.   
Radiation safety:  The whole body dose from 370MBq (10 mCi) of FDG is 0.43rem 
(4.3mSv).  A low milliampere CT scan of the brain, done as part of the hybrid FDG 
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PET/CT, has a dose of 0.2 rem (2.0 mSv).  The total dose from the FDG PET/CT 
examination is 0.63 rem (6.3 mSv), which is well below the annual radiation dose limit of 
50 mSv, and within typical doses for imaging cancer patients. Pregnant and/or breast-
feeding women will not be included in this study. 
 
MRI of the Brain: MRI is a proven safe and noninvasive technique that entails no radiation 
risk. MRI involves magnetic and radiofrequency energy. Therefore, subjects who have 
implanted metal devices, such as pacemakers, certain aneurysm clips, or shrapnel or 
metal in the eye are at risk, and will not be scanned. There are no known risks or adverse 
effects resulting directly from exposure to magnetic fields and radiofrequency energy used 
in this study.   
Some people feel claustrophobic in the MRI scanner. If the subject is unable to tolerate 
being in the scanner, the technologist can stop the scan immediately at any time. Other 
rare risks of MRI include neurostimulation effects, such as muscle twitches and tingling 
sensations, due to the rapid switching of magnetic fields, and a slight increase in body 
temperature that may occur in the presence of radio frequency energy. These are very 
unlikely under current operational guidelines.  
 
Risks and side effects related to the IV catheter are similar to those for PET/CT, and may 
include discomforting pain at the site of injection, bleeding, and bruising.  Gd-DTPA is a 
very safe IV contrast agent, with severe adverse reactions reported in 1/350,000-450,000 
cases and death in 1/10,000,000 cases. More common side effects such as headaches, 
hives, nausea/vomiting usually quickly and spontaneously resolve. Medications and 
intravenous fluids may be given at the discretion of the radiologist if necessary to treat 
these symptoms. Severe anaphylactic reactions are extremely rare; if this should occur, 
institution wide protocols for treating contrast reactions, supporting the airway and 
cardiovascular system would be implemented. Nephrogenic systemic fibrosis (NSF) is a 
rare, fatal disease in patients with severe renal failure requiring prolonged hemodialysis 
that receive multiple doses of gadolinium. NSF is thought to reflect a cumulative, toxic 
effect of gadolinium in these patients with severe renal failure. We will conservatively 
exclude patients with known renal failure defined as serum creatinine >2.0 from this study. 
Only the standard dose of gadolinium contrast (0.1 mmol/kg) is given for each MRI  this 
represents the dose that the patient would have received even if he or she had not 
participated in this study. In other words, no additional Gd-DTPA is necessary to perform 
the proposed MRI perfusion sequence. The MRI perfusion sequence is FDA approved and 
readily available on all commercial MRI machines. The patient will need to stay in the 
scanner for approximately 5 extra minutes to acquire the perfusion sequence.  
The patient will be allowed to withdraw from the study if desired. If only PET or MRI 
perfusion is acquired, the data may be used for subanalysis of the acquired technique. If 
no PET or MRI perfusion sequence is acquired, then the patient will be removed from the 
study as described under Section 10 (Criteria for removal from study, Refusal of patient to 
continue treatment and/or observations). In this situation, efforts will be made to accrue an 
additional patient. 
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9.0 
PRIMARY OUTCOMES 
We will use the PET/CT and MRI perfusion to independently predict whether or not an 
increased enhancing lesion represents radiation injury or tumor progression. The 
diagnosis will be established by a neuro-oncologist and/or a radiation oncologist according 
to pathology results if available, or by clinical and radiological follow up after a minimum of 
6 months. If diagnosis is rendered by follow up, then the clinician will review available 
chart records and imaging studies after blinding of the PET/CT and MRI perfusion results 
by a third party (e.g., research assistant). Based on clinical practice, we anticipate that 
approximately 18 patients will undergo repeat surgery and have pathological evidence of 
the diagnosis.  
 
10.0 CRITERIA FOR REMOVAL FROM STUDY 
1. Inability to undergo MRI (e.g., pacemaker, claustrophobia) or PET/CT scan  
2. Found to be ineligible for the protocol as described in the section on Criteria for 
Patient/Subject Eligibility 
3. Patient and/or guardian requests to withdraw from study for any reason  
4. Referring physician requests to withdraw from study for any reason, including believing 
 
5. Refusal of patient to continue treatment and/or observations 
6. Loss to follow-up 
7. Patient death, unless an autopsy is performed to render a diagnosis of the 
indeterminate brain lesion 
 
11.0 
BIOSTATISTICS 
The purpose of this nonrandomized study is to test the predictive value of PET/CT and 
MRI perfusion in distinguishing radiation injury from tumor progression.  
 
11.1 Entire cohort analyses 
Despite the heterogeneity of potential tumor types, radiation injury has a common 
mechanism in all patients: blood brain barrier disruption, inflammation, gadolinium contrast 
leakage into the interstitial space, and enhancement. In most clinical scenarios, we expect 
lower MRI perfusion and lower FDG PET/CT measurements for radiation injury regardless 
of the original tumor type. When considering the target accrual of 150 patients with 
indeterminate lesions, we anticipate that tumor progression will occur more commonly 
(approximately 90 patients) than radiation injury (approximately 42 patients) or uncertain 
diagnoses (approximately 8 patients). We anticipate that only 20-30% (28-42 patients) will 
require the entire 6 month follow up period to establish their diagnosis. Some patients may 
require >6 months and be followed up to 1 year to establish their diagnosis. Loss to follow 
up or death prior to determining a definitive diagnosis is expected to be uncommon (<5 
patients). Unless an autopsy is performed to render a diagnosis for the brain lesion, death 
will be a criterion for removal from the study as described in Section 10. 
We will perform one-sided two-sample t-tests (because previous analysis showed that 
MRI perfusion measurements are reasonably symmetric, have a small range and are 
usually lower in radiation injury than in tumor progression). To approximately assess the 
power of the analysis, we focus on the one-sided two sample t-test with the type I error 
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(claiming a difference while there is not) rate of 5%. With 150 patients over 2 years and 
assuming the effect size is 0.5 (meaning that the difference is half of the pooled standard 
deviation), type II error (failure to detect a difference that actually exists) rate is about  
10%. If the effect size is 0.7, the type II error rate is about 1%. Here we used generic 
mean/standard deviation ratios because multiple measurements will be examined.  
An interim analysis is also planned at  half of the expected total. An 
-Fleming 
boundary will be used to ensure the type I error rate is not inflated. Specifically, this 
requires the p-value must be <0.0088 at the interim analysis to stop the trial early and 
declare statistical significance and <0.0467 at the final analysis to declare statistical 
significance. Moreover, if the interim analysis p-value is >0.50 then we will stop the trial 
and declare futility. Under null hypothesis (that tumor and necrosis cannot be differentiated 
by the new imaging method) the early stopping probability is 0.5 for declaring futility and is 
0.0088 for declaring significance. Under the alternative hypothesis with the effect size of 
0.7, the early stopping probability is 0.002 for declaring futility and is 0.69 for declaring 
significance.  
To quantify predictive power of the MRI perfusion package, receiver operating 
characteristic (ROC) analyses will be used. 
For the analysis of PET/CT, similar approaches will be used. To compare the predictive 
power of various MRI perfusion measurements and PET/CT measurements, ROC curves 
will be drawn, and the area under the curve (AUC) will be computed and compared among 
MRI perfusion and PET/CT measurements. Bootstrap confidence intervals will be 
constructed to establish confidence levels and the difference between the two AUCs will 
be calculated and examined whether it is significantly different from 0. Due to the multiple 
comparisons needed, a false discovery rate (FDR) approach will be employed to control 
for the family-wise error rate. The positive FDR approach will yield new quantities called q-
values for making statistical inferences.53, 54 The purpose of implementing an FDR 
approach is to adjust the p-values from multiple tests (due to multiple MRI perfusion and 
PET/CT parameters to be examined).  
For the exploratory objective to examine increasing non-enhancing masses, similar 
analyses will be done. We estimate 5-10 patients with recurrent tumors may receive anti-
angiogenic therapy. If the numbers are small, we will summarize the results descriptively 
and suggest future research directions. If the numbers are sufficient, we will perform 
similar sensitivity, specificity, ROC and AUC analyses.  
To further consider the variation among radiation doses, fractionations and schedules 
(which may be employed as per the standard of care for the specific tumor type in each 
patient), a more complicated ANCOVA (analysis of variance with covariates) will be used 
with the above parameters specified as covariates. If the numbers are small, we will 
summarize the results descriptively and suggest future research directions. We estimate 
that 15-25% (21-35 patients of the total) will undergo repeat surgical resection or biopsy to 
determine the diagnosis. A separate subset analysis will examine for potential differences 
between lesions diagnosed by pathology vs. lesions diagnosed by clinical and radiological 
follow up.  
 
Most of the time, the two imaging methods (i.e., MRI perfusion and PET/CT) are expected 
to yield concordant results (>80%). Therefore, it is meaningful to compare the predictive 
power of various MRI perfusion measurements and PET/CT measurements. Due to the 
multiple comparisons needed, an FDR approach will be employed to control for the family-
wise error rate. We may further construct a decision rule by combining results from both 
techniques in the hope of identifying an even more powerful predictive tool, although its 
feasibility would depend on the exact number of discordant cases and the individual 
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predictive power (if both MRI perfusion and PET/CT have sufficient predictive power and 
there are too few discordant cases then the combination may not show significant 
improvement).  
As mentioned above, an interim analysis will be performed after 1 year or accrual of 48 
(1/2 of expected total) subjects. Statistical tools may be adjusted at that time point if 
necessary to account for higher or lower than expected accruals within subgroups. For 
example, if many more than expected patients have uncertain outcomes or death before 
diagnosis (without autopsy), then we will may increase the target accrual to compensate.  
11.2 Subcohort analyses 
 
The patients will also be grouped according to the following clinical scenarios: 
 
1) Gliomas after radiation therapy with increased or new enhancing lesions 
 
2) Gliomas after radiation therapy in patients receiving bevacizumab or other anti-
angiogenic chemotherapy with increased or new enhancing and/or non-enhancing lesions 
 
3) Metastases after radiation therapy with increased or new enhancing lesions  
 
4) Metastases after radiation therapy who may be receiving bevacizumab or other anti-
angiogenic chemotherapy for systemic or brain disease 
Although we anticipate similar changes in MRI perfusion and PET/CT for radiation injury 
(smaller values) vs. tumor (larger values) regardless of the clinical scenario, it is possible 
for different results to occur in gliomas vs. metastases, or initially treated vs. recurrent 
disease. Each scenario encompasses similar tumor types that are expected to receive 
similar standardized radiation therapy plans (in terms of dose, fractionation and schedule). 
For each subcohort of patients, we will determine the efficacy of MRI perfusion and 
PET/CT in predicting radiation injury vs. tumor progression in an exploratory fashion.  
11.3 Multiple lesions 
Cluster analysis will be performed to take into account the correlation among lesions from 
the same patient. For this generalized estimating equation (GEE) techniques will be used 
to estimate regression parameters. Moreover, subcohort regression analysis will be 
performed after the whole set analysis is done in order to preliminarily explore possible 
heterogeneity among the subcohorts. We acknowledge that the small subset sample sizes 
may not allow us to reach statistical significance, and thus nonsignificant results would not 
necessarily prove homogeneity, in which case we will report the summary statistics and 
point out future research directions. 
11.4 RSI Cellularity 
RSI cellularity indices will be measured. Similar t-tests and ROC analysis will be 
performed. If insufficient data is acquired for this exploratory aim, only summary statistics 
will be provided with suggestions for future study. 
12.0 
 RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
12.1 
Research Participant Registration 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. Obtain 
informed consent, by following procedures defined in section entitled Informed Consent 
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Procedures. During the registration process registering individuals will be required to 
complete a protocol specific Eligibility Checklist. The individual signing the Eligibility 
Checklist is confirming whether or not the participant is eligible to enroll in the study. Study 
staff are responsible for ensuring that all institutional requirements necessary to enroll a 
participant to the study have been completed. See related Clinical Research Policy and 
Procedure #401 (Protocol Participant Registration).  
12.2 
Randomization 
No randomization will occur in this study. 
13.0 
DATA MANAGEMENT ISSUES 
A Research Study Assistant (RSA) will be assigned to the study.  The responsibilities of 
the RSA include project compliance, data collection, abstraction and entry, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordinate the activities of 
the protocol study team.   
 
The data collected for this study will be entered into a secure database.  Source 
documentation will be available to support the computerized patient record. 
 13.1 Quality Assurance 
Weekly registration reports will be generated to monitor patient accruals and 
completeness of registration data.  Routine data quality reports will be generated to 
assess missing data and inconsistencies.  Accrual rates and extent and accuracy of 
evaluations and follow-up will be monitored periodically throughout the study period and 
potential problems will be brought to the attention of the study team for discussion and 
action. 
 
Random-sample data quality and protocol compliance audits will be conducted by the 
study team, at a minimum of  two times per year, more frequently if indicated. 
 
13.2 
Data and Safety Monitoring 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001.  The plans address 
   
http://www.cancer.gov/clinicaltrials/conducting/dsm-guidelines/page1.    
 
The DSM Plans at MSKCC were established and are monitored by the Office of Clinical 
Research.  The MSKCC Data and Safety Monitoring Plans can be found on the MSKCC 
Intranet at:  
 
http://inside2/clinresearch/Documents/MSKCC%20Data%20and%20Safety%20Monitorin
g%20Plans.pdf 
 
There are several different mechanisms by which clinical trials are monitored for data, 
safety and quality.  There are institutional processes in place for quality assurance (e.g., 
protocol monitoring, compliance and data verification audits, therapeutic response, and 
staff education on clinical research QA) and departmental procedures for quality 
control, plus there are two institutional committees that are responsible for monitoring the 
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activities of our clinical trials programs. The committees: Data and Safety Monitoring 
Committee (DSMC) for Phase I and II clinical trials, and the Data and Safety Monitoring 
Board (DSMB) for Phase III clinical trials, report 
Institutional Review Board.   
  
During the protocol development and review process, each protocol will be assessed for 
its level of risk and degree of monitoring required.  Every type of protocol (e.g., NIH 
sponsored, in-house sponsored, industrial sponsored, NCI cooperative group, etc.) Will be 
addressed and the monitoring procedures will be established at the time of protocol 
activation. 
14.0 
PROTECTION OF HUMAN SUBJECTS 
Risks: There are no expected additional risks to the patients who participate in this study. 
Patients will receive the current standard of care for their disease. MRI and PET/CT are 
considered minimal risk procedures. MRI and PET/CT are standard diagnostic tests 
utilized in the diagnosis and management of patients with brain tumors. No additional risk 
will be incurred from magnetic and/or radiofrequency exposure to acquire the FDA 
approved MRI perfusion sequence. Patients may experience pain and/or discomfort 
related to the IV catheter, but they would commonly require IV contrast for their routine 
scan anyway.  
 
Costs: The patient and/or patie
part of the standard of care. No financial reimbursement or other financial incentive will be 
provided for patients to enroll in this study.  
 
Benefits: We do not expect patients to derive any clinical benefit from this clinical trial. We 
hope that in the future, knowledge from this trial will help better evaluate treatment 
response in subsequent patients with brain tumors.  
 
All patients will sign informed consents and have all their questions fully addressed before 
enrolling in this study. During the informed consent process, it will be made clear to the 
potential patient that participation is entirely voluntary, and will not impact the care that 
they receive at MSKCC. Potential patients will be advised of alternatives to the proposed 
study, including not participating in the study. All the data will be held confidential, 
maintained in a password protected electronic database, and comply with all HIPAA 
guidelines.  
 
14.1 
Privacy 
ffice may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure 
of protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
 
14.2 
Serious Adverse Event (SAE) Reporting 
An adverse event is considered serious if it results in ANY of the following outcomes: 
 
Memorial Sloan Kettering Cancer Center
IRB Number: 12-067 A(25)
Approval date: 02-Feb-2023

 
Page 24 of 29 
-threatening adverse event
existing hospitalization 
conduct normal life functions 
 
or require hospitalization may be considered serious when, based upon medical 
judgment, they may jeopardize the patient or participant and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
SAE reporting is required as soon as the participant starts investigational 
treatment/intervention. SAE reporting is required for 30-
investigational treatment/intervention. Any event that occur after the 30-day period that is 
unexpected and at least possibly related to protocol treatment must be reported. 
Please note: Any SAE that occurs prior to the start of investigational treatment/intervention 
and is related to a screening test or procedure (i.e., a screening biopsy) must be reported. 
All SAEs must be submitted in PIMS. If an SAE requires submission to the HRPP office 
per IRB SOP RR-
submitted within 5 calendar days of the event. All other SAEs must be submitted within 30 
calendar days of the event. 
The report should contain the following information: 
 
 
 
 
 
des the following 
o An explanation of how the AE was handled 
 
o Indication if the participant remains on the study 
 
Memorial Sloan Kettering Cancer Center
IRB Number: 12-067 A(25)
Approval date: 02-Feb-2023

 
Page 25 of 29 
nanticipated Problem
For IND/IDE protocols: The SAE report should be completed as per above instructions. If 
appropriate, the report will be forwarded to the FDA by the IND Office 
15.0 
INFORMED CONSENT PROCEDURES 
Before protocol-specified procedures are carried out, consenting professionals will explain 
full details of the protocol and study procedures as well as the risks involved to 
participants prior to their inclusion in the study. Participants will also be informed that they 
are free to withdraw from the study at any time. All participants must sign an IRB/PB-
approved consent form indicating their consent to participate. This consent form meets the 
requirements of the Code of Federal Regulations and the Institutional Review 
Board/Privacy Board of this Center. The consent form will include the following:  
1. The nature and objectives, potential risks and benefits of the intended study.  
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of 
supportive care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and 
to withdraw from participation at any time.  
Before any protocol-specific procedures can be carried out, the consenting professional 
will fully explain the aspects of patient privacy concerning research specific information.  In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant 
must receive a copy of the signed informed consent form. 
 
16.0 
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17.0 
APPENDICES 
 
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IRB Number: 12-067 A(25)
Approval date: 02-Feb-2023

 
Page 29 of 29 
Definition of feature-based analysis descriptors.
Texture55: 
 
 Contrast is a statistical measure of the range of intensity over an input image, 
calculated as the distance moment of the image matrix. 
 Homeogeneity is a statistical measure of point-to-point variability within an input 
image, calculated as the angular second-moment of the image matrix. 
 Entropy is a statistical measure of randomness that can be used to characterize 
the texture of the input image. 
 Skewness is a measure of the asymmetry of the data around the sample mean. If 
skewness is negative, the data are spread out more to the left of the mean than to the 
right. If skewness is positive, the data are spread out more to the right. The skewness of 
the normal distribution (or any perfectly symmetric distribution) is zero. 
 Kurtosis is a measure of how outlier-prone a distribution is. The kurtosis of the 
normal distribution is 3. Distributions that are more outlier-prone than the normal 
distribution have kurtosis greater than 3; distributions that are less outlier-prone have 
kurtosis less than 3.  
  
Shape31: 
 
 Eccentricity is a measure of non-circularity defined in terms of the ratio of the minor 
axis to the major axis of the best-fitted ellipsoid to the defined structure of interest. 
 Solidity is a measurement of convexity and is defined as the proportion of pixels in 
the convex hull that are also in the region. The convex hull is defined as the smallest 
convex polygon that can contain the region.Extent is similar to solidity except that it 
represents the proportion of pixels in the bounding box that are also in the region. The 
bounding box is defined as the smallest rectangle containing the region. 
Memorial Sloan Kettering Cancer Center
IRB Number: 12-067 A(25)
Approval date: 02-Feb-2023