Chemotherapy and Radiation Therapy in Treating Young Patients With Newly Diagnosed, Previously Untreated, High-Risk Medulloblastoma/PNET

Study Overview
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Brief Summary
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This randomized phase III trial studies different chemotherapy and radiation therapy regimens to compare how well they work in treating young patients with newly diagnosed, previously untreated, high-risk medulloblastoma. Drugs used in chemotherapy, such as vincristine sulfate, cisplatin, cyclophosphamide, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving more than one drug (combination chemotherapy) may kill more tumor cells. Radiation therapy uses high-energy x-rays to kill tumor cells. Carboplatin may make tumor cells more sensitive to radiation therapy. It is not yet known which chemotherapy and radiation therapy regimen is more effective in treating brain tumors.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine whether carboplatin radiosensitization increases long term event-free survival for high risk medulloblastoma/primitive neuroectodermal tumor (PNET) patients. II. To determine whether isotretinoin increases long term event-free survival for high risk medulloblastoma/PNET patients. SECONDARY OBJECTIVES: I. To compare residual disease response to radiation alone versus radiation plus carboplatin. II. To identify molecular prognostic indicators suitable for patient stratification in future trials. III. To evaluate the health-related quality of life (HRQOL) during phases of active treatment specific to treatment modalities. IV. To describe the neuropsychological functioning of the study population and to evaluate the relationship between neuropsychological status and health related quality of life. OUTLINE: Patients are randomized to Arm A or Arm B (Arms C and D closed to accrual as of Amendment 3 1/27/15). ARM A (standard chemoradiotherapy and standard maintenance therapy): CHEMORADIOTHERAPY: Patients undergo radiation therapy once daily (QD) five days a week for 6 weeks. Patients also receive vincristine sulfate intravenously (IV) over 1 minute once weekly for 6 weeks. Six weeks after completion of chemoradiotherapy, patients proceed to maintenance therapy. MAINTENANCE THERAPY: Patients receive cisplatin IV over 6 hours on day 1, vincristine sulfate IV over 1 minute on days 1 and 8, and cyclophosphamide IV over 1 hour on days 2 and 3. Patients also receive filgrastim subcutaneously (SC) or IV beginning on day 4 and continuing until blood counts recover (at least 10 days). Treatment repeats every 28 days for a total of 6 courses in the absence of disease progression or unacceptable toxicity. ARM B (standard chemoradiotherapy plus carboplatin and standard maintenance therapy): CHEMORADIOTHERAPY: Patients receive vincristine sulfate and undergo radiation therapy as in Arm I. Patients also receive carboplatin IV over 15 minutes on each day of radiation therapy. Six weeks after completion of chemoradiotherapy, patients proceed to maintenance therapy. MAINTENANCE THERAPY: Patients receive maintenance therapy as in Arm I. ARM C (standard chemoradiotherapy, standard maintenance therapy plus isotretinoin, and continuation therapy with isotretinoin - CLOSED TO ACCRUAL 1/27/15): CHEMORADIOTHERAPY: Patients undergo chemoradiotherapy as in Arm I. Six weeks after completion of chemoradiotherapy, patients proceed to maintenance therapy. MAINTENANCE THERAPY: Patients receive isotretinoin orally (PO) twice daily (BID) on day 1 and days 16-28 and cisplatin, vincristine sulfate, cyclophosphamide, and filgrastim as in Arm I maintenance therapy. Treatment repeats every 28 days for a total of 6 courses in the absence of disease progression or unacceptable toxicity. Patients then proceed to continuation therapy. CONTINUATION THERAPY: Patients receive isotretinoin PO BID on days 15-28 every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. ARM D (standard chemoradiotherapy plus carboplatin, standard maintenance therapy plus isotretinoin, and continuation therapy with isotretinoin - CLOSED TO ACCRUAL 1/27/15): CHEMORADIOTHERAPY: Patients undergo chemoradiotherapy as in Arm II. Six weeks after completion of chemoradiotherapy, patients proceed to maintenance therapy. MAINTENANCE THERAPY: Patients receive maintenance therapy as in Arm III. Patients then proceed to continuation therapy. CONTINUATION THERAPY: Patients receive continuation therapy as in Arm III. After completion of study treatment, patients are followed up periodically for 1 year.

Official Title
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Efficacy of Carboplatin Administered Concomitantly With Radiation and Isotretinoin as a Pro-Apoptotic Agent in Other Than Average Risk Medulloblastoma/PNET Patients

Conditions
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Anaplastic Medulloblastoma, Medulloblastoma

Intervention / Treatment
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* Drug: Carboplatin
* Drug: Cisplatin
* Drug: Cyclophosphamide
* Biological: Filgrastim
* Drug: Isotretinoin
* Other: Laboratory Biomarker Analysis
* Other: Quality-of-Life Assessment
* Radiation: Radiation Therapy
* Drug: Vincristine Sulfate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed, previously untreated: (1) M0 medulloblastoma with > 1.5 cm^2 residual; (2) M+ medulloblastoma; patients with diffusely anaplastic medulloblastoma are eligible regardless of M-stage or residual tumor As of amendment # 2, enrollment of patients with supratentorial PNET has been discontinued All patients with M4 disease are not eligible A pre-operative magnetic resonance imaging (MRI) scan of the brain with and without contrast is required; NOTE: computed tomography (CT) scans are NOT sufficient for study eligibility Post-operative head MRI scan with and without contrast (preferably within 72 hours post-surgery); for patients who undergo stereotactic biopsy only, either a pre or post-operative MRI is sufficient; for patients with M2 and M3 disease, a post-op MRI is strongly encouraged, but not mandatory Spinal MRI imaging with and without gadolinium is required within 10 days of surgery if done pre-operatively or within 28 days of surgery if done post-operatively; for posterior fossa tumors, pre-operative MRI scans are preferred Lumbar cerebrospinal fluid (CSF) cytology examination must be obtained pre-operatively or within 31 days following surgery; the optimal time for obtaining CSF is prior to surgery or 1-3 weeks following surgery; ventricular CSF (either pre- or post-op) may be used only if a post-operative spinal tap is contraindicated; if a spinal tap is contraindicated and there is no ventricular CSF available, then CSF cytology can be waived for patients with supratentorial tumors or if there is documentation of spinal subarachnoid metastases (M3); patients who are categorized as M1 must have either an intra-operative positive CSF (via lumbar puncture at the end of the procedure) or a positive lumbar CSF obtained > 7 days post-operatively Patients must have a Karnofsky performance level of >= 30 for patients > 16 years of age or a Lansky performance scale of >= 30 for patients =< 16 years of age and life expectancy > 8 weeks No previous chemotherapy or radiation therapy Corticosteroids should not be used during chemotherapy administration as an antiemetic Selected strong inhibitors of cytochrome P450, family 3, subfamily A, polypeptide 4 (cytochrome P450 3A4) include azole antifungals, such as fluconazole, voriconazole, itraconazole, ketoconazole, and strong inducers include drugs such as rifampin, phenytoin, phenobarbitol, carbamazepine, and St. John's wort; the use of these drugs should be avoided with vincristine (vincristine sulfate) CYP450 3A4 stimulators or inhibitors should be avoided or used with great caution when taking cyclophosphamide; aprepitant should also be used with caution with etoposide or vincristine chemotherapy Cisplatin should be used with caution with nephrotoxic drug; aminoglycoside should be avoided or used with caution during or shortly after cisplatin administration and concomitant use with amphotericin B should probably also be avoided; patients receiving cisplatin and other potentially ototoxic drugs such as aminoglycoside or loop diuretics concomitantly should be closely monitored for signs of ototoxicity Plasma levels of anticonvulsant agents should be monitored and doses adjusted during therapy with cisplatin No other experimental therapy is permitted while on study Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 OR a serum creatinine based on age/gender as follows: 0.8 mg/dL (2 to < 6 years of age) 1.0 mg/dL (6 to < 10 years of age) 1.2 mg/dL (10 to < 13 years of age) 1.5 mg/dL (male) or 1.4 mg/dL (female) (13 to < 16 years of age) 1.7 mg/dL (male) or 1.4 mg/dL (female) (>= 16 years of age) Total bilirubin < 1.5 x upper limit of normal (ULN) for age Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5 x upper limit of normal (ULN) for age; for patients on anti-seizure medications, SGOT (AST) or SGPT (ALT) must be < 5 x ULN Absolute neutrophil count (ANC) >= 1,000/uL Platelets >= 100,000/uL (untransfused) Hemoglobin >= 8 g/dl (may be transfused) Female patients who are post-menarchal must have a negative pregnancy test; lactating female patients must agree not to breast-feed while on this trial; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method All patients and/or their parents or legal guardians must sign a written informed consent All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 21 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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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A (chemoradiotherapy)<br>CHEMORADIOTHERAPY: Patients undergo radiation therapy QD five days a week for 6 weeks. Patients also receive vincristine sulfate IV over 1 minute once weekly for 6 weeks. Six weeks after completion of chemoradiotherapy, patients proceed to maintenance therapy. MAINTENANCE THERAPY: Patients receive cisplatin IV over 6 hours on day 1, vincristine sulfate IV over 1 minute on days 1 and 8, and cyclophosphamide IV over 1 hour on days 2 and 3. Patients also receive filgrastim SC or IV beginning on day 4 and continuing until blood counts recover (at least 10 days). Treatment repeats every 28 days for a total of 6 courses in the absence of disease progression or unacceptable toxicity. | Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Biological: Filgrastim<br>* Given IV or SC<br>* Other names: Tevagrastim;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Radiation: Radiation Therapy<br>* Undergo radiation therapy<br>* Other names: Therapy, Radiation;Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|
| Experimental: Arm B (chemoradiotherapy)<br>CHEMORADIOTHERAPY: Patients receive vincristine sulfate and undergo radiation therapy as in Arm A. Patients also receive carboplatin IV over 15 minutes on each day of radiation therapy. Six weeks after completion of chemoradiotherapy, patients proceed to maintenance therapy. MAINTENANCE THERAPY: Patients receive maintenance therapy as in Arm A. | Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Biological: Filgrastim<br>* Given IV or SC<br>* Other names: Tevagrastim;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Radiation: Radiation Therapy<br>* Undergo radiation therapy<br>* Other names: Therapy, Radiation;Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|
| Experimental: Arm C (chemoradiotherapy, isotretinoin-CLOSED TO ACCRUAL)<br>CHEMORADIOTHERAPY: Patients undergo chemoradiotherapy as in Arm A. Six weeks after completion of chemoradiotherapy, patients proceed to maintenance therapy. MAINTENANCE THERAPY: Patients receive isotretinoin PO BID on day 1 and days 16-28 and cisplatin, vincristine sulfate, cyclophosphamide, and filgrastim as in Arm A maintenance therapy. Treatment repeats every 28 days for a total of 6 courses in the absence of disease progression or unacceptable toxicity. Patients then proceed to continuation therapy. CONTINUATION THERAPY: Patients receive isotretinoin PO BID on days 15-28 every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. | Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Biological: Filgrastim<br>* Given IV or SC<br>* Other names: Tevagrastim;Drug: Isotretinoin<br>* Given PO<br>* Other names: ZENATANE;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Radiation: Radiation Therapy<br>* Undergo radiation therapy<br>* Other names: Therapy, Radiation;Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|
| Experimental: Arm D (chemoradiotherapy, isotretinoin-CLOSED TO ACCRUAL)<br>CHEMORADIOTHERAPY: Patients undergo chemoradiotherapy as in Arm B. Six weeks after completion of chemoradiotherapy, patients proceed to maintenance therapy. MAINTENANCE THERAPY: Patients receive maintenance therapy as in Arm C. Patients then proceed to continuation therapy. CONTINUATION THERAPY: Patients receive continuation therapy as in Arm C. | Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Biological: Filgrastim<br>* Given IV or SC<br>* Other names: Tevagrastim;Drug: Isotretinoin<br>* Given PO<br>* Other names: ZENATANE;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Radiation: Radiation Therapy<br>* Undergo radiation therapy<br>* Other names: Therapy, Radiation;Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Probability of Event-free Survival (EFS) for Patients With Medulloblastoma | The Kaplan-Meier method will be used to estimate 5-year EFS, defined as the time from study enrollment to disease progression or recurrence, second malignant neoplasm, or death from any cause, or to date of last contact. Estimates are reported with 95% confidence intervals. Data below represents all molecular subgroups combined. | Up to 5 years | 
| Percent Probability of Event-free Survival (EFS) for Patients With Supratentorial Primitive Neuroectodermal Tumor (SPNET) | The Kaplan-Meier method will be used to estimate 5-year EFS, defined as the time from study enrollment to disease progression or recurrence, second malignant neoplasm, or death from any cause, or to date of last contact. Estimates are reported with 95% confidence intervals. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor Response to Radiation Therapy for Patients With Medulloblastoma | Percentages of patients with responses after radiation therapy (induction therapy) are reported with 95% confidence intervals. Complete and partial responses were considered responses. | 12 weeks after treatment initiation | 
| Tumor Response to Radiation Therapy for Patients With Supratentorial Primitive Neuroectodermal Tumor (SPNET) | Percentages of patients with responses after radiation therapy (induction therapy) are reported with 95% confidence intervals. Complete and partial responses were considered responses. SPNET is no longer recognized by WHO (World Health Organization) as a disease entity. Additional trial information can be found under PubMed® # 30332335. | 12 weeks after treatment initiation | 
| Percent Probability of Overall Survival (OS) for Patients With Medulloblastoma | The Kaplan-Meier method will be used to estimate 5-year OS, defined as the time from study enrollment to death from any cause, or to date of last contact. Estimates are reported with 95% confidence intervals. Data below represents all molecular subgroups combined. | Up to 5 years | 
| Percent Probability of Overall Survival (OS) for Patients With Supratentorial Primitive Neuroectodermal Tumor (SPNET) | The Kaplan-Meier method will be used to estimate 5-year OS, defined as the time from study enrollment to death from any cause, or to date of last contact. | Up to 5 years | 
| The Estimated Full-scale IQ (FSIQ) at 9+/-3 Months Post Diagnosis for Medulloblastoma Patients | Post-treatment neurocognitive function was assessed. Full-scale IQ (FSIQ) is a representative measurement for neurocognitive function. FSIQ was measured by IQ tests. Assessments within the time window, from eligible and evaluable patients are reported. The time window is 9+/-3 months post diagnosis, only the assessments before progression date were reported. The Range of FSIQ is 50-150. A higher FSIQ is better. Mean and standard deviation of FSIQ were calculated and reported. | 6 - 12 months post diagnosis | 
| The Estimated Full-scale IQ (FSIQ) at 30+/-6 Months Post Diagnosis for Medulloblastoma Patients | Post-treatment neurocognitive function was assessed. Full-scale IQ (FSIQ) is a representative measurement for neurocognitive function. FSIQ was measured by IQ tests. Assessments within the time window, from eligible and evaluable patients are reported. The time window is 30+/-6 months post diagnosis, only the assessments before progression date were reported. The Range of FSIQ is 50-150. A higher FSIQ is better. Mean and standard deviation of FSIQ were calculated and reported. | 24 - 36 months post diagnosis | 
| The Estimated Full-scale IQ (FSIQ) at 60+/-12 Months Post Diagnosis for Medulloblastoma Patients | Post-treatment neurocognitive function was assessed. Full-scale IQ (FSIQ) is a representative measurement for neurocognitive function. FSIQ was measured by IQ tests. Assessments within the time window, from eligible and evaluable patients are reported. The time window is 60+/-12 months post diagnosis, only the assessments before progression date were reported. The Range of FSIQ is 50-150. A higher FSIQ is better. Mean and standard deviation of FSIQ were calculated and reported. | 48 - 72 months post diagnosis | 
| The Estimated Full-scale IQ (FSIQ) at 9+/-3 Months Post Diagnosis for SPNET Patients | Post-treatment neurocognitive function was assessed. Full-scale IQ (FSIQ) is a representative measurement for neurocognitive function. FSIQ was measured by IQ tests. Assessments within the time window, from eligible and evaluable patients are reported. The time window is 9+/-3 months post diagnosis, only the assessments before progression date were reported. The Range of FSIQ is 50-150. A higher FSIQ is better. Mean and standard deviation of FSIQ were calculated and reported. | 6 - 12 months post diagnosis | 
| The Estimated Full-scale IQ (FSIQ) at 30+/-6 Months Post Diagnosis for SPNET Patients | Post-treatment neurocognitive function was assessed. Full-scale IQ (FSIQ) is a representative measurement for neurocognitive function. FSIQ was measured by IQ tests. Assessments within the time window, from eligible and evaluable patients are reported. The time window is 30+/-6 months post diagnosis, only the assessments before progression date were reported. The Range of FSIQ is 50-150. A higher FSIQ is better. Mean and standard deviation of FSIQ were calculated and reported. | 24 - 36 months post diagnosis | 
| The Estimated Full-scale IQ (FSIQ) at 60+/-12 Months Post Diagnosis for SPNET Patients | Post-treatment neurocognitive function was assessed. Full-scale IQ (FSIQ) is a representative measurement for neurocognitive function. FSIQ was measured by IQ tests. Assessments within the time window, from eligible and evaluable patients are reported. The time window is 60+/-12 months post diagnosis, only the assessments before progression date were reported. The Range of FSIQ is 50-150. A higher FSIQ is better. Mean and standard deviation of FSIQ were calculated and reported. | 48 - 72 months post diagnosis | 
| Metacognition Index (MI) on the Behavior Rating Inventory of Executive Function (BRIEF) at 9+/-3 Months Post Diagnosis for Medulloblastoma Patients | Metacognition index (MI) was measured by BRIEF test. Assessments within the time window, from eligible and evaluable patients are reported. If the patient had disease progression, only the assessments before progression date were reported. The MI is a standard T- score, and it ranges from 0 to 100. The higher score reported suggests a higher level of dysfunction. Mean and standard deviation of MI were calculated and reported. | 6 - 12 months post diagnosis | 
| Metacognition Index (MI) on the Behavior Rating Inventory of Executive Function (BRIEF) at 30+/-6 Months Post Diagnosis for Medulloblastoma Patients | Metacognition index (MI) was measured by BRIEF test. Assessments within the time window, from eligible and evaluable patients are reported. If the patient had disease progression, only the assessments before progression date were reported. The MI is a standard T- score, and it ranges from 0 to 100. The higher score reported suggests a higher level of dysfunction. Mean and standard deviation of MI were calculated and reported. SPNET is no longer recognized by WHO (World Health Organization) as a disease entity. Additional trial information can be found under PubMed® # 30332335. | 24 - 36 months post diagnosis | 
| Metacognition Index (MI) on the Behavior Rating Inventory of Executive Function (BRIEF) at 60+/-12 Months Post Diagnosis for Medulloblastoma Patients | Metacognition index (MI) was measured by BRIEF test. Assessments within the time window, from eligible and evaluable patients are reported. If the patient had disease progression, only the assessments before progression date were reported. The MI is a standard T- score, and it ranges from 0 to 100. The higher score reported suggests a higher level of dysfunction. Mean and standard deviation of MI were calculated and reported. | 48 - 72 months post diagnosis | 
| Metacognition Index (MI) on the Behavior Rating Inventory of Executive Function (BRIEF) at 9+/-3 Months Post Diagnosis for SPNET Patients | Metacognition index (MI) was measured by BRIEF test. Assessments within the time window, from eligible and evaluable patients are reported. If the patient had disease progression, only the assessments before progression date were reported. The MI is a standard T- score, and it ranges from 0 to 100. The higher score reported suggests a higher level of dysfunction. Mean and standard deviation of MI were calculated and reported. | 6 - 12 months post diagnosis | 
| Metacognition Index (MI) on the Behavior Rating Inventory of Executive Function (BRIEF) at 30+/-6 Months Post Diagnosis for SPNET Patients | Metacognition index (MI) was measured by BRIEF test. Assessments within the time window, from eligible and evaluable patients are reported. If the patient had disease progression, only the assessments before progression date were reported. The MI is a standard T- score, and it ranges from 0 to 100. The higher score reported suggests a higher level of dysfunction. Mean and standard deviation of MI were calculated and reported. | 24 - 36 months post diagnosis | 
| Metacognition Index (MI) on the Behavior Rating Inventory of Executive Function (BRIEF) at 60+/-12 Months Post Diagnosis for SPNET Patients | Metacognition index (MI) was measured by BRIEF test. Assessments within the time window, from eligible and evaluable patients are reported. If the patient had disease progression, only the assessments before progression date were reported. The MI is a standard T- score, and it ranges from 0 to 100. The higher score reported suggests a higher level of dysfunction. Mean and standard deviation of MI were calculated and reported. | 48 - 72 months post diagnosis |