Natural History of Brain Function, Quality of Life, and Seizure Control in Patients With Brain Tumor Who Have Undergone Surgery

Study Overview
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Brief Summary
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This trial studies the natural history of brain function, quality of life, and seizure control in patients with brain tumor who have undergone surgery. Learning about brain function, quality of life, and seizure control in patients with brain tumor who have undergone surgery may help doctors learn more about the disease and find better methods of treatment and on-going care.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine if there is difference in the average changes of neurocognitive function (NCF) scores from baseline to the time of radiologic tumor progression or up to 5 years (whichever occurs first), between radiologically progressed and non-progressed patients. SECONDARY OBJECTIVES: I. To determine if there is difference in the time to neurocognitive decline, as defined by the Reliable Change Index - Within subjects Standard Deviation (RCI-WSD), between radiologically progressed and non-progressed patients. II. To evaluate NCF during the postoperative observational period of progression-free survival (PFS) and after radiological progression for a total time on study of 5 years. III. To determine if the changes in cognitive functioning are an early warning biomarker for radiological progression. IV. To explore the effect of salvage therapy on cognitive outcomes in patients who progress during the study period for up to 5 years. V. To evaluate quality-of-life (QOL) as measured by the European Organization for Research and Treatment of Cancer (EORTC) QOL-30 and QOL brain module (BCN20) and health utilities as measured by the European Quality of Life-5 Dimensions (EQ-5D), for a total time on study of 5 years. VI. To evaluate seizure control for a total time on study of 5 years. VII. To evaluate molecular correlates of QOL, NCF, seizure control, and PFS. VIII. To characterize aberrant molecular pathways in low-grade gliomas (LGGs) and test the hypothesis that activation of signaling pathways will predict worse PFS and overall survival (OS). IX. To explore the relationship between change in cognitive function and symptomatic progression (defined as worsening seizures or new or progressive neurologic deficits) or clinical progression (defined as initiation of treatment interventions such as radiotherapy, chemotherapy, or additional surgery). OUTLINE: Patients undergo neurocognitive assessment using the CogState Test battery (the Detection Test (DET), the Identification Test (IDN), the One Card Learning Test (OCLT), and the Groton Maze Learning Test (GMLT)) at baseline* and at 12, 24, 36, 42, 48, 54, and 60 months. Patients also complete the EORTC Quality of Life Questionnaire-Core 30 (QOL-30), the Brain Cancer Module-20 (BCM20), and the European Quality of Life-5 Dimensions (EQ-5D) questionnaires at baseline*, at 12, 24, 36, 48, and 60 months afterwards, and before undergoing any further treatment. Patients are instructed to complete a seizure and medication diary during study. Patients undergo MRI scans at baseline*, at 12, 24, 36, 48, and 60 months, and at the time of radiological, clinical, or neurological failure. NOTE: * 12 weeks after surgery.

Official Title
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Natural History of Postoperative Cognitive Function, Quality of Life, and Seizure Control in Patients With Supratentorial Low-Risk Grade II Glioma

Conditions
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Adult Diffuse Astrocytoma, Adult Mixed Glioma, Adult Oligodendroglioma, Cognitive/Functional Effects, Neurotoxicity, Psychosocial Effects of Cancer and Its Treatment, Seizure

Intervention / Treatment
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* Procedure: cognitive assessment
* Procedure: magnetic resonance imaging
* Other: laboratory biomarker analysis
* Other: questionnaire administration
* Procedure: quality-of-life assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Central pathology confirmed diagnosis of supratentorial grade II oligodendroglioma, astrocytoma, or mixed oligoastrocytoma prior to step 2 registration No multifocal disease, based upon the following minimum diagnostic work-up: History/physical examination, including neurologic examination, within 84 days prior to step 2 registration Brain MRI with and without contrast within 84 days prior to Step 2 registration (Note: MRI 70 days after surgery is preferred and highly encouraged) The patient must be within one of the following categories: Maximal safe resection with minimal residual disease defined as follows: Removal of T2/fluid-attenuated inversion recovery (FLAIR) abnormalities thought to be primarily tumor, with a residual ≤ 2 cm maximal tumor diameter/T2 FLAIR abnormality on MRI to be done within 84 days post-operatively If there is > 2 cm post-operative residual T2/FLAIR abnormality and the neurosurgeon believes this represents edema and not primarily tumor, the neurosurgeon is encouraged to repeat imaging within the allowed study period (up to 84 days post-operatively) to confirm resolution of edema MRI at the time of enrollment must document a ≤ 2 cm residual maximal tumor diameter/T2 FLAIR abnormality Patients who required a second surgery to obtain a maximal safe resection will be eligible if the second surgery is performed within 84 days of the initial diagnostic procedure Age < 40 (any extent of resection) Age < 50 and preoperative tumor diameter < 4 cm (any extent of resection) Karnofsky performance status ≥ 80% No prior invasive malignancy (except non-melanomatous skin cancer) unless disease-free for a minimum of 3 years (For example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible) Must be able to undergo MRI of the brain with gadolinium No plans for adjuvant radiotherapy or chemotherapy after surgery No more than 84 days (12 weeks) since prior surgery No brain tumor recurrence No prior brain tumor surgery, radiation therapy and/or chemotherapy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Supportive care (neurocognitive assessment and MRI)<br>Patients undergo neurocognitive assessment using the CogState Test battery (the DET, the IDN, the OCLT, and the GMLT) at baseline* and at 12, 24, 36, 42, 48, 54, and 60 months. Patients also complete the EORTC QOL-30, the BCM20, and the EQ-5D questionnaires at baseline*, at 12, 24, 36, 48, and 60 months afterwards, and before undergoing any further treatment. Patients are instructed to complete a seizure and medication diary during study. Patients undergo MRI scans at baseline*, at 12, 24, 36, 48, and 60 months, and at the time of radiological, clinical, or neurological failure. | Procedure: cognitive assessment<br>* Undergo neurocognitive assessment<br>Procedure: magnetic resonance imaging<br>* Undergo MRI<br>* Other names: nuclear magnetic resonance imaging;Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: questionnaire administration<br>* Ancillary studies<br>Procedure: quality-of-life assessment<br>* Ancillary studies<br>* Other names: quality of life assessment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NCF as measured by each of the 4 neurocognitive tests (DET, IDN, OCLT, GMLT) | Each of the battery's tests will be evaluated using the 2-sample t-test with a 2-sided significance level of 0.05 to determine if there is a clinically meaningful difference in the average change of NCF score from baseline to the time of radiologic tumor progression or up to 5 years (whichever occurs first) between radiologically progressed and non-progressed patients. In order to adjust for multiple comparisons and maintain the overall type I error of 0.05, Hochberg's procedure will be applied. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to neurocognitive decline in patients who progress and who do not progress radiologically, as defined by the RCI-WSD | The cumulative incidence approach will be used to estimate the median time to neurocognitive impairment to account for the competing risk of death and to determine if there is a clinically meaningful difference in the time to neurocognitive decline, as defined by the RCI-WSD (reliable change index-within-subjects standard deviation), between radiologically progressed and non-progressed patients. | Up to 5 years | 
| PFS | Estimated using the Kaplan-Meier method, and difference between the activation of different signaling pathways will be tested using the log rank test. Multivariate analyses with the Cox proportional hazards model for PFS will be performed to assess the activation of the signaling pathway effect adjusting for patient-specific risk factors. The covariates to be evaluated for the multivariate models are: activation of signaling pathway status, age, tumor size, and other prognostic factors. | The interval from registration to progression or death, whichever occurs first, assessed up to 5 years | 
| Radiological progression | To determine if the NCF decline is an earlier warning biomarker to radiologic progression, we will use NCF change as a time-dependent covariate in a Cox proportional hazards (PH) regression model with radiological progression as the endpoint. The Cox model estimates the ratio of hazard rate of radiographic failure with and without neurocognitive decline. Anticonvulsant use, tumor size, tumor histology, and further treatment received if recurrence is discovered, which may also have impact on the radiological progression, will also be considered in this Cox PH regression analysis. | Up to 5 years | 
| Effect of salvage therapy on cognitive outcomes in patients who progress |  | Up to 5 years | 
| QOL as measured by the EORTC QOL-30, EORTC QOL-BCN20, and EQ-5D | The general linear mixed-effects model will be used to evaluate the changes of QOL and health utilities over time. | Up to 5 years | 
| Frequency of seizures, evaluated using patient seizure diary | Marginal models will be used to evaluate the change of frequencies of seizures over time for up to 5 years. Anticonvulsant use, tumor size, tumor histology, further treatment received if recurrence is discovered, and other prognostic factors will also be included in the covariates sets. The available molecular marker information will also be included as a covariate to evaluate the molecular correlates of seizure frequency. | Up to 5 years | 
| Molecular correlates of QOL, NCF, seizure control, and PFS |  | Up to 5 years | 
| OS | Estimated using the Kaplan-Meier method, and difference between the activation of different signaling pathways will be tested using the log rank test. Multivariate analyses with the Cox proportional hazards model for OS will be performed to assess the activation of the signaling pathway effect adjusting for patient-specific risk factors. The covariates to be evaluated for the multivariate models are: activation of signaling pathway status, age, tumor size, and other prognostic factors. | Up to 5 years | 
| Symptomatic or clinical progression | Symptomatic and clinical progression will be explored for the correlation with cognitive changes in addition to radiological progression. | Up to 5 years |