Comparison of Radiation Therapy Regimens in Combination With Chemotherapy in Treating Young Patients With Newly Diagnosed Standard-Risk Medulloblastoma

Study Overview
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Brief Summary
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This randomized phase III trial is studying how well standard-dose radiation therapy works compared to reduced-dose radiation therapy in children 3-7 years of age AND how well standard volume boost radiation therapy works compared to smaller volume boost radiation therapy when given together with chemotherapy in treating young patients who have undergone surgery for newly diagnosed standard-risk medulloblastoma. Radiation therapy uses high-energy x-rays to damage tumor cells. Drugs used in chemotherapy, such as vincristine, cisplatin, lomustine, and cyclophosphamide, work in different ways to stop tumor cells from dividing so they stop growing or die. Giving radiation therapy with chemotherapy after surgery may kill any remaining tumor cells. It is not yet known whether standard-dose radiation therapy is more effective than reduced-dose radiation therapy when given together with chemotherapy after surgery in treating young patients with medulloblastoma.

Detailed Description
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PRIMARY OBJECTIVES: I. Compare event-free survival (EFS) of pediatric patients (3 to 7 years of age) with newly diagnosed standard-risk medulloblastoma treated with standard-dose versus (vs.) reduced-dose craniospinal radiotherapy (SDCSI vs. LDCSI). II. Compare EFS of patients (3-21 years of age) treated with standard-dose craniospinal radiotherapy and posterior fossa boost vs tumor bed boost radiotherapy in combination with this chemotherapy regimen. SECONDARY OBJECTIVES: I. Compare overall survival (OS) of pediatric patients (3-7 years of age) with newly diagnosed standard-risk medulloblastoma treated with SDCSI vs. LDCSI. II. Compare OS of patients (3-21 years of age) with newly diagnosed standard-risk medulloblastoma treated with PFRT vs. IFRT. III. To evaluate patterns of failure in patients treated with an irradiation boost volume smaller than conventional posterior fossa volumes. IV. To reduce the cognitive, auditory, and endocrinologic effects of treatment of average-risk medulloblastoma by reducing the dose of craniospinal irradiation therapy. V. To determine if the audiologic and endocrinologic toxicity will be reduced with the use of limited tumor boost volume irradiation compared to patients treated with conventional target volumes of radiation. VI. Develop an optimal gene expression medulloblastoma outcome predictor, validated prospectively in a multi-institution randomized clinical trial. VII. To improve compliance with long-term quality of life (QoL) and functional status data submission by educating institutional nurses to administer and submit for analysis a battery of four instruments (Behavior Assessment System for Children- 2nd Edition (BASC-2), Adaptive Behavior Assessment System - 2nd Edition (ABAS-II), Behavior Rating Inventory of Executive Function (BRIEF) and PedsQLTM 4.0). OUTLINE: Patients 3-7 years of age are randomized to 1 of 4 arms (Arm I-IV). Patients 8-21 years of age are randomized to 1 of 2 arms (Arm V or VI). Within 31 days after definitive surgery, all patients begin therapy. Patients undergo radiation therapy with doses according to their Arm randomization on days 1-5, 8-12, 15-19, 22-26, 29-33, 36-40, and 43-47 (weeks 0-6). All patients receive vincristine intravenously (IV) over 1 minute (or infusion via minibag as per institutional policy) on days 8, 15, 22, 29, 36, and 43 (weeks 1-6). ARM I: Patients 3-7 years of age undergo lowered dose craniospinal irradiation (LDCSI) with involved-field radiation therapy (IFRT) boost. ARM II: Patients 3-7 years of age undergo LDCSI with whole posterior fossa radiation therapy (PFRT) boost. ARM III: Patients 3-7 years of age undergo standard dose craniospinal irradiation (SDCSI) with IFRT boost. ARM IV: Patients 3-7 years of age undergo SDCSI with PFRT boost. ARM V: Patients 8-21 years of age undergo SDCSI with IFRT boost. ARM VI: Patients 8-21 years of age undergo SDCSI with PFRT boost. MAINTENANCE CHEMOTHERAPY: Beginning 4 weeks after completion of chemoradiotherapy, patients receive 2 different regimens of maintenance chemotherapy for a total of 9 courses. Each course in regimen A is 6 weeks (42 days) in duration. Each course in regimen B is 4 weeks (28 days) in duration. REGIMEN A (courses 1, 2, 4, 5, 7, and 8): Patients receive lomustine orally and cisplatin IV over 6 hours on day 1 and vincristine IV on days 1, 8, and 15 of weeks 11, 17, 27, 33, 43, and 49. REGIMEN B (courses 3, 6, and 9): Patients receive cyclophosphamide IV over 1 hour on days 1 and 2 and vincristine IV on days 1 and 8 of weeks 23, 39, and 55. Treatment continues in the absence of disease progression or unacceptable toxicity. Quality of life is assessed at 3-6 months after completion of radiotherapy and at 3-4 years after study entry. Neurocognitive function may also be assessed. Patients are followed every 3 months for 1 year, every 6 months for 2 years, and then annually thereafter.

Official Title
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A Study Evaluating Limited Target Volume Boost Irradiation and Reduced Dose Craniospinal Radiotherapy (18.00 Gy) and Chemotherapy in Children With Newly Diagnosed Standard Risk Medulloblastoma: A Phase III Double Randomized Trial

Conditions
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Untreated Childhood Medulloblastoma

Intervention / Treatment
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* Drug: Cisplatin
* Radiation: Craniospinal Irradiation
* Drug: Cyclophosphamide
* Radiation: Involved-Field Radiation Therapy
* Other: Laboratory Biomarker Analysis
* Drug: Lomustine
* 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: Histologically confirmed medulloblastoma located in the posterior fossa Standard-risk disease Minimal volume, non-disseminated disease, defined by the following: Residual tumor ≤ 1.5 cm^2 confirmed by MRI with contrast imaging within 21 days after surgery No metastatic disease in the head, spine, or cerebrospinal fluid (CSF) confirmed by both of the following: Enhanced MRI of the spine within 5 days before surgery OR within 28 days after surgery Negative cytological examination of CSF after surgery, but before study enrollment Brain stem involvement allowed Performance status - Karnofsky 50-100% (> 16 years of age) Performance status - Lansky 30-100% (≤ 16 years of age) Absolute neutrophil count > 1,500/uL Platelet count > 100,000/uL (transfusion independent) Hemoglobin > 10 g/dL (transfusions allowed) Bilirubin < 1.5 times upper limit of normal (ULN) for age AST or ALT < 1.5 times ULN for age Creatinine clearance OR radioisotope glomerular filtration rate >= 70 mL/min/1.73m^2 or a serum creatinine based on age/gender as follows: Age Maximum Serum Creatine (mg/dL) 1month to < 6 months male: 0.4 female: 0.4 6 months to <1 year male: 0.5 female: 0.5 1 year to < 2 years male: 0.6 female: 0.6 2 to < 6 years male: 0.8 female: 0.8 6 to < 10 years male: 1 female: 1 10 to < 13 years male: 1.2 female: 1.2 13 to < 16 years male: 1.5 female: 1.4 >= 16 years male: 1.7 female: 1.4 Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No prior chemotherapy Prior corticosteroids allowed No prior radiotherapy

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 |
| --- | --- |
| Experimental: Arm I (3-7 years of age, LDCSI, IFRT)<br>See Detailed Description (Arm I) | Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Radiation: Craniospinal Irradiation<br>* Undergo craniospinal Irradiation<br>Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Radiation: Involved-Field Radiation Therapy<br>* Undergo smaller volume boost (involved-field radiation therapy)<br>* Other names: Involved field radiotherapy;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Lomustine<br>* Given orally<br>* Other names: WR-139017;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|
| Experimental: Arm II (3-7 years of age, LDCSI, PFRT)<br>See Detailed Description (Arm II) | Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Radiation: Craniospinal Irradiation<br>* Undergo craniospinal Irradiation<br>Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Lomustine<br>* Given orally<br>* Other names: WR-139017;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Radiation: Radiation Therapy<br>* Undergo standard volume boost (whole posterior fossa radiation therapy)<br>* Other names: Therapy, Radiation;Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|
| Experimental: Arm III (3-7 years of age, SDCSI, IFRT)<br>See Detailed Description (Arm III) | Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Radiation: Craniospinal Irradiation<br>* Undergo craniospinal Irradiation<br>Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Radiation: Involved-Field Radiation Therapy<br>* Undergo smaller volume boost (involved-field radiation therapy)<br>* Other names: Involved field radiotherapy;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Lomustine<br>* Given orally<br>* Other names: WR-139017;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|
| Active Comparator: Arm IV (3-7 years of age, SDCSI, PFRT)<br>See Detailed Description (Arm IV) | Radiation: Craniospinal Irradiation<br>* Undergo craniospinal Irradiation<br>Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Lomustine<br>* Given orally<br>* Other names: WR-139017;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Radiation: Radiation Therapy<br>* Undergo standard volume boost (whole posterior fossa radiation therapy)<br>* Other names: Therapy, Radiation;Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|
| Experimental: Arm V (8-21 years of age, SDCSI, IFRT)<br>See Detailed Description (Arm V) | Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Radiation: Craniospinal Irradiation<br>* Undergo craniospinal Irradiation<br>Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Radiation: Involved-Field Radiation Therapy<br>* Undergo smaller volume boost (involved-field radiation therapy)<br>* Other names: Involved field radiotherapy;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Lomustine<br>* Given orally<br>* Other names: WR-139017;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|
| Active Comparator: Arm VI (8-21 years of age, SDCSI, PFRT)<br>See Detailed Description (Arm VI) | Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Radiation: Craniospinal Irradiation<br>* Undergo craniospinal Irradiation<br>Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Lomustine<br>* Given orally<br>* Other names: WR-139017;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Radiation: Radiation Therapy<br>* Undergo standard volume boost (whole posterior fossa 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 |
| --- | --- | --- |
| Event-free Survival (EFS) | EFS was defined as the time interval from date of study entry to date of disease progression, disease recurrence, second malignant neoplasm or death from any cause, whichever occurs first, or to the date of last follow-up for patients without events. EFS was estimated using the method of Kaplan and Meier. 3-year estimates are reported with 95% confidence intervals (CI's). | Assessed at 3 years | 
| Overall Survival (OS) | OS was defined as the time interval from date of study entry to date of death from any cause or to the date of last follow-up for survivors. OS was estimated using the method of Kaplan and Meier. 3-year estimates are reported with 95% CI's. For purposes of this analysis, arms I, III and V (involved field radiation therapy [IFRT]) are combined and compared to arms II, IV and VI (posterior fossa irradiation [PFRT]). | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local Posterior Fossa (LPF) Failure Rate | LPF failure was defined as tumor recurrence/progression within the tumor bed. The cumulative incidence (CI) of LPF failure was estimated; 3-year estimates were reported with 95% confidence intervals. Patients with other failure types (e.g., NPF) and with other events prior to LPF failure (e.g., death, second malignancy) were considered as having competing events. | 3 years | 
| Non-local Posterior Fossa (NLPF) Failure Rate | NLPF failure was defined as tumor recurrence/progression outside the radiation therapy clinical target volume boost (CTV-boost) but within the posterior fossa CTV (CTV-PF). The cumulative incidence (CI) of NLPF failure was estimated; 3-year estimates were reported with 95% confidence intervals. Patients with other failure types (e.g., NPF, LPF) and with other events prior to NLPF failure (e.g., death, second malignancy) were considered as having competing events. | 3 years | 
| Non-posterior Fossa (NPF) Failure Rate | NPF failure was defined as tumor recurrence within the neuroaxis but outside the radiation therapy clinical target volume (CTV). The cumulative incidence (CI) of NPF failure was estimated; 3-year estimates were reported with 95% confidence intervals. Patients with other failure types (e.g., LPF failure) and with other events prior to NPF failure (e.g., death, second malignancy) were considered as having competing events. | 3 years | 
| Post-treatment Endocrine Function by CSI Group | Post-treatment endocrine function was measured by laboratory assessment of the thyroid stimulating hormone (TSH). The mean TSH will be reported. | Up to 3 years | 
| Post-treatment Grade 3+ Hearing Loss as Measured by Common Terminology Criteria for Adverse Events (CTCAE) Version (v)4 | Proportions of patients with grade 3+ hearing loss after the completion of therapy will be calculated and reported separately for low dose craniospinal irradiation (LDCSI) versus (vs.) standard dose craniospinal irradiation (SDCSI) patients. Eligible and evaluable patients 3-7 years of age will be used. | Up to 3 years | 
| Post-treatment Neurocognitive Function as Measured by the Estimated Full-scale IQ (FSIQ) by CSI Group Within Time Window 1 (4 - 15 Months Post Diagnosis). | 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 4-15 months post diagnosis, only the assessments before progression date were reported. The Range of FSIQ is 50-150. A higher FSIQ is better. | 4 -15 months post diagnosis | 
| Post-treatment Neurocognitive Function as Measured by the Estimated Full-scale IQ (FSIQ) by CSI Group Within Time Window 2 (27 - 48 Months Post Diagnosis) | 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 27-48 months post diagnosis, only the assessments before progression date were reported. The range of FSIQ is 50 - 150. A higher FSIQ is better. | 27 - 48 months post diagnosis | 
| Post-treatment Neurocognitive Function as Measured by the Estimated Full-scale IQ (FSIQ) by CSI Group Within Time Window 3 (49 - 72 Months Post Diagnosis) | 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 49-72 months post diagnosis, only the assessments before progression date were reported. The Range of FSIQ is 50-150. A higher FSIQ is better. | 49 - 72 months post diagnosis | 
| Incidence of Grade 3+ Hearing Loss at 1-year Post Treatment as Assessed by CTCAE v4 | Proportions of patients with grade 3+ hearing impairment as assessed by CTCAE v4 at 1-year post treatment were calculated. | Up to 3 years | 
| Incidence of Endocrine Dysfunction as Measured by Growth Hormone Stimulation Tests at the Time of Completion of Therapy by Radiotherapy (RT) Group | Endocrine dysfunction was assessed by growth hormone stimulation (GHS) tests. We report the percentage of patients with abnormal growth hormone stimulation tests. | Post-treatment up to 3 years | 
| Overall Survival (OS) by Molecular Subgroup Based on Methylation Arrays | OS was defined as the time interval from date of study entry to date of death from any cause or to date of last contact for survivors. OS was estimated using the method of Kaplan and Meier. 3-year estimates are reported with 95% CI's. | 3 years | 
| Progression-free Survival (PFS) by Molecular Subgroup Based on Methylation Arrays | PFS was defined as the time interval from date of study entry to disease progression, relapse or death due to cancer or to last follow-up. Second malignancies and deaths from causes clearly not associated with tumor progression or recurrence were censored. PFS was estimated using the method of Kaplan and Meier. 3-year estimates are reported with 95% CI's. | 3 years | 
| Post-treatment Metacognition Index (MI) on the Behavior Rating Inventory of Executive Function (BRIEF) by CSI Group Within Time Window 1 (4-15 Months Post Diagnosis) | 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. | 4 - 15 months post diagnosis | 
| Post-treatment Metacognition Index (MI) on the Behavior Rating Inventory of Executive Function (BRIEF) by CSI Group Within Time Window 2 (27-48 Months Post Diagnosis) | 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. | 27-48 months post diagnosis | 
| Post-treatment Metacognition Index (MI) on the Behavior Rating Inventory of Executive Function (BRIEF) by CSI Group Within Time Window 3 (49 - 72 Months Post Diagnosis) | 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. | 49 - 72 months post diagnosis | 
| Compliance Rates for All Eligible and Evaluable Patients Enrolled Within Time Window 1 (4-15 Months Post Diagnosis) | Compliance rates are calculated to monitor the compliance with long-term quality of life and functional status data submission. A patient will be compliant if the patient has metacognition index score. Compliance rates will be assessed at each of the 3 neurocognitive/quality of life assessment time windows. All eligible and evaluable patients enrolled will be used. Patients removed from treatment prior to the time of neuropsychological assessment (for reasons such as disease progression, death, withdrawal of consent, etc.) will not be included in the denominator to assess the compliance rate. The time window is 4 - 15 months post diagnosis. | 4-15 months post diagnosis | 
| Compliance Rates for All Eligible and Evaluable Patients Enrolled Within Time Window 2 (27-48 Months Post Diagnosis) | Compliance rates are calculated to monitor the compliance with long-term quality of life and functional status data submission. A patient will be compliant if the patient has metacognition index score. Compliance rates will be assessed at each of the 3 neurocognitive/quality of life assessment time windows. All eligible and evaluable patients enrolled will be used. Patients removed from treatment prior to the time of neuropsychological assessment (for reasons such as disease progression, death, withdrawal of consent, etc.) will not be included in the denominator to assess the compliance rate. The time window is 27 - 48 months post diagnosis. | 27-48 months post diagnosis | 
| Compliance Rates for All Eligible and Evaluable Patients Enrolled Within Time Window 3 (49 - 72 Months Post Diagnosis) | Compliance rates are calculated to monitor the compliance with long-term quality of life and functional status data submission. A patient will be compliant if the patient has metacognition index score. Compliance rates will be assessed at each of the 3 neurocognitive/quality of life assessment time windows. All eligible and evaluable patients enrolled will be used. Patients removed from treatment prior to the time of neuropsychological assessment (for reasons such as disease progression, death, withdrawal of consent, etc.) will not be included in the denominator to assess the compliance rate. The time window is 49 - 72 months post diagnosis. | 49 - 72 months post diagnosis |