Combination Chemotherapy in Treating Children With Progressive Brain Tumors

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells. PURPOSE: This randomized phase III trial is studying two different combination chemotherapy regimens and comparing how well they work in treating children with low-grade astrocytomas or other residual tumors of the brain.

Detailed Description
-----------------
OBJECTIVES: Compare the event free survival as a result of treatment with carboplatin and vincristine versus thioguanine, procarbazine, lomustine, and vincristine in children with progressive brain tumors. Estimate tumor response rates to each regimen of chemotherapy in these patients. Determine toxic effects and quality of life of children treated with each regimen of chemotherapy. Investigate biological and clinical factors which may predict tumor response and early progression (tumor size, location, pathologic subtype, cytogenetics, and proliferative index by MIB-1 (Ki67)) in these patients. Investigate factors contributing to neuropsychological and endocrine status of children with brain tumors treated without irradiation. OUTLINE: This is a randomized study. Patients are stratified according to site of disease, status at entry, and pathology. Patients are randomized to one of two treatment arms. Patients with neurofibromatosis are nonrandomly assigned to arm II. Arm I: Patients receive induction with carboplatin and vincristine for 10 weeks followed by 2 weeks of rest. Induction is followed by 8 courses of maintenance beginning on day 84 of induction or upon hematopoietic recovery. Each course consists of 4 weekly doses of carboplatin and 3 weekly doses of vincristine (given concurrently with the first 3 weeks of carboplatin), followed by 2 weeks of rest. Arm II: Patients receive oral thioguanine, procarbazine, and lomustine on days 0-4, followed by vincristine IV on days 14 and 28. Treatment continues every 6 weeks for a maximum of 8 courses. PROJECTED ACCRUAL: A total of 280-340 patients will be accrued over 4 years.

Official Title
-----------------
Chemotherapy for Progressive Low Grade Astrocytoma in Children Less Than Ten Years Old

Conditions
-----------------
Brain Tumors, Central Nervous System Tumors

Intervention / Treatment
-----------------
* Drug: carboplatin
* Drug: lomustine
* Drug: procarbazine hydrochloride
* Drug: thioguanine
* Drug: vincristine sulfate


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Pathologically confirmed low grade residual astrocytomas or other eligible residual tumors of the brain interpreted as low grade (WHO grades I and II) such as the following: Glial Tumors Astrocytic tumors Low grade astrocytoma (variants: fibrillary, protoplasmic, gemistocytic) Pilocytic astrocytoma Pleomorphic xanthoastrocytomas Subependymal giant cell astrocytoma Infantile desmoplastic astrocytoma Low grade oligodendroglial tumors Low grade oligodendroglioma Low grade mixed gliomas Oligo-astrocytoma Neuronal Tumors Ganglioglioma (excluding tumors with anaplastic astrocytic components) Infantile desmoplastic ganglioglioma Chiasmatic-hypothalamic tumor without histologic confirmation All of the following diagnostic tests (radiological or clinical evidence of progression, surgery, or confirmatory MRI) must be carried out within 6 weeks of enrollment into this study Progressive disease following surgical excision based on clear radiological or clinical evidence of progression, or an incomplete excision (less than 95% or greater than 1.5 cm2) with necessity to begin treatment because of a risk of neurologic impairment with progression Chiasmatic lesions that have contiguous extensions of tumor into other regions of the visual pathways demonstrated on contrast MRI will be eligible for study without histopathological confirmation Patients with neurofibromatosis who have radiographic diagnosis of chiasmatic-hypothalamic tumor are eligible for the study, without requiring a biopsy confirmation of tumor histology, but not unless tumor progression is documented radiographically No intrinsic brain stem tumors of the pons or isolated optic nerve tumors without definitive involvement of the optic chiasm PATIENT CHARACTERISTICS: Age: Under 10 Performance status: Not specified Life expectancy: Not specified Hematopoietic: Absolute neutrophil count greater than 1,000/mm^3 (arm II) Platelet count greater than 100,000/mm^3 (arm II) Hepatic: Not specified Renal: Creatinine less than 1.5 times upper limit of normal for age OR Creatinine clearance or radioisotope GFR greater than 70 mL/min or equivalent GFR as determined by the institutional normal range PRIOR CONCURRENT THERAPY: Biologic therapy: Not specified Chemotherapy: No prior chemotherapy for the tumor Endocrine therapy: Prior corticosteroid therapy allowed Radiotherapy: No prior radiotherapy for the tumor Surgery: See Disease characteristics Other: Prior diuretic therapy allowed

Ages Eligible for Study
-----------------
Maximum Age: 9 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Regimen A (CV Chemotherapy)<br>Induction will consist of 10 weeks of therapy (carboplatin, vincristine sulfate),followed by 2 weeks without chemotherapy. Induction should only be interrupted in the event of grade 3 neurotoxicity, grade 2 renal toxicity, grade 4 hematologic toxicity, or tumor progression. Maintenance-Four Courses (2 cycles/course) commences on Day 84 (week 12) of Induction or when peripheral counts recover with ANC >1,000/$L and platelet count >100,000/$L. Each cycle will consist of 4 weekly doses of carboplatin, three weekly doses of vincristine sulfate (given concomitantly with the first 3 weeks of carboplatin), followed by two weeks of rest for a total of 6 weeks. Maintenance will continue for a total of 8 cycles. | Drug: carboplatin<br>* Given IV<br>* Other names: NSC-241240;Drug: vincristine sulfate<br>* Given PO and IV<br>* Other names: NSC-675574;|
| Experimental: Regimen B (TPCV Chemotherapy)<br>Each cycle of chemotherapy consists of 4 days of oral chemotherapy (Thioguanine, procarbazine hydrochloride, Lomustine and Vincristine sulfate beginning Day 0, followed by vincristine sulfate IV on Days 14 and 28. The cycle is repeated every 6 weeks (42 days). A total of 8 cycles will be given. | Drug: lomustine<br>* Given IV<br>* Other names: NSC-79037;Drug: procarbazine hydrochloride<br>* Given PO<br>* Other names: NSC-77213;Drug: thioguanine<br>* Given PO<br>* Other names: NSC-752;Drug: vincristine sulfate<br>* Given PO and IV<br>* Other names: NSC-675574;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event Free Survival | Compare the event-free survival as a result of treatment with either CV or TPCV | Time from study entry until disease progression, death without progression of disease, occurrence of a second malignant neoplasm or last follow-up, whichever comes first, assessed up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival | Defined as the time to death from any cause. | 5 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
recurrent childhood brain stem glioma, recurrent childhood visual pathway glioma, recurrent childhood cerebellar astrocytoma, recurrent childhood cerebral astrocytoma, childhood low-grade cerebellar astrocytoma, childhood low-grade cerebral astrocytoma