Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma
Conditions
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.
Detailed description
PRIMARY OBJECTIVES: I. 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: I. 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. II. 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). III. To assess the correlation between highest tissue:cerebellum ratio \[T/Cmax\] and T/Bmax at baseline. IV. 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.
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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. |
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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)) |
| 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. |
| 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) |
| 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 |
| 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 |
Countries
United States
Participant flow
Recruitment details
Fifty patients with newly diagnosed GBM were enrolled from 11 academic centers in the United States.
Pre-assignment details
All participants were scheduled to receive both FMISO and MRI (DCE, DSC, DWI, MRS) imaging two weeks before initiation of chemoradiotherapy with temozolomide
Participants by arm
| Arm | Count |
|---|---|
| Newly Diagnosed Glioblastoma Multiforme Patients 42 eligible, consented patients with newly diagnosed GBM who received both FMISO-PRT and MRI imaging two weeks before initiation of chemoradiotherapy with temozolomide | 42 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | FMISO production failure | 2 |
| Overall Study | Withdrawal by Subject | 6 |
Baseline characteristics
| Characteristic | Newly Diagnosed Glioblastoma Multiforme Patients |
|---|---|
| Age, Continuous | 57 years STANDARD_DEVIATION 9.07 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 36 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Median Tumor Volume | 14.94 mm^3 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 38 Participants |
| Sex: Female, Male Female | 15 Participants |
| Sex: Female, Male Male | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 42 | 0 / 38 | 0 / 37 | 0 / 31 | 0 / 39 |
| other Total, other adverse events | 0 / 42 | 0 / 38 | 0 / 37 | 0 / 31 | 0 / 39 |
| serious Total, serious adverse events | 0 / 42 | 0 / 38 | 0 / 37 | 0 / 31 | 0 / 39 |
Outcome results
Primary
Association of Baseline FMISO PET and MRI Features With OS as Assessed Using Cox-regression Model
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
Population: 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 | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Evaluable | Association of Baseline FMISO PET and MRI Features With OS as Assessed Using Cox-regression Model | OS-1 Alive | 25 Participants |
| Evaluable | Association of Baseline FMISO PET and MRI Features With OS as Assessed Using Cox-regression Model | OS-1 Death | 17 Participants |
| FMISO-PET | Association of Baseline FMISO PET and MRI Features With OS as Assessed Using Cox-regression Model | OS-1 Alive | 22 Participants |
| FMISO-PET | Association of Baseline FMISO PET and MRI Features With OS as Assessed Using Cox-regression Model | OS-1 Death | 16 Participants |
| DSC MRI | Association of Baseline FMISO PET and MRI Features With OS as Assessed Using Cox-regression Model | OS-1 Alive | 24 Participants |
| DSC MRI | Association of Baseline FMISO PET and MRI Features With OS as Assessed Using Cox-regression Model | OS-1 Death | 13 Participants |
| DCE MRI | Association of Baseline FMISO PET and MRI Features With OS as Assessed Using Cox-regression Model | OS-1 Death | 11 Participants |
| DCE MRI | Association of Baseline FMISO PET and MRI Features With OS as Assessed Using Cox-regression Model | OS-1 Alive | 20 Participants |
| DWI-MRI | Association of Baseline FMISO PET and MRI Features With OS as Assessed Using Cox-regression Model | OS-1 Alive | 24 Participants |
| DWI-MRI | Association of Baseline FMISO PET and MRI Features With OS as Assessed Using Cox-regression Model | OS-1 Death | 15 Participants |
Comparison: 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.p-value: 0.04895% CI: [1, 2.36]Regression, Cox
Comparison: 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 ratep-value: 0.595% CI: [0.75, 1.81]Regression, Cox
Comparison: 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.p-value: 0.90.97% CI: [0.97, 1.03]Regression, Cox
Comparison: 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.p-value: 0.02495% CI: [1.02, 1.34]Regression, Cox
Comparison: 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.p-value: 0.04595% CI: [1.01, 1.72]Regression, Cox
Comparison: 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.p-value: 0.3195% CI: [0.9, 1.37]Regression, Cox
Comparison: 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.p-value: 0.5195% CI: [0.88, 1.29]Regression, Cox
Comparison: 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.p-value: 0.9795% CI: [0.79, 1.26]Regression, Cox
Comparison: 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.p-value: 0.900795% CI: [0.91, 1.09]Regression, Cox
Secondary
Association of Baseline FMISO PET and MRI Features With Time-to-Progression (TTP)
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
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Evaluable | Association of Baseline FMISO PET and MRI Features With Time-to-Progression (TTP) | 6 month Progression Status | Progression Free | 29 Participants |
| Evaluable | Association of Baseline FMISO PET and MRI Features With Time-to-Progression (TTP) | 9 Month Progression Status | Progressed | 23 Participants |
| Evaluable | Association of Baseline FMISO PET and MRI Features With Time-to-Progression (TTP) | 6 month Progression Status | Progressed | 13 Participants |
| Evaluable | Association of Baseline FMISO PET and MRI Features With Time-to-Progression (TTP) | 9 Month Progression Status | Progression Free | 19 Participants |
| FMISO-PET | Association of Baseline FMISO PET and MRI Features With Time-to-Progression (TTP) | 9 Month Progression Status | Progressed | 21 Participants |
| FMISO-PET | Association of Baseline FMISO PET and MRI Features With Time-to-Progression (TTP) | 6 month Progression Status | Progressed | 12 Participants |
| FMISO-PET | Association of Baseline FMISO PET and MRI Features With Time-to-Progression (TTP) | 6 month Progression Status | Progression Free | 26 Participants |
| FMISO-PET | Association of Baseline FMISO PET and MRI Features With Time-to-Progression (TTP) | 9 Month Progression Status | Progression Free | 17 Participants |
| DSC MRI | Association of Baseline FMISO PET and MRI Features With Time-to-Progression (TTP) | 6 month Progression Status | Progressed | 10 Participants |
| DSC MRI | Association of Baseline FMISO PET and MRI Features With Time-to-Progression (TTP) | 6 month Progression Status | Progression Free | 27 Participants |
| DSC MRI | Association of Baseline FMISO PET and MRI Features With Time-to-Progression (TTP) | 9 Month Progression Status | Progressed | 19 Participants |
| DSC MRI | Association of Baseline FMISO PET and MRI Features With Time-to-Progression (TTP) | 9 Month Progression Status | Progression Free | 18 Participants |
| DCE MRI | Association of Baseline FMISO PET and MRI Features With Time-to-Progression (TTP) | 9 Month Progression Status | Progression Free | 12 Participants |
| DCE MRI | Association of Baseline FMISO PET and MRI Features With Time-to-Progression (TTP) | 6 month Progression Status | Progressed | 11 Participants |
| DCE MRI | Association of Baseline FMISO PET and MRI Features With Time-to-Progression (TTP) | 6 month Progression Status | Progression Free | 20 Participants |
| DCE MRI | Association of Baseline FMISO PET and MRI Features With Time-to-Progression (TTP) | 9 Month Progression Status | Progressed | 19 Participants |
| DWI-MRI | Association of Baseline FMISO PET and MRI Features With Time-to-Progression (TTP) | 9 Month Progression Status | Progressed | 21 Participants |
| DWI-MRI | Association of Baseline FMISO PET and MRI Features With Time-to-Progression (TTP) | 6 month Progression Status | Progression Free | 28 Participants |
| DWI-MRI | Association of Baseline FMISO PET and MRI Features With Time-to-Progression (TTP) | 6 month Progression Status | Progressed | 11 Participants |
| DWI-MRI | Association of Baseline FMISO PET and MRI Features With Time-to-Progression (TTP) | 9 Month Progression Status | Progression Free | 18 Participants |
Comparison: Apparent Diffusion Coefficient (ADC) high values were modeled with a univariate Logistic regression model for PFS6p-value: 0.192195% CI: [0.735, 1.064]Regression, Logistic
Comparison: 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.p-value: 0.3395% CI: [0.8, 1.91]Regression, Cox
Comparison: 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.p-value: 0.7295% CI: [0.61, 1.4]Regression, Cox
Comparison: 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.p-value: 0.35595% CI: [0.98, 1.04]Regression, Cox
Comparison: 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.p-value: 0.07495% CI: [0.99, 1.23]Regression, Cox
Comparison: 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.p-value: 0.02195% CI: [1.04, 1.63]Regression, Cox
Comparison: 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.p-value: 0.009695% CI: [1.06, 1.54]Regression, Cox
Comparison: 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.p-value: 0.03895% CI: [1.01, 1.38]Regression, Cox
Comparison: Logistic regression for SUVpeak to predict PFS6p-value: 0.325395% CI: [0.318, 1.463]Regression, Logistic
Comparison: TBmax was modeled with a univariate logistic regression model for PFS6.p-value: 0.983695% CI: [0.403, 2.434]Regression, Logistic
Comparison: Hypoxic Volume (HV) was modeled with a logistic regression model for 6month progression free survival (PFS6) .p-value: 0.156695% CI: [0.9, 1.017]Regression, Logistic
Comparison: 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.p-value: 0.955495% CI: [0.775, 1.273]Regression, Logistic
Comparison: 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 PFS6p-value: 0.694195% CI: [0.602, 1.402]Regression, Logistic
Comparison: 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.p-value: 0.13495% CI: [0.506, 1.095]Regression, Logistic
Comparison: 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.p-value: 0.264295% CI: [0.58, 1.161]Regression, Logistic
Comparison: Apparent Diffusion Coefficient (ADC) low values were modeled with a univariate logistic regression model for PFS6p-value: 0.506995% CI: [0.539, 1.357]Regression, Logistic
Comparison: 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 PFS9.95% CI: [0.42, 0.79]
Comparison: 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 PFS9.95% CI: [0.39, 0.78]
Comparison: 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 PFS9.95% CI: [0.46, 0.83]
Comparison: 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 PFS9.95% CI: [0.42, 0.83]
Comparison: 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 PFS9.95% CI: [0.44, 0.84]
Comparison: nRCBV provides a measure of tumor vasculature Receiver Operating Characteristic(ROC) analysis was perform to determine the accuracy of this marker to predict PFS9.95% CI: [0.54, 0.89]
Comparison: 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 PFS9.95% CI: [0.55, 0.89]
Secondary
Correlation Between MRS Markers and MR Imaging Markers of Vascularity as Well as Between MRS Markers and PET Markers of Tumor Hypoxia
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
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Evaluable | Correlation Between MRS Markers and MR Imaging Markers of Vascularity as Well as Between MRS Markers and PET Markers of Tumor Hypoxia | NAA/Cho Tumor | -0.38 correlation coefficient |
| Evaluable | Correlation Between MRS Markers and MR Imaging Markers of Vascularity as Well as Between MRS Markers and PET Markers of Tumor Hypoxia | NAA/Cho Periphery | -0.33 correlation coefficient |
| Evaluable | Correlation Between MRS Markers and MR Imaging Markers of Vascularity as Well as Between MRS Markers and PET Markers of Tumor Hypoxia | Cho/Cr Tumor | 0.24 correlation coefficient |
| Evaluable | Correlation Between MRS Markers and MR Imaging Markers of Vascularity as Well as Between MRS Markers and PET Markers of Tumor Hypoxia | Cho/Cr Periphery | 0.17 correlation coefficient |
| Evaluable | Correlation Between MRS Markers and MR Imaging Markers of Vascularity as Well as Between MRS Markers and PET Markers of Tumor Hypoxia | Lac/Cr Tumor | -0.27 correlation coefficient |
| Evaluable | Correlation Between MRS Markers and MR Imaging Markers of Vascularity as Well as Between MRS Markers and PET Markers of Tumor Hypoxia | Lac/Cr Periphery | -0.09 correlation coefficient |
| Evaluable | Correlation Between MRS Markers and MR Imaging Markers of Vascularity as Well as Between MRS Markers and PET Markers of Tumor Hypoxia | Lac/NAA Tumor | -0.02 correlation coefficient |
| Evaluable | Correlation Between MRS Markers and MR Imaging Markers of Vascularity as Well as Between MRS Markers and PET Markers of Tumor Hypoxia | Lac/NAA Periphery | -0.01 correlation coefficient |
| FMISO-PET | Correlation Between MRS Markers and MR Imaging Markers of Vascularity as Well as Between MRS Markers and PET Markers of Tumor Hypoxia | Lac/Cr Periphery | -0.11 correlation coefficient |
| FMISO-PET | Correlation Between MRS Markers and MR Imaging Markers of Vascularity as Well as Between MRS Markers and PET Markers of Tumor Hypoxia | Lac/Cr Tumor | -0.25 correlation coefficient |
| FMISO-PET | Correlation Between MRS Markers and MR Imaging Markers of Vascularity as Well as Between MRS Markers and PET Markers of Tumor Hypoxia | NAA/Cho Periphery | -0.34 correlation coefficient |
| FMISO-PET | Correlation Between MRS Markers and MR Imaging Markers of Vascularity as Well as Between MRS Markers and PET Markers of Tumor Hypoxia | Lac/NAA Periphery | -0.01 correlation coefficient |
| FMISO-PET | Correlation Between MRS Markers and MR Imaging Markers of Vascularity as Well as Between MRS Markers and PET Markers of Tumor Hypoxia | Lac/NAA Tumor | -0.01 correlation coefficient |
| FMISO-PET | Correlation Between MRS Markers and MR Imaging Markers of Vascularity as Well as Between MRS Markers and PET Markers of Tumor Hypoxia | Cho/Cr Periphery | 0.20 correlation coefficient |
| FMISO-PET | Correlation Between MRS Markers and MR Imaging Markers of Vascularity as Well as Between MRS Markers and PET Markers of Tumor Hypoxia | Cho/Cr Tumor | 0.28 correlation coefficient |
| FMISO-PET | Correlation Between MRS Markers and MR Imaging Markers of Vascularity as Well as Between MRS Markers and PET Markers of Tumor Hypoxia | NAA/Cho Tumor | -0.41 correlation coefficient |
| DSC MRI | Correlation Between MRS Markers and MR Imaging Markers of Vascularity as Well as Between MRS Markers and PET Markers of Tumor Hypoxia | Lac/NAA Tumor | 0.23 correlation coefficient |
| DSC MRI | Correlation Between MRS Markers and MR Imaging Markers of Vascularity as Well as Between MRS Markers and PET Markers of Tumor Hypoxia | Cho/Cr Tumor | -0.2 correlation coefficient |
| DSC MRI | Correlation Between MRS Markers and MR Imaging Markers of Vascularity as Well as Between MRS Markers and PET Markers of Tumor Hypoxia | Cho/Cr Periphery | -0.27 correlation coefficient |
| DSC MRI | Correlation Between MRS Markers and MR Imaging Markers of Vascularity as Well as Between MRS Markers and PET Markers of Tumor Hypoxia | Lac/Cr Tumor | -0.06 correlation coefficient |
| DSC MRI | Correlation Between MRS Markers and MR Imaging Markers of Vascularity as Well as Between MRS Markers and PET Markers of Tumor Hypoxia | Lac/Cr Periphery | 0.10 correlation coefficient |
| DSC MRI | Correlation Between MRS Markers and MR Imaging Markers of Vascularity as Well as Between MRS Markers and PET Markers of Tumor Hypoxia | Lac/NAA Periphery | 0.33 correlation coefficient |
| DSC MRI | Correlation Between MRS Markers and MR Imaging Markers of Vascularity as Well as Between MRS Markers and PET Markers of Tumor Hypoxia | NAA/Cho Tumor | -0.08 correlation coefficient |
| DSC MRI | Correlation Between MRS Markers and MR Imaging Markers of Vascularity as Well as Between MRS Markers and PET Markers of Tumor Hypoxia | NAA/Cho Periphery | 0.14 correlation coefficient |
| DCE MRI | Correlation Between MRS Markers and MR Imaging Markers of Vascularity as Well as Between MRS Markers and PET Markers of Tumor Hypoxia | Cho/Cr Tumor | 0.03 correlation coefficient |
| DCE MRI | Correlation Between MRS Markers and MR Imaging Markers of Vascularity as Well as Between MRS Markers and PET Markers of Tumor Hypoxia | Cho/Cr Periphery | 0.11 correlation coefficient |
| DCE MRI | Correlation Between MRS Markers and MR Imaging Markers of Vascularity as Well as Between MRS Markers and PET Markers of Tumor Hypoxia | NAA/Cho Periphery | -0.41 correlation coefficient |
| DCE MRI | Correlation Between MRS Markers and MR Imaging Markers of Vascularity as Well as Between MRS Markers and PET Markers of Tumor Hypoxia | NAA/Cho Tumor | -.33 correlation coefficient |
| DCE MRI | Correlation Between MRS Markers and MR Imaging Markers of Vascularity as Well as Between MRS Markers and PET Markers of Tumor Hypoxia | Lac/Cr Tumor | -0.29 correlation coefficient |
| DCE MRI | Correlation Between MRS Markers and MR Imaging Markers of Vascularity as Well as Between MRS Markers and PET Markers of Tumor Hypoxia | Lac/NAA Periphery | -0.04 correlation coefficient |
| DCE MRI | Correlation Between MRS Markers and MR Imaging Markers of Vascularity as Well as Between MRS Markers and PET Markers of Tumor Hypoxia | Lac/NAA Tumor | -0.18 correlation coefficient |
| DCE MRI | Correlation Between MRS Markers and MR Imaging Markers of Vascularity as Well as Between MRS Markers and PET Markers of Tumor Hypoxia | Lac/Cr Periphery | -0.15 correlation coefficient |
Secondary
Correlation Between T/Cmax and T/Bmax
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Evaluable | Correlation Between T/Cmax and T/Bmax | 0.98 correlation coefficient |
Secondary
Reproducibility of the Baseline FMISO PET Uptake Parameters as Assessed by Baseline Test and Retest PET Scans
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)
Population: Analysis will be performed SUVmax and SUV Peak, average and maximum values, across patients and by target tumor.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Evaluable | Reproducibility of the Baseline FMISO PET Uptake Parameters as Assessed by Baseline Test and Retest PET Scans | SUVmax : Average across all lesions by participant | 7.03 Within Subj. Coefficient of Variation % |
| Evaluable | Reproducibility of the Baseline FMISO PET Uptake Parameters as Assessed by Baseline Test and Retest PET Scans | SUVmax : Maximum across all lesions by participant | 9.60 Within Subj. Coefficient of Variation % |
| Evaluable | Reproducibility of the Baseline FMISO PET Uptake Parameters as Assessed by Baseline Test and Retest PET Scans | SUVmax : Target Lesion | 8.18 Within Subj. Coefficient of Variation % |
| Evaluable | Reproducibility of the Baseline FMISO PET Uptake Parameters as Assessed by Baseline Test and Retest PET Scans | SUVpeak: Average across all lesions by participant | 7.08 Within Subj. Coefficient of Variation % |
| Evaluable | Reproducibility of the Baseline FMISO PET Uptake Parameters as Assessed by Baseline Test and Retest PET Scans | SUVpeak: Maximum across all lesions by participant | 9.20 Within Subj. Coefficient of Variation % |
| Evaluable | Reproducibility of the Baseline FMISO PET Uptake Parameters as Assessed by Baseline Test and Retest PET Scans | SUVpeak: Target Lesion | 8.24 Within Subj. Coefficient of Variation % |
Other Pre-specified
DWI Apparent Diffusion Coefficient (ADC)
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
Population: Participants having a usable FMISO\\PET and DWI\\MRI scans
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Evaluable | DWI Apparent Diffusion Coefficient (ADC) | High | 1.48 mm^2/s | Standard Deviation 0.39 |
| Evaluable | DWI Apparent Diffusion Coefficient (ADC) | Low | 0.99 mm^2/s | Standard Deviation 0.15 |
Other Pre-specified
Hypoxic Volume as a Measure of Tumor Hypoxia
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Evaluable | Hypoxic Volume as a Measure of Tumor Hypoxia | 14.21 milliliters | Standard Deviation 11.61 |
Other Pre-specified
Normalized Relative Cerebral Blood Volume (nRCBV) and Normalized Cerebral Blood Flow (nCBF)
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
Population: Evaluable participants with both usable FMISO\\PET and DSC\\MRI.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Evaluable | Normalized Relative Cerebral Blood Volume (nRCBV) and Normalized Cerebral Blood Flow (nCBF) | nRCBV | 3.13 ratio | Standard Deviation 1.86 |
| Evaluable | Normalized Relative Cerebral Blood Volume (nRCBV) and Normalized Cerebral Blood Flow (nCBF) | nCBF | 3.36 ratio | Standard Deviation 2.02 |
Other Pre-specified
Overall and Progression Free Survival
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)
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Evaluable | Overall and Progression Free Survival | Median OS time | 408 days |
| Evaluable | Overall and Progression Free Survival | Median PFS | 258 days |
Other Pre-specified
Summary of Mean and Median Ktrans Across Participants.
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
Population: Evaluable patients with usable FMISO\\PET and DCE\\MRI
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Evaluable | Summary of Mean and Median Ktrans Across Participants. | Median kTrans | 0.03 1/min | Standard Deviation 0.07 |
| Evaluable | Summary of Mean and Median Ktrans Across Participants. | Mean kTrans | 0.04 1/min | Standard Deviation 0.03 |
Other Pre-specified
SUVpeak and T/Bmax as Measures of Tumor Hypoxia
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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Evaluable | SUVpeak and T/Bmax as Measures of Tumor Hypoxia | T/Bmax | 2.13 ratio | Standard Deviation 0.77 |
| Evaluable | SUVpeak and T/Bmax as Measures of Tumor Hypoxia | SUVpeak | 2.49 ratio | Standard Deviation 0.89 |