Dose Escalated MRSI Guided Radiation Therapy in Glioblastoma
Condition: Glioblastoma
MeSH terms: Glioblastoma
Intervention: Intensity Modulated Radiation Therapy; Temozolomide; Functional Assessment of Cancer Therapy-Brain (FACT-Br); Stereotactic Radiosurgery Boost; Simultaneous Integrated Boost; 3D MRSI
Intervention description: IMRT treatment will consist of 60 Gy in 30 fractions to PTV 60; Concurrently during radiation therapy. Adjuvant therapy administered daily on days 1 - 5 for 12 cycles. One cycle = 28 days:
Concurrent during Radiation Therapy: 75 mg/m^2 orally for 6 weeks;
Post-radiation, adjuvant therapy: 150 mg/m^2 - 200 mg/m^2 orally daily on days 1 - 5 of each cycle.; FACT-Br Quality of Life (QOL) questionnaire to be completed by study patients as protocol specific timepoints; Patients will undergo SRS boost in a single fraction dose prior to IMRT treatment:
HTV Maximum dimension vs. Prescribed Dose to HTV: ≤ 20 mm = 21 Gy; 21 mm - 30 mm = 18 Gy; 31 mm - 40 mm = 15 Gy.; Treatment shall consist of 60 Gy in 30 fractions to planning target volume (PTV) 60 and 75 Gy in 30 fractions to PTV 75.; Three Dimensional Magnetic Resonance Spectroscopy Imaging (MRSI) during pre-treatment, week 3 during radiation therapy, end of radiation therapy; will include standard gadolinium enhanced MRI prior to cycle 1, 5, 9, and post cycle 12 of adjuvant temozolomide therapy, per protocol.
Intervention MeSH terms: Temozolomide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 1.0
Sex: All
Minimum age: 19 Years
Healthy volunteers: No
Keywords: Glioblastoma; Gliosarcoma; GBM

Summary:

      In summary, the overall prognosis of glioblastoma (GBM) patients remains poor. Although
      clinical gains have been achieved in the past, these have been modest, with a majority of
      patients succumbing to local disease progression within 2 years. New strategies for treatment
      need to be identified which enhance local control above the current treatment regimen in
      order to achieve further clinical gains in this disease. Favorable early experience with
      magnetic resonance spectroscopy imaging (MRSI) demonstrates that metabolic imaging can
      identify active tumor beyond standard MRI as well as high risk regions at risk for local
      failure. There is also clinical evidence that limited field dose escalation with either
      simultaneous integrated boost (SIB) or stereotactic radiosurgery (SRS) is feasible and safe.
      Coupling these findings provide the rationale for this proposed Phase II trial designed to
      define efficacy and toxicity of the novel treatment approach of whole brain volumetric 3D
      MRSI guided dose-escalated radiation therapy (RT) in newly diagnosed GBM patients.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Histologically proven diagnosis of glioblastoma (WHO grade IV). Since gliosarcoma is a
             variant of glioblastoma, gliosarcoma is also an eligible diagnosis.

          2. The tumor must have a supratentorial component

          3. Patients must have recovered from the effects of surgery, postoperative infection and
             other complications

          4. Karnofsky performance status > 70

          5. Age > 18 years

          6. Adequate bone marrow function defined as follows:

               -  Absolute neutrophil count (ANC) >/= 1500 cells/mm^3

               -  Platelet count > 100,000 cells/mm^3

               -  Hemoglobin > 10.0 g/dL (Note: the use of transfusion or other intervention to
                  achieve Hgb > 10.0 g/dL is acceptable.)

          7. Patients on full-dose anticoagulants (e.g., warfarin or low-molecular weight (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 international normalized ratio (INR) (usually between 2 and 3) on a
                  stable dose of oral anticoagulant or on a stable dose of low molecular weight
                  heparin

          8. Adequate renal function, defined as follows:

               -  Blood urea nitrogen (BUN) < 30 mg/dL

               -  Serum creatinine < 1.5 x upper limit of normal (ULN)

          9. Adequate hepatic function, as defined below:

               -  Bilirubin < 1.5 normal range

               -  Alanine transaminase (ALT) < 3x normal range

               -  Aspartate transaminase (AST) < 3x normal range

         10. Patients must not be pregnant (positive pregnancy test) or breast feeding; pregnancy
             test must be done within 7 days prior to registration. Effective contraception (men
             and women) must be used in patients of child-bearing potential while on study
             treatment and for 6 months after.

         11. Ability to understand and the willingness to sign a written informed consent document

         12. Ability to have MRI Scans

         13. Ability to swallow capsules

        Exclusion Criteria:

          1. 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)

          2. Recurrent malignant glioma or evidence of leptomeningeal spread

          3. Metastases detected below the tentorium or beyond the cranial vault

          4. Prior use of Gliadel wafers or any other intratumoral or intracavitary treatment

          5. Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in
             overlap of radiation therapy fields

          6. Prior radiation therapy or chemotherapy for glioblastoma

          7. Severe, active co-morbidity, defined as follows:

               -  Symptomatic congestive heart failure of New York heart Association Class III or
                  IV

               -  Unstable angina pectoris, symptomatic congestive heart failure, myocardial
                  infarction within the last 6 months, serious uncontrolled cardiac arrhythmia or
                  any other clinically significant cardiac disease

               -  Severely impaired lung function as defined as spirometry and diffusing capacity
                  of the lung for carbon monoxide (DLCO) that is 50% of the normal predicted value
                  and/or 02 saturation that is 88% or less at rest on room air

               -  Uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN

               -  Active (acute or chronic) or uncontrolled severe infections requiring intravenous
                  antibiotics

               -  Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent
                  hepatitis

               -  Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease
                  Control and Prevention (CDC) definition or known HIV seropositivity. Note,
                  however, that HIV testing is not required for entry into this protocol. The need
                  to exclude patients with HIV/AIDS from this protocol is necessary because the
                  treatments involved in this protocol may be 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

               -  Other major medical illnesses or psychiatric impairments that in the
                  investigator's opinion will prevent administration or completion of protocol
                  therapy

          8. Pregnancy

          9. Women who are breast feeding

         10. Prior allergic reaction to temozolomide

         11. Treatment on any other therapeutic clinical protocol

         12. Impairment of gastrointestinal function or gastrointestinal disease that may
             significantly alter their absorption of temozolomide (e.g. ulcerative disease,
             uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel
             resection)

         13. Contraindications to MRI including but not limited to, pacemaker, aneurysm clips,
             neurostimulators, cochlear implants, metal in eyes, steelworker or other implants

         14. Need to continue treatment with any prohibited medication (e.g. antioxidants) or have
             not completed the appropriate washout period.