Radiation Therapy Compared With Chemotherapy and Radiation Therapy in Treating Patients With Newly Diagnosed Primary Central Nervous System (CNS) Germ Cell Tumor
Radiation Therapy Compared With Chemotherapy and Radiation Therapy in Treating Patients With Newly Diagnosed Primary Central Nervous System (CNS) Germ Cell Tumor
RATIONALE: Radiation therapy uses high-energy x-rays to damage tumor cells. Drugs used in
 chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or
 die. It is not yet known whether radiation therapy alone is as effective as chemotherapy plus
 radiation therapy in treating germ cell tumor.

 PURPOSE: This randomized phase III trial is studying radiation therapy alone to see how well
 it works compared to chemotherapy and radiation therapy in treating patients with newly
 diagnosed primary CNS germ cell tumor.
OBJECTIVES:

 Primary

 -  Compare event-free survival and overall survival of patients with newly diagnosed
 primary CNS germ cell tumor treated with conventional radiotherapy alone (regimen A) vs
 chemotherapy followed by tumor response-based radiotherapy (regimen B).

 Secondary

 -  Determine the complete response rate in patients treated with regimen B.

 -  Determine the acute and subacute toxicity of regimen B in these patients.

 -  Compare treatment-related morbidity, in terms of verbal learning and memory, executive
 functioning, and quality of life, in patients treated with these regimens.

 -  Determine the prognostic value of baseline serum, lumbar, and intraventricular levels of
 human chorionic gonadotropin levels from patients treated with these regimens.

 -  Determine the prognostic value of extent of disease (M+ vs modified M+ vs M0) on
 event-free survival and overall survival of patients treated with these regimens.

 OUTLINE: This is a randomized, multicenter study. Patients are stratified according to tumor
 location (pineal vs suprasellar vs pineal + suprasellar or other), and disease stage
 (disseminated vs occult multi-focal vs localized). Patients are randomized to 1 of 2
 treatment regimens.

 All patients undergo an operative procedure (endoscopic biopsy, stereotactic biopsy, or open
 craniotomy) to confirm the diagnosis of pure germ cell germinoma followed by an
 intraoperative and perioperative staging evaluation.

 -  Regimen A (radiotherapy only): Within 52 days of surgery, patients undergo standard-dose
 radiotherapy once daily on days 1-5 for approximately 5-6 weeks.

 -  Regimen B (chemotherapy plus radiotherapy):

 -  Courses 1 and 2: Patients receive carboplatin IV over 1 hour on days 1 and 2 and
 etoposide IV over 2 hours on days 1-3. Treatment repeats every 21 days for 2
 courses.

 Patients achieving a complete response (CR) proceed to reduced-dose radiotherapy. Patients
 with minimal residual disease (MRD), a partial response (PR), or stable disease (SD) receive
 chemotherapy courses 3 and 4 as outlined below. Patients with progressive disease undergo a
 second surgical procedure for biopsy and are restaged. Patients with a confirmed diagnosis of
 germ cell tumor with no change in tumor markers and no new lesions after restaging proceed to
 chemotherapy courses 3 and 4.

 -  Courses 3 and 4: Patients receive cisplatin IV over 6 hours on day 1, cyclophosphamide
 IV over 1 hour on days 2 and 3, and filgrastim (G-CSF) subcutaneously or IV beginning on
 day 4 and continuing until blood counts recover. Treatment repeats every 21 days for 2
 courses.

 Patients achieving a CR or MRD proceed to reduced-dose radiotherapy. Patients with a PR, SD,
 or progressive disease are restaged. Patients with a confirmed diagnosis of germ cell tumor
 after restaging undergo standard radiotherapy as in regimen A.

 -  Reduced-dose radiotherapy: Within 6 weeks of starting course 4, patients undergo
 lower-dose radiotherapy once daily on days 1-5 for 5 weeks.

 Treatment in both regimens continues in the absence of unacceptable toxicity or in the event
 that a non-germinomatous germ cell tumor is detected.

 Quality of life and neuropsychological function within the domains of intelligence,
 attention-concentration, memory, and executive functioning are assessed at 9, 30, and 60
 months after diagnosis.

 Patients are followed every 4 months for 2 years, and then annually thereafter.

 PROJECTED ACCRUAL: A total of 225 patients (approximately 112 per treatment regimen) will be
 accrued for this study within 5 years.
DISEASE CHARACTERISTICS:

 -  Histologically confirmed primary CNS pure germ cell tumor

 -  Diagnosed within the past 31 days

 -  Meets any 1 OR none (i.e., M0 [localized disease]) of the following staging criteria:

 -  M+ (disseminated disease)

 -  Leptomeningeal or intraventricular metastases visualized on MRI scans of the
 brain and spine

 -  Clumps of tumor cells on lumbar cerebrospinal fluid (CSF) cytology

 -  Visible tumor studding the walls of the lateral or third ventricles noted
 during endoscopy or surgery

 -  Primary tumor arising within the parenchyma of the brain, brainstem, or
 spinal cord

 -  Measurable multi-focal tumors arising in both the pineal and suprasellar
 regions (i.e., multiple midline tumors)

 -  Infiltrative, intra-axial extension on brain MRI > 1 cm beyond enhancing
 tumor

 -  Modified M+ (occult multi-focal disease)

 -  M0 at diagnosis with a localized pineal region tumor with signs and symptoms
 of diabetes insipidus without measurable disease in the suprasellar region

 -  Lumbar CSF assay meeting criteria for the following marker profiles:

 -  Serum and CSF beta human chorionic gonadotropin (β-HCG) ≤ 50 IU/dL

 -  Serum alpha fetoprotein (AFP) ≤ 10 IU/L AND ≤ institutional norm

 -  CSF AFP ≤ 2.0 IU/L AND ≤ institutional norm

 PATIENT CHARACTERISTICS:

 Age

 -  3 to 25

 Performance status

 -  Not specified

 Life expectancy

 -  Not specified

 Hematopoietic

 -  Absolute neutrophil count > 1,000/mm^3

 -  Platelet count > 100,000/mm^3 (transfusion independent)

 -  Hemoglobin > 10.0 g/dL (transfusion allowed)

 Hepatic

 -  Bilirubin ≤ 1.5 times upper limit of normal (ULN)

 -  aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 2.5 times ULN

 Renal

 -  Creatinine adjusted according to age as follows*:

 -  No greater than 0.4 mg/dL (≤ 5 months)

 -  No greater than 0.5 mg/dL (6 months -11 months)

 -  No greater than 0.6 mg/dL (1 year-23 months)

 -  No greater than 0.8 mg/dL (2 years-5 years)

 -  No greater than 1.0 mg/dL (6 years-9 years)

 -  No greater than 1.2 mg/dL (10 years-12 years)

 -  No greater than 1.4 mg/dL (13 years and over [female])

 -  No greater than 1.5 mg/dL (13 years to 15 years [male])

 -  No greater than 1.7 mg/dL (16 years and over [male]) AND

 -  Creatinine clearance OR radioisotope glomerular filtration rate > 70 mL/min

 Other

 -  Not pregnant or nursing

 -  Negative pregnancy test

 -  Fertile patients must use effective contraception

 -  Euthyroid (with or without levothyroxine sodium therapy) as determined by normal T4 ±
 thyroid-stimulating hormone levels*

 -  Diabetes insipidus allowed provided patient is relatively stable on desmopressin
 acetate

 -  Normal endogenous cortisol function*

 -  Adequate antidiuretic hormone reserves* NOTE: *Unless receiving replacement therapy

 PRIOR CONCURRENT THERAPY:

 Biologic therapy

 -  Not specified

 Chemotherapy

 -  Not specified

 Endocrine therapy

 -  Concurrent replacement hormones allowed (e.g., corticosteroids, levothyroxine sodium,
 and desmopressin acetate)

 Radiotherapy

 -  Not specified

 Surgery

 -  Prior surgery for germ cell tumor allowed

 Other

 -  No other prior therapy for germ cell tumor

 -  Concurrent anticonvulsants allowed