External Validation of the Graded Prognostic Assessment in Patients with Brain Metastases from Small Cell Lung Cancer.

BACKGROUND: Recently, graded prognostic assessment (GPA) for small cell lung cancer (SCLC) patients with brain metastases has been developed. This includes age, performance status, number of brain metastases and presence of extracranial metastases. The aim of the present study was to validate this four-tiered prognostic score in a European cohort of patients. METHODS: The retrospective validation study included 180 patients from two centers in Germany and Norway. RESULTS: Median survival from radiological diagnosis of brain metastases was 7 months. The GPA point sum as continuous variable (0-4 points) was significantly associated with survival (p < 0.001). However, no significant survival difference was observed between patients in the two strata with better survival (3.5-4 and 2.5-3 points, respectively). Long-term survival in the poor prognosis group (0-1 points) was better than expected. CONCLUSION: This study supports the prognostic impact of all four parameters contributing to the GPA. The original way of grouping the parameters and breaking the final strata did not give optimal results in this cohort. Therefore, additional validation databases from different countries should be created and evaluated.

Long-term survival results after treatment for oligometastatic brain disease.

AIM: The aim of this study was to characterize the survival results of patients with up to four brain metastases after intense local therapy (primary surgery or stereotactic radiotherapy) if extracranial metastases were absent or limited to one site, e.g. the lungs. BACKGROUND: Oligometastatic disease has repeatedly been reported to convey a favorable prognosis. MATERIAL AND METHODS: This retrospective study included 198 German and Norwegian patients treated with individualized approaches, always including brain radiotherapy. Information about age, extracranial spread, number of brain metastases, performance status and other variables was collected. Uni- and multivariate tests were performed. RESULTS: Median survival was 16.5 months (single brain metastasis) and 9.8 months (2-4, comparable survival for 2, 3 and 4), respectively (p = 0.001). After 5 years, 15 and 2% of the patients were still alive. In patients alive after 2 years, added median survival was 23 months and the probability of being alive 5 years after treatment was 26%. In multivariate analysis, extracranial metastases were not significantly associated with survival, while primary tumor control was. CONCLUSION: Long-term survival beyond 5 years is possible in a minority of patients with oligometastatic brain disease, in particular those with a single brain metastasis. The presence of extracranial metastases to one site should not be regarded a barrier towards maximum brain-directed therapy.

Hippocampus-avoidance whole-brain radiation therapy with a simultaneous integrated boost for multiple brain metastases.

BACKGROUND: The current study was aimed at investigating the feasibility of hippocampus-avoidance whole-brain radiation therapy with a simultaneous integrated boost (HA-WBRT+SIB) for metastases and at assessing tumor control in comparison with conventional whole-brain radiation therapy (WBRT) in patients with multiple brain metastases. METHODS: Between August 2012 and December 2016, 66 patients were treated within a monocentric feasibility trial with HA-WBRT+SIB: hippocampus-avoidance WBRT (30 Gy in 12 fractions, dose to 98% of the hippocampal volume ≤ 9 Gy) and a simultaneous integrated boost (51 or 42 Gy in 12 fractions) for metastases/resection cavities. Intracranial tumor control, hippocampal failure, and survival were subsequently compared with a retrospective cohort treated with WBRT via propensity score matching analysis. RESULTS: After 1:1 propensity score matching, there were 62 HA-WBRT+SIB patients and 62 WBRT patients. Local tumor control (LTC) of existing metastases was significantly higher after HA-WBRT+SIB (98% vs 82% at 1 year; P = .007), whereas distant intracranial tumor control was significantly higher after WBRT (82% vs 69% at 1 year; P = .016); this corresponded to higher biologically effective doses. Intracranial progression-free survival (PFS; 13.5 vs 6.4 months; P = .03) and overall survival (9.9 vs 6.2 months; P = .001) were significantly better in the HA-WBRT+SIB cohort. Four patients (6.5%) developed hippocampal metastases after hippocampus avoidance. The neurologic death rate after HA-WBRT+SIB was 27.4%. CONCLUSIONS: HA-WBRT+SIB can be an efficient therapeutic option for patients with multiple brain metastases and is associated with improved LTC of existing metastases, higher intracranial PFS, a reduction of the neurologic death rate, and an acceptable risk of radiation necrosis. The therapy has the potential to prevent neurocognitive adverse effects, which will be further evaluated in the multicenter, phase 2 HIPPORAD trial.

Validation of the graded prognostic assessment for gastrointestinal cancers with brain metastases (GI-GPA).

PURPOSE: The purpose of this study was to validate a new prognostic model (GI-GPA) originally derived from a multi-center database (USA, Canada, Japan). PATIENTS AND METHODS: This retrospective study included 92 German and Norwegian patients treated with individualized approaches, always including brain radiotherapy. Information about age, extracranial spread, number of brain metastases, performance status and other variables was collected. The GI-GPA score was calculated as described by Sperduto et al. RESULTS: Median survival was 4 months. The corresponding figures for the 4 different prognostic strata were 2.3, 4.4, 9.4 and 12.7 months, respectively (p = 0.0001). Patients whose management included surgical resection had longer median survival than those who were treated with other approaches (median 11.9 versus 3.0 months, p = 0.002). Comparable results were seen for additional systemic therapy (median 8.5 versus 3.5 months, p = 0.01). CONCLUSION: These results confirm the validity of the GI-GPA in an independent dataset from a different geographical region, despite the fact that overall survival was shorter in all prognostic strata, compared to Sperduto et al. Potential explanations include differences in molecular tumor characteristics and treatment selection, both brain metastases-directed and extracranially. Long-term survival beyond 5 years is possible in a small minority of patients.

Age-dependent semiology of frontal lobe seizures.

INTRODUCTION: Frontal lobe epilepsy is the second most frequent origin of focal epilepsy. Various studies have discussed localizing aspects of ictal signs in frontal lobe epilepsy; the effect of age on semiological manifestations has, however, not been analyzed so far. MATERIAL AND METHODS: We retrospectively analyzed video-documented semiological signs in a cohort of 122 consecutive patients aged 0-70 years (mean age: 24.9 years) with EEG/MR evidence for frontal lobe epilepsy undergoing video-EEG telemetry assessment between 1999 und 2016. RESULTS: In this patient cohort, most common etiologies were focal cortical dysplasia (48%) and tumors (16%). Most frequent ictal manifestations overall were impaired language comprehension (60.3%), unilateral tonic posturing (58.9%), unilateral cloni (46.6%), versive movements (44.5%), vocalization (42.5%) and impaired reactivity to non-verbal stimuli (40.4%). With increasing age, sign of four (p = 0.019), dystonic posturing (p = 0.026), changes in heart rate (p = 0.014) and impaired reactivity to non-verbal stimuli (p = 0.009) occurred significantly more frequently. In contrast, myoclonic components were significantly less frequent observed in the higher age group (p = 0.037). CONCLUSIONS: Frontal lobe seizures can be categorized into different behavioral manifestations related to involved symptomatic brain regions, including clonic, bilateral asymmetric tonic seizures and complex motor phenomena. In this cross-sectional study, we found age-related changes in the frequency of both, motor and non-motor semiological elements. Especially simple lateralized motor signs like dystonic posturing, sign of four and version were more common with increasing age. Age-dependent alterations in phenomenology may reflect maturation in connectivity and seizure propagation within and beyond the frontal lobe, and affect the localizing and lateralizing value of ictal phenomena.

Tolerability, efficacy and retention rate of Brivaracetam in patients previously treated with Levetiracetam: A monocenter retrospective outcome analysis.

PURPOSE: To determine the potential for improvement of tolerability and efficacy by the use of Brivaracetam (BRV) in patients previously treated with Levetiracetam (LEV). METHODS: We retrospectively analyzed data from patients treated with BRV at the Freiburg Epilepsy Center. RESULTS: 102 patients with a minimum follow up of 6 months were included. The mean duration of treatment was 301.6 (± 156.8) days. 60 patients underwent an overnight switch from LEV to BRV, 42 patients have had LEV at some time in the past. Out of 46 patients with a quantifiable seizure baseline and follow-up of 6 months 10 patients (21.7%) had an increase in seizure frequency, 15 (32.6%) were 50%-responders, and 10 patients (21.7%) became newly seizure-free. Patients with an overnight switch from LEV to BRV who had a reduction in seizure frequency had the highest dose ratio of the final BRV dose to LEV (1:10.1) and the biggest difference between the starting and final dose of BRV, suggesting that previously seizure control was limited by the tolerated LEV dosage. The retention rate after 6 months was 80.4%. 28 out of 49 (57.1%) patients directly switched from LEV to BRV because of psychiatric side effects reported an improved tolerability. 10 out of 42 (23.8%) patients not directly switched but with a history of LEV use had predominantly psychiatric side effects during BRV treatment. CONCLUSION: Overall, intolerability or ineffectiveness of prior treatment with LEV seems not to preclude a good response to BRV. BRV was substantially better tolerated than LEV.

Rapid antiepileptic drug withdrawal may obscure localizing information obtained during presurgical EEG recordings.

Withdrawal of antiepileptic drugs (AEDs) is a standard procedure during presurgical epilepsy assessment. Rapid and, at times, even pre-hospital withdrawal of medication is performed in some centres to enhance the yield of recorded seizures during video-EEG monitoring. AED withdrawal, however, affects the propensity and speed of propagation of epileptic activity, may evoke more severe seizures, and may cause pitfalls in EEG interpretation. We report a case which had been recommended to undergo intracranial EEG recordings in order to clarify apparently discordant MRI findings and ictal EEG patterns when monitoring was performed following complete AED withdrawal. Re-evaluation to assess scalp EEG patterns at several drug levels during slow AED tapering showed a loss of localizing information with AED withdrawal due to contralateral and bitemporal spread of frontal epileptic activity. Our report demonstrates that in individual cases, rapid AED withdrawal during presurgical video-EEG monitoring can impair the validity of EEG recordings and lead to unnecessary risks and investigations during workup.

Validation of the Graded Prognostic Assessment for Melanoma Using Molecular Markers (Melanoma-molGPA).

BACKGROUND: It has been suggested to replace the diagnosis-specific graded prognostic assessment (DS-GPA, based on performance status and number of brain metastases) for patients with primary malignant melanoma with the new Melanoma-molGPA. The latter is a more complex assessment, which also includes BRAF mutation status, age and extracranial metastases. To test the performance of the Melanoma-molGPA, we performed a validation study of this new survival prediction tool. METHODS: A retrospective analysis of patients treated at two different academic institutions was performed. The four-tiered Melanoma-molGPA was calculated as suggested in the original study. RESULTS: Median overall survival was 5.4 months (95% confidence interval: 3.1 - 7.7 months). Median survival in the four prognostic classes was 2.1, 7.8, 11.8, and 18.0 months, respectively. The 1-year survival rates were 3%, 25%, 43%, and 80%, respectively. The difference between the Kaplan-Meier curves was significant (P = 0.0001, log-rank test). CONCLUSIONS: The present survival outcomes support the use of the Melanoma-molGPA. However, survival was better in each of the four groups in the original study. Possible reasons include lead-time bias and different treatment policies.

Short Survival Time after Palliative whole Brain Radiotherapy: Can We Predict Potential Overtreatment by Use of a Nomogram?

BACKGROUND: Many patients with brain metastases undergoing whole brain radiotherapy (WBRT) have very limited survival. The purpose of this study was to validate a nomogram derived from a large American database and to examine its ability to better predict short survival (cut-off 2 months) than previous models. MATERIAL AND METHODS: This retrospective study included 254 European patients treated with primary WBRT. In addition, an exploratory analysis of patients managed with best supportive care (BSC) was performed too. RESULTS: Median survival after WBRT was 3.0 months. The median nomogram point sum was 122 (range 31-212). The nomogram-predicted median survival for a patient with 122 points is 3.3 months. Despite the nomogram's ability to stratify the patients into different prognostic groups, the survival curves of patients with intermediate point sum in the range of 90-139 points were largely superimposable. The poorest prognostic group with ≥180 points had a median and maximum survival of 1.8 and 4.6 months, respectively. Among these 18 patients (7%) 9 survived for less than and 9 for more than 2 months. Comparable survival outcomes were observed after BSC in a smaller group of 8 patients with ≥180 points. CONCLUSIONS: Because of several differences between the original and validation findings, the nomogram should be examined in additional large databases. Its ability to predict poor survival is promising and possibly comparable to our previously published models. The final goal of developing a validated model that allows poor prognosis patients to safely forego WBRT without compromising survival or quality of life requires further research efforts.

Validation of the graded prognostic assessment for lung cancer with brain metastases using molecular markers (lung-molGPA).

BACKGROUND: Many patients with brain metastases from non-small cell lung cancer have limited survival, while others survive for several years, depending on patterns of spread, EGFR and ALK alterations, among others. The purpose of this study was to validate a new prognostic model (Lung-molGPA) originally derived from a North American database. PATIENTS AND METHODS: This retrospective study included 269 German and Norwegian patients treated with individualized approaches, always including brain radiotherapy. Information about age, extracranial spread, number of brain metastases, performance status, histology, EGFR and ALK alterations was collected. The Lung-molGPA score was calculated as described by Sperduto et al. RESULTS: Median survival was 5.4 months. The score predicted survival in patients with adenocarcinoma histology and those with other types. For example, median survival was 3.0, 6.2, 14.7 and 25.0 months in the 4 different prognostic strata for adenocarcinoma. The corresponding figures were 2.4, 5.5 and 12.5 months in the 3 different prognostic strata for non-adenocarcinoma. CONCLUSIONS: These results confirm the validity of the Lung-molGPA in an independent dataset from a different geographical region. However, median survival was shorter in 6 of 7 prognostic strata. Potential explanations include lead time bias and differences in treatment selection, both brain metastases-directed and systemically.

Predicted survival in patients with brain metastases from colorectal cancer: Is a current nomogram helpful?

OBJECTIVE: To examine the clinical applicability of a new nomogram by comparing survival of patients with brain metastases from colorectal cancer treated with surgery and/or radiotherapy in the authors' institutions with nomogram-predicted median survival. METHODS: Retrospective analysis of 64 patients treated with comparable approaches and during the same time period as the patients in the nomogram study. Points were assigned for age, performance status, number and site of brain metastases, as required for nomogram use. RESULTS: In 46 patients (72%), the observed survival was shorter than the predicted median. The median deviation was -1.4 months. The nomogram underestimated the survival of patients treated with radiosurgery/surgery by a median of 4.2 months, whereas it overestimated the survival of patients treated with whole-brain radiotherapy (WBRT) by a median of 2.1 months (p=0.0001). Nevertheless, all 5 patients with predicted median survival ≤3 months died within 3 months. Among 8 patients with predicted median survival >12 months, 6 (75%) survived for >12 months. Not all prognostic factors in the nomogram correlated with survival. In the multivariate Cox model, only performance status and number of brain metastases were significant, both with p=0.0001. CONCLUSION: Despite differences in prognostic factors and survival of many individual patients, especially those with intermediate prognosis, the nomogram performed promising in poor- and good-prognosis patients. Evaluation of separate prediction tools for patients treated with WBRT and more aggressive local approaches appears warranted in order to minimize the influence of better local control of the brain metastases.

The challenge of durable brain control in patients with brain-only metastases from breast cancer.

The vast majority of patients with brain metastases from breast cancer have extracranial metastases, e.g., in the liver, lungs or bones, with serious impact on prognosis. Limited research has been performed on patients with brain-only disease. We analyzed patterns of treatment, brain control and survival in uni- and multivariate analyses. All 25 patients with brain-only disease were treated with radiotherapy (whole-brain radiotherapy (WBRT) with or without stereotactic radiotherapy/radiosurgery (SRS) or surgical resection) and most patients with systemic treatment later during the disease trajectory. Only a minority of patients remained free from brain progression at 1 year after their initial therapy, regardless of initial treatment approach (median brain progression-free survival 6.2 months). However, overall survival was significantly better after initial surgical resection/SRS as compared to upfront WBRT (median 24.1 and 5.2 months, respectively). For all patients combined, median survival was 11.7 months (2-year survival rate 28 %). Several prognostic factors for shorter survival were identified in multivariate regression analysis: lower KPS, triple-negative tumor, coordination deficit, older age, lack of upfront surgical resection or SRS, and lack of endocrine or HER2-directed therapy after brain metastases treatment. Although durable brain control and long-term survival beyond 5 years could be achieved in a subset of patients (largely after successful salvage), progression of brain metastases during the first year after diagnosis was common. Prognosis was influenced by patient-, disease- and treatment-related factors.

Perampanel in the management of partial-onset seizures: a review of safety, efficacy, and patient acceptability.

Perampanel (PER) is a novel antiepileptic drug recently introduced for the adjunctive treatment in epilepsy patients aged 12 years or older with partial-onset seizures with or without secondary generalization in the US and Europe. Its antiepileptic action is based on noncompetitive inhibition of postsynaptic AMPA receptors, decreasing excitatory synaptic transmission. Evaluation of efficacy in three placebo-controlled randomized Phase III studies showed that add-on therapy of PER decreased seizure frequencies significantly compared to placebo at daily doses between 4 mg/day and 12 mg/day. PER's long half-life of 105 hours allows for once-daily dosing that is favorable for patient compliance with intake. Long-term extension studies showed a 62.5%-69.6% adherence of patients after 1 year of treatment, comparing favorably with other second-generation antiepileptic drugs. Whereas these trials demonstrated an overall favorable tolerability profile of PER, nonspecific central nervous system adverse effects like somnolence, dizziness, headache, and fatigue may occur. In addition, neuropsychiatric disturbances ranging from irritability to suicidality were reported in several case reports; both placebo-controlled and prospective long-term extension trials showed a low incidence of such behavioral and psychiatric complaints. For early recognition of neuropsychiatric symptoms like depression, anxiety, and aggression, slow titration and close monitoring during drug introduction are mandatory. This allows on the one hand to recognize patients particularly susceptible to adverse effects of the drug, and on the other hand to render the drug's full potential of seizure control available for the vast majority of patient groups tolerating the drug well.