From 2005, state-of-the-art therapy in glioblastoma consists of maximal safe resection followed by combined radiotherapy and chemotherapy with temozolomide, according to Stupp regimen 1) , 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). 2).
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 3).
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) 7) and 48% in RTOG-0825 8). 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 9).
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 10).
see Glioblastoma surgery.
The recommended treatment for O6-methylguanine-DNA methyltransferase (MGMT) promoter unmethylated glioblastoma (GBM) is radiation therapy with concurrent/adjuvant temozolomide (TMZ). However, it is well known that the clinical benefit from TMZ is lower in these patients.
Waiting time after surgery and overall time data do not indicate a relevant time factor in the treatment of glioblastoma multiforme in a large contemporary single-centre cohort. Although a study was limited by its retrospective nature, its results indicate that short delays of postoperative radiochemotherapy, e.g. for screening of a patient for a clinical trial, may be uncritical 11).
Glioblastoma multiforme antiangiogenic therapy
Molecular targeted therapy of glioblastoma
GBM is one of the most active areas of research. Significant efforts are being made to look beyond basic morphology.
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 13).
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.
ALK inhibitor for Glioblastoma
Not good candidates for surgery
Extensive dominant lobe glioblastoma