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.

Condition	Treatment or Intervention	Phase
childhood central nervous system germ cell tumor	Drug: carboplatin  Drug: cisplatin  Drug: cyclophosphamide  Drug: etoposide  Drug: filgrastim  Procedure: biological response modifier therapy  Procedure: chemotherapy  Procedure: colony-stimulating factor therapy  Procedure: cytokine therapy  Procedure: radiation therapy	Phase III

Further Study Details: 

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 (M0 vs M1) 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 age (< 10 vs ≥ 10), tumor location (pineal vs suprasellar vs non-pineal/non-suprasellar), and extent of dissemination (localized vs metastatic). 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 28 days of surgery, patients undergo standard-dose radiotherapy once daily on days 1-5 for approximately 5-6 weeks.
• 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.
• 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 completing chemotherapy, 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 2, 24, and 48 months after completion of radiotherapy.

Patients are followed every 4 months for 2 years, every 6 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.

Ages Eligible for Study:  3 Years   -   25 Years,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed primary CNS pure germ cell tumor
• Diagnosed within the past 21 days
• Lumbar cerebrospinal fluid (CSF) assay meeting criteria for the following marker profiles:
• Serum and CSF beta human chorionic gonadotropin (β-HCG) ≤ 50 IU/dL
• Alpha fetoprotein (AFP) ≤ 10 IU/L OR ≤ institutional norm
• CSF AFP ≤ 2.0 IU/L OR ≤ 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)
• AST or ALT < 2.5 times ULN

Renal

• Creatinine ≤ 1.5 times ULN
• 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

Study chairs or principal investigators

Jeffrey C. Allen, MD,  Study Chair,  Beth Israel Medical Center - Singer Division   
Bernadine Donahue, MD,  Tisch Hospital   

Study ID Numbers:  CDR0000367294; COG-ACNS0232; NCT00085098
Record last reviewed:  May 2004
Last Updated:  March 10, 2005
Record first received:  June 10, 2004
ClinicalTrials.gov Identifier:  NCT00085098
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08