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This phase II trial studies the best approach to combine chemotherapy and radiation therapy (RT) based on the patient's response to induction chemotherapy in patients with non-germinomatous germ cell tumors (NGGCT) that have not spread to other parts of the brain or body (localized). This study has 2 goals: 1) optimizing radiation for patients who respond well to induction chemotherapy to diminish spinal cord relapses, 2) utilizing higher dose chemotherapy followed by conventional RT in patients who did not respond to induction chemotherapy. Chemotherapy drugs, such as carboplatin, etoposide, ifosfamide, and thiotepa, 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. Radiation therapy uses high energy x-rays or high-energy protons to kill tumor cells and shrink tumors. Studies have shown that patients with newly-diagnosed localized NGGCT, whose disease responds well to chemotherapy before receiving radiation therapy, are more likely to be free of the disease for a longer time than are patients for whom the chemotherapy does not efficiently eliminate or reduce the size of the tumor. The purpose of this study is to see how well the tumors respond to induction chemotherapy to decide what treatment to give next. Some patients will be given RT to the spine and a portion of the brain. Others will be given high dose chemotherapy and a stem cell transplant before RT to the whole brain and spine. Giving treatment based on the response to induction chemotherapy may lower the side effects of radiation in some patients and adjust the therapy to a more efficient one for other patients with localized NGGCT.

PRIMARY OBJECTIVES:

I. To monitor outcome to ensure that children and young adults with localized central nervous system (CNS) non-germinomatous germ cell tumors (NGGCT) treated with induction chemotherapy followed by response evaluation and whole ventricular + spinal canal irradiation (WVSCI) will maintain the excellent 2-year progression free survival (PFS) rate as compared to ACNS0122 (NCT00047320).

II. To improve disease control by decreasing the number of spinal relapses for patients who achieve a complete response (CR) or partial response (PR) and receive WVSCI as compared to whole ventricular radiation on ACNS1123 (NCT01602666).

SECONDARY OBJECTIVES:

I. To estimate the response rates to induction chemotherapy and WVSCI for localized NGGCT patients who achieve a CR/PR.

II. To estimate the PFS and overall survival (OS) for localized NGGCT patients who achieve a CR/PR and receive WVSCI.

III. To estimate the PFS and OS for patients with less than a CR/PR following Induction who subsequently receive high-dose chemotherapy with peripheral stem cell rescue (HDCSCR).

IV. To estimate the response rate for patients with less than a CR/PR following Induction who subsequently receive HDCSCR.

EXPLORATORY OBJECTIVES:

I. To prospectively compare outcomes based on radiation modality, photon versus proton, including cognitive, social and behavioral functioning, auditory, and neuro-endocrine function.

II. To compare spinal column growth and cell counts following radiation as measured by height and weight, and complete blood count (CBC) values during and after radiation therapy, based on treatment modality (photon versus \[vs.\] proton therapy) and planned inclusion/exclusion of the vertebral body in patients \< 13 years of age.

III. To compare local vs. central review recommendations for second-look surgery and document barriers for performing such surgeries as well as their clinical benefit in pediatric NGGCT.

IV. To prospectively evaluate and longitudinally model the cognitive, social, and behavioral functioning of children and young adults with localized CNS NGGCT with testing as per the Children's Oncology Group (COG) Standardized Neuropsychological and Behavioral Battery.

V. To evaluate patterns of disease recurrence/failure with respect to radiation dose distribution.

OUTLINE:

INDUCTION CHEMOTHERAPY: Patients receive carboplatin intravenously (IV) over 15-60 minutes on day 1 and etoposide IV over 90-120 minutes on days 1-3 of cycles 1, 3, and 5. Patients also receive ifosfamide IV over 60 minutes and etoposide IV over 60-120 minutes on days 1-5 of cycles 2, 4, and 6. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

Patients are assigned to 1 of 2 plans (ventricular + spinal canal irradiation \[WVSCI\] or high-dose chemotherapy with peripheral stem cell rescue \[HDCSCR\]) based on response to induction chemotherapy:

* Patients who achieve radiographic CR/PR with marker normalization proceed to WVSCI. Patients who achieve radiographic CR without marker normalization proceed to HDCSCR.
* Patients who achieve less than radiographic CR/PR with marker normalization proceed to second-look surgery (unless contraindicated). If second-look surgery reveals mature teratoma or non-viable tumor, proceed to WVSCI. If second-look surgery reveals viable tumor, proceed to HDCSCR. Patients who are unable to undergo second-look surgery are removed from protocol therapy but remain on study for follow-up.
* Patients who achieve less than radiographic CR/PR without marker normalization proceed to second-look surgery (unless contraindicated). Patients then proceed to HDCSCR regardless of whether or not a second-look surgery is performed.
* Patients who achieve radiographic PR without marker normalization proceed to second-look surgery (unless contraindicated). Patients then proceed to HDCSCR regardless of whether or not a second-look surgery is performed.

PLAN A (WVSCI THERAPY): Within 6 weeks of the end of induction chemotherapy or second-look surgery, patients undergo WVSCI once daily (QD) for 5 days weekly (17 fractions followed by a boost dose for 13 fractions) for 6 weeks in the absence of disease progression or unacceptable toxicity.

PLAN B (CONSOLIDATION THERAPY \[HDCSCR\]): Within 6-8 weeks of the end of induction chemotherapy or second-look surgery, patients receive etoposide IV and thiotepa IV over 3 hours on days -5 to -3 and undergo peripheral blood stem cell (PBSC) transplant on day 0. Patients then undergo radiation therapy QD for 5 days weekly (20 fractions followed by a boost dose for 10 fractions) for 6 weeks in the absence of disease progression or unacceptable toxicity.

Patients also undergo magnetic resonance imaging (MRI), as well as collection of cerebral spinal fluid (CSF) and blood sample throughout the trial.

After completion of study treatment, patients are followed for up to 10 years.

A Study of a New Way to Treat Children and Young Adults With a Brain Tumor Called NGGCT

A Phase 2 Trial of Chemotherapy Followed by Response-Based Whole Ventricular &Amp; Spinal Canal Irradiation (WVSCI) for Patients With Localized Non-Germinomatous Central Nervous System Germ Cell Tumor

Will be assessed by the Wechsler Preschool and Primary Scale of Intelligence 4th Edition (WPPSI-IV), Wechsler Intelligence Scale for Children 5th Edition (WISC-V), and the Wechsler Adult Intelligence Scale 4th Edition (WAIS-IV), depending on patient's age. One-sample confidence intervals will be used to estimate mean pairwise changes in intelligence scores between 2 time points within each treatment arm.

Will be assessed by the Wechsler Preschool and Primary Scale of Intelligence 4th Edition (WPPSI- IV), Wechsler Intelligence Scale for Children 5th Edition (WISC V), and the Wechsler Adult Intelligence Scale 4th Edition (WAIS-IV), depending on patient's age. A 2-sample confidence interval approach will be used to estimate the difference in score changes between the two cohorts (WVSCI versus HDCSCR) in order to describe differential effects of the 2 treatment strategies.

Will be assessed by the WISC-V or WAIS-IV processing speed index tasks. One-sample confidence intervals will be used to estimate mean pairwise changes in scores between 2 time points within each treatment arm.

Will be assessed by the WISC-V or WAIS-IV processing speed index tasks. A 2-sample confidence interval approach will be used to estimate the difference in score changes between the two cohorts (WVSCI versus HDCSCR) in order to describe differential effects of the 2 treatment strategies.

Will be assessed by the Children's Memory Scale and California Verbal Learning Test. One-sample confidence intervals will be used to estimate mean pairwise changes in scores between 2 time points within treatment arms, as appropriate.

Will be assessed by the Behavior Assessment System for Children - 3rd Edition. One-sample confidence intervals will be used to estimate mean pairwise changes in scores between 2 time points within treatment arms, as appropriate.

Will be assessed by the Adaptive Behavior Assessment System - 3rd Edition. One-sample confidence intervals will be used to estimate mean pairwise changes in scores between 2 time points within treatment arms, as appropriate.

Will be assessed by the Pediatric Quality of Life Inventory version 4.0. One-sample confidence intervals will be used to estimate mean pairwise changes in scores between 2 time points within treatment arms, as appropriate.

Will be assessed by the Pediatric Quality of Life Inventory version 4.0. 2-sample confidence interval approach will be used to estimate the difference in score changes between the two cohorts (WVSCI versus HDCSCR) in order to describe differential effects of the 2 treatment strategies.

Will summarize and compare functional outcomes, including cognitive, social and behavioral functioning, and auditory and neuro-endocrine function, in the context of the radiation therapy modality used. Two sample t-tests for specified timepoints within each of the two treatment cohorts (WVSCI versus HDCSCR) will be used for comparisons.

Will compare early and late outcomes for proton and photon therapy with and without vertebral body sparing. Height and weight of subjects who are \< 13 years at the time of radiation therapy will be collected until subjects go off study or reach the age of 21, whichever is earlier. Percentile values standardizing height and weight based on appropriate growth curves will be used to compare cohorts treated with proton- versus photon-based radiation therapy.

Complete blood count values during radiation therapy will be used to compare these outcomes in the context of proton- versus photon-based radiation therapy.

Will summarize the local versus central review recommendations for second-look surgery and document any discrepancies.

Will be measured by the number of progressions or deaths within 2 years of enrollment for the cohort treated with whole ventricular + spinal canal irradiation (WVSCI). The final analysis will include an exact binomial confidence interval of the failure rate for each of the failure types (local, distant/spinal or both) without adjustment for multiplicity.

Will be measured by the number of spinal relapses (spine alone or distant relapses including the spine) within 2 years of enrollment in patients treated with WVSCI. The final analysis will include an exact binomial confidence interval of spinal failure rate.

Will be assessed in patients treated with induction chemotherapy. Will be estimated using an exact binomial approach and its confidence interval.

Will be assessed in patients treated with HDCSCR. Will be estimated using an exact binomial approach and its confidence interval.

Will be estimated separately for those treated with WVSCI and with HDCSCR + radiation therapy. Kaplan-Maier based PFS curve estimates will be included, where patients who are lost to follow up will be treated as censored observations as part of the primary analyses.

Will be estimated separately for those treated with WVSCI and with HDCSCR + radiation therapy. Kaplan-Maier based OS curve estimates will be included, where patients who are lost to follow up will be treated as censored observations as part of the secondary analyses.

Will be analyzed in an exploratory manner with respect to radiation dose distribution.

National Cancer Institute (NCI)

Children's Oncology Group

Spots Global Cancer Trial Database for pineal region germ cell tumor