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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Radiotherapy Alone Versus Chemotherapy Followed By Response-Based Radiotherapy For Newly Diagnosed Primary CNS Germinoma

Conditions
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Brain Tumor, Central Nervous System Tumor

Intervention / Treatment
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* Biological: filgrastim
* Drug: carboplatin
* Drug: cisplatin
* Drug: cyclophosphamide
* Drug: etoposide
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 25 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Regimen A (radiotherapy only)<br>Within 52 days of surgery, patients will undergo standard-dose radiation therapy 5 days a week for approximately 5-6 weeks. | Radiation: radiation therapy<br>* Patients undergo radiotherapy 5 days a week<br>|
| Experimental: Regimen B (chemotherapy plus radiotherapy)<br>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 | Biological: filgrastim<br>* Given by infusion or injection<br>* Other names: NSC #61462;Drug: carboplatin<br>* Given IV over 1 hour<br>* Other names: NSC #241240;Drug: cisplatin<br>* Given IV over 6 hours<br>* Other names: NSC #119875;Drug: cyclophosphamide<br>* Given IV over 1 hour<br>* Other names: NSC #26271;Drug: etoposide<br>* Given IV over 2 hours<br>* Other names: NSC #141540;Radiation: radiation therapy<br>* Patients undergo radiotherapy 5 days a week<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free Survival | Data will be summarized as number of patients in the following categories at the time of data cutoff for analyses of 3-year EFS: 1)Experienced a qualifying event (QE) (see below);2)Event-free through 3 years of follow-up;3)Event-free until data cutoff (if less than 3 years of follow-up);4)Withdrew from study;5)Lost to follow-up. QEs: 1)disease progression, defined as increase >= 40% in tumor volume or >= 25% in tumor area of target lesions;2)development of new lesions;3)occurrence of a second malignant neoplasm, defined as a malignancy with different histological type from trial-qualifying diagnosis;4)death from any cause. Stat. analyses will be based on time from enrollment to the earliest of: 1)occurrence of any of the QEs;2)withdrawal from study or lost to follow-up;3)completion of three years of follow-up event-free;4)data cutoff for completion of the statistical analyses for the protocol's primary objective. NOTE: Reported data are through May 2009 (see Caveats section). | Study enrollment until date of earliest qualifying event (QE), date last known to be QE-free if the patient is followed for less than three years and is QE-free at the time of analysis, or 3 years if the patient is QE-free at 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a Response to Regimen B | To assess the complete response rate to pre-radiotherapy chemotherapy (Reg B only). Response was determined after completing 2-4 cycles of chemotherapy on Reg B. Complete Response (CR) is defined as disappearance of all target lesions. | 5 years from beginning of treatment | 
| Toxicity and Safety as Assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 | The analysis of toxicity will focus on estimating the rates of key acute and subacute toxicity occurring during the first induction chemotherapy. The list of toxicities of interest include Anemia or Febrile Neutropenia; Nausea or Vomiting; Infections and Infestations; Neutrophil or White blood count decrease; and Hypokalemia or Hyponatremia | From the beginning of treatment, assessed up to 5 years | 
| Quality of Life (QOL) and Neurocognitive Assessment (NP) | The primary endpoints for QOL and NP assessments will be the global scale value from each of these instruments at the two-year time point. Analyses of subscales (if they exist) and of assessments at other times will be of secondary interest. It is assumed that scale values are standardized to a reference normal population. The scores range from 0 to 100 with higher score reflecting better QoL or neurocognitive assessment. | 2 years from beginning of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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childhood central nervous system germ cell tumor