Outcome of Adult Brain Tumor Consortium (ABTC) prospective dose-finding trials of I-125 balloon brachytherapy in high-grade gliomas: challenges in clinical trial design and technology development when MRI treatment effect and recurrence appear similar.

OBJECTIVES: The aim of this study is to define the maximal safe radiation dose to guide further study of the GliaSite balloon brachytherapy (GSBT) system in untreated newly diagnosed glioblastoma (NEW-GBM) and recurrent high-grade glioma (REC-HGG). GBST is a balloon placed in the resection cavity and later filled through a subcutaneous port with liquid I-125 Iotrex, providing radiation doses that diminish uniformly with distance from the balloon surface. METHODS: The Adult Brain Tumor Consortium initiated prospective dose-finding studies to determine maximum tolerated dose in NEW-GBM treated before standard RT or after surgery for REC-HGG. Patients were inevaluable if there was progression before the 90-day posttreatment toxicity evaluation point. RESULTS: Ten NEW-GBM patients had the balloon placed, and 2/10 reached the 90 day timepoint. Five REC-HGG enrolled and two were assessable at the 90-day evaluation endpoint. Imaging progression occurred before 90-day evaluation in 7/12 treated patients. The trials were closed as too few patients were assessable to allow dose escalation, although no dose-limiting toxicities (DLTs) were observed. Median survival from treatment was 15.3 months (95 % CI 7.1-23.6) for NEW-GBM and 12.8 months (95 % CI 4.2-20.9) for REC-HGG. CONCLUSION: These trials failed to determine a maximum tolerated dose (MTD) for further testing as early imaging changes, presumed to be progression, were common and interfered with the assessment of treatment-related toxicity. The survival outcomes in these and other related studies, although based on small populations, suggest that GSBT may be worthy of further study using clinical and survival endpoints, rather than standard imaging results. The implications for local therapy development are discussed.

Radiation safety issues with high activities of liquid I-125: techniques and experience.

The handling of a liquid radioactive source is a procedure that is uncommon for the average clinical medical physicist. A newly approved treatment device utilizes high activities of liquid I-125 solution as the source of radiation. The radiation safety issues and our experience utilizing high activity liquid I-125 sources are presented. To date we have treated 22 patients with infused activities ranging up to 26.8 GBq (724 mCi). The careful manipulation of such solutions is important to maintain a safe environment for the patients and the involved medical staff.

Low-grade gliomas.

Low-grade gliomas are uncommon primary brain tumors classified as histologic grades I or II in the World Health Organization (WHO) classification. The most common variants are pilocytic and low-grade astrocytomas, oligodendrogliomas, and mixed oligo-astrocytomas located in the cerebral hemispheres. Prognostic factors that predict progression-free and overall survival include young age, pilocytic histology, good Karnofsky performance status, gross total resection, lack of enhancement on imaging, and small preoperative tumor volumes. Edema and vasogenic effects are typically managed with corticosteroids. Dexamethasone is given at an initial dosage of 4 mg given four times daily. Anticonvulsants are given prophylactically after resection and for patients who present with seizures. The rationale for open craniotomy depends on the need for immediate palliation of symptoms by reduction of intracranial pressure or focal mass effect, and/or improved oncologic control. Gross total resection of tumor is generally defined as the absence of residual enhancement on contrast-enhanced postoperative MRI scan. Most retrospective studies suggest that patients who have undergone a gross total resection of tumor have improved survival. Depending upon the proximity of the tumor to eloquent brain, gross total resection may or may not be possible. In these cases a stereotactic biopsy is required to provide the histologic diagnosis. Adjuvant radiotherapy is recommended for patients with incompletely resected grade II tumors or for patients older than age 40 regardless of extent of resection. It may be considered for any pilocytic astrocytoma from which a biopsy has been performed. Phase III randomized prospective trials have shown statistically significantly improved progression-free survival at 5 years with the addition of radiotherapy, though overall survival does not appear different. Based on prospective randomized phase III trials, 50.4 Gy to 54 Gy of conventionally fractionated radiotherapy appears to be a safe and effective regimen with minimal neurotoxicity; 45 Gy may be adequate for biopsied pilocytic astrocytomas. Currently, RTOG trial 98-02 is investigating the efficacy of postradiation PCV chemotherapy (procarbazine, CCNU, and vincristine) in the treatment of newly diagnosed unfavorable low-grade gliomas. Other areas of investigation include Temozolomide chemotherapy and the association of 1p and 19q chromosomal deletions with prolonged survival in oligodendrogliomas and sensitivity to PCV chemotherapy. Radiosurgery and/or experimental chemotherapy may provide some measure of local control in the recurrent disease setting.