Radiation Therapy Compared With Chemotherapy and Radiation Therapy in Treating Patients With Newly Diagnosed Primary Central Nervous System (CNS) Germ Cell Tumor

Children's Oncology Group

Status and phase: Completed; Phase 3

Conditions: Brain Tumor; Central Nervous System Tumor

Treatments: Drug: carboplatin; Biological: filgrastim; Radiation: radiation therapy; Drug: cisplatin; Drug: etoposide; Drug: cyclophosphamide

Study type: Interventional

Funder types: NETWORK; NIH

Identifiers

NCT00085098

COG-ACNS0232 (Other Identifier)

CDR0000367294 (Other Identifier)

ACNS0232

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 24 patients

Sex: All

Ages: 3 to 25 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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24 participants in 2 patient groups

Regimen A (radiotherapy only)

Experimental group

Description:

Within 52 days of surgery, patients will undergo standard-dose radiation therapy 5 days a week for approximately 5-6 weeks.

Treatment:

Radiation: radiation therapy

Regimen B (chemotherapy plus radiotherapy)

Experimental group

Description:

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. Within 3 weeks of completing chemotherapy, patients with CR undergo low-dose radiation therapy 5 days a week for 5 weeks. Patients with MRD, a PR, or SD receive chemotherapy courses 3 and 4 as outlined below. 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), subcutaneous (SC) 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 (PD) are restaged and may undergo standard radiation therapy as in regimen A. Reduced-dose radiation therapy: Within 6 weeks of starting course 4, patients undergo lower-dose radiation therapy once daily on days 1-5 for 5 weeks

Treatment:

Drug: cyclophosphamide

Drug: etoposide

Drug: cisplatin

Radiation: radiation therapy

Biological: filgrastim

Drug: carboplatin