Randomized Phase II Trial of Hypofractionated Dose-Escalated Photon IMRT or Proton Beam Therapy Versus Conventional Photon Irradiation with Comcomitant and Adjuvant Temozolomide in Patients with Newly Diagnosed Glioblastoma

Protocol # :
Adult Giant Cell Glioblastoma
Adult Glioblastoma
Adult Gliosarcoma
Disease Sites
Brain and Nervous System
Principal Investigator
Shih, Helen, A
Site Investigator
Alexander, Brian, M.
Soto, Daniel, E.
Site Research Nurses
Aste, Marie, Francesca
Gribbin, Nicola
Hibyan, Lauren, M.
Leahy, Noreen
Lyons, Hannah, Felton

Trial Description

This randomized phase II trial studies how well dose-escalated photon intensity-modulated
radiation therapy (IMRT) or proton beam radiation therapy works compared with standard-dose
radiation therapy when given with temozolomide in patients with newly diagnosed glioblastoma.
Radiation therapy uses high-energy x-rays and other types of radiation to kill tumor cells
and shrink tumors. Specialized radiation therapy that delivers a high dose of radiation
directly to the tumor may kill more tumor cells and cause less damage to normal tissue.
Drugs, such as temozolomide, may make tumor cells more sensitive to radiation therapy. It is
not yet known whether dose-escalated photon IMRT or proton beam radiation therapy is more
effective than standard-dose radiation therapy with temozolomide in treating glioblastoma.

Eligibility Requirements

Inclusion Criteria:


- 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


- 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

- 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

- 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

- 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

- 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.