Purpose: To develop a valid treatment strategy for recurrent high-grade gliomas using stereotactic hypofractionated reirradiation based on biologic imaging and temozolomide. Patients and Methods: The trial included a total of 44 patients with recurrent high-grade gliomas (1 patient with anaplastic oligodendroglioma, 8 with anaplastic astrocytoma, 33 with glioblastoma multiforme, and 2 with gliosarcoma) after previous surgery and postoperative conventional radiotherapy ± chemotherapy. For fractionated stereotactic radiotherapy (SFRT) treatment planning, the gross tumor volume was defined by 11 C-methionine positron emission tomography (MET-PET) or 123 I-α-methyl-tyrosine (IMT) single-photon computed emission tomography (SPECT)/computed tomography (CT)/magnetic resonance imaging (MRI) fusion in 82% of the patients and by CT/T1+gadolinium-MRI image fusion in 18% of the patients. Six fractions of 5 Gy were administered in 6 days. In 29 of 44 patients (66%), chemotherapy with temozolomide (200 mg/m 2 body surface/day) was given in one to two cycles before and four to five cycles after SFRT. The patients were evaluated in follow-up by clinical investigators and MRI or CT every 3 months after SFRT until death. In cases suspicious for radiation necrosis, a MET-PET or IMT-SPECT investigation was performed. Results: The median survival time in the whole group was 8 months. Treatment planning based on PET(SPECT)/CT/MRI imaging was associated with improved survival in comparison to treatment planning using CT/MRI alone: median survival time 9 months vs. 5 months ( p = 0.03, log–rank). Median survival time were 11 months for patients who received SFRT based on biologic imaging plus temozolomide and significantly lower, 6 months for patients treated with SFRT without biologic imaging, without temozolomide or without both ( p = 0.008, log rank). The most important prognostic factor in univariate analysis was a long interval between initial diagnosis and recurrence ( p = 0.0002, log–rank). In the multivariate model, time interval to retreatment ( p = 0.006) and temozolomide ( p = 0.04) remained statistically significant. No acute neurologic toxicity Grade 3 or higher and no Grade 4 hematologic toxicity was observed. Conclusion: This is the first study of biologic imaging optimized SFRT plus temozolomide in recurrent high-grade gliomas. It demonstrates the feasibility and safety of this approach. The most striking result of the trial is the statistically significant longer survival time in the univariate analysis for patients reirradiated using MET-PET or IMT-SPECT/CT/MRI image fusion in the treatment planning, in comparison to patients treated based on MRI/CT alone. Multivariate analysis confirmed a significant survival benefit from multimodal treatment (i.e., addition of temozolomide), despite the limited number of patients. Whether treatment planning with SPECT/PET independently influences survival has to be studied in a larger series of patients.

Reirradiation of recurrent high-grade gliomas using amino acid PET (SPECT)/CT/MRI image fusion to determine gross tumor volume for stereotactic fractionated radiotherapy.

Glioblastoma multiforme (GBM) is one of the most aggressive primary brain tumors, with a grim prognosis despite maximal treatment. Advancements in the past decades have not significantly increased the overall survival of patients with this disease. The recurrence of GBM is inevitable, its management often unclear and case dependent. In this report, the authors summarize the current literature regarding the natural history, surveillance algorithms, and treatment options of recurrent GBM. Furthermore, they provide brief discussions regarding current novel efforts in basic and clinical research. They conclude that although recurrent GBM remains a fatal disease, the literature suggests that a subset of patients may benefit from maximal treatment efforts. Nevertheless, further research effort in all aspects of GBM diagnosis and treatment remains essential to improve the overall prognosis of this disease.

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Recurrent glioblastoma multiforme: a review of natural history and management options

A comparison of treatment results for recurrent malignant gliomas

Computerized tomographic and pathologic studies of the untreated, quiescent and recurrent glioblastoma multiforme

We sought to characterize the effects of radiation alone and in combination with BCNU and dexamethasone on malignant glioma invasion A model of malignant glioma invasion into a gel matrix of collagen type I was used to characterize response to radiation treatment for four malignant glioma cell lines (C6, U251, U373, A172) and nine primary human glioblastoma explants A radiation dose dependent inhibition of invasion was noted for the C6 astrocytoma cell line but not the other cell lines or explants Addition of BCNU and dexamethasone to radiation produced additional inhibition of invasion among the cell lines and explants but could not suppress invasion entirely

Effects of Radiation on a Model of Malignant Glioma Invasion

Recurrence of malignant glioma following radiotherapy most commonly occurs in close proximity to the original contrast enhancing CT/MRI tumor volume. For this reason current radiation planning favors focal radiotherapy fields designed to cover the preoperative tumor contrast enhancing volume ± surrounding edema with a 2–4 centimetre margin. Two patients with bifrontal malignant gliomas treated with such radiotherapy fields experienced out of field tumor progression while on treatment. Posterior extension along the corpus callosum, not evident on pretreatment imaging, was hypothesized as the cause of the geographic miss. The literature documenting recurrence patterns of malignant glioma following radiotherapy support focal field radiotherapy fields for most patients with malignant glioma. Reporting bias may exist in the literature, however, due to the whole brain radiotherapy used in older series reporting recurrence patterns and exclusion of patients with bihemispheric or more locally extensive tumors in more modern series. Tumor location and pattern of growth at presentation may be important factors in predicting patterns of spread and relapse after radiotherapy.

Cairncross Jg

Papers

Bihemispheric malignant glioma: one size does not fit all.