MRI and PET/FMISO In Assessing Tumor Hypoxia in Patients With Newly Diagnosed Glioblastoma Multiforme

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00902577
• Collaborator: (none)
• Enrollment: 50
• Locations: 14
• Arm: 1
• Actual Duration (Months): 101.3
• Patients Per Site: 3.6
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This phase II trial is studying how well positron emission tomography (PET) scan using 18F-fluoromisonidazole works when given together with magnetic resonance imaging (MRI) ) in assessing tumor hypoxia in patients with newly diagnosed glioblastoma multiforme (GBM). Diagnostic procedures, such as MRI and PET scan using 18F-fluoromisonidazole (FMISO), may help predict the response of the tumor to the treatment and allow doctors to plan better treatment.

Condition or Disease	Intervention/Treatment	Phase
Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma	Drug: FMISO; Other: MRI; Other: PET; Other: MRS	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To determine the association of baseline FMISO PET uptake (hypoxic volume [HV]), highest tumor:blood ratio [T/Bmax]) and MRI parameters (Ktrans, CBV) with overall survival (OS) in participants with newly diagnosed GBM.

SECONDARY OBJECTIVES:

1. To determine the association of baseline FMISO PET uptake (HV, T/Bmax) and MRI parameters (Ktrans, CBV) with time to progression (TTP) and 6-month progression free survival (PFS-6) in participants with newly diagnosed GBM.

2. To assess the reproducibility of the baseline FMISO PET uptake parameters by implementing baseline "test" and "retest" PET scans (performed within 1 to 7 days of each other).

3. To assess the correlation between highest tissue:cerebellum ratio [T/Cmax] and T/Bmax at baseline.

4. To assess the correlation between other MRI parameters (for example Gadolinium-enhanced T1-weighted (T1Gd), vessel caliber index (VCI), , CBV-S, apparent diffusion coefficient (ADC) , N-acetylaspartate (NAA) to choline (Cho) ratio, blood oxygenation level-dependent (BOLD), T2) and OS, TTP, and PFS-6.

OUTLINE: This is a multicenter study.

Two weeks before initiation of chemoradiotherapy with temozolomide, patients undergo MRI and PET scan using FMISO. A subset of 15 patients undergo FMISO PET scans approximately 1 week before chemoradiotherapy. Blood samples are collected at baseline and periodically during study to compare image measures of tissue uptake of FMISO to blood concentrations. Tumor samples are collected from diagnostic biopsy or surgery for analysis of tumor hypoxic markers and methylguanine methyl transferase by immunohistochemical and Polymerase chain reaction (PCR) assays.

After completion of study therapy, patients are followed up every 3 months for up to 5 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Diagnostic
• Official Title: Multicenter, Phase II Assessment of Tumor Hypoxia in Glioblastoma Using 18F-Fluoromisonidazole (FMISO) With PET and MRI
• Actual Study Start Date: Aug 24, 2009
• Actual Primary Completion Date: Jan 31, 2018
• Actual Study Completion Date: Jan 31, 2018

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Diagnostic (MRI and PET using FMISO) Two weeks before initiation of chemoradiotherapy with temozolomide, patients undergo MRI (DSC, DCE,DWI and MRS) and PET scan using FMISO. A subset of 15 patients undergo FMISO PET scans approximately 1 week before chemoradiotherapy.

Drug: FMISO; FMISO PET scans; Other Names: 18F-fluoromisonidazole 18F-MISO 18F-Misonidazole ; Other: MRI; Undergo MRI; Other Names: Magnetic Resonance Imaging (MRI) Magnetic Resonance Imaging Scan Medical Imaging, Magnetic Resonance MRI Scan NMR Imaging Nuclear Magnetic Resonance Imaging (NMRI) Nuclear Magnetic Resonance Imaging Medical Imaging, Nuclear Magnetic Resonance Magnetic Resonance (MR) ; Other: PET; Undergo FMISO PET scan; Other Names: Medical Imaging, Positron Emission Tomography PET Scan Positron Emission Tomography Positron Emission Tomography Scan Positron-Emission Tomography proton magnetic resonance spectroscopic imaging ; Other: MRS; Other Names: Magnetic Resonance Spectroscopy (MRS) Magnetic Resonance Imaging Spectroscopy (MRIS) Magnetic Resonance Spectroscopy Imaging (MRSI)

Outcome Measures

Primary Outcome Measures

1. Association of Baseline FMISO PET and MRI Features With OS as Assessed Using Cox-regression Model ["assessed from baseline up to 5 years, survival status at 1-year reported]

   Overall Survival (OS) was evaluated every 3 months through end of the study (up to 5 years). A variety of continuous quantitative (functional) imaging features measuring abnormal tumor vasculature (MRI) and hypoxia (FMISO) were evaluated at baseline for their association with Survival time. Features include PET Hypoxia measures: Peak standardized uptake values (SUVpeak); maximum tumor:blood ratio (T/Bmax); and Hypoxia Volume (HV) DCE MRI perfusion measures: Mean/median volume transfer constant for gadolinium between blood plasma and the tissue extravascular extracellular space (ktrans) DSC MRI tumor vasculature: Normalized Relative cerebral blood volume (nRCBV); and Cerebral blood flow (CBF) DWI MRI magnitude of diffusion of water through tissue (cell density): Apparent diffusion coefficient (ADC) using low and high Gaussian distributions

Secondary Outcome Measures

1. Association of Baseline FMISO PET and MRI Features With Time-to-Progression (TTP) [assessed from baseline up to 5 years, progression status at months 6 and 9 reported]

   Disease progression was defined by Macdonald criteria. PFS was evaluated every 3months through the end of study (up to 5yrs), features were measured at baseline. Quantitative imaging features measuring abnormal tumor vasculature (MRI) and hypoxia (FMISO) were evaluated for their association with TTP (cox model) and to discriminate between responders and non-responders at 6 and 9 mos (PFS6 and PFS9) (logistic) Features include PET Hypoxia measures: Peak standardized uptake values (SUVpeak); maximum tumor:blood ratio (T/Bmax); and Hypoxia Volume (HV) DCE MRI perfusion measures: Mean/median volume transfer constant for gadolinium between blood plasma and the tissue extravascular extracellular space (ktrans) DSC MRI tumor vasculature: Normalized Relative cerebral blood volume (nRCBV); and Cerebral blood flow (CBF) DWI MRI magnitude of diffusion of water through tissue (cell density): Apparent diffusion coefficient (ADC) using low and high Gaussian distributions

2. Reproducibility of the Baseline FMISO PET Uptake Parameters as Assessed by Baseline "Test" and "Retest" PET Scans [Baseline and retest within 1 to 7 days after (but prior to the start of therapy)]

   Reproducibility, defined as the variation of repeated measurements in an experiment performed under the same conditions, will be measured as the within subject coefficient of variation with upper an lower repeatability coefficients (LRC, URC) computed as percents from log-transformed data, per Velaquez, et al (J Nucl Med. 2009 Oct;50(10):1646-54. doi: 10.2967/jnumed.109.063347. Epub 2009 Sep 16. PMID: 19759105 ). Where Within Subject Coefficient of Variation (wCV) is a percentage defined as wCV(%)=100* (exp( SD[ld]/√2) - 1) and LRC and URC are calculated as: RC=100 (exp(±1.96 SD[ld]) -1). here SD[ld] is the standard deviation of the difference of the log-transformed PET measurements. These bounds provide an estimate of the lower and upper bounds of percent change observed between scans for each measurement.

3. Correlation Between T/Cmax and T/Bmax [At baseline]

   Pearson correlation coefficient will be used to quantify the correlation between T/Bmax, the maximum tissue-to-blood ratio activity value, and T/Cmax, the tissue-to-cerebellum activite value Since T/Cmax does not requiring blood sampling and is image derived, a high correlation would indicate that T/Cmax could be an advantageous surrogate for T/Bmax.

4. Correlation Between MRS Markers and MR Imaging Markers of Vascularity as Well as Between MRS Markers and PET Markers of Tumor Hypoxia [baseline]

   Correlation between MRS markers and MR imaging markers and PET markers of tumor hypoxia MRS markers include: NAA/Cho, Cho/Cr, Lac/Cr, and Lac/NAA measured within tumor and at the periphery. MR imaging markers of vascularity include: CBV, CBF, and ktrans PET tumor hypoxia marker: SUVmax

Other Outcome Measures

1. Overall and Progression Free Survival [Baseline, every 3 months through study completion (up to 5 years for progression and survivorship)]

   Disease progression was defined by Macdonald criteria. Survival and Progression were evaluated every 3months and at the end of study (up to 5 years) and time to event evaluated.

2. SUVpeak and T/Bmax as Measures of Tumor Hypoxia [baseline]

   The FMISO image data were normalized by the average blood activity to produce pixel level tissue-to-blood ratio (T/B) values for all image slices. And the severity of the hypoxia was determined by the pixel with the maximum T/B value (TBmax). FMISO SUVpeak was determined as the average SUV from a 1 cm circular ROI centered over the hottest pixel. Since FMISO selectively binds to hypoxic tissues, SUVpeak within a region provides a measure of tumor hypoxia.

3. Hypoxic Volume as a Measure of Tumor Hypoxia [baseline]

   The hypoxic volume (HV) was determined as the volume of pixels in the tumor on in the FMISO\PET with a tumor to blood activity ratio ≥ 1.2. HV is a measure of the spatial extent of tumor hypoxia (in milliliters)

4. DWI Apparent Diffusion Coefficient (ADC) [baseline]

   Apparent Diffusion Coefficient (ADC) measures water diffusion through tissue (mm^2/s). Cerebral infarction leads to diffusion restriction resulting in a low ADC signal in the infarcted area. A double Gaussian mixed model was fit to the ADC histogram and the mean of the lower and the mean of the higher ADC curves were evaluated

5. Normalized Relative Cerebral Blood Volume (nRCBV) and Normalized Cerebral Blood Flow (nCBF) [baseline]

   Relative cerebral blood volume (RCBV) maps, computed from the integral of ∆R2*(t), were corrected for leakage effects and normalized to normal appearing white matter (nRCBV); nRCBV provides a measure of tumor vasculature Cerebral blood flow (CBF) maps were was normalized to the mean of the region of interest (ROI) in normal appearing white matter (nCBF); nCBF provides a measure of vascular permeability and perfusion

6. Summary of Mean and Median Ktrans Across Participants. [baseline]

   ktrans is a measure of vascular permeability and reflects the rate of gadolinium moves from plasma to extravascular extracellular space (predominantly though blood flow and capillary leakage), which can be represented by the mean or median rate. Mean & Median ktrans within subject were computed using a matrix-based linearization method to fit tissue ∆R1(t) to the extended Tofts model. The mean across subjects is presented below (Mean (Mean-ktrans) and Mean(Median-Ktrans))

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Must be able to provide a written informed consent

• Newly diagnosed glioblastoma multiforme (GBM), World Health Organization (WHO) grade IV based on pathology confirmation

• Residual tumor after surgery (amount of residual tumor will not impact patient eligibility and visible residual disease can include T2/FLAIR hyperintensity)

• Note: If patient had a biopsy only, postoperative MRI is not needed to assess residual tumor prior to enrollment

• Scheduled to receive standard fractionated radiation therapy

• Scheduled to receive Temozolomide (TMZ) in addition to radiation therapy

• Karnofsky Performance Score > 60

Exclusion Criteria:

• Pregnant or breastfeeding (if a female is of child-bearing potential, and unsure of pregnancy status, a standard urine pregnancy test should be done)

• Scheduled to receive chemotherapy, immunotherapy, or investigational agents in trials unwilling to share data with ACRIN (i.e., additional therapy added to radiation and TMZ is allowed if ACRIN is able to obtain treatment information)

• Not suitable to undergo MRI or use the contrast agent Gd because of:

• Claustrophobia

• Presence of metallic objects or implanted medical devices in body (i.e., cardiac pacemaker, aneurysm clips, surgical clips, prostheses, artificial hearts, valves with steel parts, metal fragments, shrapnel, tattoos near the eye, or steel implants)

• Sickle cell disease

• Renal failure

• Reduced renal function, as determined by Glomerular Filtration Rate (GFR) < 30 mL/min/1.73 m^2 based on a serum creatinine level obtained within 28 days prior to registration

• Presence of any other co-existing condition which, in the judgment of the investigator, might increase the risk to the subject

• Presence of serious systemic illness, including: uncontrolled intercurrent infection, uncontrolled malignancy, significant renal disease, or psychiatric/social situations which might impact the survival endpoint of the study or limit compliance with study requirements

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to FMISO; an allergic reaction to nitroimidazoles is highly unlikely

• Not suitable to undergo PET or MRI, including weight greater than 350 lbs (the weight limit for the MRI and PET table)

• Prior treatment with implanted radiotherapy or chemotherapy sources such as wafers of polifeprosan 20 with carmustine

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama	United States	35233
2	USC / Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
3	Moffitt Cancer Center	Tampa	Florida	United States	33612
4	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland	United States	21287
5	Massachusetts General Hospital Cancer Center	Boston	Massachusetts	United States	02114
6	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
7	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
8	Mount Sinai Hospital	New York	New York	United States	10029
9	Duke University Medical Center	Durham	North Carolina	United States	27710
10	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
11	Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center	Cleveland	Ohio	United States	44195
12	American College of Radiology Imaging Network	Philadelphia	Pennsylvania	United States	19103
13	University of Pennsylvania/Abramson Cancer Center	Philadelphia	Pennsylvania	United States	19104
14	University of Washington Medical Center	Seattle	Washington	United States	98195

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Elizabeth Gerstner, American College of Radiology Imaging Network

Study Documents (Full-Text)

• Study Protocol, Statistical Analysis Plan, and Informed Consent Form - Jan 24, 2012

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00902577
• Other Study ID Numbers: NCI-2011-01912; NCI-2011-01912; CDR0000640413; ACRIN 6684; ACRIN-6684; U01CA080098
• First Posted: May 15, 2009
• Last Update Posted: Apr 8, 2019
• Last Verified: Mar 1, 2019

• Additional relevant MeSH terms: Glioblastoma; Gliosarcoma; Hypoxia; Misonidazole

Study Results

Participant Flow

Recruitment Details	Fifty patients with newly diagnosed GBM were enrolled from 11 academic centers in the United States.
Pre-assignment Detail	All participants were scheduled to receive both FMISO and MRI (DCE, DSC, DWI, MRS) imaging two weeks before initiation of chemoradiotherapy with temozolomide

Arm/Group Title	Newly Diagnosed Glioblastoma Multiforme Patients
Arm/Group Description	Patients with Newly diagnosed GBM scheduled to have FMISO Positron Emission Tomography (PET) two weeks before initiation of chemoradiotherapy with temozolomide, with diagnostic DCE/DSE/DWI MRI
Period Title: Overall Study
STARTED	50
FMISO/PET	38
DCE MRI	31
DSE MRI	37
DWI MRI	39
COMPLETED	42
NOT COMPLETED	8

Baseline Characteristics

Arm/Group Title	Newly Diagnosed Glioblastoma Multiforme Patients
Arm/Group Description	42 eligible, consented patients with newly diagnosed GBM who received both FMISO-PRT and MRI imaging two weeks before initiation of chemoradiotherapy with temozolomide
Overall Participants	42
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57 (9.07)
Sex: Female, Male (Count of Participants)
Female	15 35.7%
Male	27 64.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 11.9%
Not Hispanic or Latino	36 85.7%
Unknown or Not Reported	1 2.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 2.4%
Asian	1 2.4%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 4.8%
White	38 90.5%
More than one race	0 0%
Unknown or Not Reported	0 0%
Median Tumor Volume (mm^3) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mm^3]	14.94

Outcome Measures

1. Primary Outcome

Title	Association of Baseline FMISO PET and MRI Features With OS as Assessed Using Cox-regression Model
Description	Overall Survival (OS) was evaluated every 3 months through end of the study (up to 5 years). A variety of continuous quantitative (functional) imaging features measuring abnormal tumor vasculature (MRI) and hypoxia (FMISO) were evaluated at baseline for their association with Survival time. Features include PET Hypoxia measures: Peak standardized uptake values (SUVpeak); maximum tumor:blood ratio (T/Bmax); and Hypoxia Volume (HV) DCE MRI perfusion measures: Mean/median volume transfer constant for gadolinium between blood plasma and the tissue extravascular extracellular space (ktrans) DSC MRI tumor vasculature: Normalized Relative cerebral blood volume (nRCBV); and Cerebral blood flow (CBF) DWI MRI magnitude of diffusion of water through tissue (cell density): Apparent diffusion coefficient (ADC) using low and high Gaussian distributions
Time Frame	"assessed from baseline up to 5 years, survival status at 1-year reported

Outcome Measure Data

Analysis Population Description

FMISO-PET identifies the primary analysis population containing participants with interpretable FMISO images.The Evaluable study population consisted of enrolled GBM patients having an FMISO-PET procedure. Additional groups include functional MRI, with available/interpretable images.

Arm/Group Title	Evaluable	FMISO-PET	DSC MRI	DCE MRI	DWI-MRI
Arm/Group Description	42 participants with imaging (FMISO-PET, DCE/DSC/DWI MRI)	Quantitative PET measurements Hypoxic Volume (HV) Max tumor:blood ratio (TBmax) Peak Standardized uptake Values (SUVpeak)	Quantitative DSC measurements: Normalized rCBV [Relative cerebral blood volume] Normalized rCBF[Relative cerebral blood flow]	Quantitative DCE measurements Mean vascular permeability (ktrans) Median Ktrans	Apparent diffusion coefficient (ADC) Low and High
Measure Participants	42	38	37	31	39
OS-1 Alive	25 59.5%	22 NaN	24 NaN	20 NaN	24 NaN
OS-1 Death	17 40.5%	16 NaN	13 NaN	11 NaN	15 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FMISO-PET
	Comments	FMISO selectively binds to hypoxic tissues so that SUVpeak within a region provides a measure of tumor hypoxia.: This marker was modeled with a univariate Cox regression model for overall survival (OS) time. The hazard ratio, along with its 95% confidence interval and the p-value based on Wald's statistic are reported.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.048
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.54
	Confidence Interval	(2-Sided) 95%; 1.0 to 2.36
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FMISO-PET
	Comments	T/Bmax is the pixel in the tumor region with the maximum tumor:blood ratio (T/Bmax) and T/Bmax depicts the magnitude of the hypoxia TBmax was modeled with a univariate Cox regression model for OS time. The hazard ratio, along with its 95% confidence interval and the p-value based on Wald's statistic are reported. The study was designed to enroll 46 evaluable participants to detect a log hazard ratio of 1.279 for TBmax with HV as a covariate with a 50% event rate
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.50
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.16
	Confidence Interval	(2-Sided) 95%; .75 to 1.81
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FMISO-PET
	Comments	Hypoxia Volume (HV) depicts the volume of tumor that has crossed the threshold for hypoxia. Hypoxic Volume (HV) was modeled with a univariate Cox regression model for overall survival (OS) time. The hazard ratio, along with its 95% confidence interval and the p-value based on Wald's statistic are reported.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.90
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.00
	Confidence Interval	(2-Sided) 0.97%; 0.97 to 1.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	DCE MRI
	Comments	ktrans reflects the rate of gadolinium moves from plasma to extravascular extracellular space (predominantly though blood flow and capillary leakage). Mean ktrans were computed using a matrix-based linearization method to fit tissue ∆R1(t) to the extended Tofts model Mean ktrans was modeled with a univariate Cox regression model for overall survival (OS) time. The hazard ratio, along with its 95% confidence interval and the p-value based on Wald's statistic are reported.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.024
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.17
	Confidence Interval	(2-Sided) 95%; 1.02 to 1.34
	Parameter Dispersion	Type: Value:
	Estimation Comments	HR reported per 0.01 increase

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	DCE MRI
	Comments	ktrans reflects the rate of gadolinium moves from plasma to extravascular extracellular space (predominantly though blood flow and capillary leakage). Median ktrans were computed using a matrix-based linearization method to fit tissue ∆R1(t) to the extended Tofts model. Median ktrans was modeled with a univariate Cox regression model for overall survival (OS) time. The hazard ratio, along with its 95% confidence interval and the p-value based on Wald's statistic are reported.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.045
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.32
	Confidence Interval	(2-Sided) 95%; 1.01 to 1.72
	Parameter Dispersion	Type: Value:
	Estimation Comments	HR reported per 0.01 increase

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	DSC MRI
	Comments	Relative cerebral blood volume (RCBV) maps, computed from the integral of ∆R2*(t), were corrected for leakage effects and normalized to normal appearing white matter (nRCBV); nRCBV provides a measure of tumor vasculature and was modeled with a univariate Cox regression model for overall survival (OS) time. The hazard ratio, along with its 95% confidence interval and the p-value based on Wald's statistic are reported.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.31
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.11
	Confidence Interval	(2-Sided) 95%; 0.90 to 1.37
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	DSC MRI
	Comments	cerebral blood flow (CBF) maps were was normalized to the mean of the region of interest (ROI) in normal appearing white matter to produce the nCBF and provide another measure of vascular permeability and perfusion nCBF was modeled with a univariate Cox regression model for overall survival (OS) time. The hazard ratio, along with its 95% confidence interval and the p-value based on Wald's statistic are reported.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.51
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.07
	Confidence Interval	(2-Sided) 95%; 0.88 to 1.29
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	DWI-MRI
	Comments	Apparent Diffusion Coefficient (ADC) measures water diffusion through tissue. Cerebral infarction leads to diffusion restriction resulting in a low ADC signal in the infarcted area. A double Gaussian mixed model was fit to the ADC histogram and the mean of the lower ADC curve, was modeled with a univariate Cox regression model for overall survival (OS) time. The hazard ratio, along with its 95% confidence interval and the p-value based on Wald's statistic are reported.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9700
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.00
	Confidence Interval	(2-Sided) 95%; 0.79 to 1.26
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	DWI-MRI
	Comments	Apparent Diffusion Coefficient (ADC) measures water diffusion through tissue. Cerebral infarction leads to diffusion restriction resulting in a low ADC signal in the infarcted area. A double Gaussian mixed model was fit to the ADC histogram and the mean of the higher ADC curve, was modeled with a univariate Cox regression model for overall survival (OS) time. The hazard ratio, along with its 95% confidence interval and the p-value based on Wald's statistic are reported.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9007
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.99
	Confidence Interval	(2-Sided) 95%; 0.91 to 1.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Association of Baseline FMISO PET and MRI Features With Time-to-Progression (TTP)
Description	Disease progression was defined by Macdonald criteria. PFS was evaluated every 3months through the end of study (up to 5yrs), features were measured at baseline. Quantitative imaging features measuring abnormal tumor vasculature (MRI) and hypoxia (FMISO) were evaluated for their association with TTP (cox model) and to discriminate between responders and non-responders at 6 and 9 mos (PFS6 and PFS9) (logistic) Features include PET Hypoxia measures: Peak standardized uptake values (SUVpeak); maximum tumor:blood ratio (T/Bmax); and Hypoxia Volume (HV) DCE MRI perfusion measures: Mean/median volume transfer constant for gadolinium between blood plasma and the tissue extravascular extracellular space (ktrans) DSC MRI tumor vasculature: Normalized Relative cerebral blood volume (nRCBV); and Cerebral blood flow (CBF) DWI MRI magnitude of diffusion of water through tissue (cell density): Apparent diffusion coefficient (ADC) using low and high Gaussian distributions
Time Frame	assessed from baseline up to 5 years, progression status at months 6 and 9 reported

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Evaluable	FMISO-PET	DSC MRI	DCE MRI	DWI-MRI
Arm/Group Description	42 participants with imaging (FMISO-PET, DCE/DSC/DWI MRI)	Quantitative PET measurements Hypoxic Volume (HV) Max tumor:blood ratio (TBmax) Peak Standardized uptake Values (SUVpeak)	Quantitative DSC measurements: Normalized rCBV [Relative cerebral blood volume] Normalized rCBF[Relative cerebral blood flow]	Quantitative DCE measurements Mean vascular permeability (ktrans) Median Ktrans	Apparent diffusion coefficient (ADC) Low and High
Measure Participants	42	38	37	31	39
Progression Free	29 69%	26 NaN	27 NaN	20 NaN	28 NaN
Progressed	13 31%	12 NaN	10 NaN	11 NaN	11 NaN
Progression Free	19 45.2%	17 NaN	18 NaN	12 NaN	18 NaN
Progressed	23 54.8%	21 NaN	19 NaN	19 NaN	21 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FMISO-PET
	Comments	FMISO selectively binds to hypoxic tissues so that SUVpeak within a region provides a measure of tumor hypoxia. This marker was modeled with a univariate Cox regression model for Progression Free Survival time. The hazard ratio, along with its 95% confidence interval and the p-value based on Wald's statistic are reported.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.33
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.24
	Confidence Interval	(2-Sided) 95%; .80 to 1.91
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FMISO-PET
	Comments	T/Bmax is the pixel in the tumor region with the maximum tumor:blood ratio (T/Bmax) and T/Bmax depicts the magnitude of the hypoxia TBmax was modeled with a univariate Cox regression model for PFS time. The hazard ratio, along with its 95% confidence interval and the p-value based on Wald's statistic are reported.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.72
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.93
	Confidence Interval	(2-Sided) 95%; .61 to 1.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FMISO-PET
	Comments	Hypoxia Volume (HV) depicts the volume of tumor that has crossed the threshold for hypoxia. Hypoxic Volume (HV) was modeled with a univariate Cox regression model for PFS time. The hazard ratio, along with its 95% confidence interval and the p-value based on Wald's statistic are reported.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.355
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.01
	Confidence Interval	(2-Sided) 95%; .98 to 1.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	DCE MRI
	Comments	ktrans reflects the rate of gadolinium moves from plasma to extravascular extracellular space (predominantly though blood flow and capillary leakage). Mean ktrans were computed using a matrix-based linearization method to fit tissue ∆R1(t) to the extended Tofts model. Mean ktrans was modeled with a univariate Cox regression model for PFS time. The hazard ratio, along with its 95% confidence interval and the p-value based on Wald's statistic are reported.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.074
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.10
	Confidence Interval	(2-Sided) 95%; 0.99 to 1.23
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	DCE MRI
	Comments	ktrans reflects the rate of gadolinium moves from plasma to extravascular extracellular space (predominantly though blood flow and capillary leakage). Median ktrans were computed using a matrix-based linearization method to fit tissue ∆R1(t) to the extended Tofts model. Median ktrans was modeled with a univariate Cox regression model for PFS time. The hazard ratio, along with its 95% confidence interval and the p-value based on Wald's statistic are reported.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.021
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.30
	Confidence Interval	(2-Sided) 95%; 1.04 to 1.63
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	DSC MRI
	Comments	Relative cerebral blood volume (RCBV) maps, computed from the integral of ∆R2*(t), were corrected for leakage effects and normalized to normal appearing white matter (nRCBV); nRCBV provides a measure of tumor vasculature and was modeled with a univariate Cox regression model for PFS time. The hazard ratio, along with its 95% confidence interval and the p-value based on Wald's statistic are reported.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0096
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.28
	Confidence Interval	(2-Sided) 95%; 1.06 to 1.54
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	DSC MRI
	Comments	cerebral blood flow (CBF) maps were was normalized to the mean of the region of interest (ROI) in normal appearing white matter to produce the nCBF and provide another measure of vascular permeability and perfusion. nCBF was modeled with a univariate Cox regression model for PFS time. The hazard ratio, along with its 95% confidence interval and the p-value based on Wald's statistic are reported.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.038
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.18
	Confidence Interval	(2-Sided) 95%; 1.01 to 1.38
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	FMISO-PET
	Comments	Logistic regression for SUVpeak to predict PFS6
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3253
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.682
	Confidence Interval	(2-Sided) 95%; 0.318 to 1.463
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	FMISO-PET
	Comments	TBmax was modeled with a univariate logistic regression model for PFS6.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9836
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.991
	Confidence Interval	(2-Sided) 95%; 0.403 to 2.434
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	FMISO-PET
	Comments	Hypoxic Volume (HV) was modeled with a logistic regression model for 6month progression free survival (PFS6) .
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1566
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.957
	Confidence Interval	(2-Sided) 95%; 0.900 to 1.017
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	DCE MRI
	Comments	Mean ktrans were computed using a matrix-based linearization method to fit tissue ∆R1(t) to the extended Tofts model. Mean ktrans was modeled with a univariate logistic regression model for PFS6.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9554
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.993
	Confidence Interval	(2-Sided) 95%; 0.775 to 1.273
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	DCE MRI
	Comments	Median ktrans were computed using a matrix-based linearization method to fit tissue ∆R1(t) to the extended Tofts model. Median ktrans was modeled with a univariate logistic regression model for PFS6
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6941
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.919
	Confidence Interval	(2-Sided) 95%; 0.602 to 1.402
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	DSC MRI
	Comments	Relative cerebral blood volume (RCBV) maps were corrected for leakage effects and normalized to normal appearing white matter (nRCBV). nRCBV was modeled with a univariate logistic regression model for PFS6.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1340
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.744
	Confidence Interval	(2-Sided) 95%; 0.506 to 1.095
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	DSC MRI
	Comments	cerebral blood flow (CBF) maps were was normalized to the mean of the region of interest (ROI) in normal appearing white matter to produce the nCBF. nCBF was modeled with a univariate logistic regression model for PFS6.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2642
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.821
	Confidence Interval	(2-Sided) 95%; 0.580 to 1.161
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	DWI-MRI
	Comments	Apparent Diffusion Coefficient (ADC) low values were modeled with a univariate logistic regression model for PFS6
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5069
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.855
	Confidence Interval	(2-Sided) 95%; 0.539 to 1.357
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	DWI-MRI
	Comments	Apparent Diffusion Coefficient (ADC) high values were modeled with a univariate Logistic regression model for PFS6
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1921
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.884
	Confidence Interval	(2-Sided) 95%; 0.735 to 1.064
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	FMISO-PET
	Comments	FMISO selectively binds to hypoxic tissues so that SUVpeak within a region provides a measure of tumor hypoxia. Receiver Operating Characteristic(ROC) analysis was perform to determine the accuracy of this marker to predict PFS9.
	Type of Statistical Test	Other
	Comments	An Area Under the Curve (AUC) with a lower bound of at least 0.5 is considered statistically significant.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Area Under the Curve (AUC)
	Estimated Value	0.61
	Confidence Interval	(2-Sided) 95%; 0.42 to 0.79
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	FMISO-PET
	Comments	T/Bmax is the pixel in the tumor region with the maximum tumor:blood ratio (T/Bmax) and T/Bmax depicts the magnitude of the hypoxia. Receiver Operating Characteristic(ROC) analysis was perform to determine the accuracy of this marker to predict PFS9.
	Type of Statistical Test	Other
	Comments	An Area Under the Curve (AUC) with a lower bound of at least 0.5 is considered statistically significant.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Area Under the Curve (AUC)
	Estimated Value	0.59
	Confidence Interval	(2-Sided) 95%; 0.39 to 0.78
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	FMISO-PET
	Comments	Hypoxia Volume (HV) depicts the volume of tumor that has crossed the threshold for hypoxia. Receiver Operating Characteristic(ROC) analysis was perform to determine the accuracy of this marker to predict PFS9.
	Type of Statistical Test	Other
	Comments	An Area Under the Curve (AUC) with a lower bound of at least 0.5 is considered statistically significant.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Area Under the Curve (AUC)
	Estimated Value	0.64
	Confidence Interval	(2-Sided) 95%; 0.46 to 0.83
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	DCE MRI
	Comments	mean ktrans reflects the rate of gadolinium moves from plasma to extravascular extracellular space (predominantly though blood flow and capillary leakage). Receiver Operating Characteristic(ROC) analysis was perform to determine the accuracy of mean ktrans to predict PFS9.
	Type of Statistical Test	Other
	Comments	An Area Under the Curve (AUC) with a lower bound of at least 0.5 is considered statistically significant.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Area Under the Curve (AUC)
	Estimated Value	0.62
	Confidence Interval	(2-Sided) 95%; 0.42 to 0.83
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	DCE MRI
	Comments	Median ktrans reflects the rate of gadolinium moves from plasma to extravascular extracellular space (predominantly though blood flow and capillary leakage). Receiver Operating Characteristic(ROC) analysis was perform to determine the accuracy of Median ktrans to predict PFS9.
	Type of Statistical Test	Other
	Comments	An Area Under the Curve (AUC) with a lower bound of at least 0.5 is considered statistically significant.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Area Under the Curve (AUC)
	Estimated Value	0.64
	Confidence Interval	(2-Sided) 95%; 0.44 to 0.84
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	DSC MRI
	Comments	nRCBV provides a measure of tumor vasculature Receiver Operating Characteristic(ROC) analysis was perform to determine the accuracy of this marker to predict PFS9.
	Type of Statistical Test	Other
	Comments	An Area Under the Curve (AUC) with a lower bound of at least 0.5 is considered statistically significant.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Area Under the Curve (AUC)
	Estimated Value	0.72
	Confidence Interval	(2-Sided) 95%; 0.54 to 0.89
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	DSC MRI
	Comments	nCBF provides a measure of vascular permeability and perfusion. Receiver Operating Characteristic(ROC) analysis was perform to determine the accuracy of this marker to predict PFS9.
	Type of Statistical Test	Other
	Comments	An Area Under the Curve (AUC) with a lower bound of at least 0.5 is considered statistically significant.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Area Under the Curve (AUC)
	Estimated Value	0.72
	Confidence Interval	(2-Sided) 95%; 0.55 to 0.89
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Reproducibility of the Baseline FMISO PET Uptake Parameters as Assessed by Baseline "Test" and "Retest" PET Scans
Description	Reproducibility, defined as the variation of repeated measurements in an experiment performed under the same conditions, will be measured as the within subject coefficient of variation with upper an lower repeatability coefficients (LRC, URC) computed as percents from log-transformed data, per Velaquez, et al (J Nucl Med. 2009 Oct;50(10):1646-54. doi: 10.2967/jnumed.109.063347. Epub 2009 Sep 16. PMID: 19759105 ). Where Within Subject Coefficient of Variation (wCV) is a percentage defined as wCV(%)=100* (exp( SD[ld]/√2) - 1) and LRC and URC are calculated as: RC=100 (exp(±1.96 SD[ld]) -1). here SD[ld] is the standard deviation of the difference of the log-transformed PET measurements. These bounds provide an estimate of the lower and upper bounds of percent change observed between scans for each measurement.
Time Frame	Baseline and retest within 1 to 7 days after (but prior to the start of therapy)

Outcome Measure Data

Analysis Population Description

Analysis will be performed SUVmax and SUV Peak, average and maximum values, across patients and by target tumor.

Arm/Group Title	FMISO Reproducibility
Arm/Group Description	Participants with two FMISO PET scans within 1 to 7 days of each other and prior to Visit 2 to test reproducibility of FMISO PET removing 5 participants with protocol variations which could affect the SUV measurements
Measure Participants	29
SUVmax : Average across all lesions by participant	7.03
SUVmax : Maximum across all lesions by participant	9.60
SUVmax : Target Lesion	8.18
SUVpeak: Average across all lesions by participant	7.08
SUVpeak: Maximum across all lesions by participant	9.20
SUVpeak: Target Lesion	8.24

4. Secondary Outcome

Title	Correlation Between T/Cmax and T/Bmax
Description	Pearson correlation coefficient will be used to quantify the correlation between T/Bmax, the maximum tissue-to-blood ratio activity value, and T/Cmax, the tissue-to-cerebellum activite value Since T/Cmax does not requiring blood sampling and is image derived, a high correlation would indicate that T/Cmax could be an advantageous surrogate for T/Bmax.
Time Frame	At baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	DSC MRI
Arm/Group Description	Participant with DSC MRI
Measure Participants	38
Number [correlation coefficient]	0.98

5. Secondary Outcome

Title	Correlation Between MRS Markers and MR Imaging Markers of Vascularity as Well as Between MRS Markers and PET Markers of Tumor Hypoxia
Description	Correlation between MRS markers and MR imaging markers and PET markers of tumor hypoxia MRS markers include: NAA/Cho, Cho/Cr, Lac/Cr, and Lac/NAA measured within tumor and at the periphery. MR imaging markers of vascularity include: CBV, CBF, and ktrans PET tumor hypoxia marker: SUVmax
Time Frame	baseline

Outcome Measure Data

Analysis Population Description

Seventeen participants from four sites had analyzable 3D MRSI datasets acquired on Philips, GE or Siemens scanners at either 1.5T or 3T. MRSI data were analyzed using LCModel to quantify metabolites N-acetylaspartate (NAA), creatine (Cr), choline (Cho), and lactate (Lac)

Arm/Group Title	nrCBV	nCBF	Median K-trans	SUV Max
Arm/Group Description	17 participants with measured MRS markers and nRCBV: relative cerebral blood volume, corrected for leakage effects and normalized to normal-appearing white matter;	17 participants with measured MRS markers and nCBF: cerebral blood flow, normalized to normal-appearing white matter;	17 participants with measured MRS markers and k-trans: vascular permeability	17 participants with measured MRS markers and SUVmax: standardized uptake value
Measure Participants	17	17	17	17
NAA/Cho Tumor	-0.38	-0.41	-0.08	-.33
NAA/Cho Periphery	-0.33	-0.34	0.14	-0.41
Cho/Cr Tumor	0.24	0.28	-0.2	0.03
Cho/Cr Periphery	0.17	0.20	-0.27	0.11
Lac/Cr Tumor	-0.27	-0.25	-0.06	-0.29
Lac/Cr Periphery	-0.09	-0.11	0.10	-0.15
Lac/NAA Tumor	-0.02	-0.01	0.23	-0.18
Lac/NAA Periphery	-0.01	-0.01	0.33	-0.04

6. Other Pre-specified Outcome

Title	Overall and Progression Free Survival
Description	Disease progression was defined by Macdonald criteria. Survival and Progression were evaluated every 3months and at the end of study (up to 5 years) and time to event evaluated.
Time Frame	Baseline, every 3 months through study completion (up to 5 years for progression and survivorship)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Newly Diagnosed Glioblastoma Multiforme Patients
Arm/Group Description	42 eligible, consented patients with newly diagnosed GBM who received both FMISO-PRT and MRI imaging two weeks before initiation of chemoradiotherapy with temozolomide
Measure Participants	42
Median OS time	408
Median PFS	258

7. Other Pre-specified Outcome

Title	SUVpeak and T/Bmax as Measures of Tumor Hypoxia
Description	The FMISO image data were normalized by the average blood activity to produce pixel level tissue-to-blood ratio (T/B) values for all image slices. And the severity of the hypoxia was determined by the pixel with the maximum T/B value (TBmax). FMISO SUVpeak was determined as the average SUV from a 1 cm circular ROI centered over the hottest pixel. Since FMISO selectively binds to hypoxic tissues, SUVpeak within a region provides a measure of tumor hypoxia.
Time Frame	baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	FMISO-PET
Arm/Group Description	Quantitative PET measurements Max tumor:blood ratio (TBmax) Peak Standardized uptake Values (SUVpeak)
Measure Participants	38
SUVpeak	2.49 (0.89)
T/Bmax	2.13 (0.77)

8. Other Pre-specified Outcome

Title	Hypoxic Volume as a Measure of Tumor Hypoxia
Description	The hypoxic volume (HV) was determined as the volume of pixels in the tumor on in the FMISO\PET with a tumor to blood activity ratio ≥ 1.2. HV is a measure of the spatial extent of tumor hypoxia (in milliliters)
Time Frame	baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	FMISO-PET
Arm/Group Description	Quantitative PET measurements Max tumor:blood ratio (TBmax) Peak Standardized uptake Values (SUVpeak)
Measure Participants	38
Mean (Standard Deviation) [milliliters]	14.21 (11.61)

9. Other Pre-specified Outcome

Title	DWI Apparent Diffusion Coefficient (ADC)
Description	Apparent Diffusion Coefficient (ADC) measures water diffusion through tissue (mm^2/s). Cerebral infarction leads to diffusion restriction resulting in a low ADC signal in the infarcted area. A double Gaussian mixed model was fit to the ADC histogram and the mean of the lower and the mean of the higher ADC curves were evaluated
Time Frame	baseline

Outcome Measure Data

Analysis Population Description

Participants having a usable FMISO\PET and DWI\MRI scans

Arm/Group Title	DWI-MRI
Arm/Group Description	Apparent diffusion coefficient (ADC) Low and High
Measure Participants	39
Low	0.99 (0.15)
High	1.48 (0.39)

10. Other Pre-specified Outcome

Title	Normalized Relative Cerebral Blood Volume (nRCBV) and Normalized Cerebral Blood Flow (nCBF)
Description	Relative cerebral blood volume (RCBV) maps, computed from the integral of ∆R2*(t), were corrected for leakage effects and normalized to normal appearing white matter (nRCBV); nRCBV provides a measure of tumor vasculature Cerebral blood flow (CBF) maps were was normalized to the mean of the region of interest (ROI) in normal appearing white matter (nCBF); nCBF provides a measure of vascular permeability and perfusion
Time Frame	baseline

Outcome Measure Data

Analysis Population Description

Evaluable participants with both usable FMISO\PET and DSC\MRI.

Arm/Group Title	DSC MRI
Arm/Group Description	Quantitative DSC measurements: Normalized rCBV [Relative cerebral blood volume] Normalized rCBF[Relative cerebral blood flow]
Measure Participants	37
nRCBV	3.13 (1.86)
nCBF	3.36 (2.02)

11. Other Pre-specified Outcome

Title	Summary of Mean and Median Ktrans Across Participants.
Description	ktrans is a measure of vascular permeability and reflects the rate of gadolinium moves from plasma to extravascular extracellular space (predominantly though blood flow and capillary leakage), which can be represented by the mean or median rate. Mean & Median ktrans within subject were computed using a matrix-based linearization method to fit tissue ∆R1(t) to the extended Tofts model. The mean across subjects is presented below (Mean (Mean-ktrans) and Mean(Median-Ktrans))
Time Frame	baseline

Outcome Measure Data

Analysis Population Description

Evaluable patients with usable FMISO\PET and DCE\MRI

Arm/Group Title	DCE MRI
Arm/Group Description	Quantitative DCE measurements Mean vascular permeability (ktrans) Median Ktrans
Measure Participants	31
Mean kTrans	0.04 (0.03)
Median kTrans	0.03 (0.07)

Adverse Events

Time Frame	until 24hrs after FMISO administration, evaluated up to 72hours post FMISO injection.
Adverse Event Reporting Description	The adverse reporting period is 10 half-lives after the administration of the investigational imaging radiotracer, with a minimum reporting period of at least 24hours post injection. Participants must be reassessed for events between 24 and 72hours post injection.
Arm/Group Title	Evaluable Cases		Diagnostic PET (Using FMISO)		Diagnostic MRI (DCE MRI)		Diagnostic MRI (DSE MRI)		Diagnostic MRI (DWI MRI)
Arm/Group Description	Patients with Newly diagnosed GBM scheduled to have FMISO PET/CT two weeks before initiation of chemoradiotherapy with temozolomide.		Patients with Newly diagnosed GBM who have FMISO PET/CT Imaging two weeks before initiation of chemoradiotherapy with temozolomide.		Patients with Newly diagnosed GBM who have FMISO PET/CT and Dynamic Contrast Enhanced (DCE) MR Imaging two weeks before initiation of chemoradiotherapy with temozolomide.		Patients with Newly diagnosed GBM who have FMISO PET/CT and Dynamic Susceptibility Contrast Enhanced (DSC) MR Imaging two weeks before initiation of chemoradiotherapy with temozolomide.		Patients with Newly diagnosed GBM who have FMISO PET/CT and Diffusion-Weighted Imaging (DWI) MR Imaging two weeks before initiation of chemoradiotherapy with temozolomide.
All Cause Mortality
	Evaluable Cases		Diagnostic PET (Using FMISO)		Diagnostic MRI (DCE MRI)		Diagnostic MRI (DSE MRI)		Diagnostic MRI (DWI MRI)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/42 (0%)		0/38 (0%)		0/37 (0%)		0/31 (0%)		0/39 (0%)
Serious Adverse Events
	Evaluable Cases		Diagnostic PET (Using FMISO)		Diagnostic MRI (DCE MRI)		Diagnostic MRI (DSE MRI)		Diagnostic MRI (DWI MRI)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/42 (0%)		0/38 (0%)		0/37 (0%)		0/31 (0%)		0/39 (0%)
Other (Not Including Serious) Adverse Events
	Evaluable Cases		Diagnostic PET (Using FMISO)		Diagnostic MRI (DCE MRI)		Diagnostic MRI (DSE MRI)		Diagnostic MRI (DWI MRI)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/42 (0%)		0/38 (0%)		0/37 (0%)		0/31 (0%)		0/39 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.