Neoplasms

All Conditions

Rare Diseases

Medulloblastoma

Sarcoma, Ewing

Neuroectodermal Tumors, Primitive, Peripheral

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Micronutrients

Dermatologic Agents

Vitamins

Cyclophosphamide

Carboplatin

Vincristine

Cisplatin

Lenograstim

Isotretinoin

Tretinoin

Vitamin A

Retinol palmitate

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Trace Elements

Adjuvants, Immunologic

Tubulin Modulators

Antimitotic Agents

Keratolytic Agents

Retinol

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.

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.

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.

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.

Filgrastim

Laboratory Biomarker Analysis

Quality-of-Life Assessment

Radiation Therapy

Vincristine Sulfate

James M Olson

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.

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.

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

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

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.

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.

Percentages of patients with responses after radiation therapy (induction therapy) are reported with 95% confidence intervals. Complete and partial responses were considered responses.

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.

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.

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.

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.

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.

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.

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.

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.

National Cancer Institute (NCI)

Children's Oncology Group

Adverse event reporting is collected routinely using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution via expedited reporting (NCI AdEERs / CAeRs). All remaining CTCAEs collected by means other than expedited reporting are non-serious and are reported in the "AE Other" table. Ineligible patients are excluded from reporting of adverse events. All-Cause Mortality includes all deaths collected on the study.

Medulloblastoma patients who received regimen A (no carboplatin / no isotretinoin)

Regimen A (Medulloblastoma Patients)

Medulloblastoma patients who received regimen B (carboplatin / no isotretinoin)

Regimen B (Medulloblastoma Patients)

Medulloblastoma patients who received regimen C (no carboplatin / isotretinoin)

Regimen C (Medulloblastoma Patients)

Medulloblastoma patients who received regimen D (carboplatin / isotretinoin)

Regimen D (Medulloblastoma Patients)

SPNET patients who received regimen A (no carboplatin / no isotretinoin)

Regimen A (SPNET Patients)

SPNET patients who received regimen B (carboplatin / no isotretinoin)

Regimen B (SPNET Patients)

SPNET patients who received regimen C (no carboplatin / isotretinoin)

Regimen C (SPNET Patients)

SPNET patients who received regimen D (carboplatin / isotretinoin)

Regimen D (SPNET Patients)

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Only eligible patients were included in the baseline characteristics results. For example, of the 93 Regimen B medulloblastoma patients, 4 were ineligible (see patient flow) and excluded from baseline measures reporting leaving 89 eligible regimen B medulloblastoma patients.

Results Reporting Coordinator

Eligible medulloblastoma patients are included.

Percent Probability of Event-free Survival (EFS) for Patients With Medulloblastoma

Percent Probability of Event-free Survival (EFS) for Patients With Supratentorial Primitive Neuroectodermal Tumor (SPNET)

83 of 87 eligible Arm A medulloblastoma patients were evaluated for response after induction, as were 85/89, 48/53, and 55/56 arm B, C, and D patients, respectively.

Tumor Response to Radiation Therapy for Patients With Medulloblastoma

23 of 23 eligible Arm A SPNET patients were evaluated for response after induction, as were 18/19, 21/21, and 19/22 arm B, C, and D patients, respectively.

Tumor Response to Radiation Therapy for Patients With Supratentorial Primitive Neuroectodermal Tumor (SPNET)

Percent Probability of Overall Survival (OS) for Patients With Medulloblastoma

Percent Probability of Overall Survival (OS) for Patients With Supratentorial Primitive Neuroectodermal Tumor (SPNET)

The Estimated Full-scale IQ (FSIQ) at 9+/-3 Months Post Diagnosis for Medulloblastoma Patients

The Estimated Full-scale IQ (FSIQ) at 30+/-6 Months Post Diagnosis for Medulloblastoma Patients

The Estimated Full-scale IQ (FSIQ) at 60+/-12 Months Post Diagnosis for Medulloblastoma Patients

The Estimated Full-scale IQ (FSIQ) at 9+/-3 Months Post Diagnosis for SPNET Patients

The Estimated Full-scale IQ (FSIQ) at 30+/-6 Months Post Diagnosis for SPNET Patients

The Estimated Full-scale IQ (FSIQ) at 60+/-12 Months Post Diagnosis for SPNET Patients

Metacognition Index (MI) on the Behavior Rating Inventory of Executive Function (BRIEF) at 9+/-3 Months Post Diagnosis for Medulloblastoma Patients

Metacognition Index (MI) on the Behavior Rating Inventory of Executive Function (BRIEF) at 30+/-6 Months Post Diagnosis for Medulloblastoma Patients

Metacognition Index (MI) on the Behavior Rating Inventory of Executive Function (BRIEF) at 60+/-12 Months Post Diagnosis for Medulloblastoma Patients

Metacognition Index (MI) on the Behavior Rating Inventory of Executive Function (BRIEF) at 9+/-3 Months Post Diagnosis for SPNET Patients

Metacognition Index (MI) on the Behavior Rating Inventory of Executive Function (BRIEF) at 30+/-6 Months Post Diagnosis for SPNET Patients

Metacognition Index (MI) on the Behavior Rating Inventory of Executive Function (BRIEF) at 60+/-12 Months Post Diagnosis for SPNET Patients

Overall Study

Supratentorial Primitive Neuroectodermal Tumor

Childhood Supratentorial Embryonal Tumor, Not Otherwise Specified

Reproductive Control Agents

Hematinics

Bone Density Conservation Agents

Leucovorin

Etoposide

Levoleucovorin

Methotrexate

Calcium

Folic Acid

Etoposide phosphate

Podophyllotoxin

Thiotepa

Calcium, Dietary

Vitamin B Complex

Hormones

Antimetabolites

Enzyme Inhibitors

Folic Acid Antagonists

Antidotes

Protective Agents

Folinic Acid

Folate

Vitamin B9

Patients receive vincristine IV over 1 minute on days 1, 8, and 15; etoposide IV over 1 hour on days 1-3; cyclophosphamide IV over 1 hour on days 1 and 2; cisplatin IV over 6 hours on day 3. Treatment repeats every 3 weeks for 3 courses.

Within 6 weeks after completion of induction therapy, patients receive consolidation therapy comprising carboplatin IV over 2 hours and thiotepa IV over 2 hours on days 1 and 2 and G-CSF IV or SC beginning on day 5 and continuing until blood counts recover. Patients also receive autologous PBSC IV on day 4. Treatment repeats every 4 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.

Patients receive vincristine IV over 1 minute on days 1, 8, and 15; high-dose methotrexate IV over 4 hours on day 1; and leucovorin calcium IV or PO every 6 hours beginning on day 2 and continuing until methotrexate levels are in a safe range. Patients then receive etoposide IV over 1 hour on approximately days 4, 5, and 6, cyclophosphamide IV over 1 hour on approximately days 4 and 5, and cisplatin IV over 6 hours on approximately day 6. Treatment repeats every 3 weeks for 3 courses.

Within 6 weeks after completion of induction therapy, patients receive consolidation therapy comprising carboplatin IV over 2 hours and thiotepa IV over 2 hours on days 1 and 2 and G-CSF IV or SC beginning on day 5 and continuing until blood counts recover. Patients also receive autologous PBSC IV on day 4. Treatment repeats every 4 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.

Autologous Hematopoietic Stem Cell Transplantation

Leucovorin Calcium

Claire M Mazewski

This randomized phase III trial is studying two different combination chemotherapy regimens to compare how well they work in treating young patients with newly diagnosed supratentorial primitive neuroectodermal tumors or high-risk medulloblastoma when given before additional intense chemotherapy followed by peripheral blood stem cell rescue. It is not yet known which combination chemotherapy regimen is more effective when given before a peripheral stem cell transplant in treating supratentorial primitive neuroectodermal tumors or medulloblastoma.

PRIMARY OBJECTIVES:

I. To determine if treatment of infants with high risk primitive neuroectodermal tumors (PNET) central nervous system (CNS) tumors with intensive chemotherapy plus high-dose methotrexate and peripheral blood stem cell rescue results in a higher complete response rate then the same regimen without methotrexate.

SECONDARY OBJECTIVES:

I. To determine whether biologic characterization of these tumors will refine therapeutic stratification separating atypical teratoid rhabdoid tumors (AT/RT) from primitive neuroectodermal tumors (PNETs) and possibly identifying other markers of value for stratification within the group of PNETs.

II. To determine if event free survival (EFS) and patterns of failure differ between the methotrexate arm versus the arm without methotrexate.

III. To compare the acute, chronic and late effects of these two very intensive regimens, especially as to the tolerance of the same consolidation regimen following the differing induction regimens.

IV. To compare the gastrointestinal and nutritional toxicities of these intense regimens.

V. To describe and compare the quality of life outcomes and neuropsychological effects of these intense systemic therapies.

OUTLINE: Patients are randomized to 1 of 2 treatment arms

INDUCTION THERAPY:

ARM I: Patients receive vincristine IV over 1 minute on days 1, 8, and 15; etoposide IV over 1 hour on days 1-3; cyclophosphamide IV over 1 hour on days 1 and 2; cisplatin IV over 6 hours on day 3; and filgrastim (G-CSF) IV or subcutaneously (SC) beginning on day 4 and continuing until blood counts recover. Treatment repeats every 3 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive vincristine IV over 1 minute on days 1, 8, and 15; high-dose methotrexate IV over 4 hours on day 1; and leucovorin calcium IV or orally (PO) every 6 hours beginning on day 2 and continuing until methotrexate levels are in a safe range. Once methotrexate levels are in a safe range, patients then receive etoposide IV over 1 hour on approximately days 4, 5, and 6, cyclophosphamide IV over 1 hour on approximately days 4 and 5, and cisplatin IV over 6 hours on approximately day 6. Patients also receive G-CSF IV or SC beginning 24 hours after the completion of chemotherapy and continuing until blood counts recover. Treatment repeats every 3 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.

In both arms, patients with stable disease or partial response after induction therapy proceed to second-look surgery followed by consolidation therapy. Patients with a complete response after induction therapy proceed directly to consolidation therapy.

CONSOLIDATION THERAPY: Beginning no more than 6 weeks after completion of induction therapy, patients receive consolidation therapy comprising carboplatin IV over 2 hours and thiotepa IV over 2 hours on days 1 and 2 and G-CSF IV or SC beginning on day 5 and continuing until blood counts recover. Patients also receive autologous peripheral blood stem cells (PBSC) IV on day 4. Treatment repeats every 4 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed up periodically for 4 years and then annually thereafter.

Combination Chemotherapy Followed By Peripheral Stem Cell Transplant in Treating Young Patients With Newly Diagnosed Supratentorial Primitive Neuroectodermal Tumors or High-Risk Medulloblastoma

A Phase III Randomized Trial for the Treatment of Newly Diagnosed Supratentorial PNET and High Risk Medulloblastoma in Children &lt; 36 Months Old With Intensive Induction Chemotherapy With Methotrexate Followed by Consolidation With Stem Cell Rescue vs. the Same Therapy Without Methotrexate

At the end of consolidation, the number of evaluable patients treated with intensive chemotherapy with methotrexate who achieved CR or not will be compared to those who achieved CR or not after treated with the same intensive chemotherapy without methotrexate. The CR rates between these two groups will be compared at a significance level of 0.1 using one-sided Chi-square test. Complete Response (CR) requires: CR for target lesions: disappearance of all target lesions, CR for non-target lesions: disappearance of all non-target lesions and no new lesions. No CR is any response not fitting the definition of CR.

The number of patients will be reported for this analysis by Molecular Sub-types of MB, CNS-PNETs/EBTs

EFS was defined as time from enrollment to the occurrence of first event (disease progression/relapse, secondary malignancy, death from any cause) or date of last contact for patients who are event-free. The percentage of participants with EFS and 90% confidence interval were provided. The difference in incidence for the two treatment regimens were compared using a one-sided log-rank test with a significance level of 0.1.

The patterns of failure for relapse/disease progression will be provided for patients treated with/without methotrexate drug in three categories, namely local, distant, and both local and distant. The number of patients with each type of failure will be listed per arm. The two groups will be compared to determine if the pattern of failure distribution is different between the two arms using Fisher exact test.

Event is defined as the first occurrence of any acute toxicity. Estimates will be obtained using life-table methods. Patients who have progression or recurrence of disease will be censored in this analysis. Difference in incidence for the two treatment regimens will be compared using log-rank test.

Per protocol, hearing was assessed pretreatment and at regular specified intervals during treatment and off therapy, using DPOAE, audiogram or Brainstem Evoked Auditory. Per CTCAE V4.0 grade 3 Hearing impaired is defined as follows; Pediatric (on a 1,2,3,4, 6 and 8 kHz audiogram): hearing loss sufficient to indicate therapeutic intervention, including hearing aids, threshold shift \>20 dB at 3 kHz and above in at least one ear, additional speech-language related services as indicated. Per CTCAE V4.0 grade 4 Hearing impaired is defined as follows; Pediatric Audiologic indication for cochlear implant and additional speech-language related services as indicated.

Thyroid function was assessed as per ACNS0334 Endocrine Guidelines. "Normal" and "Abnormal" are defined at each institution by the laboratory standards where the blood tests are run. Primary Hypothyroidism/Subclinical Compensatory Hypothyroidism is defined as patients with Free T4 level less than "Institutional" Normal or equal to "Institutional" Normal with TSH level greater than "Institutional" Normal.

Thyroid function was assessed as per ACNS0334 Endocrine Guidelines. "Normal" and "Abnormal" are defined at each institution by the laboratory standards where the blood tests are run. Central Hypothyroidism is defined as Free T4 level less than "Institutional" Normal with TSH less than or equal to "Institutional" Normal.

Low Somatomedin C is defined as patients with somatomedin C value less than institutional normal. As numbers are too small, descriptive statistics such as number will be reported for this analysis. Growth hormone function was assessed as per ACNS0334 Endocrine Guidelines. Low Somatomedin C levels are defined at each institution by the laboratory standards where the blood tests are run.

The number of patients who had "Diabetes Insipidus" and on DDAVP will be reported for this analysis due to small numbers..

The number of patients who had secondary malignancy will be reported for this analysis due to small numbers.

The number of patients who are reported to have abnormal hearing, graded according to CTCAE 4.0 or not, with onset while on therapy or when off therapy which persisted after off therapy will be reported and will be compared using Fisher exact test.

Rates of gastrointestinal toxicities reported as Adverse Events during therapy for each cycle will be summarized using standard descriptive methods (such as number of patients). The difference in number of patients with gastrointestinal toxicities between the two treatment regimens will be compared using a Chi-square test.

Rates of nutritional toxicities reported as Adverse Events during therapy for each cycle will be summarized using standard descriptive methods (such as number of patients). The difference in number of patients with nutritional toxicities between the two treatment regimens will be compared using a Chi-square test.

Three tools are used to assess intelligence (IQ) depending on age. The range of IQ scores is 40-160 (mean=100, SD=15); range for the Processing Speed Index (PSI)=45-155. Higher scores represent better functioning. (1) Wechsler Preschool and Primary Scale of Intelligence-4th Edition (WPPSI-IV) is used for ages 2.5 to 6 years. Bug Search and Cancellation subtests are summed to calculate PSI. (2) Wechsler Intelligence Scales for Children-5th Edition (WISC-V) is used for ages 6 - 16 years. Symbol Search and Coding subtests are summed to calculate PSI. (3) Wechsler Adult Intelligence Scales-4th Edition (WAIS-IV) is used for ages 16 and older. Symbol Search and Coding subtests are summed to calculate PSI.

The Pediatric Quality of Life Inventory Version 4 (PedsQL) measures health-related quality of life (QOL). Parents complete the measure for children ages 2-17, and patients \> 18 complete a self-report version. Total scores range from 0-100, with higher scores representing better QOL.

Adverse Events/Serious Adverse Events were reported for all eligible patients (n=77) by treatment arm in the study. The total number of participants at risk represents total number of eligible patients in the study by treatment arm.

Patients receive vincristine sulfate IV on days 1, 8, and 15; etoposide IV over 1 hour on days 1-3; cyclophosphamide IV over 1 hour on days 1 and 2; cisplatin IV over 6 hours on day 3. Treatment repeats every 3 weeks for 3 courses.

Within 6 weeks after completion of induction therapy, patients receive consolidation therapy comprising carboplatin IV over 2 hours and thiotepa IV over 2 hours on days 1 and 2 and filgrastim (G-CSF) IV or SC beginning on day 54 and continuing until blood counts recover. Patients also receive autologous PBSC IV on day 4. Treatment repeats every 3 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.

Arm I (Patients Treated Without Methotrexate (MTX))

Patients receive vincristine sulfate IV on days 1, 8, and 15; high-dose methotrexate IV over 4 hours on day 1; and leucovorin calcium IV or orally every 6 hours beginning on day 2 and continuing until methotrexate levels are in a safe range. Patients then receive etoposide IV over 1 hour on approximately days 4, 5, and 6, cyclophosphamide IV over 1 hour on approximately days 4 and 5, and cisplatin IV over 6 hours on approximately day 6. Treatment repeats every 3 weeks for 3 courses.

Within 6 weeks after completion of induction therapy, patients receive consolidation therapy comprising carboplatin IV over 2 hours and thiotepa IV over 2 hours on days 1 and 2 and filgrastim (G-CSF) IV or SC beginning on day 54 and continuing until blood counts recover. Patients also receive autologous PBSC IV on day 4. Treatment repeats every 3 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.

Arm II (Patients Treated With MTX)

Only eligible patients are included in the baseline characteristics. Seven patients were excluded in each treatment arm.

Data will not be available for reporting Secondary Outcome Measure #15 until December 2018 due to the limiting factor, being that the tissue has not yet been shipped from the Biopath Center to the designated laboratory for analysis.

The CR rates between these two groups will be compared at a significance level of 0.1 using one-sided Chi-square test.

Per protocol, only evaluable patients are included.

Number of Patients Who Have Either a Complete Response (CR) Rate or No Complete Response Rate

12 patients without molecular data, because of lack of sufficient materials or poor quality of the data, were not included in this analysis.

Number of Participants With Molecular Sub-types of MB, CNS-PNETs/EBTs Represented in the ACNS0334 Cohort

The difference in incidence for the two treatment regimens will be compared using a one-sided log-rank test with a significance level 0.1.

Per protocol all eligible patients randomized to treatment should be included in the analysis.

Percentage of Participants With Event Free Survival (EFS)

The two groups will be compared for patterns of failure to detect a statistically significant difference using Fisher exact test.

All Eligible Participants who relapsed/disease progressed in the study.

Patterns of Failure

Difference in incidence for the two treatment regimens will be compared using log-rank test.

Percentage of Participants With Any Acute Adverse Events

The rate of acute hearing loss between two treatment regimens will be be compared using Fisher exact test.

Number of Participants With Acute Hearing Loss and No Acute Hearing Loss

Number of Participants With Chronic Primary Hypothyroidism/Subclinical Compensatory HypothyroidismHypothyroidism/Subclinical Compensatory Hypothyroidism

Number of Participants With Chronic Central Hypothyroidism

Number of Participants With Chronic Low Somatomedin C

Number of Participants With Chronic Diabetes Insipidus

Number of Participants With Secondary Malignancies

The rate of chronic hearing loss between two treatment regimens will be be compared using Fisher exact test.

Number of Participants With Chronic/Late Hearing Loss and No Chronic/Late Hearing Loss

Rates of gastrointestinal toxicities in Induction Phase I. The difference in number of patients with/without gastrointestinal toxicities between the two treatment regimens will be compared using a Chi-square test.

Rates of gastrointestinal toxicities in Induction Phase II. The difference in number of patients with/without gastrointestinal toxicities between the two treatment regimens will be compared using a Chi-square test.

Rates of gastrointestinal toxicities in Induction Phase III. The difference in number of patients with/without gastrointestinal toxicities between the two treatment regimens will be compared using a Chi-square test.

Rates of gastrointestinal toxicities in Consolidation Phase 1. The difference in number of patients with/without gastrointestinal toxicities between the two treatment regimens will be compared using a Chi-square test.

Rates of gastrointestinal toxicities in Consolidation Phase 2. The difference in the number of patients with/without gastrointestinal toxicities between the two treatment regimens will be compared using a Chi-square test.

Rates of gastrointestinal toxicities in Consolidation Phase III. The difference in number of patients with/without gastrointestinal toxicities between the two treatment regimens will be compared using a Chi-square test.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Chemotherapy and Radiation Therapy in Treating Young Patients With Newly Diagnosed, Previously Untreated, High-Risk Medulloblastoma/PNET	NCT00392327	Anaplastic Medu... Medulloblastoma	Carboplatin Cisplatin Cyclophosphamid... Filgrastim Isotretinoin Laboratory Biom... Quality-of-Life... Radiation Thera... Vincristine Sul...	3 Years - 21 Years	Children's Oncology Group
Combination Chemotherapy Followed By Peripheral Stem Cell Transplant in Treating Young Patients With Newly Diagnosed Supratentorial Primitive Neuroectodermal Tumors or High-Risk Medulloblastoma	NCT00336024	Anaplastic Medu... Medulloblastoma Supratentorial ... Untreated Child...	Autologous Hema... Carboplatin Cisplatin Cyclophosphamid... Etoposide Filgrastim Laboratory Biom... Leucovorin Calc... Methotrexate Quality-of-Life... Thiotepa Vincristine Sul...	- 2 Years	Children's Oncology Group

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