MRI and PET Scan Using 18F-Fluoromisonidazole In Assessing Tumor Hypoxia in Patients With Newly Diagnosed Glioblastoma Multiforme

• Association of baseline FMISO PET uptake (HV and T/Bmax) and MRI parameters (Ktrans and CBV) with OS as assessed using Cox-regression model [ Time Frame: Up to 5 years after completion of study ] [ Designated as safety issue: No ]
  The number of pixels in the tumor volume with a T/B ratio > 1.2, indicating hypoxia, is multiplied by the known volume/voxel for the scanner to yield milliliter units to measure the HV. T/Bmax is the pixel in the tumor region with the maximum T/B (tumor:blood) ratio. HV depicts the volume of tumor that has crossed the threshold for hypoxia and T/Bmax depicts the magnitude of the hypoxia. Uni-variate analysis will be carried out for each parameter individually. Any parameter that has achieved statistical significance (P ≤ 0.05) will be included in the multi-variate Cox model.
  
  

• Association of baseline FMISO PET uptake (HV and T/Bmax) and MRI parameters (Ktrans and CBV) with TTP and PFS-6 as assessed using multi-variate Cox model and multi-variate Logistic regression model [ Time Frame: Up to 5 years after completion of study ] [ Designated as safety issue: No ]

  Cox-regression model will be used to study the relationship between TTP and baseline FMISO PET uptake and MRI parameters. Logistic regression model will be used to study the relationship between PFS-6 and baseline FMISO PET uptake and MRI parameters. Uni-variate analysis will be carried out for each parameter individually. Any parameter that has achieved statistical significance (P ≤ 0.05) will be included.

  Disease progression defined by Macdonald criteria: ≥ 25% increase of enhancing tumor area; Neurological status worsened; Stable or increased dose of steroids

  
  
• Reproducibility of the baseline FMISO PET uptake parameters as assessed by baseline "test" and "retest" PET scans [ Time Frame: Baseline and retest within 1 to 7 days after (but prior to the start of therapy) ] [ Designated as safety issue: No ]

  The reproducibility of the baseline FMISO PET will be quantified through intra-class correlation coefficient (ICC) which is defined as the ratio of σb^2 and (σb^2+ σc^2) where σb^2 is the variance of measurements between participants and σc^2 is the variance of measurements within participants.

  For a subset of 15 participants who enroll in the test-retest substudy only. Patients must be scanned using the same ACRIN-approved PET scanner used for trial qualification, using the same protocol-specific parameters consistently at each time point.

  
  
• Correlation between T/Cmax and T/Bmax [ Time Frame: At baseline, week 4, and week 10 ] [ Designated as safety issue: No ]
  Pearson correlation coefficient and Spearman's rank correlation coefficient will be used to quantify the correlation between T/Cmax and T/Bmax.
  
  
• Correlation between other MRI parameters (T1Gd, VCI, small vessel CBV, ADC, NAA-Cho ratio, changes in BOLD signal, and T2 lesion volume) and OS, TTP, and PFS-6 [ Time Frame: Baseline and every 3 months for up to 5 years after completion of study ] [ Designated as safety issue: No ]

  Other MRI parameters include: initial size of the lesion measured on T1 post Gd images [T1Gd], vessel caliber index [VCI], small vessel CBV, apparent diffusion coefficient [ADC], values measured from MR spectroscopy such as NAA-Cho ratio, changes in BOLD signal with transient exposure to hyperoxia, and T2 lesion volume.

  Cox-regression model will be used to study the relationship between OS and other MRI parameters. Logistic regression model will be used to study the relationship between PFS-6 and other MRI parameters. Uni-variate analysis will be carried out for each parameter individually.

  
  
• Levels of hypoxic marker expression (HIF1-alpha, GLUT1, CAIX, CD31, and alpha-SMA) as assessed by immunohistochemical staining and MGMT methylation-specific polymerase chain reaction (MSP) [ Time Frame: Tumor tissue obtained at time of diagnosis for marker expression analysis; Patients evaluated for FMISO uptake, PFS-6, and OS every 3 months for up to 5 years after completion of study ] [ Designated as safety issue: No ]
  HIF1-alpha, GLUT1, and CAIX will be used to evaluate degree of hypoxia. CD31 and alpha-SMA will be used to look at tumor blood vessels and pericyte coverage. HIF1-alpha will be scored for percentage of tumor cells positive for cytoplasmic (non-activated) and nuclear (activated) staining; GLUT1 and CAIX will be scored for percentage of tumor cells demonstrating positive membrane staining; CD31 and alpha-SMA staining will be scored by standard microvascular density techniques in the areas of highest vessel density. Each biopsy will be assigned a composite score for each marker.
  
  

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 (T1Gd, VCI, CBV-S, ADC, NAA-Cho, 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 PCR assays.

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