Glioblastoma treatment
As the biological challenges and genetic basis of glioblastoma have become more understood, new therapeutic strategies may lead to more durable clinical responses and long-term remissions 1)
Due to the lack of consensus, there exists variability amongst surgeons and centers regarding glioblastoma treatment decisions. Though, objective data about the extent of this heterogeneity is still lacking. Gerritsen et al. aimed to evaluate and analyze the similarities and differences in neurosurgical practice patterns.
The survey was distributed to members of the neurosurgical societies of the Netherlands (NVVN), Europe (EANS), the United Kingdom (SBNS), and the United States (CNS) between January and March 2021 with questions about the selection of surgical modality and decision making in glioblastoma patients.
Survey respondents (224 neurosurgeons) were from 41 countries. Overall, the most notable differences observed were the presence and timing of a multidisciplinary tumor board; the importance and role of various perioperative factors in the decision-making process, and the preferred treatment in various glioblastoma cases case variants. Tumor boards were more common at academic centers. The intended extent of resection for glioblastoma resections in eloquent areas was limited more often in European neurosurgeons. They found a strong relationship between the surgeon’s theoretical survey answers and their actual approach in presented patient cases. In general, the factors which were found to be theoretically the most important in surgical decision-making were confirmed to influence the respondents’ decisions to the greatest extent in practice as well.
This survey illustrates the theoretical and practical heterogeneity among surgeons and centers in their decision-making and treatment selection for glioblastoma patients. These data invite further evaluations to identify key variables that can be optimized and may therefore benefit from consensus 2).
The gold standard for High-Grade Glioma treatment recommends beginning chemoradiation within 6 weeks after. glioblastoma surgery.
The standard of care management for newly diagnosed glioblastoma multiforme (GBM) includes surgery, radiation, temozolomide (TMZ) chemotherapy, and tumor treating fields 3).
From 2005 chemotherapy with temozolomide, according to Stupp protocol 4) , particularly in patients that demonstrate MGMT promoter methylation.
Conflicting reports have emerged regarding the importance of the time interval between these 2 treatments and there is no clear association between duration from surgery to initiation of chemoradiation on overall survival (OS). 5).
Treatment consists of maximal safe resection, radiotherapy, and chemotherapy. Trials of patients with newly diagnosed grade III glioma have shown survival benefit from adding chemotherapy to radiotherapy compared with initial treatment using radiotherapy alone. Both temozolomide and the combination of procarbazine, lomustine, and vincristine provide survival benefit. In contrast, trials that compare single modality treatment of chemotherapy alone with radiotherapy alone did not observe survival differences. Currently, for patients with grade III gliomas who require postsurgical treatment, the preferred treatment consists of a combination of radiotherapy and chemotherapy 6).
After treatment, all patients have to undergo brain magnetic resonance imaging procedure quarterly or half-yearly for 5 years and then on an annual basis. In patients with recurrent tumor, wherever possible re-resection or re-irradiation or chemotherapy can be considered along with supportive and palliative care. High-grade malignant glioma should be managed in a multidisciplinary center
CATNON trial
see CATNON trial.
Postoperative management
The criteria used to assess extent of resection (EOR) have an impact on findings of association between EOR and survival. Current assessment of EOR mainly relies on pre and postoperative contrast-enhanced T1 weighted images (CE-T1WI).
This method is subject to several inherent limitations, including failure to evaluate nonenhancing components of glioma.
To solve this problem, fluid attenuated inversion recovery (FLAIR) imaging is added in the RANO criteria 7).
From the introduction of the first standard of care (SOC) established in 2005 in patients with a new diagnosis of GBM, a great number of trials have been conducted to improve the actual SOC, but the real turning point has never been achieved or is yet to come. Surgical gross total resection, with at least one more reoperation, radiation therapy plus concomitant and adjuvant temozolomide chemotherapy currently remains the current SOC for patients with GBM 8).
Antiepileptic medications may increase radiosensitivity, and therefore improve clinical outcomes, specifically in glioblastoma multiforme patients 9).
The recommended treatment for MGMT promoter unmethylated glioblastoma (GBM) is radiation therapy with concurrent/adjuvant temozolomide (TMZ).
Although overall survival (OS) is the standard for determining GBM treatment efficacy, using OS as an endpoint when studying new therapeutic strategies can be problematic because of potential influence of therapies prior to or subsequently following the therapy being studied. For example, it is difficult to definitively conclude that bevacizumab has no efficacy in GBM when a large percentage of patients in the placebo arms in both III trials studying efficacy of bevacizumab (i.e. AVAglio and RTOG 0825) eventually crossed over and received bevacizumab (31% in AVAglio) 10) and 48% in RTOG-0825 11). If bevacizumab increased OS when given at any time during treatment, we may expect both treatment arms to have similar median OS since most patients eventually were treated with bevacizumab, disguising any therapeutic effects of the drug. Together, these results suggest OS may not be a suitable endpoint when studying new therapeutics or when there is a high chance of cross over in the control arm 12).
To overcome the limitations associated with using OS as the primary endpoint in studies involving new therapeutics, progression free survival (PFS) and objective response rate (ORR) should be considered important end points 13).
Surgery
see Glioblastoma surgery.
Glioblastoma Maximal Safe Resection
Glioblastoma Maximal Safe Resection
Glioblastoma Radiochemotherapy
Glioblastoma radiochemotherapy.
Glioblastoma chemotherapy
Glioblastoma multiforme antiangiogenic therapy
see Glioblastoma multiforme antiangiogenic therapy.
Molecular targeted therapy of glioblastoma
see Molecular targeted therapy of glioblastoma.
Future Direction
GBM is one of the most active areas of research. Significant efforts are being made to look beyond basic morphology.
The retrospective analysis of the AVAglio trial reported 4.3 months incremental survival in the proneural glioblastoma subgroup 14).
Hence, patient selection and personalization of treatment should be done with more appropriateness in future. However, the complexity of performing these molecular assays in the lab appears to be labor and cost intensive and may limit routine use. In this context, a simplified model incorporating MGMT methylation, human telomerase (TERT) methylation, and IDH mutation may be formulated to dictate the optimum treatment. Treatment personalization may further be refined with the incorporation of these molecular factors along with patient factors like age, performance status, etc., (molecular-clinical profiling). A Large number of newer drugs and virus based therapy are being evaluated in different phase III and phase II trials as well.
The subventricular zone (SVZ) forms the lining the lateral ventricles and represents the origin of neural and some cancer stem cells. Gupta et al. reported on dose volume parameters of SVZ in 40 patients of adult GBM. Dose to the ipsilateral SVZ dose was found to be an independent predictor of survival in multivariate analysis in this study. Although a novel finding, this requires further validation in a prospective study 15).
Citalopram with standard RT and Temozolomide TMZ
RT alone versus RT and TMZ for elderly
CCNU/TMZ combination therapy versus standard TMZ (MGMT-methylated cases)
Standard RT plus concomitant and adjuvant OSAG 101 (Theraloc°) plusTMZ versus standard RT plus concomitant and adjuvant TMZ
Rindopepimut/GM-CSF with adjuvantTMZ in EGFvall-positive GBM CDX110-04
DCVax-L, autologous dendritic cells pulsed with tumor Iysate antigen 020221
Adjuvant TMZ with or without Interferon-alpha NCT 01765088
Adjuvant RT and temozolomide with or without Velipari b NCT 02152982
CCNU – Lomustine; TMZ -Temozolomide; MGMT – O‘-methylguanine—DNA methyltransferase; GBM – Glioblastoma multiforme; RT – Radiotherapy,-
GM-CSF -Granulocyte-monocyte colony stimulating factor,- EGFRvIII – Epidermal growth factor receptor variant III.
Immunotherapy
see Glioblastoma immunotherapy.
ALK inhibitor for Glioblastoma
ALK inhibitor for Glioblastoma.
Alternating electric field therapy for Glioblastoma
Alternating electric field therapy for Glioblastoma
Not good candidates for surgery
Extensive dominant lobe glioblastoma
Glioblastoma in elderly patients
Karnofsky performance score < 70
Recurrent glioblastoma treatment
see Recurrent glioblastoma treatment.
Hyperbaric oxygen therapy for Glioblastoma
Hyperbaric oxygen therapy for Glioblastoma.
Palliative care
Palliative care for Glioblastoma.
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