The aim of this thesis was to assess the efficacy (part 1) and tolerability (part 2) of antiseizure medications (ASMs) in glioma patients with epilepsy. In addition, we aimed to get insight into... Show moreThe aim of this thesis was to assess the efficacy (part 1) and tolerability (part 2) of antiseizure medications (ASMs) in glioma patients with epilepsy. In addition, we aimed to get insight into the ASM prescription behavior and treatment policy in brain tumor-related epilepsy (part 3).First-line levetiracetam seems to be the most efficacious ASM in glioma patients, with favourable tolerability. This is demonstrated in multicenter retrospective observational cohort studies, a systematic review, and is the opinion among the vast majority of European neuro-oncology professionals. Enzyme-inducing AMSs should be avoided in glioma patients due to the high risk of adverse effects. ASM use was not independently associated with neuropsychiatric symptoms in glioma patients, but alternative factors seem to pose a greater risk for developing neuropsychiatric symptoms. If patients experience uncontrolled seizures on ASM monotherapy, levetiracetam combined with valproic acid has better efficacy than other ASM combinations in glioma patients, while toxicity is similar. Subsequently, potential add-on ASMs in glioma patients experiencing uncontrolled seizures on ASM dual therapy include clobazam, lamotrigine, and lacosamide. Show less
BackgroundFocused ultrasound (FUS) shows promise for enhancing drug delivery to the brain by temporarily opening the blood-brain barrier (BBB), and it is increasingly used in the clinical setting... Show moreBackgroundFocused ultrasound (FUS) shows promise for enhancing drug delivery to the brain by temporarily opening the blood-brain barrier (BBB), and it is increasingly used in the clinical setting to treat brain tumours. It remains however unclear whether FUS is being introduced in an ethically and methodologically sound manner. The IDEAL-D framework for the introduction of surgical innovations and the SYRCLE and ROBINS-I tools for assessing the risk of bias in animal studies and non-randomized trials, respectively, provide a comprehensive evaluation for this.Objectives and methodsA comprehensive literature review on FUS in neuro-oncology was conducted. Subsequently, the included studies were evaluated using the IDEAL-D framework, SYRCLE, and ROBINS-I tools.ResultsIn total, 19 published studies and 12 registered trials were identified. FUS demonstrated successful BBB disruption, increased drug delivery, and improved survival rates. However, the SYRCLE analysis revealed a high risk of bias in animal studies, while the ROBINS-I analysis found that most human studies had a high risk of bias due to a lack of blinding and heterogeneous samples. Of the 15 pre-clinical stage 0 studies, only six had formal ethical approval, and only five followed animal care policies. Both stage 1 studies and stage 1/2a studies failed to provide information on patient data confidentiality. Overall, no animal or human study reached the IDEAL-D stage endpoint.ConclusionFUS holds promise for enhancing drug delivery to the brain, but its development and implementation must adhere to rigorous safety standards using the established ethical and methodological frameworks. The complementary use of IDEAL-D, SYRCLE, and ROBINS-I tools indicates a high risk of bias and ethical limitations in both animal and human studies, highlighting the need for further improvements in study design for a safe implementation of FUS in neuro-oncology. Show less
Despite improved surgical and adjuvant treatment options, malignant brain tumors remain non-curable to date. The thin line between treatment effectiveness and patient harms underpins the importance... Show moreDespite improved surgical and adjuvant treatment options, malignant brain tumors remain non-curable to date. The thin line between treatment effectiveness and patient harms underpins the importance of tailoring clinical management to the individual brain tumor patient. Over the past decades, the volume and complexity of clinically-derived patient data (i.e., imaging, genomics, free-text etc.) is increasing exponentially. Machine learning provides a vast range of algorithms that can learn from this data and guide clinical decision-making by providing accurate patient-level predictions. The current thesis describes several studies along the continuum of the machine learning spectrum as it applies to neurosurgical oncology. Part I investigates postoperative complications and risk factors in patients operated for a primary malignant brain tumor. Part II describes de development of a model for the prediction of individual-patient survival in glioblastoma patients. Part III encompasses the development of a natural language processing framework for automated medical text analysis. Machine learning algorithms should be considered as an extension to statistical approaches and exist along a continuum determined by how much is specified by humans and how much is learnt by the machine. Although machine learning algorithms can produce highly accurate predictions based on high-dimensional data, clinicians and researchers should interpret the clinical implications of these predictions on case-by-case basis. Show less
Purpose Although standard-of-care has been defined for the treatment of glioblastoma patients, substantial practice variation exists in the day-to-day clinical management. This study aims to... Show morePurpose Although standard-of-care has been defined for the treatment of glioblastoma patients, substantial practice variation exists in the day-to-day clinical management. This study aims to compare the use of laboratory tests in the perioperative care of glioblastoma patients between two tertiary academic centers-Brigham and Women's Hospital (BWH), Boston, USA, and University Medical Center Utrecht (UMCU), Utrecht, the Netherlands. Methods All glioblastoma patients treated according to standard-of-care between 2005 and 2013 were included. We compared the number of blood drawings and laboratory tests performed during the 70-day perioperative period using a Poisson regression model, as well as the estimated laboratory costs per patient. Additionally, we compared the likelihood of an abnormal test result using a generalized linear mixed effects model. Results After correction for age, sex, IDH1 status, postoperative KPS score, length of stay, and survival status, the number of blood drawings and laboratory tests during the perioperative period were 3.7-fold (p < 0.001) and 4.7-fold (p < 0.001) higher, respectively, in BWH compared to UMCU patients. The estimated median laboratory costs per patient were 82 euros in UMCU and 256 euros in BWH. Furthermore, the likelihood of an abnormal test result was lower in BWH (odds ratio [OR] 0.75, p < 0.001), except when the prior test result was abnormal as well (OR 2.09, p < 0.001). Conclusions Our results suggest a substantially lower clinical threshold for ordering laboratory tests in BWH compared to UMCU. Further investigating the clinical consequences of laboratory testing could identify over and underuse, decrease healthcare costs, and reduce unnecessary discomfort that patients are exposed to. Show less
The aim of this thesis was to answer currently unanswered questions regarding health-related quality of life (HRQoL) in glioma patients by undertaking powerful detailed secondary analyses of... Show moreThe aim of this thesis was to answer currently unanswered questions regarding health-related quality of life (HRQoL) in glioma patients by undertaking powerful detailed secondary analyses of existing pooled individual HRQoL patient data, which was previously collected in 15 RCTs in glioma patients.In total, data of 6048 glioma patients was included in the CODAGLIO database and 5 manuscripts were written that provide relevant information both for clinical practice as well as for clinical trials. Results of these studies entailed information on the added prognostic value of HRQoL at baseline in predicting survival. Furthermore, symptom clusters were identified and their association with functioning was investigated, and the impact of both (progression of) the disease and treatment on HRQoL deterioration was studied. Moreover, the ‘net clinical benefit’, weighing HRQoL and survival was calculated and different analytical methods to calculate change in HRQoL were compared.The CODAGLIO project, the largest individual patient data (IPD) project in neuro-oncology research so far, showed to represent an unique opportunity for secondary hypothesis testing, to answer clinically relevant questions with respect to HRQoL. Show less
The goal of this thesis was to provide guidance for the neuro-oncologist’s daily clinical practice with respect to tailoring antiepileptic drug (AED) treatment and improving the radiological... Show moreThe goal of this thesis was to provide guidance for the neuro-oncologist’s daily clinical practice with respect to tailoring antiepileptic drug (AED) treatment and improving the radiological assessment of tumor response and progression in patients with gliomas and brain metastases. Part I of this thesis focused on the impact of AEDs on clinical outcome, such as survival, and the consequence of AED withdrawal on seizure recurrence and radiological outcome. Part II focused on the impact of antitumor treatment on clinical and radiological outcome, especially regarding the assessment of (pseudo)progression. Show less
Dirven, L.; Luerding, R.; Beier, D.; Bumes, E.; Reinert, C.; Seidel, C.; ... ; Hau, P. 2020
Background Combined radiochemotherapy followed by maintenance chemotherapy with cisplatin, lomustine and vincristine within the NOA-07 study resulted in considerable short-term toxicity in adult... Show moreBackground Combined radiochemotherapy followed by maintenance chemotherapy with cisplatin, lomustine and vincristine within the NOA-07 study resulted in considerable short-term toxicity in adult medulloblastoma patients. Here we investigated the long-term impact of this treatment, focusing on neurocognitive functioning and health-related quality of life (HRQoL). Methods Neurocognitive functioning and HRQoL scores over time were determined, and differences between the post-treatment and follow-up assessments were calculated up to 18 months for neurocognition and 60 months for HRQoL. Results 28/30 patients were analyzed. The three preselected HRQoL scales (role, social and cognitive functioning) showed improved scores, to a clinically relevant extent (>= 10 points), compared to post-treatment levels up to 30 months, but decreased afterwards. Z-scores for verbal working memory were worse during follow-up compared to post-treatment scores and remained impaired during 18 months follow-up (i.e. z-score below - 1 standard deviation). Attention was impaired post-treatment, and remained impaired to a clinically relevant extent during follow-up. Coordination/processing speed and lexical verbal fluency improved compared to post-treatment scores, and remained within the normal range thereafter. Other tests of verbal fluency were stable over time, with z-scores within the normal range. Conclusions This long-term follow-up study showed that the NOA-07 treatment regimen was not associated with a deterioration in HRQoL in the post-treatment period. Verbal working memory deteriorated, while other neurocognitive domains did not seem to be impacted negatively by the treatment. Show less
Background It is unknown if the implementation of an advance care planning (ACP) program is feasible in daily clinical practice for glioblastoma patients. We aimed to develop an ACP program and... Show moreBackground It is unknown if the implementation of an advance care planning (ACP) program is feasible in daily clinical practice for glioblastoma patients. We aimed to develop an ACP program and assess the preferred content, the best time to introduce such a program in the disease trajectory, and possible barriers and facilitators for participation and implementation. Methods A focus group with health care professionals (HCPs) and individual semi-structured interviews with patients and proxies (of both living and deceased patients) were conducted. Results All predefined topics were considered relevant by participants, including the current situation, worries/fears, (supportive) treatment options, and preferred place of care/death. Although HCPs and proxies of deceased patients indicated that the program should be implemented relatively early in the disease trajectory, patient-proxy dyads were more ambiguous. Several patient-proxy dyads indicated that the program should be initiated later in the disease trajectory. If introduced early, topics about the end of life should be postponed. A frequently mentioned barrier for participation was that the program would be too confronting, while a facilitator was adequate access to information. Conclusion This study resulted in an ACP program specifically for glioblastoma patients. Although participants agreed on the program content, the optimal timing of introducing such a program was a matter of debate. Our solution is to offer the program shortly after diagnosis but let patients and proxies decide which topics they want to discuss and when. The impact of the program on several patient- and care-related outcomes will be evaluated in the next step. Show less
