Radiation Therapy (RT) and Temozolomide (TMZ) in Treating Patients With Newly Diagnosed Glioblastoma or Gliosarcoma

OBJECTIVES:

Primary

- Determine if dose-intensifying (increasing the "dose-density") the adjuvant
temozolomide component of the chemoradiation treatment enhances treatment efficacy as
measured by overall survival of patients with newly diagnosed glioblastoma or
gliosarcoma.

Secondary

- Determine if dose-intensifying the adjuvant temozolomide component of the
chemoradiation treatment enhances treatment efficacy as measured by progression-free
survival.

- Determine in patients with unmethylated MGMT (O6-methylguanine-DNA methyltransferase)
if dose-intensifying the adjuvant temozolomide component of the chemoradiation
treatment enhances treatment efficacy (overall and progression-free survival) compared
with patients receiving conventional temozolomide dosing.

- Determine in patients with methylated MGMT if dose-intensifying the adjuvant
temozolomide component of the chemoradiation treatment enhances treatment efficacy
(overall and progression-free survival) compared with patients receiving conventional
temozolomide dosing.

- Determine if there is an association between tumor MGMT gene methylation status and
treatment response.

- Compare and record the toxicities of the conventional and dose-intense chemotherapy
regimens.

- Evaluate whether 6-month progression-free survival is associated with overall survival.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to
recursive partitioning analysis class (III vs IV vs V), MGMT gene methylation status
(methylated vs nonmethylated vs indeterminate), and radiotherapy criteria used (standard vs
revised European).

Patients undergo radiotherapy daily, 5 days per week for 6 weeks. Patients also receive oral
temozolomide daily during radiotherapy. Patients are then randomized to 1 of 2 treatment
arms. Randomized treatment begins approximately 4 weeks after completion of radiotherapy.

- Arm I: Patients receive oral temozolomide on days 1-5.

- Arm II: Patients receive oral temozolomide on days 1-21. In both arms, treatment
repeats every 28 days for up to 6 courses in the absence of disease progression or
unacceptable toxicity. Patients with responding disease may receive up to 6 more
courses of temozolomide.

After completion of study treatment, patients are followed every 3 months for 1 year, every
4 months for 2 years, and then every 6 months thereafter.

Peer Reviewed and Funded or Endorsed by Cancer Research UK

PROJECTED ACCRUAL: This study requires 750 patients randomized to the two treatment arms.

DISEASE CHARACTERISTICS:

- Histologically proven glioblastoma or gliosarcoma

- Diagnosis must be made by open biopsy or tumor resection

- Diagnosis by stereotactic biopsy not allowed

- Tumor must have supratentorial component

- Contrast-enhanced MRI or CT scan (if MRI is not available) of the brain must be
performed preoperatively and postoperatively prior to initiation of
radiotherapy, within 28 days prior to study entry

- If pre- and postoperative contrast-enhanced CT scans are obtained, must be
of sufficient quality

- Meets 1 of the following recursive positioning analysis classifications:

- Class III

- Age < 50 years and Karnofsky performance status (KPS) 90-100%

- Class IV, meeting 1 of the following criteria:

- Age < 50 years and KPS < 90%

- Age ≥ 50 years and KPS 70-100% and underwent prior partial or total tumor
resection with no worse than minor neurofunction impairment

- Class V, meeting 1 of the following criteria:

- Age ≥ 50 years and KPS 70-100% and underwent prior partial or total tumor
resection with worse than minor neurofunction impairment

- Age ≥ 50 years and KPS 70-100% and underwent prior tumor biopsy only

- Age ≥ 50 years and KPS < 70%

- Underwent most recent brain tumor surgery within the past 5 weeks

- No recurrent or multifocal malignant gliomas

- At least 1 block of tissue available for analysis of MGMT gene methylation status

- No metastases detected below the tentorium or beyond the cranial vault

PATIENT CHARACTERISTICS:

- KPS 60-100%

- Absolute neutrophil count ≥ 1,500 cells/mm^3

- Platelet count ≥ 100,000 cells/mm^3

- Hemoglobin ≥ 10 g/dL (transfusion or other intervention allowed)

- BUN (blood urea nitrogen) ≤ 25 mg/dL

- Creatinine ≤ 1.7 mg/dL

- Bilirubin ≤ 2.0 mg/dL

- AST (aspartate aminotransferase ) and ALT (alanine amino transferase) ≤ 3 times
normal

- Negative pregnancy test

- Not pregnant or nursing

- Fertile patients must use effective contraception

- No prior invasive malignancy (except for nonmelanomatous skin cancer) unless patient
is disease free for ≥ 3 years (e.g., carcinoma in situ of the breast, oral cavity, or
cervix allowed)

- No severe, active comorbidity, including any of the following:

- Unstable angina and/or congestive heart failure requiring hospitalization

- Transmural myocardial infarction within the last 6 months

- Acute bacterial or fungal infection requiring intravenous antibiotics at the
time of registration

- Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy at the time of
registration

- Known hepatic insufficiency resulting in clinical jaundice and/or coagulation
defects

- Known AIDS based upon current CDC (Center for Disease Control) definition

- Major medical illnesses or psychiatric impairments that, in the investigator's
opinion, will prevent administration or completion of protocol therapy

- Active connective tissue disorders, such as lupus or scleredema that, in the
opinion of the treating physician, may put the patient at high risk for
radiation toxicity

- No prior allergic reaction to temozolomide

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- Recovered from the effects of surgery, postoperative infection, and other
complications prior to study entry

- No prior chemotherapy or radiosensitizers (including polifeprosan 20 with carmustine
implant [Gliadel wafers] or any other intratumoral or intracavitary treatment) for
cancers of the head and neck region

- Prior chemotherapy for a different cancer is allowed

- No prior radiotherapy to the head or neck (except for T1 glottic cancer) that would
result in an overlap of radiation fields

- No treatment on other therapeutic clinical protocols within 30 days prior to study
entry or during participation in the study

- No concurrent prophylactic growth factors

- No other concurrent investigational drugs

- No concurrent surgical procedures for tumor debulking

- No other concurrent chemotherapy, immunotherapy, or biologic therapy

- No additional concurrent stereotactic boost radiotherapy

- No concurrent intensity-modulated radiotherapy

- Concurrent steroids allowed provided dose is stable or decreasing in the past 5 days