Accelerated hyperfractionation plus temozolomide in glioblastoma

Einführung: Gliome sind der häufigste primäre Tumor des zentralen Nervensystems bei Erwachsenen. Der häufigste und bösartigste Typ des Glioms ist das Glioblastom. Derzeitige Behandlungsstandards bestehen aus Resektion, adjuvanter normal fraktionierter Radiotherapie mit gleichzeitiger Gabe von Temozolomid und Temozolomid Gabe nach Radiotherapie. Hyperfraktionierte Radiotherapien oder hyperfraktionierte akzelerierte Radiotherapien (HART) werden aufgrund einer hypothetischen Reduktion später Bestrahlungsschäden sowie einer Verhinderung der Repopulation des Tumorbetts diskutiert. Die hyperfraktionierte Radiotherapie und die HART wurden vor Einführung von Temozolomid als Standard in der Chemotherapie des Glioblastoms ausgiebig untersucht, ohne eindeutige Ergebnisse. In dieser Studie untersuchten wir die Rolle der hyperfraktionierten akzelerierten Radiotherapie in der Temozolomid Ära. Material und Methoden: Wir verglichen für den Behandlungszeitraum von Februar 2009 bis Oktober 2014 vierundsechzig Patienten, behandelt mit HART, mit siebenundsechzig Patienten, die mit klassischer, normal fraktionierter Radiotherapie behandelt wurden. 62 der mit einer HART behandelten und 64 der mit klassischer Radiotherapie behandelten Patienten erhielten Temozolomid. Follow-up Daten wurden bis Januar 2015 analysiert. Ergebnisse: Das mediane Overall-survival (OS) betrug 13 Monate für alle Patienten. Für mit klassischer RT behandelte Patienten betrug das mediane OS 15 Monate, für mit HART behandelte Patienten 10 Monate. In der univariablen und multivariablen Analyse besaß das Regime der Fraktionierung keinen Vorhersagewert für das Überleben. Diskussion: In der univariablen und multivariablen Analyse ließen sich keine signifikanten Unterschiede zwischen den klassischen RT und HART Regimen nachweisen. Die Vorzüge sind offenkundig: das akzelerierte Regime verkürzt bedeutsam die Dauer der Hospitalisierung für ein Patientenkollektiv mit stark eingeschränkter Lebenserwartung. Wir schlagen eine weitere Untersuchung der Rolle einer HART in Kombination mit Temozolomid in zukünftigen prospektiv angelegten Studien vor.Introduction: Gliomas are the most common primary tumors of the central nervous system in adults. The most common and most malignant type of glioma is glioblastoma. Current standard of care comprises resection, adjuvant normofractionated radiotherapy with concurrent temozolomide and post-RT temozolomide. Hyperfractionated (HFRT) or accelerated hyperfractionated radiotherapy (AHFRT) have been discussed based on a hypothesized reduction of late radiation injury and prevention of repopulation. HFRT and AHFRT have been examined extensively in the pre-Temozolomide era with inconclusive results. In this study we examined the role of accelerated hyperfractionation in the Temozolomide era. Materials and methods: Sixty-four patients who underwent AHFRT (62 of which received Temozolomide) were compared to sixty-seven patients who underwent normofractionated (64 of which received Temozolomide) between 02/2009 and 10/2014. Follow-up data were analyzed until 01/2015. Results: Median overall survival (OS) was 13 months for all patients. For patients treated with NFRT median OS was 15 months, for patients treated with AHFRT median OS was 10 months. The fractionation regimen was not a predictor of survival in univariable- or multivariable analysis. Discussion: Univariable and multivariable analysis did not show significant differences between the NFRT and AHFRT fractionation regimens. The benefits are immanent: the regimen does significantly shorten hospitalization time in a patient collective with a highly impaired life expectancy. We propose that the role of AHFRT in combination with Temozolomide should be further examined in future prospective trials

Understanding Brain Mechanisms of Reactive Aggression

PURPOSE OF REVIEW To review the current literature on biobehavioral mechanisms involved in reactive aggression in a transdiagnostic approach. RECENT FINDINGS Aggressive reactions are closely related to activations in the brain's threat circuitry. They occur in response to social threat that is experienced as inescapable, which, in turn, facilitates angry approach rather than fearful avoidance. Provocation-induced aggression is strongly associated with anger and deficits in cognitive control including emotion regulation and inhibitory control. Furthermore, the brain's reward system plays a particular role in anger-related, tit-for-tat-like retaliatory aggression in response to frustration. More research is needed to further disentangle specific brain responses to social threat, provocation, and frustration. A better understanding of the psychological and neurobiological mechanisms involved in reactive aggression may pave the way for specific mechanism-based treatments, involving biological or psychotherapeutic approaches or a combination of the two

Accelerated hyperfractionation plus temozolomide in glioblastoma

Introduction Hyperfractionated (HFRT) or accelerated hyperfractionated radiotherapy (AHFRT) have been discussed as a potential treatment for glioblastoma based on a hypothesized reduction of late radiation injury and prevention of repopulation. HFRT and AHFRT have been examined extensively in the pre-Temozolomide era with inconclusive results. In this study we examined the role of accelerated hyperfractionation in the Temozolomide era. Materials and methods Sixty-four patients who underwent AHFRT (62 of which received Temozolomide) were compared to 67 patients who underwent normofractionated radiotherapy (NFRT) (64 of which received TMZ) between 02/2009 and 10/2014. Follow-up data were analyzed until 01/2015. Results Median progression-free survival (PFS) was 6 months for the entire cohort. For patients treated with NFRT median PFS was 7 months, for patients treated with AHFRT median PFS was 6 months. Median overall survival (OS) was 13 months for all patients. For patients treated with NFRT median OS was 15 months, for patients treated with AHFRT median OS was 10 months. The fractionation regimen was not a predictor of PFS or OS in univariable- or multivariable analysis. There was no difference in acute toxicity profiles between the two treatment groups. Conclusions Univariable and multivariable analysis did not show significant differences between NFRT and AHFRT fractionation regimens in terms of PFS or OS. The benefits are immanent: the regimen does significantly shorten hospitalization time in a patient collective with highly impaired life expectancy. We propose that the role of AHFRT + TMZ should be further examined in future prospective trials

Locally dose-escalated radiotherapy may improve intracranial local control and overall survival among patients with glioblastoma

Abstract Background The dismal overall survival (OS) prognosis of glioblastoma, even after trimodal therapy, can be attributed mainly to the frequent incidence of intracranial relapse (ICR), which tends to present as an in-field recurrence after a radiation dose of 60 Gray (Gy). In this study, molecular marker-based prognostic indices were used to compare the outcomes of radiation with a standard dose versus a moderate dose escalation. Methods This retrospective analysis included 156 patients treated between 2009 and 2016. All patients were medically fit for postoperative chemoradiotherapy. In the dose-escalation cohort a simultaneous integrated boost of up to 66 Gy (66 Gy RT) within small high-risk volumes was applied. All other patients received daily radiation to a total dose of 60 Gy or twice daily to a total dose of 59.2 Gy (60 Gy RT). Results A total of 133 patients received standard 60 Gy RT, while 23 received 66 Gy RT. Patients in the 66 Gy RT group were younger (p <  0.001), whereas concomitant temozolomide use was more frequent in the 60 Gy RT group (p <  0.001). Other intergroup differences in known prognostic factors were not observed. Notably, the median time to ICR was significantly prolonged in the 66 Gy RT arm versus the 60 Gy RT arm (12.2 versus 7.6 months, p = 0.011), and this translated to an improved OS (18.8 versus 15.3 months, p = 0.012). A multivariate analysis revealed a strong association of 66 Gy RT with a prolonged time to ICR (hazard ratio = 0.498, p = 0.01) and OS (hazard ratio = 0.451, p = 0.01). These differences remained significant after implementing molecular marker-based prognostic scores (ICR p = 0.008, OS p = 0.007) and propensity-scored matched pairing (ICR p = 0.099, OS p = 0.023). Conclusion Radiation dose escalation was found to correlate with an improved time to ICR and OS in this cohort of glioblastoma patients. However, further prospective validation of these results is warranted