Dose-Escalated Photon IMRT or Proton Beam Radiation Therapy Versus Standard-Dose Radiation Therapy and Temozolomide in Treating Patients With Newly Diagnosed Glioblastoma

PRIMARY OBJECTIVES:

I. To determine if dose-escalated and -intensified photon IMRT or proton beam therapy (using
a dose-per-fraction escalation with simultaneous integrated boost) with concomitant and
adjuvant temozolomide improves overall survival, as compared to standard-dose photon
irradiation with concomitant and adjuvant temozolomide.

SECONDARY OBJECTIVES:

I. To indirectly compare dose-escalated and -intensified photon IMRT to dose-escalated and
-intensified proton beam therapy in terms of overall survival.

II. To indirectly compare and record toxicities of dose-escalated and -intensified photon
IMRT versus dose-escalated and -intensified proton beam therapy and directly compare the
toxicities of these approaches versus standard-dose photon irradiation on the backbone of
concomitant and adjuvant temozolomide.

III. To indirectly determine if dose-escalated and -intensified proton beam therapy with
concomitant and adjuvant temozolomide improves perceived cognitive symptom severity, as
compared to dose-escalated and -intensified photon IMRT, and to directly compare symptom
burden with these approaches versus standard-dose photon irradiation on the backbone of
concomitant and adjuvant temozolomide.

IV. To indirectly determine if dose-escalated and -intensified proton beam therapy with
concomitant and adjuvant temozolomide improves neurocognitive function, as compared to
dose-escalated and -intensified photon IMRT, and to directly compare neurocognitive function
with these approaches versus standard-dose photon irradiation on the backbone of concomitant
and adjuvant temozolomide.

TERTIARY OBJECTIVES:

I. Tissue banking for future translational science projects that will be determined based on
the state of the science at the time the primary endpoint is reported and will be submitted
to National Cancer Institute (NCI) for review and approval.

II. To prospectively compare cluster of differentiation (CD)4 lymphopenia between
dose-escalated and intensified proton beam therapy, dose-escalated and -intensified photon
IMRT, and standard-dose photon irradiation.

III. To explore the most appropriate and clinically relevant technological parameters to
ensure quality and effectiveness throughout radiation therapy processes, including imaging,
simulation, patient immobilization, target and critical structure definition, treatment
planning, image guidance and delivery.

- To establish feasibility and clinical relevancy of quality assurance guidelines.

- To evaluate efficacy of quality assurance tools.

OUTLINE: Patients are assigned to 1 of 2 groups depending on enrolling institution. Within
each group, patients will be randomized 1:2 in favor of the experimental arms.

GROUP I (PHOTON IMRT CENTERS): Patients are randomized to 1 of 2 treatment arms.

ARM A1: Patients undergo standard-dose photon irradiation using 3-dimensional conformal
radiation therapy (3D-CRT) or IMRT once daily (QD), 5 days a week for 23 fractions plus a
boost of 7 additional fractions.

ARM B: Patients undergo dose-escalated and -intensified photon IMRT QD, 5 days a week for a
total of 30 fractions.

GROUP II (PROTON CENTERS): Patients are randomized to 1 of 2 treatment arms.

ARM A2: Patients undergo standard-dose photon irradiation using 3D-CRT or IMRT as in Arm A1.

ARM C: Patients undergo dose-escalated and -intensified proton beam radiation therapy QD, 5
days a week for a total of 30 fractions.

In all treatment arms, patients receive temozolomide orally (PO) QD on days 1-49 of radiation
therapy. Beginning 4 weeks later, patients receive temozolomide PO QD on days 1-5. Treatment
repeats every 28 days for up to 12 courses in the absence of disease progression or
unacceptable toxicity.

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

Inclusion Criteria:

- PRIOR TO STEP 1 REGISTRATION

- A diagnostic contrast-enhanced magnetic resonance imaging (MRI) (no other scan type
allowed) of the brain must be performed postoperatively within 72 hours of resection;
the enhancing tumor must have a maximal diameter of 5 cm; the tumor diameter will be
the greatest diameter as measured on the contrast-enhanced postoperative MRI and will
include residual disease and/or the postoperative surgical cavity as appropriate; for
cases where residual disease or postoperative surgical cavity is NOT identifiable
(e.g., polar glioblastomas [GBMs] where a polar lobectomy is performed), the patient
will be excluded from the trial

- The GBM tumor must be located in the supratentorial compartment only (any component
involving the brain stem or cerebellum is not allowed)

- Patients must provide study-specific informed consent prior to step 1 registration

- PRIOR TO STEP 2 REGISTRATION

- Histologically proven diagnosis of glioblastoma (World Health Organization [WHO] grade
IV) confirmed by central review prior to step 2 registration

- Tumor tissue that is determined by central pathology review prior to step 2
registration to be of sufficient quantity for analysis of
O6-methylguanin-DNA-methyltransferase (MGMT) status

- Patients must have at least 1 block of tumor tissue; submission of 2 blocks is
strongly encouraged to maximize the chances of eligibility; at least 1 cubic
centimeter of tissue composed primarily of tumor must be present

- Diagnosis must be made by surgical excision, either partial or complete;
stereotactic biopsy or cavitron ultrasonic suction aspirator (CUSA) technique are
not allowed

- History/physical examination within 28 days prior to step 2 registration

- The patient must have recovered from effects of surgery, postoperative infection, and
other complications within 28 days prior to step 2 registration

- Documentation of steroid doses within 28 days prior to step 2 registration

- Karnofsky performance status >= 70 within 28 days prior to step 2 registration

- Age >= 18

- Absolute neutrophil count (ANC) >= 1,800 cells/mm^3

- Platelets >= 100,000 cells/mm^3

- Hemoglobin >= 10.0 g/dl (note: the use of transfusion or other intervention to achieve
hemoglobin (Hgb) >= 10.0 g/dl is acceptable)

- Bilirubin =< 1.5 upper limit of normal (ULN)

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN

- Negative serum pregnancy test obtained for females of child-bearing potential within
28 days prior to step 2 registration

Exclusion Criteria:

- Prior invasive malignancy (except non-melanomatous skin cancer) unless disease-free
for a minimum of 3 years; (for example, carcinoma in situ of the breast, oral cavity,
or cervix are all permissible)

- Recurrent or multifocal malignant gliomas

- Any site of distant disease (for example, drop metastases from the GBM tumor site)

- Prior chemotherapy or radiosensitizers for cancers of the head and neck region; note
that prior chemotherapy for a different cancer is allowable (except temozolomide)

- Prior use of Gliadel wafers or any other intratumoral or intracavitary treatment are
not permitted

- Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in
overlap of radiation fields

- Severe, active co-morbidity, defined as follows:

- Unstable angina at step 2 registration

- Transmural myocardial infarction within the last 6 months prior to step 2
registration

- Evidence of recent myocardial infarction or ischemia by the findings of S-T
elevations of >= 2 mm using the analysis of an electrocardiogram (EKG) performed
within 28 days prior to step 2 registration

- New York Heart Association grade II or greater congestive heart failure requiring
hospitalization within 12 months prior to step 2 registration

- Serious and inadequately controlled arrhythmia at step 2 registration

- Serious or non-healing wound, ulcer or bone fracture or history of abdominal
fistula, intra-abdominal abscess requiring major surgical procedure, open biopsy
or significant traumatic injury within 28 days prior to step 2 registration, with
the exception of the craniotomy for surgical resection

- Acute bacterial or fungal infection requiring intravenous antibiotics at the time
of step 2 registration

- Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects;
note, however, that laboratory tests for coagulation parameters are not required
for entry into this protocol

- Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy at the time of step 2
registration

- Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease
Control and Prevention (CDC) definition; note, however, that human
immunodeficiency virus (HIV) testing is not required for entry into this protocol

- Any other severe immunocompromised condition

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

- End-stage renal disease (ie, on dialysis or dialysis has been recommended)

- Any other major medical illnesses or psychiatric treatments that in the
investigator's opinion will prevent administration or completion of protocol
therapy

- Pregnancy or women of childbearing potential and men who are sexually active and not
willing/able to use medically acceptable forms of contraception

- Patents treated on any other therapeutic clinical protocols within 30 days prior to
step 2 registration

- Inability to undergo MRI (e.g., due to safety reasons, such as presence of a
pacemaker, or severe claustrophobia)

- Postoperative tumor plus surgical bed size exceeds 5 cm in maximum diameter.