Phase III Study of Radiation Therapy with or without Temozolomide for Symptomatic or Progressive Low-Grade Gliomas E3F05
Primary Objectives: -To determine whether the addition of temozolomide to fractionated radiotherapy improves the progression-free survival (PFS) of patients requiring treatment for lowgrade gliomas. -To determine whether the addition of temozolomide to fractionated radiotherapy improves the median overall survival (OS) of patients with low-grade gliomas requiring treatment. Secondary Objectives: -To determine whether combination therapy with temozolomide and radiotherapy improves or maintains cognition and quality of life (QOL) compared to radiotherapy alone. -To compare the severe or worse toxicities (? grade 3) of patients receiving radiation therapy alone or radiation therapy plus temozolomide chemotherapy. -To assess the impact of the presence or absence of 1p and 19q deletion on PFS and OS, and to determine the impact of 1p and 19q status on PFS and OS in patients receiving chemotherapy. -To create a tumor and tissue bank, including plasma and germ line DNA, within the ECOG Pathology Coordinating Office (PCO).
Pre-registration: -Age greater than 18 years. -Tumors must be supratentorially located. -Pathological diagnosis of astrocytoma grade 2, oligodendroglioma grade 2, or oligoastrocytoma grade 2 (mixed glioma containing astrocytoma and oligodendroglioma). Pilocytic astrocytoma, ganglioglioma, pleomorphic xanthastrocytoma, or dysembryoplastic neuroepithelial tumors are not eligible. NOTE: If the pathology from multiple procedures supports the diagnosis of a brain tumor, the qualifying pathology of grade 2 astrocytoma, oligodendroglioma, or oligoastrocytoma must be the most recent pathological diagnosis, and a pathological diagnosis of a grade 3 or grade 4 glioma must not have been made at any time. -Patients must have paraffin-embedded tumor specimen available for submission for confirmation of pathological diagnosis and determination of 1p/19q deletion status. -The patient must currently have at least one of the following: 1. Uncontrolled symptoms, defined as any of the following: headaches associated with mass effect;uncontrolled seizures despite 2 different antiepileptic drug regimens (i.e., 2 antiepileptic drugs tested either sequentially or in combination); focal neurological symptoms; cognitive symptoms or deficits OR 2. Tumor progression by serial MRIs, defined as any of the following: new or progressive enhancement;new or progressive T2 or FLAIR signal abnormality OR 3. Age greater than 40 years. -Patient must be able to undergo MRI with and without contrast. Patients who are unable to undergo MRI are ineligible. -MRI and chest x-ray within 6 weeks prior to pre-registration. If resection was performed, MRI after surgery is required. -No previous radiation, cytotoxic chemotherapy, radio surgery, or investigational treatment directed at the brain tumor at any time. No limit on number of previous surgical procedures of this tumor. -No previous radiation treatment to the head (unless the ports for that radiation entirely excluded the brain) for any condition. -Karnofsky performance status greater than 60%. -No other diagnosed malignancy (except non-melanoma skin cancer or cervical carcinoma in situ, which are allowable), unless the patient has been disease-free for at least 5 years. -No medical disorder that increases risks of radiation or TMZ chemotherapy. No uncontrolled infection. No known positivity for human immunodeficiency virus (HIV), as temozolomide is known to cause immunosuppression and increase risk of opportunistic infection. No other disorder limiting expected survival to less than 5 years. -Patients who have undergone gross total resection and have no detectable residual disease are eligible. Randomization: -Eligibility per pathologic diagnosis confirmed by central review and 1p/19q deletion status assessment have been received from the central reviewers. -Must be able to start treatment with RT within 2 weeks or 10 working days at a qualified center (to be defined by the Radiation Oncology chair) and to start TMZ prescribed at a participating center within 2 weeks or 10 working days of randomization. -CBC requirements within 14 days prior to randomization: 1. White blood count (WBC) greater than 3,000 /mm3 2. Absolute neutrophil count (ANC) greater than 1,500 /mm3 3. Platelets greater than 100,000 /mm3 4. Hematocrit greater than 30% -Chemistry requirements within 14 days prior to randomization: 1. Bilirubin less than 2 x upper limit of normal (ULN) 2. AST less than 3 x ULN (SGOT) 3. Creatinine less than 2.0 x ULN 4. ALT less than 3 x ULN (SGPT) -Women must not be pregnant or breast-feeding due to known and potential teratogenic effects of radiotherapy and temozolomide and the uncertain safety of temozolomide in lactation. All females of childbearing potential must have a blood test or urine study within 2 weeks prior to randomization to rule out pregnancy. -Women of childbearing potential and sexually active males are strongly advised to use an accepted and effective method of contraception. -Patient must be at least two weeks post any brain surgery at the time of randomization.
Patients will be preregistered to the study to have pathology specimen assessed for 1p/19q deletion status. Qualifying patients will then be randomized to either Arm A or Arm B for treatment. Treatment for Arm A includes radiation therapy alone. The total given dose will be 5040 cGy in 28 daily fractions of 180 cGy each. Treamtent for Arm B includes radiation therapy as described previously in addition to concomitant and subsequent chemotherapy with Temozolomide. Temozolomide will be given at 75 mg/m2 daily during radiotherapy for approximately 5.5 weeks. If the duration of radiotherapy exceeds 6 weeks, then concurrent treatment with temozolomide will be stopped after 42 days. Subsequent Temozolomide therapy will be given at 150 mg/m2 daily on days 1-5 every 28 days with cycle one beginning 28 days post-radiotherapy. In the absence of grade 3 or 4 AE, a single dose escalation to 200 mg/m2/day may be attempted for cycle 2 and, if tolerated, that dose should be continued for all subsequent cycles. Cycles will be repeated every 28 days for a total of 12 cycles. Patients will receive scheduled protocol therapy unless: if at any time the constraints of this protocol are detrimental to the patient's health, unacceptable toxicities when radiation is held 2 weeks or more or if chemotherapy is held more than 4 weeks, the treatment physician determines continued treatment is not in the best interest of the patient, or the patient has definitive progression. All patients, including those who discontinue protocol treatment, will be followed for progression and for survival for 15 years from the date of pre registration. All patients must also be followed through completion of all protocol therapy.
05/25/2013 04:02 AM