Chemotherapy Followed by Radiation Therapy in Treating Younger Patients With Newly Diagnosed Localized Central Nervous System Germ Cell Tumors

PRIMARY OBJECTIVES:

I. To determine, as measured by the 3-year progression-free survival (PFS) rate and patterns
of failure, whether dose and volume of irradiation can be safely reduced to 30.6 Gy whole
ventricular-field irradiation (WVI) plus 23.4 Gy primary site boost instead of 36 Gy
craniospinal irradiation (CSI) plus primary site boost in the subgroup of children and young
adults (ages 3 to =< 21 years) with localized nongerminomatous germ cell tumor (NGGCT) who
have a magnetic resonance imaging (MRI) and tumor marker criteria (cerebrospinal fluid [CSF]
and serum) for confirmed complete response (CR) or partial response (PR) to induction
chemotherapy and negative serum and cerebrospinal fluid (CSF) tumor markers OR in patients
who have less than a PR after induction chemotherapy with negative tumor markers who undergo
a second-look surgery and are found to have only mature teratoma, residual scar or fibrosis
and fit the definition of CR/PR after second-look surgery.

II. To determine, as measured by the 3-year PFS rate and patterns of failure, whether
simplified chemotherapy followed by dose-reduced radiation therapy is effective for treating
children and young adults (ages 3 to =< 21 years) with localized primary central nervous
system (CNS) germinoma who present with serum and/or CSF human chorionic gonadotropin-beta
(hCGbeta) =< 50 mIU/mL.

III. To prospectively evaluate and longitudinally model the cognitive, social, and behavioral
functioning of children and young adults who are treated with reduced radiation dose and
volume of irradiation in Stratum 1 (NGGCT) and with dose-reduced radiation therapy in Stratum
2 (germinoma) using the ALTE07C1 protocol.

SECONDARY OBJECTIVES:

I. To estimate the PFS and overall survival (OS) distributions of patients with NGGCT treated
with 30.6 Gy WVI and involved-field radiation therapy (IFR) focal boost to 54 Gy.

II. To estimate the PFS and OS distributions of localized germinoma patients who present with
a) serum and/or CSF hCGbeta =< 50 mIU/mL and b) serum and/or CSF hCGbeta > 50 mIU/mL and =<
100 mIU/mL.

OUTLINE:

STRATUM I (NGGCT): Patients receive induction therapy comprising carboplatin intravenously
(IV) over 15-60 minutes on day 1 and etoposide IV over 60-120 minutes on days 1-3 of courses
1, 3, and 5. Patients also receive ifosfamide IV over 60 minutes and etoposide over 60-120
minutes on days 1-5 of courses 2, 4, and 6. Treatment repeats every 21 days for 6 courses in
the absence of disease progression or unacceptable toxicity. Patients achieving CR or PR
undergo 3-dimensional conformal radiation therapy (3DRT) or intensity modulated radiation
therapy (IMRT) once daily (QD) 5 days a week for 6 weeks. Patients with normalization of
markers who fail to achieve CR or PR are strongly recommended to undergo second-look surgery.
Patients who achieve CR or PR after second-look surgery undergo 3DRT or IMRT QD 5 days a week
for 6 weeks.

STRATUM II (GERMINOMA): Patients receive induction therapy comprising carboplatin IV over
15-60 minutes on day 1 and etoposide IV over 60-120 minutes on days 1-3. Treatment repeats
every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Patients with CR or continued CR (CCR) undergo 3DRT or IMRT QD 5 days a week for 4 weeks.
Patients with normalization of markers who fail to achieve CR or PR are strongly recommended
to undergo second-look surgery. Patients found to have fibrosis, scar, mature teratoma, or
non-viable tumor undergo 3DRT or IMRT QD 5 days a week for 4 weeks. Patients with stable
disease (SD) or PR with > 0.5 cm (suprasellar) or > 1 cm (pineal) but =< 1.5 cm residual
disease do not undergo second-look surgery and undergo 3DRT or IMRT QD 5 days a week for 4
weeks.

After completion of study treatment, patients are followed up at 3, 6, and 9 months, every 4
months for 24 months, 30 months, and then annually for up to 60 months.

Inclusion Criteria:

- Patients must be newly diagnosed with localized primary CNS NGGCT (Stratum 1) or
localized primary CNS germinoma (Stratum 2); germ cell tumors located in the
suprasellar, pineal, bifocal (pineal + suprasellar) and ventricles are eligible;
tumors present in the above mentioned locations and with unifocal parenchymal
extension are eligible

- Stratum 1(NGGCT): Patients must have one of the following criteria:

- Patients with serum and/or CSF hCGbeta > 100 mIU/mL or any elevation of
serum and/or CSF alpha-fetoprotein (AFP) > 10 ng/mL or greater than the
institutional normal are eligible, irrespective of biopsy results

- Patients with any of the following elements on biopsy/resection are
eligible, irrespective of serum and/or CSF hCGbeta and AFP levels:
endodermal sinus tumor (yolk sac), embryonal carcinoma, choriocarcinoma,
malignant/immature teratoma, and mixed GCT with malignant GCT elements

- Stratum 2 (Germinoma): Patients must have both serum and CSF markers obtained
(unless obtaining CSF is medically contraindicated) and must have one of the
following criteria to be eligible:

- Patients with institutional normal AFP (or =< 10 ng/mL if no institutional
normal exists) in both serum and CSF (unless medically contraindicated) AND
hCGbeta 5 to =< 50 mIU/mL in serum and/or CSF (unless medically
contraindicated) (only 1 is required to be elevated) are eligible; no
histologic confirmation required

- Patients with bifocal (pineal + suprasellar) involvement or pineal lesion
with diabetes insipidus (D1) AND hCGbeta =< 100 mIU/mL in serum and/or CSF
AND institutional normal AFP (or =< 10 ng/mL if no institutional normal
exists) in both serum and CSF (unless medically contraindicated) are
eligible; no histologic confirmation required

- Patients with histologically confirmed germinoma or germinoma mixed with
mature teratoma and hCGbeta =< 100 mIU/mL in serum and/or CSF and
institutional normal AFP (or =< 10 ng/mL if no institutional normal exists)
in both serum and CSF (unless medically contraindicated) are eligible

- All patients must have a cranial MRI with and without gadolinium at diagnosis/prior to
enrollment; if surgical resection is performed, patients must have pre-operative and
post-operative cranial MRI with and without gadolinium; the post-operative brain MRI
should be obtained within 72 hours of surgery; if patient has a biopsy only,
post-operative cranial MRI is recommended but not required; all patients must have a
spine MRI with gadolinium obtained at diagnosis/prior to enrollment; Note: if the
spine study is performed for the first time after surgical resection or biopsy, it is
recommended to be obtained with and without gadolinium

- Lumbar CSF must be obtained prior to study enrollment unless medically
contraindicated; if a patient undergoes surgery and lumbar CSF cannot be obtained at
this time, then it should be performed at least 10 days following surgery before study
enrollment; false positive cytology can occur within 10 days of surgery; Note:
patients with positive CSF cytology obtained prior to 10 days after surgery may have
cytology repeated to determine eligibility

- Patients must have CSF tumor markers obtained prior to enrollment unless medically
contraindicated; ventricular CSF obtained at the time of CSF diversion procedure (if
performed) is acceptable for tumor markers but lumbar CSF is preferred; in case CSF
diversion and biopsy/surgery are combined, CSF tumor markers should be collected first

- Patients must be enrolled on ALTE07C1 prior to enrollment on ACNS1123; patients must
be enrolled within 31 days of definitive diagnostic surgery (day 0) or clinical
diagnosis

- Peripheral absolute neutrophil count (ANC) >= 1,000/uL

- Platelet count >= 100,000/uL (transfusion independent)

- Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions)

- Creatinine clearance or radioisotope glomular filtration rate (GFR) >= 70 mL/min/1.73
m^2 OR 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) and 1.4 mg/dL (female) (13 to < 16 years of age)

- 1.7 mg/dL (male) and 1.4 mg/dL (female) (>= 16 years of age)

- Total bilirubin =< 1.5 times upper limit of normal (ULN) for age

- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and
serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5
times ULN

- Patients with seizure disorder may be enrolled if well controlled

- Patients must not be in status, coma, or assisted ventilation prior to study
enrollment

Exclusion Criteria:

- Patients with mature teratoma or completely resected immature teratoma with normal
tumor markers are not eligible

- Patients with tumors located outside the ventricles (basal ganglia, thalamus) are not
eligible

- Patients with metastatic disease by cranial or spinal MRI evaluation or CSF cytology
(unless medically contraindicated) are not eligible

- Patients must not have received any prior tumor-directed therapy other than surgical
intervention and corticosteroids

- Female patients who are pregnant are ineligible

- Lactating females are not eligible unless they have agreed not to breastfeed their
infants

- Female patients of childbearing potential are not eligible unless a negative pregnancy
test result has been obtained

- Sexually active patients of reproductive potential are not eligible unless they have
agreed to use an effective contraceptive method for the duration of their study
participation

- 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