MRI Scans in Evaluating the Effects of Radiation Therapy and Chemotherapy in Patients With Newly Diagnosed Glioblastoma Multiforme or Anaplastic Glioma

• Sponsor: Massachusetts General Hospital (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00756106
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 15
• Location: 1
• Arm: 1
• Duration (Months): 43
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

RATIONALE: Diagnostic procedures, such as MRI, may help in learning how well radiation therapy and chemotherapy work in killing tumor cells and allow doctors to plan better treatment.

PURPOSE: This clinical trial is studying MRI scans to see how well they evaluate the effects of radiation therapy and chemotherapy in patients with newly diagnosed glioblastoma multiforme or anaplastic glioma.

Condition or Disease	Intervention/Treatment	Phase
Brain and Central Nervous System Tumors	Drug: temozolomide; Other: Imaging biomarker analysis; Radiation: Photon Radiation Therapy	N/A

Detailed Description

OBJECTIVES:

Primary

• To quantitatively compare the relative cerebral blood volume/flow, mean transit time, and mean vessel diameter as measured by perfusion-weighted MRI before, during, and after chemoradiotherapy in patients with newly diagnosed glioblastoma multiforme.

• To measure the permeability-surface area product on a voxel-by-voxel basis before, during, and after chemoradiotherapy in these patients.

• To measure the full water self-diffusion tensor on a voxel-by-voxel basis before, during, and after chemoradiotherapy in these patients.

• To compare the tensor fractional anisotropy before, during, and after chemoradiotherapy in these patients.

• To compare the relative regional concentrations of choline, N-acetyl-asparate, and myoinositol as measured by magnetic resonance spectroscopy before, during, and after chemoradiotherapy to interrogate cell membrane turnover, neuronal integrity, and glial reactions.

• To test the affects of a short period of 100% oxygen inhalation on imaging of tumor and surrounding tissue regions of interest, specifically cerebral blood volume changes in each area as compared to room air.

Secondary

• To collect blood and urine samples for correlation analysis between imaging changes, molecular markers (including genetic markers), and clinical outcome of glioblastoma multiforme (phenotypic information).

• To correlate blood and urine biomarkers and blood genetic markers with tumor expression of these markers.

OUTLINE: Patients undergo radiotherapy once daily 5 days a week for 6 weeks. Patients also receive oral temozolomide once daily 7 days a week during radiotherapy. After completion of chemoradiotherapy, patients receive oral temozolomide once daily for 5 days. Treatment with temozolomide repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Patients undergo MRI, including perfusion- and diffusion-weighted MRI, diffusion tensor imaging, and magnetic resonance spectroscopy prior to initiation of chemoradiotherapy, once weekly during chemoradiotherapy, and then monthly until tumor progression or until completion of 6 courses of post chemoradiotherapy.

After completion of study treatment, patients are followed annually.

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Diagnostic
• Official Title: Quantitative Assessment of the Early and Late Effects of Radiation and Chemotherapy on Glioblastoma Using Multiple MRI Techniques
• Study Start Date: Jul 1, 2008
• Actual Primary Completion Date: Feb 1, 2012
• Actual Study Completion Date: Feb 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Temozolomide and Radiation Therapy	Drug: temozolomide; Temozolomide is administered according to standard of care practice guidelines. Dosing may be modified at the discretion of the treating investigator.; Other: Imaging biomarker analysis; MRI; Radiation: Photon Radiation Therapy; Radiation is administered to the tumor plus edema with a 1-2 centimeter margin for a total dose of 60 Gy in 30 fractions.

Outcome Measures

Primary Outcome Measures

1. Relative Cerebral Blood Volume as Measured by Perfusion-weighted MRI Before, During, and After Chemoradiotherapy [Baseline, weekly during treatment, monthly following treatment for up to six months]

   Relative cerebral blood volume (rCBV) is the blood volume in the region of interest (ROI) divided by the blood volume in the symmetrical region on the other side of the normal brain (control region). CBV was assessed using spin-echo post-contrast T1-weighted images. Multiple images were used to assess each participant at every time-point and the median value for each participant was calculated by time-point. The data presented represent the average of those median values at each time-point. The baseline value was measured twice (representing baseline 1 and 2) to make sure that the value was reproducible and to account for any variation attributable to measurement variation. CRT: Chemoradiotherapy Cx: The cycle number TMZ: temozolomide

2. Relative Cerebral Blood Flow as Measured by Perfusion-weighted MRI Before, During, and After Chemoradiotherapy [Baseline, weekly during treatment, monthly following treatment for up to six months]

   Relative cerebral blood flow (rCBF) is the blood flow rate (the volume of blood passing through the specified are over a specified period of time) in the region of interest (ROI) divided by the blood flow rate in the symmetrical region on the other side of the normal brain (control region). CBF was assessed using spin-echo post-contrast T1-weighted images. CBF was assessed using spin-echo post-contrast T1-weighted images. Multiple images were used to assess each participant at every time-point and the median value for each participant was calculated by time-point. The data presented represent the average of those median values at each time-point. The baseline value was measured twice (representing baseline 1 and 2) to make sure that the value was reproducible and to account for any variation attributable to measurement variation. CRT: Chemoradiotherapy Cx: The cycle number TMZ: temozolomide

3. Vessel Diameter as Measured by Perfusion-weighted MRI Before, During, and After Chemoradiotherapy [Baseline, weekly during treatment, monthly following treatment for up to six months]

4. Mean Transit Time as Measured by Perfusion-weighted MRI Before, During, and After Chemoradiotherapy [Baseline, weekly during treatment, monthly following treatment for up to six months]

   Mean transit time (MTT) corresponds to the average time, in seconds, that red blood cells spend within a determinate volume of capillary circulation.

5. Permeability-surface Area Product Before, During, and After Chemoradiotherapy [Baseline, weekly during treatment, monthly following treatment for up to six months]

   Permeability-surface Area Product (Ktrans). Ktrans reflects the efflux rate of contrast from blood plasma into the tissue extravascular extracellular space (EES). Ktrans was assessed using post-contrast T1-weighted images. Multiple images were used to assess each participant at every time-point and the median value for each participant was calculated by time-point. The data presented represent the average of those median values at each time-point. CRT: Chemoradiotherapy Cx: The cycle number TMZ: temozolomide

6. Apparent Diffusion Coefficient Before, During, and After Chemoradiotherapy [Baseline, weekly during treatment, monthly following treatment for up to six months]

   Apparent diffusion coefficient (ADC) is a measure of the magnitude of diffusion (of water molecules) within tissue. ADC was assessed using post-contrast T1-weighted images. Multiple images were used to assess each participant at every time-point and the median value for each participant was calculated by time-point. The data presented represent the average of those median values at each time-point. CRT: Chemoradiotherapy Cx: The cycle number TMZ: temozolomide

7. Tensor Fractional Anisotropy Before, During, and After Chemoradiotherapy [Baseline, weekly during treatment, monthly following treatment for up to six months]

   Fractional anisotropy (FA) is a measure of the directionality of the molecular motion of water.

8. Relative Regional Concentrations of Choline, N-acetyl-asparate, and Myoinositol as Measured by Magnetic Resonance Spectroscopy Before, During, and After Chemoradiotherapy to Interrogate Cell Membrane Turnover, Neuronal Integrity, and Glial Reactions [Baseline, weekly during treatment, monthly following treatment for up to six months]

9. Affects of a Short Period of 100% Oxygen Inhalation on Imaging of Tumor and Surrounding Tissue Regions of Interest, Specifically Cerebral Blood Volume Changes in Each Area as Compared to Room Air [Baseline, weekly during treatment, monthly following treatment for up to six months]

Eligibility Criteria

Criteria

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

DISEASE CHARACTERISTICS:

• Newly diagnosed anaplastic glioma (WHO grade III) or glioblastoma multiforme (WHO grade IV)

• Measurable disease

• Residual tumor size after surgery ≥ 1 cm in one dimension

• Planning to undergo standard chemoradiotherapy with temozolomide

PATIENT CHARACTERISTICS:

• Glomerular filtration rate ≥ 60 mL/min

• Mini Mental Status Exam score > 15

• Sufficiently competent to give informed consent

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective barrier contraception during and for 2 months after completion of study treatment

• No contraindication to MRI or to use of the contrast agent gadolinium, including any of the following:

• Claustrophobia

• Metallic objects or implanted medical devices (e.g., 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

• High risk for kidney disease (e.g., age > 60 years, diabetes, or history of systemic lupus erythematosus or multiple myeloma)

• No known history of chronic obstructive pulmonary disease or emphysema

• No other co-existing condition that, in the judgement of the investigator, may increase risk to the patient

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• Non-VEGF investigational agent allowed

• No concurrent chemotherapy (other than temozolomide)

• No concurrent electron, proton, particle, or implant radiotherapy

• No concurrent stereotactic radiosurgery

• No concurrent anti-VEGF anti-tumor agents

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital	Boston	Massachusetts	United States	02114

Sponsors and Collaborators

• Massachusetts General Hospital
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Elizabeth Gerstner, MD, Massachusetts General Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Elizabeth R. Gerstner, MD, MD, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT00756106
• Other Study ID Numbers: 07-292
• First Posted: Sep 19, 2008
• Last Update Posted: May 13, 2020
• Last Verified: Apr 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Elizabeth R. Gerstner, MD, MD, Massachusetts General Hospital: adult glioblastoma; adult giant cell glioblastoma; adult gliosarcoma; adult anaplastic astrocytoma; adult anaplastic ependymoma; adult anaplastic oligodendroglioma; adult mixed glioma
• Additional relevant MeSH terms: Glioblastoma; Nervous System Neoplasms; Central Nervous System Neoplasms; Temozolomide

Study Results

Participant Flow

Arm/Group Title	Temozolomide and Radiation Therapy
Arm/Group Description	temozolomide: Temozolomide is administered according to standard of care practice guidelines. Dosing may be modified at the discretion of the treating investigator. Imaging biomarker analysis: MRI Photon Radiation Therapy: Radiation is administered to the tumor plus edema with a 1-2 centimeter margin for a total dose of 60 Gy in 30 fractions.
Period Title: Overall Study
STARTED	15
COMPLETED	3
NOT COMPLETED	12

Baseline Characteristics

Arm/Group Title	Temozolomide and Radiation Therapy
Arm/Group Description	temozolomide: Temozolomide is administered according to standard of care practice guidelines. Dosing may be modified at the discretion of the treating investigator. Imaging biomarker analysis: MRI Photon Radiation Therapy: Radiation is administered to the tumor plus edema with a 1-2 centimeter margin for a total dose of 60 Gy in 30 fractions.
Overall Participants	14
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	60
Sex: Female, Male (Count of Participants)
Female	8 57.1%
Male	6 42.9%
Region of Enrollment (participants) [Number]
United States	14 100%
Karnofsky Performance Status (units on a scale) [Median (Full Range) ]
Median (Full Range) [units on a scale]	90

Outcome Measures

1. Primary Outcome

Title	Relative Cerebral Blood Volume as Measured by Perfusion-weighted MRI Before, During, and After Chemoradiotherapy
Description	Relative cerebral blood volume (rCBV) is the blood volume in the region of interest (ROI) divided by the blood volume in the symmetrical region on the other side of the normal brain (control region). CBV was assessed using spin-echo post-contrast T1-weighted images. Multiple images were used to assess each participant at every time-point and the median value for each participant was calculated by time-point. The data presented represent the average of those median values at each time-point. The baseline value was measured twice (representing baseline 1 and 2) to make sure that the value was reproducible and to account for any variation attributable to measurement variation. CRT: Chemoradiotherapy Cx: The cycle number TMZ: temozolomide
Time Frame	Baseline, weekly during treatment, monthly following treatment for up to six months

Outcome Measure Data

Analysis Population Description

One participant withdrew consent after baseline and was excluded from the analysis set. The number of patients evaluated decreased over time due to participants experiencing disease progression and discontinuing from the study

Arm/Group Title	Temozolomide and Radiation Therapy
Arm/Group Description	temozolomide: Temozolomide is administered according to standard of care practice guidelines. Dosing may be modified at the discretion of the treating investigator. Imaging biomarker analysis: MRI Photon Radiation Therapy: Radiation is administered to the tumor plus edema with a 1-2 centimeter margin for a total dose of 60 Gy in 30 fractions.
Measure Participants	14
Baseline 1	0.88
Baseline 2	0.90
Week 1 CRT	0.95
Week 2 CRT	1.0
Week 3 CRT	0.88
Week 4 CRT	0.83
Week 5 CRT	0.86
Week 6 CRT	0.76
Pre-C1 TMZ	0.68
Pre-C2 TMZ	0.61
Pre-C3 TMZ	0.59
Pre-C4 TMZ	0.65
Pre-C5 TMZ	0.61
Pre-C6 TMZ	0.64
Post-TMZ	0.32

2. Primary Outcome

Title	Relative Cerebral Blood Flow as Measured by Perfusion-weighted MRI Before, During, and After Chemoradiotherapy
Description	Relative cerebral blood flow (rCBF) is the blood flow rate (the volume of blood passing through the specified are over a specified period of time) in the region of interest (ROI) divided by the blood flow rate in the symmetrical region on the other side of the normal brain (control region). CBF was assessed using spin-echo post-contrast T1-weighted images. CBF was assessed using spin-echo post-contrast T1-weighted images. Multiple images were used to assess each participant at every time-point and the median value for each participant was calculated by time-point. The data presented represent the average of those median values at each time-point. The baseline value was measured twice (representing baseline 1 and 2) to make sure that the value was reproducible and to account for any variation attributable to measurement variation. CRT: Chemoradiotherapy Cx: The cycle number TMZ: temozolomide
Time Frame	Baseline, weekly during treatment, monthly following treatment for up to six months

Outcome Measure Data

Analysis Population Description

One participant withdrew consent after baseline and was excluded from the analysis set. The number of patients evaluated decreased over time due to participants experiencing disease progression and discontinuing from the study

Arm/Group Title	Temozolomide and Radiation Therapy
Arm/Group Description	temozolomide: Temozolomide is administered according to standard of care practice guidelines. Dosing may be modified at the discretion of the treating investigator. Imaging biomarker analysis: MRI Photon Radiation Therapy: Radiation is administered to the tumor plus edema with a 1-2 centimeter margin for a total dose of 60 Gy in 30 fractions.
Measure Participants	14
Baseline 1	0.83
Baseline 2	0.86
Week 1 CRT	0.92
Week 2 CRT	0.94
Week 3 CRT	0.80
Week 4 CRT	0.79
Week 5 CRT	0.83
Week 6 CRT	0.73
Pre-C1 TMZ	0.63
Pre-C2 TMZ	0.59
Pre-C3 TMZ	0.60
Pre-C4 TMZ	0.60
Pre-C5 TMZ	0.52
Pre-C6 TMZ	0.47
Post-TMZ	0.37

3. Primary Outcome

Title	Vessel Diameter as Measured by Perfusion-weighted MRI Before, During, and After Chemoradiotherapy
Time Frame	Baseline, weekly during treatment, monthly following treatment for up to six months

Outcome Measure Data

Analysis Population Description

Data not collected

Arm/Group Title	Temozolomide and Radiation Therapy
Arm/Group Description	temozolomide: Temozolomide is administered according to standard of care practice guidelines. Dosing may be modified at the discretion of the treating investigator. Imaging biomarker analysis: MRI Photon Radiation Therapy: Radiation is administered to the tumor plus edema with a 1-2 centimeter margin for a total dose of 60 Gy in 30 fractions.
Measure Participants	0

4. Primary Outcome

Title	Mean Transit Time as Measured by Perfusion-weighted MRI Before, During, and After Chemoradiotherapy
Description	Mean transit time (MTT) corresponds to the average time, in seconds, that red blood cells spend within a determinate volume of capillary circulation.
Time Frame	Baseline, weekly during treatment, monthly following treatment for up to six months

Outcome Measure Data

Analysis Population Description

Data not collected

Arm/Group Title	Temozolomide and Radiation Therapy
Arm/Group Description	temozolomide: Temozolomide is administered according to standard of care practice guidelines. Dosing may be modified at the discretion of the treating investigator. Imaging biomarker analysis: MRI Photon Radiation Therapy: Radiation is administered to the tumor plus edema with a 1-2 centimeter margin for a total dose of 60 Gy in 30 fractions.
Measure Participants	0

5. Primary Outcome

Title	Permeability-surface Area Product Before, During, and After Chemoradiotherapy
Description	Permeability-surface Area Product (Ktrans). Ktrans reflects the efflux rate of contrast from blood plasma into the tissue extravascular extracellular space (EES). Ktrans was assessed using post-contrast T1-weighted images. Multiple images were used to assess each participant at every time-point and the median value for each participant was calculated by time-point. The data presented represent the average of those median values at each time-point. CRT: Chemoradiotherapy Cx: The cycle number TMZ: temozolomide
Time Frame	Baseline, weekly during treatment, monthly following treatment for up to six months

Outcome Measure Data

Analysis Population Description

One participant withdrew consent after baseline and was excluded from the analysis set. The number of patients evaluated decreased over time due to participants experiencing disease progression and discontinuing from the study

Arm/Group Title	Temozolomide and Radiation Therapy
Arm/Group Description	temozolomide: Temozolomide is administered according to standard of care practice guidelines. Dosing may be modified at the discretion of the treating investigator. Imaging biomarker analysis: MRI Photon Radiation Therapy: Radiation is administered to the tumor plus edema with a 1-2 centimeter margin for a total dose of 60 Gy in 30 fractions.
Measure Participants	14
Baseline 1	0.053
Baseline 2	0.039
Week 1 CRT	0.055
Week 2 CRT	0.048
Week 3 CRT	0.055
Week 4 CRT	0.053
Week 5 CRT	0.058
Week 6 CRT	0.059
Pre-C1 TMZ	0.063
Pre-C2 TMZ	0.042
Pre-C3 TMZ	0.050
Pre-C4 TMZ	0.058
Pre-C5 TMZ	0.056
Pre-C6 TMZ	0.060
Post-TMZ	0.032

6. Primary Outcome

Title	Apparent Diffusion Coefficient Before, During, and After Chemoradiotherapy
Description	Apparent diffusion coefficient (ADC) is a measure of the magnitude of diffusion (of water molecules) within tissue. ADC was assessed using post-contrast T1-weighted images. Multiple images were used to assess each participant at every time-point and the median value for each participant was calculated by time-point. The data presented represent the average of those median values at each time-point. CRT: Chemoradiotherapy Cx: The cycle number TMZ: temozolomide
Time Frame	Baseline, weekly during treatment, monthly following treatment for up to six months

Outcome Measure Data

Analysis Population Description

One participant withdrew consent after baseline and was excluded from the analysis set. The number of patients evaluated decreased over time due to participants experiencing disease progression and discontinuing from the study

Arm/Group Title	Temozolomide and Radiation Therapy
Arm/Group Description	temozolomide: Temozolomide is administered according to standard of care practice guidelines. Dosing may be modified at the discretion of the treating investigator. Imaging biomarker analysis: MRI Photon Radiation Therapy: Radiation is administered to the tumor plus edema with a 1-2 centimeter margin for a total dose of 60 Gy in 30 fractions.
Measure Participants	14
Baseline 1	0.00110
Baseline 2	0.00113
Week 1 CRT	0.00106
Week 2 CRT	0.00110
Week 3 CRT	0.00118
Week 4 CRT	0.00122
Week 5 CRT	0.00125
Week 6 CRT	0.00125
Pre-C1 TMZ	0.00132
Pre-C2 TMZ	0.00127
Pre-C3 TMZ	0.00108
Pre-C4 TMZ	0.00133
Pre-C5 TMZ	0.00148
Pre-C6 TMZ	0.00179
Post-TMZ	0.00140

7. Primary Outcome

Title	Tensor Fractional Anisotropy Before, During, and After Chemoradiotherapy
Description	Fractional anisotropy (FA) is a measure of the directionality of the molecular motion of water.
Time Frame	Baseline, weekly during treatment, monthly following treatment for up to six months

Outcome Measure Data

Analysis Population Description

Data not collected

Arm/Group Title	Temozolomide and Radiation Therapy
Arm/Group Description	temozolomide: Temozolomide is administered according to standard of care practice guidelines. Dosing may be modified at the discretion of the treating investigator. Imaging biomarker analysis: MRI Photon Radiation Therapy: Radiation is administered to the tumor plus edema with a 1-2 centimeter margin for a total dose of 60 Gy in 30 fractions.
Measure Participants	0

8. Primary Outcome

Title	Relative Regional Concentrations of Choline, N-acetyl-asparate, and Myoinositol as Measured by Magnetic Resonance Spectroscopy Before, During, and After Chemoradiotherapy to Interrogate Cell Membrane Turnover, Neuronal Integrity, and Glial Reactions
Time Frame	Baseline, weekly during treatment, monthly following treatment for up to six months

Outcome Measure Data

Analysis Population Description

Data not collected

Arm/Group Title	Temozolomide and Radiation Therapy
Arm/Group Description	temozolomide: Temozolomide is administered according to standard of care practice guidelines. Dosing may be modified at the discretion of the treating investigator. Imaging biomarker analysis: MRI Photon Radiation Therapy: Radiation is administered to the tumor plus edema with a 1-2 centimeter margin for a total dose of 60 Gy in 30 fractions.
Measure Participants	0

9. Primary Outcome

Title	Affects of a Short Period of 100% Oxygen Inhalation on Imaging of Tumor and Surrounding Tissue Regions of Interest, Specifically Cerebral Blood Volume Changes in Each Area as Compared to Room Air
Time Frame	Baseline, weekly during treatment, monthly following treatment for up to six months

Outcome Measure Data

Analysis Population Description

Data not collected

Arm/Group Title	Temozolomide and Radiation Therapy
Arm/Group Description	temozolomide: Temozolomide is administered according to standard of care practice guidelines. Dosing may be modified at the discretion of the treating investigator. Imaging biomarker analysis: MRI Photon Radiation Therapy: Radiation is administered to the tumor plus edema with a 1-2 centimeter margin for a total dose of 60 Gy in 30 fractions.
Measure Participants	0

Adverse Events

Time Frame	Adverse event data were not collected
Adverse Event Reporting Description	Adverse event data were not collected as a part of this study
Arm/Group Title	Temozolomide and Radiation Therapy
Arm/Group Description	temozolomide: Temozolomide is administered according to standard of care practice guidelines. Dosing may be modified at the discretion of the treating investigator. Imaging biomarker analysis: MRI Photon Radiation Therapy: Radiation is administered to the tumor plus edema with a 1-2 centimeter margin for a total dose of 60 Gy in 30 fractions.
All Cause Mortality
	Temozolomide and Radiation Therapy
	Affected / at Risk (%)	# Events
Total	0/0 (NaN)
Serious Adverse Events
	Temozolomide and Radiation Therapy
	Affected / at Risk (%)	# Events
Total	0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Temozolomide and Radiation Therapy
	Affected / at Risk (%)	# Events
Total	0/0 (NaN)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.