Phase II Trial of Low-Dose Whole Brain Radiotherapy With Concurrent Temozolomide and Adjuvant Temozolomide in Patients With Newly-Diagnosed Glioblastoma Multiforme
Condition: Histologically Proven Diagnosis of Glioblastoma or Gliosarcoma (WHO Grade IV)
MeSH terms: Glioblastoma; Gliosarcoma
Intervention: Chemotherapy with Temodar.; Radiation therapy
Intervention description: Once the patient has had surgery, patients will receive 6 weeks of radiation therapy with concurrent chemotherapy on protcol. This will be followed by a maximum of 12 cycles of adjuvent chemotherapy with Temodar.
Intervention MeSH terms: Temozolomide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 24.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: GBM

Summary:

      In the current proposed trial the role of the low-dose WBRT (0.15 Gy) would be to safely
      treat the microscopic distant GBM cells outside of the high dose RT region and sensitize the
      gross tumor, while the focal radiation dose (1.85 Gy) to the gross tumor will bring the total
      tumor dose of 2 Gy per fraction which is the standard of care.

      Radiotherapy (RT) has been integral in the treatment of GBM since the 1970s when Walker et
      al. showed that post-operative whole brain radiotherapy (WBRT) offered significant
      improvements in median survival time, and even more so when given with concomitant BCNU
      chemotherapy. Ensuing dose escalation studies found the optimal dose to be 60 Gy. Patients
      could not tolerate escalation to higher doses than 60 Gy with WBRT due to unacceptable
      toxicity. Even with WBRT of 60 Gy, a huge volume of healthy brain tissue was unnecessarily
      treated with high-dose radiation; recurrences with WBRT remained overwhelmingly local.
      Hochberg and Pruitt (1980) found that after WBRT only 3% of recurrences were outside 2 cm of
      the margins of the primary tumor. With the rise of the CT scan in the 1980s and the MRI in
      the 1990s, along with subsequent improvements in three-dimensional conformal radiation,
      partial brain RT (PBRT) became practical since tumor margins could be visualized and
      irradiated more accurately. - Subsequently, WBRT was shown to provide no survival benefit
      over PBRT at the same dosage; - thus, the latter took over as the standard of care.
    

Eligibility criteria:

        Inclusion Criteria:

          -  3.1.1 Histologically proven diagnosis of glioblastoma or gliosarcoma (WHO grade IV).

        3.1.2 Infratentorial and multi-focal tumors are eligible. 3.1.3 History and physical with
        neurological examination, steroid documentation, height, and weight within 14 days of
        registration.

        3.1.4 A diagnstic contrast-enhanced MRI of the brain must be performed preoperatively and
        postoperatively prior to the initiation of radiotherapy. The postoperative scan must be
        performed within 28 days prior to registration. (contrast enhanced Brain CT is allowed if
        MRI is contraindicated) 3.1.5 Karnofsky performance status ≥ 70 or ECOG performance status
        ≤ 2. 3.1.6 Age ≥ 18. 3.1.7 CBC with differential obtained within 14 days prior to
        registration, with adequate bone marrow function defined as follows:

          -  Absolute neutrophil count (ANC) ≥ 1,800 cells/mm3.

          -  Platelets ≥ 100,000 cells/mm3.

          -  Hemoglobin ≥ 10.0 g/dl (Note: The use of transfusion or other intervention to achieve
             Hgb ≥10.0 g/dl is acceptable).

        3.1.8 Adequate renal function within 14 days prior to registration, as defined below:

          -  BUN ≤ 30 mg/dl.

          -  Creatinine ≤ 1.7 mg/dl. 3.1.9 Adequate hepatic function within 14 days prior to
             registration, as defined below:

          -  Bilirubin ≤ 2.0 mg/dl.

          -  ALT/AST ≤ 3 x upper limit of normal (ULN). 3.1.10 Systolic blood pressure ≤ 160 mg Hg
             or diastolic pressure ≤ 90 mg Hg within 14 days prior to registration.

        3.1.11 Prothrombin time/international normalized ratio (PT INR) < 1.4 for patients not on
        warfarin confirmed by testing within 14 days prior to registration. Patients on full-dose
        anticoagulants (e.g., warfarin or LMW heparin) must meet both of the following criteria:

          -  No active bleeding or pathological condition that carries a high risk of bleeding
             (e.g., tumor involving major vessels or known varices).

          -  In-range INR (between 2.5 and 3.5) on a stable dose of warfarin-based oral
             anticoagulant; or on a stable dose of low molecular weight heparin; or INR between 1.5
             and 2 if a Greenfield filter is in place.

        3.1.12 Patient must provide study specific informed consent prior to study entry.

        3.1.13 For women of child-bearing potential, negative serum pregnancy test within 14 days
        prior to registration.

        3.1.14 Women o f childbearing potential and male participants must practice adequate
        contraception.

        Exclusion Criteria:

          -  3.2.1 Prior invasive malignancy (except for non-melanomatous skin cancer) unless
             disease free for ≥ 3 years. For example, carcinoma in situ of the breast, oral cavity,
             and cervix are all permissible.

        3.2.2 Metastases beyond the cranial vault. 3.2.3 Prior use of Gliadel wafers or any other
        intratumoral or intracavitary treatment is not permitted.

        3.2.4 Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in
        significant overlap of radiation fields.

        3.2.5 Severe, active co-morbidity, defined as follows:

          -  Unstable angina and/or congestive heart failure within the last 6 months.

          -  Transmural myocardial infarction within the last 6 months.

          -  New York Heart Association grade II or greater congestive heart failure requiring
             hospitalization within 12 months prior to registration.

          -  History of stroke, cerebral vascular accident (CVA) or transient ischemic attack
             within 6 months.

          -  Serious and inadequately controlled cardiac arrhythmia.

          -  Significant vascular disease (e.g., aortic aneurysm, history of aortic dissection) or
             clinically significant peripheral vascular disease.

          -  Evidence of bleeding diathesis or coagulopathy.

          -  Serious or non-healing wound, ulcer, or bone fracture or history of abdominal fistula,
             gastrointestinal perforation or intra-abdominal abscess, major surgical procedure or
             significant traumatic injury within 28 days prior to registration, with the exception
             of the craniotomy for tumor resection or follow-on craniotomies to manage
             complications of brain tumor management such as hemorrhage or infection.

          -  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.

          -  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.

          -  Acquired immune deficiency syndrome (AIDS) based upon current CDC definition; Note,
             however, that HIV testing is not required for entry into this protocol. The need to
             exclude patients with AIDS from this protocol is necessary because the treatments
             involved in this protocol are significantly immunosuppressive.

          -  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.

          -  Any other major medical illnesses or psychiatric impairments that in the
             investigator's opinion will prevent administration or completion of protocol therapy.

          -  Cognitive impairment that precludes a patient from acting as his or her own agent to
             provide informed consent.

        3.2.6 Women of childbearing potential and men who are sexually active and not willing/able
        to use medically acceptable forms of contraception; this exclusion is necessary because the
        chemotherapeutic treatment involved in this study is significantly teratogenic.

        3.2.7 Pregnant or lactating women, due to possible adverse effects on the developing fetus
        or infant due to study treatment.

        3.2.8 Patients treated on any other therapeutic clinical protocols within 30 days prior to
        study entry or during participation in the study.

        3.2.9 Inability to undergo MRI (e.g., due to safety reasons, such as presence of a
        pacemaker).