Glioblastoma outcome

Although the exact prognosis of IDHwt GBM, WHO grade 4, with histologically LGGs remains unknown, its OS was approximately 1-2 years similar to that of histologically IDHwt GBM, WHO grade 4, despite histopathological features similar to IDHmut LrGGs. These findings reinforce the need for the analysis of molecular features, regardless of presenting similar clinical characteristics and imaging features to IDHmut LrGGs 1).

Less experienced neurosurgeons achieve similar surgical results and outcomes in elderly GBM patients within the setting of academic teaching hospitals. Adjuvant treatment and avoidance of surgery-related morbidity are crucial for generating a treatment benefit for this cohort 2)

It is the most malignant intrinsic tumor of the central nervous system(CNS), with high morbidity of 3.19/100,000 per year and a poor 5-year survival rate (< 5%) worldwide.

The disease progression, response to chemotherapy and radiotherapy at initial diagnosis, and prognosis are profoundly associated with the tumor microenvironment, especially the features of tumor-infiltrating immune cells (TII). Recurrent glioblastoma is even more challenging to manage.

The glioblastoma outcome has changed little over the past two decades, with only minor improvements in length of overall survival through the addition of temozolomide (temodal) to standard of care and the recommended use of alternating electric field therapy (optune) to newly diagnosed patients. In an effort to define novel therapeutic targets across molecularly heterogeneous disease subgroups, researchers have begun to uncover the complex interplay between epigenetics, cell signaling, metabolism, and the immunosuppressive tumor microenvironment. Indeed, IDH mutations are now recognized as a defining differential factor not only influencing global hypermethylation and patient prognosis but also degree of immune infiltration within individual tumors. Likewise, next-generation sequencing has defined subgroup-specific transcriptional profiles that correlate with different mechanisms of immune evasion, including increased PD-L1 and CTLA-4 among mesenchymal tumors. Interestingly, sequencing of the T cell repertoire from numerous patient samples suggests that the correlation between mutational burden and enrichment of tumor-specific peptides may be less convincing than originally suspected. While this raises questions over the efficacy of dendritic cell or tumor-lysate vaccines and CAR-T therapies, these avenues continue to be explored. In addition to these active immunotherapies, inhibitors of molecular hubs with wide reaching effects, including STAT3, IDO, and TGF-β, are now in early-phase clinical trials. With the potential to block intrinsic biological properties of tumor growth and invasion while bolstering the immunogenic profile of the tumor microenvironment, these new targets represent a new direction for Glioblastoma therapies. In this review, we show the advances in molecular profiling and immunophenotyping of Glioblastoma, which may lead to the development of new personalized therapeutic strategies 3).

Glioblastoma survival.

Therapeutic failure is due to the complex and heterogeneous molecular biology of glioblastoma, and also to the inability to deliver therapies to the tumor because of the blood–brain barrier (BBB) and blood–tumor barrier (BTB).

high-grade gliomas (HGGs) have remained particularly difficult to treat with no noteworthy improvements reported in the past years. This lack of progress is partly because of the invasive nature displayed by HGGs, which are able to easily infiltrate the surrounding parenchyma, making complete surgical resection impossible. Additionally, HGGs present a significant number of genetic and epigenetic alterations with an enormous impact on heterogeneity, inter and intracellular signaling, immune system dampening, resistance to treatment and proliferation. The current therapeutic standard, first established in 2005, has a low therapeutic index and presents a large number of side effects 4).

Amongst some the most important causes for the poor outcome are the immune-privileged status of the brain and the immune-suppressing attributes of the tumor and its microenvironment. Initially, it was thought that the Blood Brain Barrier was the reason behind this phenomenon; however, this theory has been disproven 5) 6) 7).

The outcome of patients with anaplastic gliomas varies considerably depending on single molecular markers, such as mutations of the isocitrate dehydrogenase (IDH) genes, as well as molecular classifications based on epigenetic or genetic profiles.

Malignant brain tumor, including the most common type glioblastoma, are histologically heterogeneous and invasive tumors known as the most devastating neoplasms with high morbidity and mortality. Despite multimodal treatment including surgery, radiotherapy, chemotherapy, and immunotherapy, the disease inevitably recurs and is fatal. This lack of curative options has motivated researchers to explore new treatment strategies and to develop new drug delivery systems (DDSs); however, the unique anatomical, physiological, and pathological features of brain tumors greatly limit the effectiveness of conventional chemotherapy 8).

The current standard of care in glioblastoma is not very effective, resulting in tumor recurrence with patients rarely surviving over 2 years. This tumor recurrence is attributed to the presence of chemo and radiation resistant glioma stem cells (GSCs).

Outcome remains dismal despite advances in therapeutic interventions including chemotherapy, radiotherapy and surgical resection.

Kawano et al., observed a gradual improvement in glioblastoma multiforme outcome, presumably because of improvements in therapeutic modalities for surgery, anticancer agents, and radiation, but the efficacy of CyberKnife-SRT remains unclear 9)

The best glioblastoma multiforme outcome is observed in patients with complete resection of the contrast enhancement tumor (CRET).

However, removal of the final 1%–2% of the contrast-enhancing tumor carries not only the greatest impact from an oncological point of view but also the greatest risk for neurological impairment, especially in glioblastomas adjacent to motor eloquent areas.

A larger prospective analysis that compares CyberKnife SRS and hypofractionated radiotherapy to focal external beam radiation therapy EBRT is warranted 10).

Elderly high-grade glioma patients show a worse overall survival (OS) compared to younger patients, with reduced ability to tolerate therapeutic interventions and higher rates of unfavorable biomarker status 11) 12)

see Glioblastoma outcome in elderly patients.

Data on the glioblastoma outcome of patients in low- and middle-income countries is sparse. Hong et al. determined whether socioeconomic factors such as marital status, place of residence, educational attainment, employment status, and income affected survival. A retrospective cohort study of surgically managed Glioblastoma patients (n = 48) in a single-center over a five-year period was conducted using chart review and telephone interviews. The mean age was 41 years, with a male predilection (62%). Most patients were married (73%), employed full-time (79%), resided in a rural location (56%), completed secondary education (44%), and had a low income (83%). Most of the tumors were > 5 cm at the time of diagnosis (90%) and involved more than one lobe (40%). The majority underwent subtotal resection (56%). Only 15% (n = 7) had adjuvant chemoradiation while 23% (n = 11) had radiotherapy alone. The median overall survival was 7.6 months. Multivariate analysis showed that extent of resection (gross total resection, p = 0.0033; subtotal resection, p = 0.0069) and adjuvant treatment (p = 0.0254) were associated with improved survival, while low income (p = 0.0178) and educational (p = 0.0206) levels and part-time employment (p = 0.0063) were associated with decreased survival. Many Glioblastoma patients at the Philippine General Hospital, Manila, presented at an advanced stage in their natural history, and the majority (62%) did not receive adjuvant treatment after surgery. As such, the median overall survival was less than that reported in developed countries. Of the socioeconomic factors analyzed, low income and educational levels, and part-time employment were negatively associated with survivorship 13).

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Korja M, Raj R, Seppä K, Luostarinen T, Malila N, Seppälä M, Mäenpää H, Pitkäniemi J. Glioblastoma survival is improving despite increasing incidence rates: a nationwide study between 2000 and 2013 in Finland. Neuro Oncol. 2019 Feb 19;21(3):370-379. doi: 10.1093/neuonc/noy164. PMID: 30312433; PMCID: PMC6380416.
Pirkkalainen JM, Jääskeläinen AS, Halonen P. Retrospective single-center study on elderly patients with glioblastoma between 2014 and 2018 evaluating the effect of age and performance status on survival. Neurooncol Pract. 2022 Jan 27;9(2):142-148. doi: 10.1093/nop/npac008. PMID: 35371528; PMCID: PMC8965048.
Hong MAC, Omar AT, Khu KJO. Socioeconomic factors affecting survivorship of glioblastoma patients in the Philippines. J Clin Neurosci. 2022 Feb 9;98:89-95. doi: 10.1016/j.jocn.2022.02.007. Epub ahead of print. PMID: 35151062.
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