Malignant Glioma
Conditions
Brief summary
This phase II trial studies how well fluorine F 18 fluorodopa (18F-DOPA)-positron emission tomography (PET) works in finding tumors in patients with newly diagnosed gliomas undergoing radiation therapy. Comparing results of diagnostic procedures done before and during radiation therapy may help doctors predict a patient's response to treatment and help plan the best treatment.
Detailed description
PRIMARY OBJECTIVES: I. Compare confirmed-progression free survival at 6 months for grade IV MGMT unmethylated glioma patients after radiation therapy targeting volumes designed with both 18F-DOPA PET and conventional magnetic resonance (MR) image information with historical controls from Mayo Clinic Rochester patients, including those treated on North Central Cancer Treatment Group (NCCTG) clinical trials. SECONDARY OBJECTIVES: I. Compare progression free survival at 12 months for grade III patients after radiation therapy targeting volumes designed with both 18F-DOPA PET and conventional MR image information with historical controls from Mayo Clinic Rochester patients, including those on NCCTG clinical trials. II. Compare patient overall survival after radiation therapy targeting volumes designed with both 18F-DOPA PET and conventional MR image information with historical controls from Mayo Clinic Rochester patients, including those on NCCTG clinical trials. III. Evaluate quality of life after radiotherapy treatment targeting dose escalated volumes defined to include high 18F-DOPA PET uptake. IV. Determine acute and late effect toxicity after radiotherapy treatment targeting dose escalated volumes defined to include high 18F-DOPA PET uptake. V. Compare confirmed-progression free survival at 12 months for grade IV MGMT methylated patients after radiation therapy targeting volumes designed with both 18F-DOPA PET and conventional MR image information with historical controls from Mayo Clinic Rochester patients, including those on NCCTG clinical trials. VI. Compare confirmed-progression free survival in grade IV MGMT un-methylated patients with similar historical controls from Mayo Clinic Rochester patients, including those on NCCTG clinical trials. VII. Compare confirmed-progression free survival in grade IV MGMT methylated patients with similar historical controls from Mayo Clinic Rochester patients, including those on NCCTG clinical trials. TERTIARY OBJECTIVES: I. Compare radiation therapy (RT) treatment volumes defined by MR only with RT treatment volumes defined with both PET and MR information for grade IV glioma patients. II. Compare timing of accurate identification of progression defined by 18F-DOPA PET, perfusion magnetic resonance imaging (pMRI) and conventional MRI for grade IV glioma patients. III. Compare patterns of failure after radiation therapy targeting volumes defined with target volumes designed to with both 18F-DOPA PET and conventional MR image information with patterns of failure for historical controls from Mayo Clinic Rochester patients, including those on NCCTG clinical trials. IV. Compare RT treatment volumes defined by MR only with RT treatment volumes defined with both PET and MR information for grade III glioma patients. V. Evaluate intra- and inter-observer variability with vs. without the addition of 18F-DOPA PET uptake for radiotherapy target volume delineation. VI. Compare timing of accurate identification of progression defined by 18F-DOPA PET, pMRI and conventional MRI for grade III glioma patients. VII. Compare predictive capabilities of 18F-DOPA PET, pMRI and diffusion tensor imaging (DTI) for localization of recurrences for patients treated with 18F-DOPA PET-guided RT dose escalation. OUTLINE: Patients undergo 18F DOPA-PET, pMRI, and DTI within 14 days before radiation therapy, 3-6 weeks after radiation therapy, and during follow-up. Patients also undergo intensity-modulated radiation therapy (IMRT) over 30 fractions and receive temozolomide. After completion of study treatment, patients are followed up periodically for up to 5 years.
Interventions
DRUGTemozolomide
Receive temozolomide
PROCEDUREPerfusion Magnetic Resonance Imaging
Undergo pMRI
PROCEDUREPositron Emission Tomography
Undergo 18F-DOPA-PET
OTHERQuality-of-Life Assessment
Ancillary studies
PROCEDUREDiffusion Weighted Imaging
Undergo DTI
Undergo 18F-DOPA-PET
RADIATIONIntensity-Modulated Radiation Therapy
Undergo IMRT
Sponsors
Mayo Clinic
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
* Histologically confirmed newly diagnosed grade IV malignant glioma; Note: grade III patients are no longer being enrolled * Computed tomography (CT) simulation, immobilization, MRI and PET imaging, treatment planning, and all follow-up MRI and PET scans to be performed at Mayo Clinic Rochester; Note: the actual radiation therapy treatments and follow-up other than imaging can be performed at Mayo Clinic Rochester, Northfield, LaCrosse, Mankato, Eau Claire, or Albert Lea * Provide written informed consent * Ability to complete questionnaire(s) by themselves or with assistance
Exclusion criteria
* Patients diagnosed with anaplastic oligodendroglioma * Unable to undergo MRI scans with contrast (e.g. cardiac pacemaker, defibrillator, kidney failure) * Unable to undergo an 18F-DOPA PET scan (e.g. Parkinson's disease, taking anti-dopaminergic, or dopamine agonist medication or less than 6 half-lives from discontinuance of dopamine agonists); NOTE: other potentially interfering drugs consist of: amoxapine, amphetamine, benztropine, bupropion, buspirone, cocaine, mazindol, methamphetamine, methylphenidate, norephedrine, phentermine, phenylpropanolamine, selegiline, paroxetine, citalopram, and sertraline; if a patient is on any of these drugs, list which ones on the on-study form * Any of the following: * Pregnant women * Nursing women * Men or women of childbearing potential who are unwilling to employ adequate contraception
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Grade IV MGMT Un-methylated Patients That Experience Confirmed-progression-free Survival at 6 Months (CPFS6) | Time from registration to the confirmed disease progression, assessed at 6 months | The proportion of Grade IV MGMT un-methylated patients that experience confirmed-progression-free survival at 6 months (CPFS6). Progression is defined by any of the following: * ≥25% increase in the sum of products of perpendicular diameters of enhancing lesions compared to the smallest tumor measurement obtained either at baseline or best response, on stable or increasing doses of corticosteroids * Significant increase in T2/FLAIR non-enhancing lesion on stable or increasing doses of corticosteroids compared to baseline scan or best response following initiation of therapy, not due to co-morbid events * Any new lesion * Clear clinical deterioration not attributable to other causes apart from the tumor or changes in corticosteroid dose. * Failure to return for evaluation due to death or deteriorating condition * Clear progression of non-measurable disease |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Up to 5 years | The median survival time and 95%CI will be estimated using the method of Kaplan-Meier. |
| Progression Free Survival | Up to 5 years | The median progression-free survival time and 95%CI will be estimated using the method of Kaplan-Meier. |
| Quality of Life Evaluated With the M. D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) Questionnaire | Up to 5 years | The MDASI-BT consists of 28 questions. Twenty-two questions are related to severity of symptoms over the last 24 hours and are answered on a scale of 0-10 where 0=not present and10=as bad as you can imagine. The remaining 6 questions are related to how symptoms have interfered with daily life over the past 24 hours and are answered on a scale of 0-10 where 0=did not interfere and 10=interfered completely. Higher scores indicate greater severity of symptoms and greater interference with daily life. Analysis will include median change percent from baseline. |
| Number of Patients Experiencing Grade 3+ Treatment-related Toxicities | Up to 5 years | Adverse events graded using Common Terminology Criteria for Adverse Events version 4.0 |
| Number of Patients Experiencing Grade 4+ Late Treatment-related Toxicities | Up to 5 years | Late treatment-related toxicities will be assessed using the Radiation Therapy Oncology Group (RTOG) European Organization for Research and the Treatment of Cancer (EORTC) toxicity criteria. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Radiation Therapy Treatment Volumes Defined by Magnetic Resonance Imaging Only or Defined With Both Positron Emission Tomography and Magnetic Resonance Imaging Information for Grade IV Glioma Patients | Up to 5 years | Paired t-test statistical analysis will be performed to determine if any differences exist and the level of statistical significance between treatment volumes defined by magnetic resonance imaging only and treatment volumes defined with both positron emission tomography and magnetic resonance imaging information. The analysis of volumes from 72 grade IV patients will have 90% power to detect differences in volumes with an effect size of 0.39 using a paired t-test with a 0.05 two-sided significance level. Alternate metrics for comparison will also be assessed, including spatial overlap, distan |
| Inter-observer Variability With or Without the Addition of 18F-DOPA Positron Emission Tomography Uptake for Radiotherapy Target Volume Delineation | Up to 5 years | The concordance correlation coefficient will be used to measure agreement between volumes generated with each method, as well as to evaluate inter-observer variability, where variability associated with magnetic resonance imaging will serve as the standard for comparison. |
| Timing of Accurate Identification of Progression Defined by 18F- DOPA Positron Emission Tomography, Perfusion Magnetic Resonance Imaging and Conventional Magnetic Resonance Imaging for Grade III Glioma Patients | Up to 5 years | Progression identification timing will be compared using Kaplan-Meier methods and paired t-tests to determine if differences exist between the modalities. An exploratory analysis of diffusion tensor imaging for detecting invasive non-enhancing tumor recurrence will also be performed. |
| Timing of Accurate Identification of Progression Defined by 18F- DOPA Positron Emission Tomography, Perfusion Magnetic Resonance Imaging and Conventional Magnetic Resonance Imaging for Grade IV Glioma Patients | Up to 5 years | The progression identification timing will be compared by calculating the percentage of time each modality was earlier than conventional magnetic resonance imaging. With a sample size of 72, if the observed percentage earlier than conventional magnetic resonance imaging is 30% for either modality, a two-sided 95% confidence interval for a single proportion using the large sample normal approximation will be +/- 10.6%. Progression identification timing will also be compared using Kaplan-Meier methods and paired t-tests to determine if differences exist between the modalities. |
| Intra-observer Variability With or Without the Addition of 18F-DOPA Positron Emission Tomography Uptake for Radiotherapy Target Volume Delineation | Up to 5 years | The concordance correlation coefficient will be used to measure agreement between volumes generated with each method, as well as to evaluate inter-observer variability, where variability associated with magnetic resonance imaging will serve as the standard for comparison. |
| Magnetic Resonance Imaging-only Defined Volumes and the Volumes Defined With the Combination of Magnetic Resonance and Positron Emission Tomography Planning | Up to 5 years | Paired t-test statistical analysis will be performed to determine if any differences exist and the level of statistical significance between treatment volumes defined by magnetic resonance imaging only and treatment volumes defined with both positron emission tomography and magnetic resonance imaging information. The analysis of volumes from 72 grade IV patients will have 90% power to detect differences in volumes with an effect size of 0.39 using a paired t-test with a 0.05 two-sided significance level. Alternate metrics for comparison will also be assessed, including spatial overlap, distanc |
| Patterns of Failure After Radiation Therapy Targeting Volumes by 18F-DOPA Positron Emission Tomography and Conventional Magnetic Resonance Imaging | Up to 5 years | Chi-square tests of proportions will be used to test for differences in the proportions of patients with central, in-field, marginal, or distant failures between the patients on this study and historical controls. |
| Predictive Capabilities of 18F-DOPA Positron Emission Tomography, Perfusion Magnetic Resonance Imaging, and Diffusion Tensor Imaging for Localization of Recurrences | Up to 5 years | Compared by identifying the recurrence volume with each modality and correlating with identification of aggressive disease in the pre-radiation therapy planning images. |
| Radiation Therapy Treatment Volumes Defined by Magnetic Resonance Imaging Only and Defined With Both Positron Emission Tomography and Magnetic Resonance Imaging Information for Grade III Glioma Patients | Up to 5 years | Paired t-test statistical analysis will be performed to determine if any differences exist and the level of statistical significance between treatment volumes defined by magnetic resonance imaging only and treatment volumes defined with both positron emission tomography and magnetic resonance imaging information. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Diagnostic (PET, pMRI, DTI, IMRT, Temozolomide) Patients undergo 18F DOPA-PET, pMRI and DTI within 14 days before radiation therapy, 3-6 weeks after radiation therapy, and during follow-up. Patients also undergo IMRT over 30 fractions and receive temozolomide. | 79 |
| Total | 79 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrew after start of treatment | 5 |
| Overall Study | Withdrew prior to receiving treatment | 7 |
Baseline characteristics
| Characteristic | Diagnostic (PET, pMRI, DTI, IMRT, Temozolomide) |
|---|---|
| Age, Continuous | 54.9 years STANDARD_DEVIATION 11.3 |
| Histologic grade of primary tumor Grade 3 | 4 Participants |
| Histologic grade of primary tumor Grade 4 | 75 Participants |
| MGMT Methylated | 25 Participants |
| MGMT NA | 15 Participants |
| MGMT Un-Methylated | 39 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 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 | 79 Participants |
| Sex: Female, Male Female | 33 Participants |
| Sex: Female, Male Male | 46 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 56 / 84 |
| other Total, other adverse events | 82 / 84 |
| serious Total, serious adverse events | 3 / 84 |
Outcome results
Primary
Proportion of Grade IV MGMT Un-methylated Patients That Experience Confirmed-progression-free Survival at 6 Months (CPFS6)
The proportion of Grade IV MGMT un-methylated patients that experience confirmed-progression-free survival at 6 months (CPFS6). Progression is defined by any of the following: * ≥25% increase in the sum of products of perpendicular diameters of enhancing lesions compared to the smallest tumor measurement obtained either at baseline or best response, on stable or increasing doses of corticosteroids * Significant increase in T2/FLAIR non-enhancing lesion on stable or increasing doses of corticosteroids compared to baseline scan or best response following initiation of therapy, not due to co-morbid events * Any new lesion * Clear clinical deterioration not attributable to other causes apart from the tumor or changes in corticosteroid dose. * Failure to return for evaluation due to death or deteriorating condition * Clear progression of non-measurable disease
Time frame: Time from registration to the confirmed disease progression, assessed at 6 months
Population: All Grade IV MGMT un-methylated patients meeting eligibility criteria who have signed a consent form and who have begun treatment with 18F-DOPA PET image-guided dose escalation RT will be evaluable for the endpoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Diagnostic (PET, pMRI, DTI, IMRT, Temozolomide) | Proportion of Grade IV MGMT Un-methylated Patients That Experience Confirmed-progression-free Survival at 6 Months (CPFS6) | 0.795 proportion of participants |
Secondary
Number of Patients Experiencing Grade 3+ Treatment-related Toxicities
Adverse events graded using Common Terminology Criteria for Adverse Events version 4.0
Time frame: Up to 5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Diagnostic (PET, pMRI, DTI, IMRT, Temozolomide) | Number of Patients Experiencing Grade 3+ Treatment-related Toxicities | 17 Participants |
Secondary
Number of Patients Experiencing Grade 4+ Late Treatment-related Toxicities
Late treatment-related toxicities will be assessed using the Radiation Therapy Oncology Group (RTOG) European Organization for Research and the Treatment of Cancer (EORTC) toxicity criteria.
Time frame: Up to 5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Diagnostic (PET, pMRI, DTI, IMRT, Temozolomide) | Number of Patients Experiencing Grade 4+ Late Treatment-related Toxicities | 0 Participants |
Secondary
Overall Survival
The median survival time and 95%CI will be estimated using the method of Kaplan-Meier.
Time frame: Up to 5 years
Population: All eligible patients were included in analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Diagnostic (PET, pMRI, DTI, IMRT, Temozolomide) | Overall Survival | Unmethylated patients | 16.0 months |
| Diagnostic (PET, pMRI, DTI, IMRT, Temozolomide) | Overall Survival | Methylated patients | 35.5 months |
Secondary
Progression Free Survival
The median progression-free survival time and 95%CI will be estimated using the method of Kaplan-Meier.
Time frame: Up to 5 years
Population: All patients eligible for analysis were included
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Diagnostic (PET, pMRI, DTI, IMRT, Temozolomide) | Progression Free Survival | Unmethylated patients | 8.7 months |
| Diagnostic (PET, pMRI, DTI, IMRT, Temozolomide) | Progression Free Survival | Methylated patients | 10.7 months |
Secondary
Quality of Life Evaluated With the M. D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) Questionnaire
The MDASI-BT consists of 28 questions. Twenty-two questions are related to severity of symptoms over the last 24 hours and are answered on a scale of 0-10 where 0=not present and10=as bad as you can imagine. The remaining 6 questions are related to how symptoms have interfered with daily life over the past 24 hours and are answered on a scale of 0-10 where 0=did not interfere and 10=interfered completely. Higher scores indicate greater severity of symptoms and greater interference with daily life. Analysis will include median change percent from baseline.
Time frame: Up to 5 years
Population: Patients that completed an assessment at baseline and at the first MRI assessment were included in analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Diagnostic (PET, pMRI, DTI, IMRT, Temozolomide) | Quality of Life Evaluated With the M. D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) Questionnaire | -0.167 percent change |
Other Pre-specified
Inter-observer Variability With or Without the Addition of 18F-DOPA Positron Emission Tomography Uptake for Radiotherapy Target Volume Delineation
The concordance correlation coefficient will be used to measure agreement between volumes generated with each method, as well as to evaluate inter-observer variability, where variability associated with magnetic resonance imaging will serve as the standard for comparison.
Time frame: Up to 5 years
Other Pre-specified
Intra-observer Variability With or Without the Addition of 18F-DOPA Positron Emission Tomography Uptake for Radiotherapy Target Volume Delineation
The concordance correlation coefficient will be used to measure agreement between volumes generated with each method, as well as to evaluate inter-observer variability, where variability associated with magnetic resonance imaging will serve as the standard for comparison.
Time frame: Up to 5 years
Other Pre-specified
Magnetic Resonance Imaging-only Defined Volumes and the Volumes Defined With the Combination of Magnetic Resonance and Positron Emission Tomography Planning
Paired t-test statistical analysis will be performed to determine if any differences exist and the level of statistical significance between treatment volumes defined by magnetic resonance imaging only and treatment volumes defined with both positron emission tomography and magnetic resonance imaging information. The analysis of volumes from 72 grade IV patients will have 90% power to detect differences in volumes with an effect size of 0.39 using a paired t-test with a 0.05 two-sided significance level. Alternate metrics for comparison will also be assessed, including spatial overlap, distanc
Time frame: Up to 5 years
Other Pre-specified
Patterns of Failure After Radiation Therapy Targeting Volumes by 18F-DOPA Positron Emission Tomography and Conventional Magnetic Resonance Imaging
Chi-square tests of proportions will be used to test for differences in the proportions of patients with central, in-field, marginal, or distant failures between the patients on this study and historical controls.
Time frame: Up to 5 years
Other Pre-specified
Predictive Capabilities of 18F-DOPA Positron Emission Tomography, Perfusion Magnetic Resonance Imaging, and Diffusion Tensor Imaging for Localization of Recurrences
Compared by identifying the recurrence volume with each modality and correlating with identification of aggressive disease in the pre-radiation therapy planning images.
Time frame: Up to 5 years
Other Pre-specified
Radiation Therapy Treatment Volumes Defined by Magnetic Resonance Imaging Only and Defined With Both Positron Emission Tomography and Magnetic Resonance Imaging Information for Grade III Glioma Patients
Paired t-test statistical analysis will be performed to determine if any differences exist and the level of statistical significance between treatment volumes defined by magnetic resonance imaging only and treatment volumes defined with both positron emission tomography and magnetic resonance imaging information.
Time frame: Up to 5 years
Other Pre-specified
Radiation Therapy Treatment Volumes Defined by Magnetic Resonance Imaging Only or Defined With Both Positron Emission Tomography and Magnetic Resonance Imaging Information for Grade IV Glioma Patients
Paired t-test statistical analysis will be performed to determine if any differences exist and the level of statistical significance between treatment volumes defined by magnetic resonance imaging only and treatment volumes defined with both positron emission tomography and magnetic resonance imaging information. The analysis of volumes from 72 grade IV patients will have 90% power to detect differences in volumes with an effect size of 0.39 using a paired t-test with a 0.05 two-sided significance level. Alternate metrics for comparison will also be assessed, including spatial overlap, distan
Time frame: Up to 5 years
Other Pre-specified
Timing of Accurate Identification of Progression Defined by 18F- DOPA Positron Emission Tomography, Perfusion Magnetic Resonance Imaging and Conventional Magnetic Resonance Imaging for Grade III Glioma Patients
Progression identification timing will be compared using Kaplan-Meier methods and paired t-tests to determine if differences exist between the modalities. An exploratory analysis of diffusion tensor imaging for detecting invasive non-enhancing tumor recurrence will also be performed.
Time frame: Up to 5 years
Other Pre-specified
Timing of Accurate Identification of Progression Defined by 18F- DOPA Positron Emission Tomography, Perfusion Magnetic Resonance Imaging and Conventional Magnetic Resonance Imaging for Grade IV Glioma Patients
The progression identification timing will be compared by calculating the percentage of time each modality was earlier than conventional magnetic resonance imaging. With a sample size of 72, if the observed percentage earlier than conventional magnetic resonance imaging is 30% for either modality, a two-sided 95% confidence interval for a single proportion using the large sample normal approximation will be +/- 10.6%. Progression identification timing will also be compared using Kaplan-Meier methods and paired t-tests to determine if differences exist between the modalities.
Time frame: Up to 5 years