Seizure control following radiotherapy in patients with diffuse gliomas: a retrospective study

Neuro-Oncology 15(12):1739 –1749, 2013. doi:10.1093/neuonc/not109 Advance Access publication July 28, 2013 N E U RO - O N CO LO GY Seizure control following radiotherapy in patients with diffuse gliomas: a retrospective study Department of Neuro-Oncology, University of Turin, Turin, Italy (R.R., U.M., L.B., E.T., C.B., R.S.); Department of Radiotherapy, University of Turin, Turin, Italy (C.M., U.R.); Department of Clinical Epidemiology, AO Città della Salute e della Scienza di Torino, Turin, Italy (A.C., C.M.) Background. Little information is available regarding the effect of conventional radiotherapy on gliomarelated seizures. Methods. In this retrospective study, we analyzed the seizure response and outcome following conventional radiotherapy in a cohort of 43 patients with glioma (33 grade II, 10 grade III) and medically intractable epilepsy. Results. At 3 months after radiotherapy, seizure reduction was significant (≥50% reduction of frequency compared with baseline) in 31/43 patients (72%) of the whole series and in 25/33 patients (76%) with grade II gliomas, whereas at 12 months seizure reduction was significant in 26/34 (76%) and in 19/25 (76%) patients, respectively. Seizure reduction was observed more often among patients displaying an objective tumor response on MRI, but patients with no change on MRI also had a significant seizure reduction. Seizure freedom (Engel class I) was achieved at 12 months in 32% of all patients and in 38% of patients with grade II tumors. Timing of radiotherapy and duration of seizures prior to radiotherapy were significantly associated with seizure reduction. Conclusions. This study showed that a high proportion of patients with medically intractable epilepsy from diffuse gliomas derive a significant and durable benefit from radiotherapy in terms of epilepsy control and that this positive effect is not strictly associated with tumor shrinkage as shown on MRI. Radiotherapy at tumor progression seems as effective as early radiotherapy after surgery. Prospective studies must confirm and better characterize the response to radiotherapy. Keywords: diffuse gliomas, radiotherapy, seizure control. S eizures are the most common presenting symptom of slowly growing diffuse gliomas, especially low-grade gliomas.1 – 3 Gross total resection is strongly associated with tumor-related seizure control.4 – 7 However, despite the favorable effect of surgery and the best treatment with antiepileptic drugs (AEDs),8,9 a number of patients still have seizures over the course of the disease. The persistence of seizures and the use of AEDs may negatively influence quality of life and cognitive functions.10,11 Radiation delivered via different modalities, such as interstitial brachytherapy,12,13 Gamma Knife radiosurgery,14 or conventional external radiotherapy,15,16 can improve seizure control in both low- and high-grade gliomas. In this regard, the efficacy of conventional radiotherapy has been supported by the results of the European Organisation for Research and Treatment of Cancer phase III trial 22845 in low-grade gliomas, showing that at 1 year after surgery 25% of patients who received adjuvant radiotherapy had seizures compared with 41% of those who had observation alone.17 Moreover, a recent retrospective study found radiotherapy to be a positive prognostic factor in terms of seizure control.18 Our aim in this current retrospective study, performed on a cohort of patients with diffuse gliomas of the adult treated at a single institution, was 2-fold: to describe seizure reduction and outcome after conventional radiotherapy and to explore the factors associated with seizure control. Materials and Methods Received November 2, 2012; accepted May 18, 2013. Patient Selection and Data Collection Corresponding Author: Roberta Rudà, MD, Department of NeuroOncology, Via Cherasco 15, 10126 Torino, Italy (). Patient information was collected from the database of the Department of Neuro-Oncology, University # The Author(s) 2013. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: . Roberta Rudà, Umberto Magliola, Luca Bertero, Elisa Trevisan, Chiara Bosa, Cristina Mantovani, Umberto Ricardi, Anna Castiglione, Chiara Monagheddu, and Riccardo Soffietti Rudà et al.: Seizure control after radiotherapy in gliomas Assessment of Seizure Reduction and Response on MRI The seizure frequency was reported by the patients based on a seizure diary, without confirmatory electrophysiological testing. We analyzed the seizure frequency before radiotherapy (baseline evaluation) and at 3, 6, and 12 months after radiotherapy. Seizure reduction was considered significant when a ≥50% reduction in seizure frequency compared with baseline was observed, with concomitant AEDs being unchanged. Any change (decrease or increase) of seizure frequency ,50% was considered as no change, while an increase in seizure frequency ≥50% was considered as a significant increase. Response of tumor on MRI was evaluated at 3, 6, and 12 months after radiotherapy according to Macdonald criteria adapted to low-grade gliomas.19,20 These criteria are based on changes in tumor size defined as the product of the two largest perpendicular diameters of the T2 or fluid attenuated inversion recovery (FLAIR) hypersignal lesion in nonenhancing tumors. In tumors displaying contrast enhancement, response criteria took into consideration the size of the T1 1740 NEURO-ONCOLOGY † D E C E M B E R 2 0 1 3 postcontrast enhancement as well. In brief, a complete response (CR) was defined as complete disappearance of all T2/FLAIR hypersignal and T1 postcontrast enhancing lesions. A partial response (PR) was defined as .50% reduction in size in both nonenhancing and enhancing (when present) lesions from baseline. Minor response (MR) was defined as a 25% to 50% reduction in the size of nonenhancing tumors; in patients with enhancing tumors, disappearance of all contrast enhancement and stable T2/FLAIR hypersignal lesion size were also considered to be MR. Stability or a reduction in the corticosteroid dose and stable neurological status were required to qualify for CR, PR, and MR. Progressive disease (PD) was defined as a .25% increase in the size of the T2/ FLAIR hypersignal or contrast enhancement, any new tumor on MRI scans, or tumor-related neurological deterioration in patients on stable or increased doses of corticosteroids. Stable disease was defined as any other clinical status not meeting the criteria for CR, PR, MR, or PD. The radiographic responses were reviewed independently by 2 investigators who were kept unaware of seizure response. Because many patients had MRI examinations with different MRI machines during the long time interval covered by the study and because the distinction between MR and PR was often difficult, we grouped together MRs and PRs into the category of objective responses. Assessment of Se (...truncated)