Increasing Seizure Activity During Radiation Treatment for High-grade Gliomas - Final Results of a Prospective Interventional Study.

BACKGROUND/AIM: Little is known regarding seizures during radiotherapy for brain tumors. This prospective study investigated seizure activity in patients irradiated for high-grade gliomas. PATIENTS AND METHODS: Using a seizure diary, progression of seizure activity was evaluated in 22 patients receiving chemoradiation for grade III (n=1) or IV (n=21) gliomas. Progression was defined as increased frequency of any and/or generalized seizures (>50%) or increased anti-epileptic medication (≥25%). Patients' satisfaction with the diary was assessed using a questionnaire (six scales of 1-7 points). Uni- and multivariable analyses were performed including baseline seizure activity, age, sex, resection, tumor site, performance score, and history of epilepsy/seizures. RESULTS: Ten patients (45%) experienced progression of seizure activity during their radiotherapy course, mainly due to increased seizure frequency (nine patients=41%). Mean values of patients' satisfaction scores ranged between 3.92 and 4.92 points. CONCLUSION: Radiotherapy of high-grade gliomas can increase seizure activity. Patients require close monitoring to initiate or adjust anti-epileptic medication.

A prospective interventional study evaluating seizure activity during a radiotherapy course for high-grade gliomas (SURF-ROGG).

BACKGROUND: Gliomas are often associated with symptoms including seizures. Most patients with high-grade gliomas are treated with radiotherapy or radio-chemotherapy. Since irradiation causes inflammation, it may initially aggravate symptoms. Studies focusing on seizure activity during radiotherapy for gliomas are not available. Such knowledge may improve patient monitoring and anti-epileptic treatment. This study evaluates seizure activity during radiotherapy for high-grade gliomas. METHODS: The primary objective this prospective interventional study is the evaluation of seizure activity during a course of radiotherapy for high-grade gliomas. Progression of seizure activity is defined as increased frequency of seizures by > 50%, increased severity of seizures, or initiation/increase by ≥25% of anti-epileptic medication. Seizure frequency up to 6 weeks following radiotherapy and electroencephalography activity typical for epilepsy will also be evaluated. Patients keep a seizure diary during and up to 6 weeks following radiotherapy. Every day, they will document number (and type) of seizures and anti-epileptic medication. Once a week, the findings of the diary are checked and discussed with a neurologist to initiate or adjust anti-epileptic medication, if necessary. Patients complete a questionnaire regarding their satisfaction with the seizure diary. If the dissatisfaction rate is > 40%, the seizure diary will be considered not suitable for the investigated indication. Thirty-five patients (32 patients plus drop-outs) should be enrolled. With this sample size, a one-sample binomial test with a one-sided significance level of 2.5% has a power of 80% to yield statistical significance, if the rate of patients with progression of seizure activity is 30% (rate under the alternative hypothesis), assuming a 'natural' background progression-rate of 10% without radiotherapy (null hypothesis). DISCUSSION: If an increase in seizure activity during a course of radiotherapy for high-grade glioma occurs, the findings of this study may pave the way for a larger prospective trial and will likely lead to closer patient monitoring and better anti-epileptic treatment. TRIAL REGISTRATION: clinicaltrials.gov ( NCT04552756 ); registered on 16th of September, 2020.

A New Survival Score for Patients Receiving Radiotherapy for Newly Diagnosed Glioblastoma Multiforme.

BACKGROUND/AIM: In a previous study investigating radiotherapy for newly diagnosed glioblastoma multiforme (GBM), significant or almost significant associations with survival were found for performance status, upfront resection, O6-methylguanine-DNA methyl-transferase (MGMT) promoter methylation and unifocal GBM. This study aimed to create a survival score based on these factors. PATIENTS AND METHODS: Most of the 81 patients included received resection of GBM followed by radiochemotherapy (59.4 Gy/33 or 60 Gy/30 fractions). The previously identified predictors of survival were re-evaluated. Factors significantly associated with survival were used for the score. RESULTS: All factors were significantly associated with survival. For each factor, 0 points (less favorable survival) or 1 point (more favorable survival) were assigned and added for each patient. Three groups were designed, 0-1 (n=10), 2 (n=21) and 3-4 points (n=50); 12-month survival rates were 0%, 38% and 78% (p<0.001). CONCLUSION: A new survival score was created for patients requiring radiotherapy for GBM that can improve treatment personalization.

Palliative Radiotherapy of Primary Glioblastoma.

BACKGROUND/AIM: Care is often palliative when patients are not fit and complete resection of glioblastomas cannot be achieved. This study aimed to identify predictors of survival after palliative radiotherapy. PATIENTS AND METHODS: Thirty-one patients irradiated after biopsy or incomplete resection of primary glioblastoma were retrospectively analyzed. Median total dose, dose per fraction and equivalent dose in 2 Gy fractions (EQD2) were 45.0 Gy, 3.0 Gy and 46.0 Gy, respectively. Median number of fractions was 15, median treatment time 3 weeks. Ten patients received temozolomide. Six factors were evaluated for survival including location of glioblastoma, Karnofsky performance score (KPS), gender, age, EQD2 and temozolomide. RESULTS: KPS ≥60 showed a trend for improved survival (p=0.141). For other factors including EQD2, no significant association with survival was found. CONCLUSION: Patients with a KPS ≤50 have a poor survival prognosis and appear good candidates for short-course radiotherapy. Selected patients with better KPS may be considered for more aggressive treatments.

Prognostic Factors of Local Control and Survival in Patients Irradiated for Glioblastoma Multiforme (GBM).

BACKGROUND/AIM: Standard treatment of glioblastoma multiforme (GBM) includes resection, longer-course radiotherapy and chemotherapy. Some patients cannot tolerate these regimens and may benefit from personalized treatments. This study aims to contribute to treatment personalization by identifying predictors of outcomes after longer-course radiotherapy. PATIENTS AND METHODS: In 91 patients, number/site/diameter of lesions, Ki-67, MGMT promoter methylation, Karnofsky performance score (KPS), symptoms, gender, age and resection were evaluated for local control and survival. RESULTS: On univariate analyses, gross resection (p=0.029) was significantly associated with improved local control. It maintained significance in the multivariate analysis [hazard ratio (HR)=1.64, p=0.025]. MGMT-methylation (p=0.004), KPS ≥80 (p=0.022) and resection (p<0.001) were significantly associated with improved survival on univariate analyses, unifocal GBM (p=0.056) showed a trend. In the multivariate analyses, MGMT-methylation (HR=3.63, p=0.009), KPS (HR=2.01, p=0.018) and resection (HR=3.29, p<0.001) were significant. CONCLUSION: Predictors of local control and survival were identified that may guide physicians when tailoring treatments to patients with GBM.

Re-Irradiation for Recurrent Glioblastoma Multiforme.

BACKGROUND/AIM: Patients requiring re-irradiation for recurrent glioblastoma multiforme (GBM) may benefit from individualized therapy. This study aimed to identify predictors of survival and contribute to treatment personalization. PATIENTS AND METHODS: In 28 patients with recurrent GBM, nine factors were analyzed for associations with survival: Main location and type of recurrence, Karnofsky performance score (KPS), age, gender, interval between primary radiotherapy and recurrence, gross total resection (GTR), equivalent dose in 2-Gy fractions (EQD2) of re-irradiation and cumulative EQD2 of primary and re-irradiation. RESULTS: On univariate analyses, GTR (p=0.047), EQD2 ≥30 Gy (p=0.029) and cumulative EQD2 ≥90 Gy (p=0.023) were significantly associated with better survival; frontal location (p=0.119) and KPS 80-100% (p=0.067) showed trends. In multivariate analyses, frontal location (p=0.032) and cumulative EQD2 ≥90 Gy (p=0.038) were significant; KPS 80-100% (p=0.110) and EQD2 ≥30 Gy (p=0.083) showed trends. CONCLUSION: Predictors of survival after re-irradiation for recurrent GBM were identified that can help when designing personalized treatments. Use of irradiation with EQD2 ≥30 Gy appeared superior to lower doses.

Radiotherapy of Grade III Gliomas: Identification of Clinical Prognostic Factors for Local Tumor Control and Survival.

BACKGROUND/AIM: The prognoses of patients with grade III gliomas require improvement, which may be achieved with personalized care. We aimed to identify prognostic factors to facilitate the process of treatment personalization. PATIENTS AND METHODS: Eight factors were analyzed for local tumor control and survival in 44 patients irradiated for grade III glioma. These factors included location and size of glioma, number of glioma sites, performance status, gender, age, neurosurgical intervention and chemotherapy. RESULTS: In the Cox regression analyses, frontal location (risk ratio=4.41, p=0.048) and unifocal glioma (risk ratio=4.65, p=0.034) were associated with improved local control, and unifocal glioma with improved survival (risk ratio=6.12, p=0.033). In addition, trends for better survival were observed for frontal location (p=0.093), age ≤49 years (p=0.070), upfront resection (p=0.099) and chemotherapy (p=0.066) on univariate analyses. CONCLUSION: Independent predictors of local tumor control and survival were identified that can be helpful for personalizing treatment and designing clinical trials.

Clinical Prognostic Factors for Local Control and Survival After Irradiation of Grade II Gliomas.

BACKGROUND/AIM: Personalized treatment for low-grade gliomas likely improves patient outcomes. This study aimed to identify predictors of local control and survival. PATIENTS AND METHODS: Twenty-five patients irradiated for grade II gliomas were retrospectively analyzed. Irradiation was performed after biopsy (n=6) or incomplete resection (n=19). Nineteen patients received additional chemotherapy. Eight factors were analyzed, namely the number of glioma sites, cumulative maximum diameter, radiotherapy technique, Karnofsky performance score (KPS), gender, age, resection and chemotherapy. RESULTS: On univariate analysis, trends for associations with local control were found for cumulative maximum diameter ≤43 mm (p=0.087) and age ≤45 years (p=0.065). In the Cox regression analysis, cumulative maximum diameter maintained significance (p=0.046). On univariate analysis, KPS 90-100 (p=0.039) and female gender (p=0.022) were significantly associated with better survival. In the Cox regression analysis, both KPS (p=0.039) and gender (p=0.016) were significant. CONCLUSION: Independent predictors of local control and survival were identified that can contribute to better treatment personalization.

Re-Evaluation of Prognostic Factors for Survival After Radiotherapy of Cerebral Gliomas: A Supplementary Analysis to a Previous Study.

BACKGROUND/AIM: Previously, we identified predictors of survival after irradiation of grade II-IV cerebral gliomas. In this supplementary analysis, survival was calculated in a more appropriate way than the original study. PATIENTS AND METHODS: Ten factors were re-evaluated for survival in patients of the original study including pre-radiotherapy seizures. In the original study, survival was calculated from the end of the last radiotherapy course (primary or re-irradiation). After re-review, this approach was considered inappropriate. Survival should have always been calculated from the first radiotherapy course, as done in this supplementary analysis. RESULTS: On multivariate analysis, WHO-grade II (p=0.006) and upfront resection (p=0.001) were associated with better survival. Unifocal glioma was significant on univariate analysis (p=0.001), where a trend could be identified for age ≤59 years (p=0.057) and seizures (p=0.060). CONCLUSION: The findings of this supplementary analysis regarding the identification of prognostic factors for survival agree with the results of the original study.

Pre-operative Seizures in Patients With Single Brain Metastasis Treated With Resection Plus Whole-Brain Irradiation and a Boost.

BACKGROUND/AIM: Seizures can be the initial symptom of brain metastases. This study investigated pre-treatment seizures in patients with a single lesion. PATIENTS AND METHODS: Pre-operative seizures were analyzed in 104 patients with a single brain metastasis receiving resection plus whole-brain irradiation and a boost. Prevalence of seizures, risk factors and associations with survival (OS) were evaluated. RESULTS: Thirty patients (34.6%) had seizures prior to neurosurgery. Significant associations between seizures and investigated characteristics were not found. However, age ≤61 years showed a trend (p=0.117) for increased incidence of seizures. Time from diagnosis of malignancy until neurosurgery >12 months was significantly associated with improved OS on univariate analysis (p=0.003). Trends for a positive association with OS were found for no seizures (p=0.054), female gender (p=0.066) and breast cancer (p=0.098). On multivariate analysis, time until neurosurgery >12 months was independently associated (p=0.019) with better OS, and seizures showed a trend (p=0.119) for improved OS. CONCLUSIONS: Considering the high prevalence of seizures in this cohort, regular screening and monitoring of these patients appears reasonable. This applies particularly to patients aged ≤61 years.

Pre-Treatment Seizures in Patients With 1-3 Cerebral Metastases Receiving Local Therapies Plus Whole-brain Radiotherapy.

BACKGROUND/AIM: Seizures impair patients' quality of life. The prognostic role of pre-treatment seizures in patients with 1-3 cerebral metastases receiving local therapies plus whole-brain radiotherapy (WBRT) was investigated. PATIENTS AND METHODS: In 249 patients, prevalence, risk factors and associations of pre-treatment seizures with survival were retrospectively evaluated. Age, gender, performance score, tumor type, number of lesions, extra-cerebral metastases, and time from tumor diagnosis to treatment of cerebral metastasis were analyzed for associations with seizures. These characteristics and pre-treatment seizures were also analyzed for associations with survival. RESULTS: The prevalence of pre-treatment seizures was 24.1%. Trends for associations were found between seizures and gender or performance score. On multivariate analysis, age (p=0.008), performance score (p=0.004), tumor type (p<0.001) and extra-cerebral metastasis (p<0.001) were significantly associated with survival. CONCLUSION: Seizures were comparably common prior to local therapies plus WBRT for cerebral metastases. No factor was found to be significantly associated with seizures, and seizures were not associated with survival.

Seizures Prior to Radiotherapy of Gliomas: Prevalence, Risk Factors and Survival Prognosis.

BACKGROUND/AIM: Seizures represent a common manifestation of gliomas. This study evaluated the prevalence of pre-radiotherapy seizures, potential risk factors and associations with survival. PATIENTS AND METHODS: Eight factors were analyzed in 222 patients for associations with seizures including number, size and location of glioma, World Health Organization (WHO) grade, performance score, gender, age and upfront resection. These factors plus pre-radiotherapy symptoms and seizures were assessed for survival. RESULTS: Prevalence of pre-radiotherapy seizures was 29.3%. A significant correlation was found for grade II (p=0.002), trends for age ≤59 years (p=0.123) and lack of upfront resection (p=0.113). Unifocal gliomas (p<0.001), grade II (p=0.045) and upfront resection (p<0.001) showed significant associations with survival (univariate analyses). A trend was found for seizures (p=0.075) and age ≤59 years (p=0.091). In the multivariate analysis, grade II (p=0.002) and upfront resection (p=0.004) maintained significance; unifocal gliomas showed a trend (p=0.062). CONCLUSION: Pre-radiotherapy seizures appeared to be correlated with WHO grade, age and lack of upfront resection, and with better survival.

Seizures Prior to Whole-brain Irradiation for Metastatic Disease: Prevalence, Risk Factors and Association With Survival.

BACKGROUND/AIM: Seizures are a serious condition for patients with brain metastases. Prevalence, risk factors and a potential association of seizures with survival prior to whole-brain irradiation (WBI) for cerebral metastases were retrospectively investigated. PATIENTS AND METHODS: In 1,934 patients, the prevalence of pre-treatment seizures (pre-WBI) was determined. Seven pre-treatment characteristics were evaluated for associations with seizures. Ten characteristics including pre-treatment symptoms (none vs. seizures only vs. seizures+others vs. others only) and seizures (yes vs. no) were analyzed for survival. RESULTS: In 251 patients (13.0%), pre-treatment seizures were documented. The occurrence of seizures was significantly associated with 1-3 brain metastases and lack of extra-cerebral spread. On multivariate analysis, age, gender, performance score, number of metastases and extra-cerebral spread were significantly associated with survival; pre-treatment symptoms and seizures showed associations on univariate but not on multivariate analyses. CONCLUSION: Few brain metastases and lack of extra-cerebral spread were independent risk factors for pre-treatment seizures. Seizures appeared positively associated with survival.

Occurrence of Seizures Prior to Single-fraction Radiosurgery or Multi-fraction Stereotactic Radiotherapy in Patients With Very Few Brain Metastases.

BACKGROUND/AIM: Seizures represent a major problem for patients with brain metastases. This study evaluated the role of seizures in patients receiving single-fraction radiosurgery (SRS) or multi-fraction stereotactic radiotherapy (FSRT). PATIENTS AND METHODS: This retrospective study included 195 patients receiving SRS (n=164) or FSRT (n=31) alone for one to three brain metastases. The prevalence of pre-SRS/FSRT seizures and correlations with pre-treatment factors were investigated. These factors plus pre-SRS/FSRT seizures were assessed in regard to survival. RESULTS: Thirty-three patients had pre-SRS/FSRT seizures (prevalence=16.9%). Seizures were significantly correlated with age ≤61 years. Trends were observed for seizures being more frequent in those with NSCLC and those without extra-cranial metastatic spread. On multivariate analysis, significant associations with improved survival were found for Karnofsky performance score ≥80%, breast cancer, and an interval from diagnosis of malignant disease to SRS/FSRT ≥21 months. CONCLUSION: Younger age, NSCLC and absence of extra-cranial spread appeared to be risk factors for seizures prior to SRS/FSRT. Having seizures prior to SRS/FSRT showed no association with survival.