Glioblastoma

Glioblastoma, previously known as glioblastoma multiforme (GBM), is the most aggressive and most common type of cancer that originates in the brain, and has a very poor prognosis for survival.<ref name="Ble2012">Template:Cite journal</ref><ref name="Tan Ashley López Malinzak 2020 pp. 299–312">Template:Cite journal</ref><ref name = "Tran_2010">Template:Cite journal</ref> Initial signs and symptoms of glioblastoma are nonspecific.<ref name="Young2015" /> They may include headaches, personality changes, nausea, and symptoms similar to those of a stroke.<ref name= Young2015/> Symptoms often worsen rapidly and may progress to unconsciousness.<ref name= WCR2014,5.16/>

The cause of most cases of glioblastoma is not known.<ref name=WCR2014,5.16>Template:Cite book</ref> Uncommon risk factors include genetic disorders, such as neurofibromatosis and Li–Fraumeni syndrome, and previous radiation therapy.<ref name= WCR2014,5.16/><ref name=Gal2015/> Glioblastomas represent 15% of all brain tumors.<ref name=Young2015>Template:Cite journal</ref> They are thought to arise from astrocytes.<ref name=WCR2014,3.8>Template:Cite book</ref> The diagnosis typically is made by a combination of a CT scan, MRI scan, and tissue biopsy.<ref name= Young2015/>

There is no known method of preventing the cancer.<ref name=Gal2015/> Treatment usually involves surgery, after which chemotherapy and radiation therapy are used.<ref name= Gal2015>Template:Cite journal</ref> The medication temozolomide is frequently used as part of chemotherapy.<ref name=Gal2015/><ref name=Hart2013>Template:Cite journal</ref><ref name="RTG1" /> High-dose steroids may be used to help reduce swelling and decrease symptoms.<ref name=Young2015/> Surgical removal (decompression) of the tumor is linked to increased survival, but only by some months.<ref>Template:Cite journal</ref>

Despite maximum treatment, the cancer almost always recurs.<ref name=Gal2015/> The typical duration of survival following diagnosis is 10–13 months, with fewer than 5–10% of people surviving longer than five years.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name=Os2019>Template:Cite journal</ref> Without treatment, survival is typically three months.<ref name=Sch2007>Template:Cite book</ref> It is the most common cancer that begins within the brain and the second-most common brain tumor, after meningioma, which is benign in most cases.<ref name=Ble2012/><ref name=Mc2016>Template:Cite journal</ref> About 3 in 100,000 people develop the disease per year.<ref name=Gal2015/> The average age at diagnosis is 64, and the disease occurs more commonly in males than females.<ref name=WCR2014,5.16/><ref name=Gal2015/>

Tumors of the central nervous system are the 10th leading cause of death worldwide, with up to 90% being brain tumors.<ref>Template:Cite journal</ref> Glioblastoma multiforme (GBM) is derived from astrocytes and accounts for 49% of all malignant central nervous system tumors, making it the most common form of central nervous system cancer. Despite countless efforts to develop new therapies for GBM over the years, the median survival rate of GBM patients worldwide is 8 months; radiation and chemotherapy standard-of-care treatment beginning shortly after diagnosis improve the median survival length to around 14 months and a five-year survival rate of 5–10%. The five-year survival rate for individuals with any form of primary malignant brain tumor is 20%.<ref>Template:Cite journal</ref> Even when all detectable traces of the tumor are removed through surgery, most patients with GBM experience recurrence of their cancer. Template:TOC limit

Signs and symptoms

Common symptoms include seizures, headaches, nausea and vomiting, memory loss, changes to personality, mood or concentration, and localized neurological problems.<ref name=Al2015>Template:Cite journal</ref> The kinds of symptoms produced depend more on the location of the tumor than on its pathological properties. The tumor can start producing symptoms quickly, but occasionally is an asymptomatic condition until it reaches an enormous size.<ref>Template:Cite journal</ref>

Risk factors

The cause of most cases is unclear.<ref name=WCR2014,5.16 /> The best known risk factor is exposure to ionizing radiation, and CT scan radiation is an important cause.<ref name="nrsCT1">Template:Cite journal</ref><ref name="nrsIR1">Template:Cite journal</ref> About 5% of cases develop from certain hereditary syndromes.<ref name=Al2015/>

Genetics

Uncommon risk factors include genetic disorders such as neurofibromatosis, Li–Fraumeni syndrome, tuberous sclerosis, or Turcot syndrome.<ref name=Al2015/> Previous radiation therapy is also a risk.<ref name=WCR2014,5.16/><ref name=Gal2015/> For unknown reasons, it occurs more commonly in males.<ref>Template:Cite journal</ref>

Environmental

Other associations include exposure to smoking, pesticides, and working in petroleum refining or rubber manufacturing.<ref name=Al2015/>

Glioblastoma has been associated with the viruses SV40,<ref>Template:Cite journal</ref> HHV-6,<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> and cytomegalovirus (CMV).<ref>Template:Cite journal</ref> Infection with an oncogenic CMV may even be necessary for the development of glioblastoma.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Other

Research has been done to see if consumption of cured meat is a risk factor. No risk had been confirmed as of 2003.<ref>Template:Cite journal</ref> Similarly, exposure to formaldehyde, and residential electromagnetic fields, such as from cell phones and electrical wiring within homes, have been studied as risk factors. As of 2015, they had not been shown to cause GBM.<ref name=Al2015/><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Pathogenesis

The cellular origin of glioblastoma is unknown. Because of the similarities in immunostaining of glial cells and glioblastoma, gliomas such as glioblastoma have long been assumed to originate from glial-type stem cells found in the subventricular zone. More recent studies suggest that astrocytes, oligodendrocyte progenitor cells, and neural stem cells could all serve as the cell of origin.<ref name="Zong_2012">Template:Cite journal</ref><ref name="Zong_2015">Template:Cite journal</ref>

GBMs usually form in the cerebral white matter, grow quickly, and can become very large before producing symptoms. Since the function of glial cells in the brain is to support neurons, they have the ability to divide, to enlarge, and to extend cellular projections along neurons and blood vessels. Once cancerous, these cells are predisposed to spread along existing paths in the brain, typically along white-matter tracts, blood vessels and the perivascular space.<ref>Template:Cite journal</ref> The tumor may extend into the meninges or ventricular wall, leading to high protein content in the cerebrospinal fluid (CSF) (> 100 mg/dl), as well as an occasional pleocytosis of 10 to 100 cells, mostly lymphocytes. Malignant cells carried in the CSF may spread (rarely) to the spinal cord or cause meningeal gliomatosis. However, metastasis of GBM beyond the central nervous system is extremely unusual. About 50% of GBMs occupy more than one lobe of a hemisphere or are bilateral. Tumors of this type usually arise from the cerebrum and may exhibit the classic infiltration across the corpus callosum, producing a butterfly (bilateral) glioma.<ref>Template:Cite journal</ref>

Glioblastoma classification

Brain tumor classification has been traditionally based on histopathology at macroscopic level, measured in hematoxylin-eosin sections. The World Health Organization published the first standard classification in 1979<ref>Template:Cite book</ref> and has been doing so since. The 2007 WHO Classification of Tumors of the Central Nervous System<ref>Template:Cite journal</ref> was the last classification mainly based on microscopy features. The new 2016 WHO Classification of Tumors of the Central Nervous System<ref>Template:Cite journal</ref> was a paradigm shift: some of the tumors were defined also by their genetic composition as well as their cell morphology.

In 2021, the fifth edition of the WHO Classification of Tumors of the Central Nervous System was released. This update eliminated the classification of secondary glioblastoma and reclassified those tumors as Astrocytoma, IDH mutant, grade 4. Only tumors that are IDH wild type are now classified as glioblastoma.<ref>Template:Cite journal</ref>

Features of glioblastoma, IDH wildtype, WHO 4<ref>Template:Cite journal</ref>

Synonyms	Glioblastoma, GBM
Cell of origin	Astrocyte
Median age at diagnosis	~62 years
Male:Female ratio	1.42:1
Median length of clinical history at diagnosis	4 months
Median overall survival
Surgery + radiotherapy	9.9 months
Surgery + radiotherapy + chemotherapy	15 months
Location	Usually supratentorial, rarely cerebellum or spine
Necrosis and microvascular proliferation	Extensive
Associated molecular/genetic mutations	TERT promoter mutation, combined gain of chromosome 7 and loss of chromosome 10; EGFR amplification

Molecular alterations

There are currently three molecular subtypes of glioblastoma that were identified based on gene expression:<ref name=qw>Template:Cite journal</ref>

• Classical: Around 97% of tumors in this subtype carry extra copies of the epidermal growth factor receptor (EGFR) gene, and most have higher than normal expression of EGFR, whereas the gene TP53 (p53), which is often mutated in glioblastoma, is rarely mutated in this subtype.<ref>Template:Cite journal</ref> Loss of heterozygosity in chromosome 10 is also frequently seen in the classical subtype alongside chromosome 7 amplification.<ref name="Sasmita_2018">Template:Cite journal</ref>
• The proneural subtype often has high rates of alterations in TP53 (p53), and in PDGFRA the gene encoding a-type platelet-derived growth factor receptor.<ref name="Integrated genomic analysis identif">Template:Cite journal</ref>
• The mesenchymal subtype is characterized by high rates of mutations or other alterations in NF1, the gene encoding neurofibromin 1 and fewer alterations in the EGFR gene and less expression of EGFR than other types.<ref>Template:Cite journal</ref>

Initial analyses of gene expression had revealed a fourth neural subtype.<ref name="Integrated genomic analysis identif"/> However, further analyses revealed that this subtype is non-tumor specific and is potential contamination caused by the normal cells.<ref name=qw/>

Many other genetic alterations have been described in glioblastoma, and the majority of them are clustered in two pathways, the RB and the PI3K/AKT.<ref>Template:Cite journal</ref> 68–78% and 88% of Glioblastomas have alterations in these pathways, respectively.<ref name="Ble2012" />

Another important alteration is methylation of MGMT, a "suicide" DNA repair enzyme. Methylation impairs DNA transcription and expression of the MGMT gene. Since the MGMT enzyme can repair only one DNA alkylation due to its suicide repair mechanism, reserve capacity is low and methylation of the MGMT gene promoter greatly affects DNA-repair capacity.<ref name="ReferenceB" /><ref name="ReferenceC">Template:Cite journal</ref> MGMT methylation is associated with an improved response to treatment with DNA-damaging chemotherapeutics, such as temozolomide.<ref>Template:Cite journal</ref>

Studies using genome-wide profiling have revealed glioblastomas to have a remarkable genetic variety.<ref>Template:Cite journal</ref>

At least three distinct paths in the development of Glioblastomas have been identified with the aid of molecular investigations.

• The first pathway involves the amplification and mutational activation of receptor tyrosine kinase (RTK) genes, leading to the dysregulation of growth factor signaling. Epithelial growth factor (EGF), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) are all recognized by transmembrane proteins called RTKs. Additionally, they can function as receptors for hormones, cytokines, and other signaling pathways.
• The second method involves activating the intracellular signaling system known as phosphatidylinositol-3-OH kinase (PI3K)/AKT/mTOR, which is crucial for controlling cell survival.
• The third pathway is defined by p53 and retinoblastoma (Rb) tumor suppressor pathway inactivation.<ref>Template:Cite bookTemplate:Page needed</ref>

Cancer stem cells

Glioblastoma cells with properties similar to progenitor cells (glioblastoma cancer stem cells) have been found in glioblastomas. Their presence, coupled with the glioblastoma's diffuse nature results in difficulty in removing them completely by surgery, and is therefore believed to be the possible cause behind resistance to conventional treatments, and the high recurrence rate.<ref>Template:Cite journal</ref> Glioblastoma cancer stem cells share some resemblance with neural progenitor cells, both expressing the surface receptor CD133.<ref>Template:Cite journal</ref> CD44 can also be used as a cancer stem cell marker in a subset of glioblastoma tumour cells.<ref>Template:Cite book</ref> Glioblastoma cancer stem cells appear to exhibit enhanced resistance to radiotherapy and chemotherapy mediated, at least in part, by up-regulation of the DNA damage response.<ref>Template:Cite journal</ref>

Metabolism

The IDH1 gene encodes for the enzyme isocitrate dehydrogenase 1 and is not mutated in glioblastoma. As such, these tumors behave more aggressively compared to IDH1-mutated astrocytomas.<ref name="ReferenceC" />

Ion channels

Furthermore, GBM exhibits numerous alterations in genes that encode for ion channels, including upregulation of gBK potassium channels and ClC-3 chloride channels. By upregulating these ion channels, glioblastoma tumor cells are hypothesized to facilitate increased ion movement over the cell membrane, thereby increasing H₂O movement through osmosis, which aids glioblastoma cells in changing cellular volume very rapidly. This is helpful in their extremely aggressive invasive behavior because quick adaptations in cellular volume can facilitate movement through the sinuous extracellular matrix of the brain.<ref>Template:Cite journal</ref>

MicroRNA

As of 2012, RNA interference, usually microRNA, was under investigation in tissue culture, pathology specimens, and preclinical animal models of glioblastoma.<ref>Template:Cite journal</ref> Additionally, experimental observations suggest that microRNA-451 is a key regulator of LKB1/AMPK signaling in cultured glioma cells<ref>Template:Cite journal</ref> and that miRNA clustering controls epigenetic pathways in the disease.<ref>Template:Cite journal</ref>

Tumor vasculature

GBM is characterized by abnormal vessels that present disrupted morphology and functionality.<ref name="Dimberg_2014">Template:Cite journal</ref> The high permeability and poor perfusion of the vasculature result in a disorganized blood flow within the tumor and can lead to increased hypoxia, which in turn facilitates cancer progression by promoting processes such as immunosuppression.<ref name="Dimberg_2014" /><ref>Template:Cite journal</ref>

Diagnosis

File:BrainCAConMark.png

GBM in the frontal right lobe as seen on CT scan

File:Glioblastoma - MR sagittal with contrast.jpg

Sagittal MRI with contrast of a glioblastoma WHO grade 4 in a 15-year-old boy

File:Diagnosis of diffuse glioma.png

Diagnostic algorithm of diffuse glioma.<ref name=Weller2020>Template:Cite journal</ref>

When viewed with MRI, glioblastomas often appear as ring-enhancing lesions. The appearance is not specific, however, as other lesions such as abscess, metastasis, tumefactive multiple sclerosis, and other entities may have a similar appearance.<ref>Template:Cite journal</ref> Definitive diagnosis of a suspected GBM on CT or MRI requires a stereotactic biopsy or a craniotomy with tumor resection and pathologic confirmation. Because the tumor grade is based upon the most malignant portion of the tumor, biopsy or subtotal tumor resection can result in undergrading of the lesion. Imaging of tumor blood flow using perfusion MRI and measuring tumor metabolite concentration with MR spectroscopy may add diagnostic value to standard MRI in select cases by showing increased relative cerebral blood volume and increased choline peak, respectively, but pathology remains the gold standard for diagnosis and molecular characterization.Template:Citation needed

Distinguishing glioblastoma from high-grade astrocytoma is important. These tumors occur spontaneously (de novo) and have not progressed from a lower-grade glioma, as in high-grade astrocytomas.<ref name=Ble2012 /> Glioblastomas have a worse prognosis and different tumor biology, and may have a different response to therapy, which makes this a critical evaluation to determine patient prognosis and therapy.<ref name="ReferenceB">Template:Cite journal</ref><ref>Template:Cite journal</ref> Astrocytomas carry a mutation in IDH1 or IDH2, whereas this mutation is not present in glioblastoma. Thus, IDH1 and IDH2 mutations are a useful tool to distinguish glioblastomas from astrocytomas, since histopathologically they are similar and the distinction without molecular biomarkers is unreliable.<ref name="ReferenceC" /> IDH-wildtype glioblastomas usually have lower OLIG2 expression compared with IDH-mutant lower grade astrocytomas.<ref>Template:Cite journal</ref> In patients aged over 55 years with a histologically typical glioblastoma, without a pre-existing lower grade glioma, with a non-midline tumor location and with retained nuclear ATRX expression, immunohistochemical negativity for IDH1 R132H suffices for the classification as IDH-wild-type glioblastoma.<ref name=Weller2020/> In all other instances of diffuse gliomas, a lack of IDH1 R132H immunopositivity should be followed by IDH1 and IDH2 DNA sequencing to detect or exclude the presence of non-canonical mutations.<ref name=Weller2020/> IDH-wild-type diffuse astrocytic gliomas without microvascular proliferation or necrosis should be tested for EGFR amplification, TERT promoter mutation and a +7/–10 cytogenetic signature as molecular characteristics of IDH-wild-type glioblastomas.<ref name=Weller2020/>

• Histopathology of glioblastoma, high magnification, annotated.jpg

  Histopathology of glioblastoma, showing high grade astrocytoma features of marked nuclear pleomorphism, multiple mitoses (one at white arrow) and multinucleated cells (one at black arrow), with cells having a patternless arrangement in a pink fibrillary background on H&E stain.

• Glioblastoma (1).jpg

  Lower magnification histopathology, showing necrosis surrounded by pseudopalisades of tumor cells, conferring a diagnosis of glioblastoma rather than anaplastic astrocytoma

Prevention

There are no known methods to prevent glioblastoma.<ref name=Gal2015/> It is the case for most gliomas, unlike for some other forms of cancer, that they happen without previous warning and there are no known ways to prevent them.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Treatment

File:Management of IDH wild type glioblastoma.png

Management of IDH wild type glioblastoma, WHO grade 4. KPS, Karnofsky performance status.<ref name=Weller2020/>

Treating glioblastoma is difficult due to several complicating factors:<ref name = "pmid12672279">Template:Cite journal</ref>

• The tumor cells are resistant to conventional therapies.
• The brain is susceptible to damage from conventional therapy.
• The brain has a limited capacity to repair itself.
• Many drugs cannot cross the blood–brain barrier to act on the tumor.

Treatment of primary brain tumors consists of palliative (symptomatic) care and therapies intended to improve survival.

Symptomatic therapy

Supportive treatment focuses on relieving symptoms and improving the patient's neurologic function. The primary supportive agents are anticonvulsants and corticosteroids.

• Historically, around 90% of patients with glioblastoma underwent anticonvulsant treatment, although only an estimated 40% of patients required this treatment. Neurosurgeons have recommended that anticonvulsants not be administered prophylactically, and should wait until a seizure occurs before prescribing this medication.<ref>Template:Cite journal</ref> Those receiving phenytoin concurrent with radiation may have serious skin reactions such as erythema multiforme and Stevens–Johnson syndrome.
• Corticosteroids, usually dexamethasone, can reduce peritumoral edema (through rearrangement of the blood–brain barrier), diminishing mass effect and lowering intracranial pressure, with a decrease in headache or drowsiness.

Surgery

File:Glioblastom (WHO Grad IV) im MRI preoperativ und postoperativ.png

Glioblastoma pre (left) and post (right) resection.

Surgery is the first stage of treatment of glioblastoma. An average GBM tumor contains 10¹¹ cells, which is on average reduced to 10⁹ cells after surgery (a reduction of 99%). Benefits of surgery include resection for a pathological diagnosis, alleviation of symptoms related to mass effect, and potentially removing disease before secondary resistance to radiotherapy and chemotherapy occurs.<ref>Template:Cite journal</ref>

The greater the extent of tumor removal, the better. In retrospective analyses, removal of 98% or more of the tumor has been associated with a significantly longer healthier time than if less than 98% of the tumor is removed.<ref>Template:Cite journal</ref> The chances of near-complete initial removal of the tumor may be increased if the surgery is guided by a fluorescent dye known as 5-aminolevulinic acid.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> GBM cells are widely infiltrative through the brain at diagnosis, and despite a "total resection" of all obvious tumor, most people with GBM later develop recurrent tumors either near the original site or at more distant locations within the brain. Other modalities, typically radiation and chemotherapy, are used after surgery in an effort to suppress and slow recurrent disease through damaging the DNA of rapidly proliferative GBM cells.<ref>Template:Cite journal</ref>

Between 60–85% of glioblastoma patients report cancer-related cognitive impairments following surgery, which refers to problems with executive functioning, verbal fluency, attention, and speed of processing.<ref name="Sinha_2020">Template:Cite journal</ref><ref name="Pendergrass_2018a">Template:Cite journal</ref><ref name="Janelsins_2014">Template:Cite journal</ref> These symptoms may be managed with cognitive behavioral therapy,<ref name="Lange_2019">Template:Cite journal</ref><ref name="Pendergrass_2018a"/> physical exercise, yoga and meditation.<ref name="Lange_2019" /><ref name="Pendergrass_2018a"/><ref name="Biegler_2009">Template:Cite journal</ref>

Radiotherapy

File:Glioblastoma radiation treatment plan (A).png

Radiation treatment planning for glioblastoma. GTV: gross tumor volume, CTV: clinical target volume, PTV: planning target volume.

Subsequent to surgery, radiotherapy becomes the mainstay of treatment for people with glioblastoma. It is typically performed along with giving temozolomide.<ref name="RTG1">Template:Cite journal</ref> A pivotal clinical trial carried out in the early 1970s showed that among 303 GBM patients randomized to radiation or best medical therapy, those who received radiation had a median survival more than double those who did not.<ref>Template:Cite journal</ref> Subsequent clinical research has attempted to build on the backbone of surgery followed by radiation. Whole-brain radiotherapy does not improve when compared to the more precise and targeted three-dimensional conformal radiotherapy.<ref>Template:Cite journal</ref> A total radiation dose of 60–65 Gy has been found to be optimal for treatment.<ref>Template:Cite journal</ref>

GBM tumors are well known to contain zones of tissue exhibiting hypoxia, which are highly resistant to radiotherapy. Various approaches to chemotherapy radiosensitizers have been pursued, with limited success Template:As of. Template:As of, newer research approaches included preclinical and clinical investigations into the use of an oxygen diffusion-enhancing compound such as trans sodium crocetinate as radiosensitizers,<ref>Template:Cite journal</ref> and Template:As of a clinical trial was underway.<ref> Template:ClinicalTrialsGov, accessed 1 February 2016</ref> Boron neutron capture therapy has been tested as an alternative treatment for glioblastoma, but is not in common use.

Chemotherapy

Most studies show no benefit from the addition of chemotherapy. However, a large clinical trial of 575 participants randomized to standard radiation versus radiation plus temozolomide chemotherapy showed that the group receiving temozolomide survived a median of 14.6 months as opposed to 12.1 months for the group receiving radiation alone.<ref name="RTG1" /><ref>Template:Cite journal</ref> This treatment regimen is now standard for most cases of glioblastoma where the person is not enrolled in a clinical trial.<ref>Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Temozolomide seems to work by sensitizing the tumor cells to radiation, and appears more effective for tumors with MGMT promoter methylation.<ref>Template:Cite journal</ref> High doses of temozolomide in high-grade gliomas yield low toxicity, but the results are comparable to the standard doses.<ref>Template:Cite journal</ref> Antiangiogenic therapy with medications such as bevacizumab control symptoms, but do not appear to affect overall survival in those with glioblastoma. A 2018 systematic review found that the overall benefit of anti-angiogenic therapies was unclear.<ref name=Amer2018>Template:Cite journal</ref> In elderly people with newly diagnosed glioblastoma who are reasonably fit, concurrent and adjuvant chemoradiotherapy gives the best overall survival but is associated with a greater risk of haematological adverse events than radiotherapy alone.<ref>Template:Cite journal</ref>

Immunotherapy

Phase 3 clinical trials of T cell-targeting immunotherapy treatments for glioblastoma have largely failed.<ref name="hab">Template:Cite journal</ref> This might be due to the presence of a distinct state of tolerized T cells in glioblastoma patients that are unresponsive to such immunotherapies.<ref>Template:Cite journal</ref>

Other procedures

Alternating electric field therapy is an FDA-approved therapy for newly diagnosed<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and recurrent glioblastoma.<ref name=NovoTTF_FDA_approval>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> In 2015, initial results from a phase-III randomized clinical trial of alternating electric field therapy plus temozolomide in newly diagnosed glioblastoma reported a three-month improvement in progression-free survival, and a five-month improvement in overall survival compared to temozolomide therapy alone,<ref name=Stupp2015>Template:Cite journal</ref><ref name=Sampson2015>Template:Cite journal</ref> representing the first large trial in a decade to show a survival improvement in this setting.<ref name=Sampson2015/> Despite these results, the efficacy of this approach remains controversial among medical experts.<ref>Template:Cite journal</ref> However, increasing understanding of the mechanistic basis through which alternating electric field therapy exerts anti-cancer effects and results from ongoing phase-III clinical trials in extracranial cancers may help facilitate increased clinical acceptance to treat glioblastoma in the future.<ref>Template:Cite journal</ref>

Studies have been conducted on the benefit of exercise and physical rehabilitation for patients with glioblastoma. Patients may not be aware of options to improve quality of life, or may not see the benefit of physical therapy treatments due to depression or despair at a terminal diagnosis. Despite this, it has been shown that with exercise and physical rehabilitation, quality of life may be improved for individuals with glioblastoma.<ref>Template:Cite journal</ref>

Prognosis

The most common length of survival following diagnosis is 10 to 13 months (although recent research points to a median survival rate of 15 months),<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name = "Tran_2010" /> with fewer than 1–3% of people surviving longer than five years.<ref name=WCR2014,5.16/><ref name=Os2019/><ref>Template:Cite journal</ref> In the United States between 2012 and 2016 five-year survival was 6.8%.<ref name=Os2019/> Without treatment, survival is typically three months.<ref name=Sch2007/> Complete cures are extremely rare, but have been reported.<ref>Template:Cite journal</ref><ref name="pmid22776797"/>

Increasing age (> 60 years) carries a worse prognostic risk. Death is usually due to widespread tumor infiltration with cerebral edema and increased intracranial pressure.<ref name="doi101093brainawm204">Template:Cite journal</ref>

A good initial Karnofsky performance score (KPS) and MGMT methylation are associated with longer survival.<ref name="doi101093brainawm204"/> A DNA test can be conducted on glioblastomas to determine whether or not the promoter of the MGMT gene is methylated. Patients with a methylated MGMT promoter have longer survival than those with an unmethylated MGMT promoter, due in part to increased sensitivity to temozolomide.<ref>Template:Cite journal</ref>

Long-term benefits have also been associated with those patients who receive surgery, radiotherapy, and temozolomide chemotherapy.<ref name="doi101093brainawm204"/> However, much remains unknown about why some patients survive longer with glioblastoma. Age under 50 is linked to longer survival in GBM, as is 98%+ resection and use of temozolomide chemotherapy and better KPSs. A recent study confirms that younger age is associated with a much better prognosis, with a small fraction of patients under 40 years of age achieving a population-based cure. Cure is thought to occur when a person's risk of death returns to that of the normal population, and in GBM, this is thought to occur after 10 years.<ref name="pmid22776797">Template:Cite journal</ref>

UCLA Neuro-oncology publishes real-time survival data for patients with this diagnosis.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}. Neurooncology.ucla.edu. Retrieved on 19 October 2010.</ref>

According to a 2003 study, GBM prognosis can be divided into three subgroups dependent on KPS, the age of the patient, and treatment.<ref>Template:Cite journal</ref>

Recursive partitioning analysis (RPA) class	Definition	Historical Median Survival Time	Historical 1-Year Survival	Historical 3-Year Survival	Historical 5-Year Survival
III	Age < 50, KPS ≥ 90	17.1 months	70%	20%	14%
IV	Age < 50, KPS < 90	11.2 months	46%	7%	4%
	Age ≥ 50, KPS ≥ 70, surgical removal with good neurologic function
V + VI	Age ≥ 50, KPS ≥ 70, no surgical removal	7.5 months	28%	1%	0%
	Age ≥ 50, KPS < 70

Epidemiology

About three per 100,000 people develop the disease a year,<ref name=Gal2015/> although regional frequency may be much higher.<ref>Template:Cite journal</ref> The frequency in England doubled between 1995 and 2015.<ref>Template:Cite journal</ref>

It is the second-most common central nervous system tumor after meningioma.<ref name=Mc2016/> It occurs more commonly in males than females.<ref name=WCR2014,5.16/><ref name=Gal2015/> Although the median age at diagnosis is 64,<ref name=WCR2014,5.16/><ref name=Gal2015/> in 2014, the broad category of brain cancers was second only to leukemia in people in the United States under 20 years of age.<ref>Template:Cite journal</ref>

History

The term glioblastoma multiforme was introduced in 1926 by Percival Bailey and Harvey Cushing, based on the idea that the tumor originates from primitive precursors of glial cells (glioblasts), and the highly variable appearance due to the presence of necrosis, hemorrhage, and cysts (multiform).<ref>Bailey & Cushing: Tumors of the Glioma Group. JB Lippincott, Philadelphia, 1926.Template:Page needed</ref>

Research

Gene therapy

Gene therapy has been explored as a method to treat glioblastoma, and while animal models and early-phase clinical trials have been successful, as of 2017, all gene-therapy drugs that had been tested in phase-III clinical trials for glioblastoma had failed.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Scientists have developed the core–shell nanostructured LPLNP-PPT (long persistent luminescence nanoparticles. PPT refers to polyetherimide, PEG and trans-activator of transcription, and TRAIL is the human tumor necrosis factor-related apoptosis-induced ligand<ref>Template:Cite journal</ref>) for effective gene delivery and tracking, with positive results. This is a TRAIL ligand that has been encoded to induce apoptosis of cancer cells, more specifically glioblastomas. Although this study was still in clinical trials in 2017, it has shown diagnostic and therapeutic functionalities, and will open great interest for clinical applications in stem-cell-based therapy.<ref>Template:Cite journal</ref>

Other gene therapy approaches have also been explored in the context of glioblastoma, including suicide gene therapy. Suicide gene therapy is a two-step approach that includes the delivery of a foreign enzyme-gene to the cancer cells followed by activation with a pro-drug causing toxicities in the cancer-cells, which induces cell death. This approach has succeeded in animal models and small clinical studies but has not shown survival benefit in larger clinical studies. Using new, more efficient delivery vectors and suicide gene-prodrug systems could improve the clinical benefit from these types of therapies.<ref>Template:Cite journal</ref>

Oncolytic virotherapy

Oncolytic virotherapy is an emerging novel treatment that is under investigation both at preclinical and clinical stages. Several viruses including herpes simplex virus, adenovirus, poliovirus, and reovirus are currently being tested in phases I and II of clinical trials for glioblastoma therapy and have shown to improve overall survival.<ref>Template:Cite journal</ref>

Intranasal drug delivery

Direct nose-to-brain drug delivery is being explored as a means to achieve higher, and hopefully more effective, drug concentrations in the brain.<ref name="ReferenceA">Template:Cite journal</ref><ref>Template:Cite journal</ref> A clinical phase-I/II study with glioblastoma patients in Brazil investigated the natural compound perillyl alcohol for intranasal delivery as an aerosol. The results were encouraging<ref name="ReferenceA"/><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> and, as of 2016, a similar trial has been initiated in the United States.<ref>Template:ClinicalTrialsGov</ref>

Enhancer RNAs (eRNAs)

Enhancer RNAs (eRNAs), a class of non-coding RNAs transcribed from enhancer regions, have emerged as critical regulators of gene expression in glioblastoma. Recent studies highlight their role in modulating oncogenic pathways, including the JAK-STAT signaling cascade, which is central to tumor progression and therapy resistance.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> For example, CYP1B1-AS1 and AC003092.1 have been identified as eRNAs associated with poor prognosis and immune microenvironment modulation in glioblastoma 14.

TMZR1-eRNA, an eRNA transcribed from the STAT3 locus, directly regulates STAT3 expression, a key driver of temozolomide (TMZ) resistance in glioblastoma. Silencing TMZR1-eRNA reduced STAT3 mRNA and protein levels, sensitizing tumor cells to TMZ-induced apoptosis. Notably, TMZR1-eRNA is overexpressed in glioblastoma but minimally expressed in healthy brain tissue and peripheral blood cells, suggesting a tumor-specific therapeutic target.<ref>Template:Cite journal</ref>

See also

• Adegramotide
• Asunercept
• Glioblastoma Foundation
• Lomustine
• List of people with brain tumors

External links

• Information about glioblastoma Template:Webarchive from the American Brain Tumor Association