Temozolomide and Targeted or Standard Brain Radiation Therapy in Treating Patients with Newly Diagnosed Glioblastoma Multiforme

Status: closed to accrual

This randomized phase II trial studies how well an increased dose of radiation therapy applied to a specific part of the brain works compared to standard radiation therapy when given with temozolomide in treating patients with a newly diagnosed brain tumor, such as glioblastoma multiforme. The brain contains cells called neural progenitor cells (NPC) that may be important in the brain’s response to injury but may also contribute to tumor recurrence. Subventricular zone radiation therapy targeting these cells may improve the local control and delay the brain tumor from coming back. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether subventricular zone radiation therapy and temozolomide are more effective than standard radiation therapy and temozolomide in treating patients with glioblastoma multiforme.

Inclusion Criteria

Patient must have newly diagnosed, histologically confirmed GBM
Patient must have undergone gross total resection, subtotal resection, or biopsy with the extent of resection determined by the treating neurosurgeon, and must begin radiation within 12 weeks of this procedure
Patients must not have received previous irradiation to the brain
Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (Karnofsky > 60%)
Patient must be scheduled to receive temozolomide concurrent with and following radiation (temozolomide may be started late due to insurance reasons, insufficient counts, or other reasons)
If a woman is of child-bearing potential, a negative urine or serum pregnancy test must be demonstrated prior to treatment; women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) for the duration of study participation and for up to 12 weeks following the study; should a women become pregnant or suspect she is pregnant while participating in this study she should inform her treating physician immediately
Patient must have the ability to understand and the willingness to sign a written informed consent document
All patients must be informed of the investigational nature of this study and must be given written informed consent in accordance with institutional and federal guidelines
Radiation therapy must begin within 12 weeks of surgery

Exclusion Criteria

No prior malignancy is allowed except for adequately treated basal cell or squamous cell skin cancer, cervical carcinoma in situ, or other cancer from which the patient has been disease free for at least 1 year
Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements will be excluded
Pregnant and breastfeeding women are excluded; women of child-bearing potential who are unwilling or unable to use an acceptable method of birth control to avoid pregnancy for the entire study period and up to 12 weeks after the study are excluded; this applies to any woman who has not experienced menarche and who has not undergone successful surgical sterilization or is not postmenopausal (defined as amenorrhea for at least 12 consecutive months); male subjects must also agree to use effective contraception for the same period as above
Use of Avastin or another vascular endothelial growth-factor (VEG-F) inhibitor prior to progression is not permitted

PRIMARY OBJECTIVE:

I. Compare progression-free survival (PFS) in patients receiving subventricular zone irradiation for newly diagnosed glioblastoma multiforme (GBM) to patients receiving neural progenitor cell sparing radiation therapy.

SECONDARY OBJECTIVES:

I. Compare the median PFS in patients receiving subventricular zone (SVZ) irradiation to patients receiving neural progenitor cell sparing radiation therapy.

II. Compare PFS in the subgroup of patients undergoing gross total resection (based on post-operative magnetic resonance imaging [MRI]) followed by temozolomide plus SVZ irradiation to patients receiving neural progenitor cell sparing radiation therapy.

III. Compare the rate of progression outside of the initial radiation treatment planning target volume in patients receiving SVZ irradiation for newly diagnosed GBM relative to patients receiving neural progenitor cell sparing radiation therapy.

IV. Compare the rate of development of multifocal disease in patients receiving SVZ irradiation for newly diagnosed GBM to patients receiving neural progenitor cell sparing radiation therapy.

V. Explore whether the location of progression in relationship to SVZ in patients treated with SVZ irradiation is different from patients receiving neural progenitor cell sparing radiation therapy.

VI. Explore if the potential change from baseline to six, twelve, and twenty-four months in neurocognitive function as measured by the Trail Making Test, Controlled Oral Word Association Test (COWAT), Hopkins Verbal Learning Test-Revised, Digit Symbol Substitution Test, Hopkins Adult Reading Test, Brief Visuospatial Memory Test-Revised, and Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV) Digit Span is greater than in patients receiving neural progenitor cell sparing radiation therapy.

VII. Evaluate composite cognitive function at 6,12, and 24 months following SVZ irradiation relative to patients receiving neural progenitor cell sparing radiation therapy.

VIII. Explore the change in neurocognitive function from baseline to six, twelve, and twenty-four months following SVZ irradiation as measured by the Brief Visuospatial Memory Test-Revised, Digit Span, Trail Making Test, Controlled Oral Word Association test (COWAT), Hopkins Verbal Learning Test-Revised, WAIS-IV Digit Symbol Substitution Test, and Hopkins Adult Reading Test.

IX. Evaluate quality of life following SVZ irradiation.

X. Estimate if radiation-associated acute and late toxicity following SVZ irradiation is greater than in patients receiving neural progenitor cell sparing radiation therapy.

XI. Estimate if the rate of pathologically confirmed necrosis in patients treated with SVZ irradiation is greater than in patients receiving neural progenitor cell sparing radiation therapy.

XII. Estimate if the rate of pseudo-progression within the first year of completion of SVZ irradiation is greater than in patients receiving neural progenitor cell sparing radiation therapy.

XIII. Compare overall survival in patients treated with SVZ irradiation to patients receiving neural progenitor cell sparing radiation therapy.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I (SVZ IRRADIATION): Patients undergo SVZ intensity-modulated radiation therapy (IMRT) 5 days a week for 6 weeks and receive concurrent temozolomide orally (PO) daily 7 days a week.

ARM II (NPC SPARING): Patients undergo standard IMRT 5 days a week for 6 weeks and receive concurrent temozolomide as in Arm I.

ADJUVANT TEMOZOLOMIDE: After completion of radiation therapy, all patients receive temozolomide PO daily on days 1-28. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 24 months.

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Temozolomide and Targeted or Standard Brain Radiation Therapy in Treating Patients with Newly Diagnosed Glioblastoma Multiforme

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