Glioblastoma

Glioblastomas also called glioblastoma multiforme (GBM) or grade 4 astrocytoma, is an aggressive and fast-growing type of brain cancer that forms from glial (supportive) tissue of the brain and spinal cord and has cells that look very different from normal cells ¹. Glioblastoma forms from cells called astrocytes and these cells support and nourish neurons (nerve cells of the brain) and form scar tissue that helps repair brain damage in response to injury. Glioblastoma can occur at any age, but tends to occur more often in older adults with median age of diagnosis is 64 years ². Glioblastoma is the most common malignant brain tumor in adults, accounting for 35-45% of malignant brain tumors and affects the brain more often than the spinal cord ³, ⁴. With a growing and aging US population, the number of glioblastoma cases is expected to increase ⁵. Based on the 2016 Central Brain Tumor Registry of the United States (CBTRUS) report, the average annual age-adjusted incidence rate of glioblastoma multiforme is 3.22/100,000 population ⁶. Approximately 14,000 cases of glioblastoma are diagnosed each year in the United States ⁷. Glioblastomas or glioblastoma multiforme (GBM) are primary tumors, meaning they originate in the brain rather than spreading to the brain from cancer elsewhere in the body ⁸. Glioblastoma tends to occur in active, otherwise healthy people, and more frequently in males. Men are 50% more likely to be diagnosed with glioblastoma than women ⁹. Whites have the highest incidence rates for glioblastoma, followed by blacks, Asian/Pacific Islanders and American Indian/Alaska Native ⁸.

Glioblastoma is uncommon in children accounting only approximately 3% of all brain and spinal cord tumors reported among 0–19 year olds ⁸.

Glioblastomas are often very aggressive that grow into surrounding brain tissue, but rarely spreads outside of the brain. Glioblastoma multiforme is located mainly in the cerebral hemispheres ¹⁰ or subtentorially in the brain stem ¹¹ and cerebellum ¹². Glioblastoma is characterized by infiltrating growth; therefore the tumor mass is not clearly distinguishable from the normal tissue ¹³. Glioblastomas frequently recur (in 75–90%) within 2–3 cm from the borders of the initial lesion and with multiple lesions observed in 5% of cases after treatment ¹⁴. A growing glioblastoma tumor causes an increase of intracranial pressure ¹⁵ and sometimes it leads to hydrocephaly ¹⁶.

Glioblastoma can cause worsening headaches, nausea, vomiting, seizures, weakness on one side of the body, difficulty thinking and speaking, and drowsiness, which may develop when the tumor begins to put excess pressure on the brain. The onset of symptoms can be sudden and acute; however, in some patients, there may be gradual changes, such as problems with language, concentration, or coordination and strength on one side of the body. Affected people may also experience other features depending on the size and location of the brain tumor.

Glioblastoma multiforme metastases by cerebrospinal fluid (CSF) ¹⁷ or blood ¹⁸ are rare and target the spleen, pleura, lungs, lymph nodes, liver, bones, pancreas and small intestine ¹⁹, ²⁰, ²¹. It has been hypothesized that the low metastatic potential of glioblastoma results from the barrier created by cerebral meninges, but also from the rapid tumor growth and short course of this disease ²². The brain is devoid of lymphatic vessels, so metastases through this pathway are impossible ¹⁹. The available literature describes 8 cases of glioblastoma multiforme metastases to the skin – tumors usually developed around post-operative sutures. This suggests implantation of glioblastoma multiforme cells around post-operative wounds during the removal of a primary tumor ²³.

Glioblastoma comprises primary and secondary subtypes that evolve through different genetic pathways affecting patients at different ages and have differences in outcomes ²⁴. Primary glioblastoma account for 80% of glioblastoma and occur in older patients with a mean age of 62 years ⁴, ²⁵. While secondary glioblastoma develop from lower-grade astrocytoma or oligodendroglioma and occur in younger patients with a mean age of 45 years ²⁶, ²⁷. Secondary glioblastoma are usually located in the frontal lobe, have a lesser degree of necrosis, and carry a better prognosis than primary glioblastoma ²⁵.

In most glioblastoma cases, the exact underlying cause is unknown; however, glioblastoma multiforme can rarely occur in people with certain genetic syndromes such as neurofibromatosis type 1, Turcot syndrome and Li Fraumeni syndrome.

The diagnostic mode of imaging for glioblastoma is contrast-enhanced magnetic resonance imaging. Studies have shown that in the majority of cases, tumor diameter is between 5-10 cm at diagnosis ²⁸, ²⁹, ³⁰. The tumor usually involves corpus callosum and grows into occipital and temporal lobes bilaterally, resulting in a butterfly pattern on imaging, thus the name “butterfly glioma” ³¹.

Glioblastoma or glioblastoma multiforme (GBM) can be very difficult to treat and a cure is often not possible. Treatments may slow progression of the cancer and reduce signs and symptoms. The standard of treatment for a glioblastoma is surgery, followed by daily radiation and oral chemotherapy for six and a half weeks, then a six-month regimen of oral chemotherapy given five days a month. To start, the neurosurgeon will remove as much of the tumor as possible and may implant medicated carmustine (BCNU)-polymer wafers (Gliadel) right into the brain. These wafers dissolve naturally and gradually release chemotherapy drugs into the tumor area over time. Another chemotherapy drug called temozolomide (Temodar) was approved by the FDA in 2013 and is commonly used to treat glioblastomas and other advanced brain cancers ³². The drug is taken in pill form and works by slowing down tumor growth. Radiation may be used to destroy additional tumor cells and treat tumors in patients who are not well enough for surgery.

Within the last two decades, temozolomide (TMZ) and a non-invasive device called the tumor-treating field (TTF; Optune®) have demonstrated clinical efficacy and achieved improved outcomes ³³. Additional treatment options that demonstrated activity include bevacizumab (Avastin), lomustine, carmustine, PCV (combination of procarbazine, lomustine and vincristine), and, more recently, multikinase inhibitor regorafenib, which demonstrated superior outcomes over lomustine in a recent phase 2 trial ³⁴, ³⁵.

Glioblastoma is usually associated with pseudoprogression, which is a sub-acute worsening of MRI findings that occur within three months after the completion of chemoradiotherapy. It is a treatment-related effect. It is important to distinguish between pseudoprogression and the true progression of the glioblastoma cancer to avoid abrupt discontinuation of treatment. The key feature to distinguish is that pseudoprogression is usually asymptomatic. Treatment should be continued if pseudoprogression is suspected unless the patient is symptomatic or worsening of clinical features occur.

Figure 1. Glioblastoma multiforme (MRI)

What is glioma brain cancer?

Glioma is brain tumor that start in glial cells. These are the supporting cells of the brain and the spinal cord. There are different types of gliomas.

There are 3 types of glial cells:

1. Astrocytes – tumor that start in these cells are called astrocytoma or glioblastoma
2. Oligodendrocytes – tumor that start in these cells are called oligodendrogliomas
3. Ependymal cells – tumor that start in these cells are called ependymomas

About 3 out of 10 of all brain tumors are gliomas. Most fast-growing brain tumors are gliomas. The most common type is called astrocytoma.

What are astrocytomas?

Astrocytomas are tumors that start in glial cells called astrocytes. Astrocytes are star shaped cells. They support the nerve cells (neurones) in the brain. Astrocytomas are the most common type of brain tumors in both adults and children. About 2 out of 10 brain tumors are astrocytomas. Symptoms of astrocytoma depend on where the tumor is in the brain. Common symptoms include headaches and seizures (fits).

Most astrocytomas can spread widely throughout the brain and blend with the normal brain tissue, which can make them very hard to remove with surgery. Sometimes they spread along the cerebrospinal fluid (CSF) pathways. It is very rare for them to spread outside of the brain or spinal cord.

As with other types of brain tumors, astrocytomas are often grouped by grade (according to how quickly they are likely to grow).

• Low-grade (grade 1 or 2) astrocytomas tend to grow slowly. These include:
  • Non-infiltrating (grade 1) astrocytomas, which do not usually grow into nearby tissues and tend to have a good prognosis. Examples include pilocytic astrocytomas and subependymal giant cell astrocytomas (SEGAs). These are more common in children than in adults.
  • Grade 2 astrocytomas, such as diffuse astrocytomas and pleomorphic xanthoastrocytomas (PXAs). These tumors tend to be slow growing, but they can grow into nearby areas, which can make them harder to remove with surgery. These tumors can become more aggressive and faster growing over time.
• High-grade (grade 3 or 4) astrocytomas tend to grow quickly and spread into the surrounding normal brain tissue. These include:
  • Anaplastic (grade 3) astrocytomas
  • Glioblastomas (grade 4) are also called glioblastoma multiforme (GBM), which are the fastest growing. These tumors make up more than half of all gliomas and are the most common malignant brain tumors in adults.

Does glioblastoma affect children?

Yes it can, but glioblastoma is much more common in adults than in children.

Glioblastoma classification

Glioblastomas are divided in the 2016 World Health Organization (WHO) Classification of Tumors of the Central Nervous System into ¹:

1. Glioblastoma isocitrate dehydrogenase (IDH)-wildtype (about 90 % of cases), which corresponds most frequently with the clinically defined primary glioblastoma or de novo glioblastoma and predominates in patients over 55 years of age ³⁶
2. Glioblastoma isocitrate dehydrogenase (IDH)-mutant (about 10 % of cases), which corresponds closely to so-called secondary glioblastoma with a history of prior lower grade diffuse glioma and preferentially arises in younger patients ³⁶
3. Glioblastoma NOS (not otherwise specified), a diagnosis that is reserved for those tumors for which full IDH evaluation cannot be performed. The definition of full IDH evaluation can differ for glioblastomas in older patients relative to glioblastomas in younger adults and relative to World Health Organization (WHO) grade 2 and grade 3 diffuse gliomas: in the latter situations, IDH sequencing is highly recommended following negative R132H IDH1 immunohistochemistry, whereas the near absence of non-R132H IDH1 and IDH2 mutations in glioblastomas from patients over about 55 years of age suggests that sequencing may not be needed in the setting of negative R132H IDH1 immunohistochemistry in such patients ³⁷.

One provisional new variant of glioblastoma has been added to the classification is epithelioid glioblastoma. It joins giant cell glioblastoma and gliosarcoma under the umbrella of IDH-wildtype glioblastoma ¹. Epithelioid glioblastomas feature large epithelioid cells with abundant eosinophilic cytoplasm, vesicular chromatin, and prominent nucleoli (often resembling melanoma cells), and variably present rhabdoid cells. They have a predilection for children and younger adults, typically present as superficial cerebral or diencephalic masses, and often harbor a BRAF V600E mutation (which can be detected immunohistochemically) ³⁸, ³⁹. In one series, rhabdoid glioblastomas were distinguished from their similarly appearing epithelioid counterparts on the basis of loss of INI1 expression ⁴⁰. IDH-wildtype epithelioid glioblastomas often lack other molecular features of conventional adult IDH-wildtype glioblastomas, such as EGFR amplification and chromosome 10 losses; instead, there are frequent hemizygous deletions of ODZ3. Such cases may have an associated low-grade precursor, often but not invariably showing features of pleomorphic xanthoastrocytoma ⁴¹.

Glioblastoma with primitive neuronal component was added as a pattern in glioblastoma. This pattern, previously referred to in the literature as glioblastoma with PNET-like component, is usually comprised of a diffuse astrocytoma of any grade (or oligodendroglioma in rare cases) that has well-demarcated nodules containing primitive cells that display neuronal differentiation (e.g., Homer Wright rosettes, gain of synaptophysin positivity and loss of GFAP expression) and that sometimes has MYC or MYCN amplification; these tumors have a tendency for craniospinal fluid dissemination ⁴². About a quarter develop in patients with a previously known lower grade glioma precursor, a subset of which shows R132H IDH1 immunoreactivity in both the glial and primitive neuronal components ⁴³. From a clinical point of view, the recognition of this pattern may prompt evaluation of the craniospinal axis to rule out tumor seeding.

Small cell glioblastoma/astrocytoma and granular cell glioblastoma/astrocytoma remain patterns, the former characterized by uniform, deceptively bland small neoplastic cells often resembling oligodendroglioma and frequently demonstrating EGFR amplification, and the latter by markedly granular to macrophage-like, lysosome-rich tumor cells. In both examples, there is a particularly poor glioblastoma-like prognosis even in the absence of microvascular proliferation or necrosis.

Glioblastoma signs and symptoms

The signs and symptoms of brain tumors differ from person to person. Some people may have symptoms that suggest there is a brain tumor, others have no obvious symptoms. Signs and symptoms depend on where the tumor forms in the brain, what the affected part of the brain controls, and the size of the tumor ¹¹, ⁴⁴.

Commonly, people with brain tumor experience long-term headaches, seizures or convulsions, difficulty thinking and speaking/finding words, personality changes, tingling or stiffness in one side of the body, a loss of balance, vision changes, nausea, and/or disorientation.

Consult with your doctor if you have any of the following symptoms:

• Headaches that are new or worsening, especially in the morning or when lying down (these are often the first symptom of a brain tumor)
• Frequent nausea or vomiting
• Dizziness, loss of balance and coordination or room spinning
• Vision, hearing, and speech problems
• Difficulty with balance and trouble walking
• Weakness on one side or part of the body
• Unusual sleepiness or change in activity level
• Changes in personality or mood, such as anger, irritability or emotional withdrawal
• Changes to how you think
• Inability to focus or vision loss
• Confusion
• Seizures
• Loss of consciousness
• Impaired sense of smell or taste
• Drowsiness and fatigue
• Endocrine dysfunction (hormone/gland changes)

You may notice other signs, like memory problems or difficulty speaking or remembering words.

Having one or more of the symptoms above does not necessarily mean that you have a brain or spinal cord tumor. All of these symptoms can have other causes. Due to these unspecific symptoms, glioma is often misdiagnosed as infections, inflammatory processes and circulatory and immunological diseases ¹¹. The occurrence of back and leg pain and sciatica may also suggest a herniated lumbar ⁴⁵. The occurrence of seizures in people who have not been previously diagnosed with epilepsy can also be an indication for neuroimaging because of glioblastoma suspicion ⁴⁶. Still, if you have any of these symptoms, especially if they don’t go away or get worse over time, see your doctor so the cause can be found and treated, if needed.

Glioblastoma causes

The exact cause of glioblastoma is still not known ⁴⁷. But there are some factors that may increase your risk of a brain tumor. Like many other cancers, glioblastoma is sporadic, although a study showed a high prevalence (17%) of prior therapeutic radiation therapy among patients with glioblastoma ⁴⁸. The latency between irradiation and the development of glioblastoma varies from a few years to several decades.

The vast majority of glioblastoma patients do not have a family history of cancer ⁴⁹. Approximately 5% of all gliomas are familial ⁵⁰ and there are multiple rare inherited syndromes that involve adult glioma and glioblastoma ⁵¹ such as: tuberous sclerosis ⁵², Turcot syndrome ⁵³, multiple endocrine neoplasia type 2A ⁵⁴ and neurofibromatosis type 1 (NF1) ⁵⁵.

Genome-wide association studies of genetic risk factors have validated 25 single nucleotide polymorphisms associated with increased risk for glioma, where 11 are specific to glioblastoma ⁵⁶. While the biological significance of these associations remains to be elucidated, this genome-wide approach identified loci containing critical glioma genes such as telomerase reverse transcriptase (TERT), RTEL1, epidermal growth factor receptor (EGFR), and cyclin-dependent kinase inhibitor 2B (CDKN2B)  ⁵⁶. The majority of these loci are associated with molecularly defined glioma subtypes ⁵⁷. Continued improvements in accurate measurement of potential risk factors and advances in technology allowing for discovery of additional germline and tumor molecular features will be critical to future understanding of causes and risk factors for glioblastoma.

Acquired head injuries, which occurred as a result of a brain contusion, may predispose to the onset of glioblastoma ⁵⁸, ⁵⁹.

Development of glioblastoma is related to deregulation of the G1/S checkpoint in the cell cycle ⁶⁰ and occurrence of many genetic disturbances in glioma cells (loss of genetic material within chromosome 10q, amplification of EGFR, FGFR2, IRS2 and AKT3 genes as well as mutations in PTEN, TP16, TP53, PARK2, PTPRD and NF1 genes) ⁶¹.

Among women, a higher risk of its occurrence is noted in postmenopausal women, so a hypothesis on the involvement of sex hormones in glioblastoma development was created ⁶². Incidence of this tumor is also related to height and body mass index (BMI) – high values of these two features increase the risk of glioblastoma incidence ⁶³.

Viruses, such as human cytomegalovirus (CMV), are also believed to be among the etiologic agents for glioma development ²⁸. Human cytomegalovirus (CMV) induces congenital encephalitis and multi-organ changes in immunocompromised adults. Human cytomegalovirus shows tropism for glial cells. The virus encodes proteins (such as IE1, US28, GB), which activate intracellular signaling pathways involved in mitogenesis, mutagenesis, apoptosis, inflammation and angiogenesis. Products of these genes cause dysregulation of the key signaling pathways (including PDGFR, Akt, STAT3), but also cause disturbances in monocyte and glial cell functions ⁶⁴. It is believed that granulocyte-colony stimulating factor (G-CSF) is involved in the development of glioblastomas – a high level of expression of this glycoprotein and its receptor (G-CSFR) was found in glioblastomas of different grades of malignancy. Granulocyte-colony stimulating factor stimulates proliferation and migration of a commercially available glioblastoma cell line. Blocking of G-CSFR by antibody results in inhibition of the cell growth and mobility in test tube study ⁶⁵.

The following chemicals are considered as potentially dangerous: pesticides, polycyclic aromatic compounds and solvents. Electromagnetic fields and certain metals are also considered to be involved in glioma development ⁶⁶. It is believed that the use of a mobile phone does not increase the risk of developing glioblastoma, but the effect of long-term use of mobile phones is still undetermined. Glioblastoma multiforme can be considered as an occupational disease – persons employed in the rubber and petrochemical industry are considered to be at a higher risk of glioma incidence ⁶⁷.

Some studies showed the risk of glioblastoma with decreased susceptibility to allergy, immune factors, immune genes, and some single nucleotide polymorphisms detected by genome-wide association studies ⁶⁸. Studies have shown a low risk of gliomas with allergies and atopic diseases ⁶⁹. Also, in the short term, less than 10 years use of anti-inflammatory medications is associated with a protective effect on glioblastoma ⁷⁰. There is no substantial evidence of glioblastoma association with lifestyle factors like smoking, alcohol consumption, drug use, or exposure to N-nitroso compounds ⁷¹.

Studies have shown that the use of mobile phones doesn’t increase the risk of development of glioblastoma; however, association with long term use needs further confirmation ²⁸.

Table 1. Inherited syndromes associated with adult gliomas and adult glioblastomas

Gene Symbol (Chromosome Location)	Disorder/Syndrome (Online Mendelian Inheritance in Man ID)	Mode of Inheritance	Phenotypic Features	Associated Brain Tumors
APC, MMR (5q21)	Familial adenomatous polyposis (FAP, 175100), Turcots syndrome type 2	Dominant	Development of multiple adenomatous colon polyps (>100), predisposition to colorectal cancer, and brain tumors	Medulloblastoma, glioma
ATM (11q22.3)	Ataxia- telangiectasia (208900)	Autosomal recessive trait	Progressive cerebellar ataxia, susceptibility to infections, predisposition to lymphoma and lymphocytic leukemia.	Astrocytoma and medulloblastoma
CDKN2A (9p21.3)	Melanoma-neural system tumor syndrome (155755)	Dominant	Predisposition to malignant melanoma and malignant brain tumors	Glioma
IDH1/IDH2 (2q33.3/15q26.1)	Ollier disease	Acquired post-zygotic mosaicism, dominant with reduced penetrance	Development of intraosseous benign cartilaginous tumors, cancer predisposition	Glioma
MLH1, PMS2	Turcots syndrome type 1	Autosomal recessive trait	Development of multiple adenomatous colon polyps (<100), predisposition to colorectal cancer, and brain tumors	Medulloblastoma, glioma,
MSH2,MLH1,MSH6,PMS2	Lynch syndrome (120435), biallelic mismatch repair deficiency, constitutional MMR deficiency	Dominant	Predisposition to gastrointestinal, endometrial and other cancers	Glioblastoma, other gliomas
MSH2,MLH1,MSH6,PMS2	Mismatch repair deficiency syndrome (276300)	Recessive	Pediatric cancer predisposition; café-au-lait spots; colon polyps	Glioma
NF1 (17q11.2)	Neurofibromatosis 1 (NF1) (162200)	Dominant	Neurofibromas, schwannomas, café-au-lait macules	Astrocytoma, schwannomas, optic nerve glioma
RB1 (13q14)	Retinoblastoma	Dominant	Development of multiple tumors of the eye, increased risk of some brain tumors	Retinoblastoma, pineoblastoma, malignant glioma
TP53 (17p13.1)	Li–Fraumeni syndrome (151623)	Dominant	Predisposition to numerous cancers, especially breast, brain, and soft-tissue sarcoma	Glioblastoma, other gliomas
TSC1,TSC2 (9q34.14,16p13.3)	Tuberous sclerosis (TSC) (191100, 613254)	Dominant	Development of multisystem nonmalignant tumors	Giant cell astrocytoma

Abbreviations: ATM = ataxia telangiectasia; APC = adenomatous polyposis coli; CDKN2A = cyclin-dependent kinase inhibitor 2A; MLH1 = MutL homolog 1, colon cancer, nonpolyposis type 2; MSH2 = MutS protein homolog 2; MSH6 = MutS protein homolog 6; OMIM = Online Mendelian Inheritance in Man; PMS2 = postmeiotic segregation increased homolog 2; RB1 = retinoblastoma transcriptional corepressor 1; TP53 = tumor protein p53.

[Source ⁷² ]

Risk factors for developing glioblastoma

Risk factors for developing glioblastoma include:

• Your age. Your risk of a brain tumor increases as you age. Gliomas are most common in adults between ages 45 and 65 years old. However, a brain tumor can occur at any age. Certain types of gliomas, such as ependymomas and pilocytic astrocytomas, are more common in children and young adults.
• Exposure to radiation. People who have been exposed to a type of radiation called ionizing radiation have an increased risk of brain tumor. Examples of ionizing radiation include radiation therapy used to treat cancer and radiation exposure caused by atomic bombs. More-common forms of radiation, such as electromagnetic fields from power lines and radiofrequency radiation from microwave ovens have not been shown to increase the risk of glioma. It isn’t clear whether cellphone use increases the risk of brain cancer. Some studies have found a possible association between cellphone use and a type of brain cancer called acoustic neuroma. Many other studies have found no association. Because cellphones are a relatively new factor, more long-term research is needed to understand the potential impact on cancer risk. For the time being, if you’re concerned about the possible link between cellphones and cancer, experts recommend limiting your exposure by using a speaker or hands-free device, which keeps the cellphone itself away from your head.
• Family history of glioma. It’s rare for glioma to run in families. But having a family history of glioma can double the risk of developing it. Some genes have been weakly associated with glioma, but more study is needed to confirm a link between these genetic variations and brain tumors.

Glioblastoma diagnosis

If it’s suspected that you have a glioblastoma, your doctor may recommend a number of tests and procedures, including:

• A neurological exam. A neurological exam may include, among other things, checking your vision, hearing, balance, coordination, strength and reflexes. Difficulty in one or more areas may provide clues about the part of your brain that could be affected by a brain tumor.
• Imaging tests. Magnetic resonance imaging (MRI) and computed tomography (CT) scans are used most often to look for brain diseases. These scans will almost always show a brain tumor, if one is present. Doctors can often also get an idea about what type of tumor it might be, based on how it looks on the scan and where it is in the brain.
  • Magnetic resonance imaging (MRI) scan. MRI scans use radio waves and strong magnets (instead of x-rays) to make pictures. A contrast material called gadolinium may be injected into a vein before the scan to help see details better. MRI scans are very good for looking at the brain and spinal cord and are considered the best way to look for tumors in these areas. The images they provide are usually more detailed than those from CT scans. But they do not pick up the bones of the skull as well as CT scans and therefore may not show the effects of tumors on the skull.
    • Special types of MRI can be useful in some situations:
      • Magnetic resonance angiography (MRA) and magnetic resonance venography (MRV): These special types of MRI may be used to look at the blood vessels in the brain. This can be very useful before surgery to help the surgeon plan an operation.
      • Magnetic resonance spectroscopy (MRS): This test can be done as part of an MRI. It measures biochemical changes in an area of the brain (displayed in graph-like results called spectra, although basic images can also be created). By comparing the results for a tumor to that of normal brain tissue, it can sometimes help determine the type of tumor (or how quickly it is likely to grow), although a biopsy of the tumor is often still needed to get an accurate diagnosis. Magnetic resonance spectroscopy (MRS) can also be used after treatment to help determine if an area that still looks abnormal on another test is remaining tumor or if it is more likely to be scar tissue.
      • Magnetic resonance perfusion: For this test, also known as perfusion MRI, a contrast dye is injected quickly into a vein. A special type of MR image is then obtained to look at the amount of blood going through different parts of the brain and tumor. Tumors often have a bigger blood supply than normal areas of the brain. A faster growing tumor may need more blood. Perfusion MRI can give doctors an idea of the best place to take a biopsy. It can also be used after treatment to help determine if an area that still looks abnormal is remaining tumor or if it is more likely to be scar tissue.
      • Functional MRI (fMRI): This test looks for tiny blood flow changes in an active part of the brain. It can be used to determine what part of the brain handles a function such as speech, thought, sensation, or movement. Doctors can use this to help determine which parts of the brain to avoid when planning surgery or radiation therapy. This test is similar to a standard MRI, except that you will be asked to do specific tasks (such as answering simple questions or moving your fingers) while the scans are being done.
  • Computed tomography (CT) scan. A CT scan uses x-rays to make detailed cross-sectional images of your brain and spinal cord (or other parts of the body). Unlike a regular x-ray, a CT scan creates detailed images of the soft tissues in the body. CT scans are not used as often as MRI scans when looking at brain or spinal cord tumors, but they can be useful in some cases. They may be used if MRI is not an option (such as in people who are very overweight or people who have a fear of enclosed spaces). CT scans also show greater detail of the bone structures near the tumor. As with MRI, you may get an injection of a contrast dye through an IV (intravenous) line before the scan (although a different dye is used for CT scans). This helps better outline any tumors that are present.
    • CT angiography (CTA): For this test, you are injected with a contrast material through an IV line while you are in the CT scanner. The scan creates detailed images of the blood vessels in the brain, which can help doctors plan surgery. CT angiography can provide better details of the blood vessels in and around a tumor than MR angiography in some cases.
  • Positron emission tomography (PET) scan. For a PET scan, you are injected with a slightly radioactive substance (usually a type of sugar known as FDG) which collects mainly in tumor cells. A special camera is then used to create a picture of areas of radioactivity in the body. The picture is not as detailed as a CT or MRI scan, but it can provide helpful information about whether abnormal areas seen on other tests (such as MRIs) are likely to be tumors or not. This test is more likely to be helpful for fast-growing (high-grade tumors) than for slower-growing tumors. This test is also useful after treatment to help determine if an area that still looks abnormal on an MRI scan is remaining tumor or if it is more likely to be scar tissue. Remaining tumor might show up on the PET scan, while scar tissue will not.
  • Chest x-ray. A chest x-ray might be done to look for tumors in the lungs if a tumor is found in the brain. This is because in adults, most tumors in the brain actually have started in another organ (most often the lung) and then spread to the brain. This test can be done in a doctor’s office, in an outpatient radiology center, or in a hospital.
• Brain or spinal cord tumor biopsy. Imaging tests such as MRI and CT scans may show an abnormal area that is likely to be a brain or spinal cord tumor. But these scans can’t always tell exactly what type of tumor it is. Often this can only be done by removing some of the tumor tissue in a procedure called a biopsy. A biopsy may be done as a procedure on its own, or it may be part of surgery to remove the tumor. Sometimes, a tumor may look so characteristically obvious on an MRI scan (for example, clearly looking like an astrocytoma) that a biopsy is not needed, especially if the tumor is in a part of the brain that would make it hard to biopsy (such as the brain stem). In rare cases a PET scan or MR spectroscopy may give enough information so that a biopsy is not needed. The 2 main types of biopsies for brain tumors are:
  • Stereotactic (needle) biopsy. Stereotactic (needle) biopsy may be used if, based on imaging tests, surgery to remove the tumor might be too risky (such as with some tumors in vital areas, those deep within the brain, or other tumors that probably can’t be removed safely with surgery) but a sample is still needed to make a diagnosis. The patient may be asleep (under general anesthesia) or awake during the biopsy. If the patient is awake, the neurosurgeon injects a local anesthetic into areas of skin above the skull to numb them. The skull and brain do not feel pain. The biopsy itself can be done in two main ways:
    • One approach is to get an MRI or CT, and then use either markers (each about the size of a nickel) placed on different parts of the scalp, or facial and scalp contours, to create a map of the inside of the head. An incision (cut) is then made in the scalp, and a small hole is drilled in the skull. An image-guidance system is then used to direct a hollow needle into the tumor to remove small pieces of tissue.
    • In another approach that’s being used less often, a rigid frame is attached to the head. An MRI or CT scan is often used along with the frame to help the neurosurgeon guide a hollow needle into the tumor. This also requires an incision in the scalp and a small hole in the skull.
    • The removed tissue is sent to a pathologist (a doctor specializing in diagnosis of diseases by lab tests). Sometimes it might need to be looked at by a neuropathologist, a pathologist who specializes in nervous system diseases. The pathologist looks at it under a microscope (and might do other lab tests) to determine if the tumor is benign or malignant (cancerous) and exactly what type of tumor it is. This is very important in determining a person’s prognosis (outlook) and the best course of treatment. A preliminary diagnosis might be available the same day, although it often takes at least a few days to get a final diagnosis.
  • Surgical or open biopsy (craniotomy). If imaging tests show the tumor can likely be treated with surgery, the neurosurgeon may not do a needle biopsy. Instead, an operation called a craniotomy might be done to remove all or most of the tumor. (If removing all of the tumor would likely damage nearby important structures, removing most of the tumor, known as debulking, might be done.) For a preliminary diagnosis, small samples of the tumor are looked at right away by the pathologist while the patient is still in the operating room. This can help guide treatment, including whether further surgery should be done at that time. A final diagnosis is made within a few days in most cases.
• Lab tests of biopsy specimens. Finding out which type of tumor someone has is very important in helping to determine their outlook (prognosis) and treatment options. But in recent years, doctors have found that changes in certain genes, chromosomes, or proteins within the cancer cells can also be important. Some tumors are now tested for these types of changes. For example:
  • Gliomas that are found to have IDH1 or IDH2 gene mutations tend to have a better outlook than gliomas without these gene mutations.
  • In high-grade gliomas, the presence of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation is linked with better outcomes and a higher likelihood of responding to chemotherapy.
  • Lab tests looking for other gene or chromosome changes might also be done.
• Lumbar puncture (spinal tap). Lumbar puncture (spinal tap) is used mainly to look for cancer cells in the cerebrospinal fluid (CSF), the liquid that surrounds the brain and spinal cord. For this test, you lie on your side on a bed or exam table with your knees up near your chest. The doctor first numbs an area in the lower part of the back near the spine. A small, hollow needle is then placed between the bones of the spine to withdraw some of the fluid. This fluid is sent to a lab to be looked at for cancer cells. Other tests may be done on the fluid as well. Lumbar punctures are usually very safe, but doctors have to make sure the test does not result in a large drop in fluid pressure inside the skull, which could possibly cause serious problems. For this reason, imaging tests such as CT or MRI scans are done first. Lumbar punctures usually aren’t done to diagnose brain tumors, but they may be done to help determine the extent of a tumor by looking for cancer cells in the CSF. They are often used if a tumor has already been diagnosed as a type that can commonly spread through the CSF, such as an ependymoma. Lumbar punctures are particularly important in people with suspected brain lymphomas because lymphoma cells often spread into the CSF.
• Blood and urine tests. Blood and urine tests rarely are part of the actual diagnosis of brain and spinal cord tumors, but they may be done to check how well the liver, kidneys, and some other organs are working. This is especially important before any planned surgery. If you are getting chemotherapy, blood tests will be done routinely to check blood counts and to see if the treatment is affecting other parts of your body.

If you’re uncertain about your diagnosis, consider seeking a second opinion at a medical center where many brain biopsies are evaluated every year.

Definitive diagnosis is based on histopathological examination of the intraoperatively removed tumor or its parts, using traditional histological, cytologic and histochemical methods ⁷³. When neurosurgical tumor resection is not possible, fine needle aspiration biopsy is performed ⁷⁴.

Testing to assess for the presence or absence of glial fibrillary acidic protein (GFAP), isocitrate dehydrogenase (IDH) mutation status [IDH1 or IDH2], and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status is usually recommended. MGMT methylation status is useful to predict response to specific chemotherapeutic agents ⁷⁵. The presence of IDH 1/2 mutation doesn’t guide directly towards specific treatment, but most IDH 1/2 mutant glioblastoma has methylation of MGMT promotor guiding therapy indirectly. Also, IDH 1/2 mutation denotes improved prognosis and eligibility for clinical trials ²⁵.

Verification of a primary diagnosis is performed on the basis of immunohistochemistry for the presence in the glioma cells of glial fibrillary acidic protein (GFAP), which is a major intermediate filament protein of mature astrocytes with the mass of 50 kD ⁷⁶, ⁷⁷. The glial fibrillary acidic protein (GFAP) is the most specific marker of astrocytes, both in normal and pathological conditions. It is believed that this protein plays a role in maturation of astrocytes. Increasing malignancy of tumors of astrocytic origin is associated with the loss of GFAP expression ⁷⁸. Similar effects are observed for glioblastoma multiforme – glioma cells negative for GFAP proliferate faster in comparison to positive cells. Loss of GFAP expression indicates significantly undifferentiated tumor cells, but does not decide about tumor progression and development ⁷⁶. Sometimes, astrocytes with GFAP and characteristic lipomatous cytoplasm can occur ⁷⁹. The acid protein S100 present in glial cells is another specific marker for tumors of the central nervous system, but its expression cannot constitute a basic criterion in differential diagnosis ⁸⁰.

Glioblastoma stage

Staging of the tumors in the brain and spinal cord is based on criteria defined by the World Health Organization (WHO) ¹, which includes assessment of their morphology, grade of malignancy (grade I–IV), proliferative index, response to treatment and survival time. Grade 1 includes non-malignant tumors, grade 2 is used for relatively non-malignant tumors, grade 3 includes tumors of low-grade malignancy, while grade 4 denotes the most malignant tumors, with median survival of 6–12 months. Glioblastoma multiforme is classified as grade 4 because they grow rapidly and invade surrounding brain tissue ⁸¹.

Completely staging most glioblastoma multiforme is neither practical nor possible because these tumors do not have clearly defined margins ⁸². Rather, glioblastoma multiforme exhibit well-known tendencies to invade locally and spread along compact white matter pathways, such as the corpus callosum, internal capsule, optic radiation, anterior commissure, fornix, and subependymal regions. Such spread may create the appearance of multiple glioblastomas or multicentric gliomas on imaging studies.

Careful histological analyses have indicated that only 2-7% of glioblastoma multiforme are truly multiple independent tumors rather than distant spread from a primary site. Despite its rapid infiltrative growth, the glioblastoma tends not to invade the subarachnoid space and, consequently, rarely metastasizes via cerebrospinal fluid (CSF). Hematogenous spread to extraneural tissues is very rare in patients who have not had previous surgical intervention, and penetration of the dura, venous sinuses, and bone is exceptional ⁸³.

Glioblastoma treatment

Glioblastoma treatment consists of surgery to safely remove as much of the brain tumor as possible followed by radiation and chemotherapy. The brain surgeon (neurosurgeon) will try to remove as much of the tumor as possible without injuring surrounding normal brain tissue and compromising normal neurological function. Surgery alone is not enough for glioblastoma as these tumors are very invasive in nature. These tumor cells invade surrounding brain tissue, making it nearly impossible to ever remove the tumor entirely. Surgery, however, is an important part of current glioblastoma therapy, because it allows for removal of the solid tumor and any cells that may make the tumor resistant to radiation and chemotherapy, debulking of the tumor, and reduction of intracranial pressure.

Glioblastoma treatment options include:

• Surgery to remove the glioblastoma. Surgery is presently an essential component to prolonging the lives of glioblastoma patients. Your brain surgeon (neurosurgeon) will work to remove the glioblastoma. The goal is to remove as much of the tumor as possible. The surgery for glioblastoma is a craniotomy. The skull is opened to reach the tumor with assistance from intra-operative mapping techniques. The patient can be awake for the surgery. The areas of the brain are mapped with the patient’s assistance. The doctor will then decide which portions of the tumor are safe to remove. But because glioblastoma grows into the normal brain tissue and complete removal isn’t possible. For this reason, most people receive additional treatments after surgery to target the remaining cells.
• Radiation therapy. Radiation therapy uses high-energy beams, such as X-rays or protons, to kill cancer cells. After surgery and once your wound has healed, radiation can begin. The goal of radiation is to kill the remaining tumor cells that have infiltrated the normal brain tissue. During radiation therapy, you lie on a table while a machine moves around you, directing beams to precise points in your brain. Radiation therapy is usually recommended after surgery and may be combined with chemotherapy. For people who can’t undergo surgery, radiation therapy and chemotherapy may be used as a primary treatment. Radiation is administered 5 days/week for 6 weeks. A total of 10 to 30 treatments are given. The use of radiation therapy provides patients with better outcomes than surgery alone.
• Chemotherapy. Chemotherapy uses drugs to kill cancer cells. In some cases, thin, circular wafers containing chemotherapy medicine may be placed in your brain during surgery. The wafers dissolve slowly, releasing the medicine and killing cancer cells. After surgery, the chemotherapy drug temozolomide (Temodar) — taken as a pill — is often used during and after radiation therapy. The drug is generally administered everyday during radiation therapy, and then for 6-12 cycles after radiation. Each cycle lasts 28 days with temozolomide given the first five days of each cycle followed by 23 days of rest. Temozolomide is only effective for about 20% of patients. Before considering chemotherapy, patients are encouraged to talk to their neuro-oncologists. Other types of chemotherapy may be recommended if your glioblastoma recurs. These other types of chemotherapy are often administered through a vein in your arm.
• Tumor treating fields (TTF) therapy. Tumor treating fields (TTF) therapy uses an electrical field to disrupt the tumor cells’ ability to multiply. Tumor treating fields (TTF) therapy involves applying adhesive pads to your scalp. The pads are connected to a portable device that generates the electrical field. TTF is combined with chemotherapy and may be recommended after radiation therapy.
• Targeted drug therapy. Targeted drugs focus on specific abnormalities in cancer cells that allow them to grow and thrive. The drugs attack those abnormalities, causing the cancer cells to die. Bevacizumab (Avastin) targets the signals that glioblastoma cells send to the body that cause new blood vessels to form and deliver blood and nutrients to cancer cells. Bevacizumab may be an option if your glioblastoma recurs or doesn’t respond to other treatments ⁸⁴.
• Clinical trials. Clinical trials are studies of new treatments. These studies give you a chance to try the latest treatment options, but the risk of side effects may not be known. Ask your doctor whether you might be eligible to participate in a clinical trial.
• Supportive (palliative) care. Palliative care is specialized medical care that focuses on providing relief from pain and other symptoms of a serious illness. Palliative care specialists work with you, your family and your other doctors to provide an extra layer of support that complements your ongoing care. Palliative care can be used while undergoing other aggressive treatments, such as surgery, chemotherapy or radiation therapy.

According to the 2020 National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology ³⁴, glioblastoma multiforme treatment options depend on patient age, performance status (performance status) and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status (methylated vs. unmethylated). Patients aged 70 years or younger with a good performance status, regardless of the tumor’s MGMT methylation status, should receive standard brain radiation therapy plus concurrent and adjuvant temozolomide (TMZ) with alternating electric field therapy ⁸⁵. Patients older than 70 years with good performance status should receive hypofractionated or standard brain radiation therapy plus concurrent and adjuvant temozolomide (TMZ) and alternating electric field therapy (TTF).

Figure 2. Newly diagnosed glioblastoma treatment algorithm

Abbreviations: GBM = glioblastoma multiforme; TMZ = temozolomide; RT = radiation therapy; MGMT = O6-methylguanine-DNA methyltransferase; TTF = tumor-treating fields.

[Source ⁴⁹ ]

Figure 3. Recurrent glioblastoma treatment algorithm

Abbreviations: GBM = glioblastoma multiforme; TMZ = temozolomide; MGMT = O6-methylguanine-DNA methyltransferase; TTF = tumor-treating fields.

[Source ⁴⁹ ]

Surgery

The goal of surgery is the maximum safe resection to preserve neurological function with improved survival. Since glioblastoma infiltrates surrounding tissues, its complete resection is not always possible ²⁸ and radiotherapy not always efficient ¹³.

Data from Surveillance, Epidemiology, and End Results (SEER) suggest gross total resection and subtotal resection is associated with improved survival compared to biopsy alone or no surgical intervention. The decision regarding subtotal resection vs. stereotactic biopsy vs. palliative surgery depends on location, age, comorbidities, and goals of care.

Most of the time, surgical resection is useful for definitive diagnosis and treatment. Postoperatively a repeat imaging should be done in 24 to 48 hours to assess the extent of resection.

Radiation therapy

The goal of radiotherapy is to deliver radiation to the tumor and to a margin of radiographically normal tissue to limit the recurrence. The radiation dose is 50-60 Gy delivered over a period of six weeks in fractions of 2 Gy ⁸⁶. The two most common methods of delivering radiotherapy include three-dimensional conformal RT (3D-CRT) and intensity-modulated RT (IMRT).

According to National Comprehensive Cancer Network guidelines, hypofractionated radiotherapy can be recommended in patients with poor performance status or age >70 irrespective of performance status or methylated status of MGMT promoter either with or without chemotherapy.

Clinical trials are ongoing regarding the role of irradiation in patients with recurrent glioblastoma. More evidence is needed regarding dose, frequency, fractionation, and prior treatments, etc ⁸⁷.

Studies have shown patients who had radiotherapy doses of 50 to 60 Gy had longer median survival than those who received lower postoperative radiation therapy doses ⁸⁸. Studies have also shown marginal or no benefit of brachytherapy for high-grade gliomas given their infiltrative nature ⁸⁹. Brachytherapy is a type of radiation therapy in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near a tumor.

Studies testing the efficacy of proton and neutron therapy are underway. Radiation sensitizers are the compounds given along with radiotherapy with an idea to increase its therapeutic effect. None of these compounds is approved for glioblastoma at present.

Side effects of radiation therapy include radiation dermatitis, neurocognitive toxicity, and endocrinopathies in the future.

Patients receiving concurrent chemotherapy with radiotherapy are at increased risk for leucopenia, thrombocytopenia, and hepatotoxicity. Weekly complete blood count (CBC) with differential and liver function tests are recommended. Severe thrombocytopenia can result in withholding of radiotherapy until blood counts are stabilized. Due to lymphopenia especially affecting CD4 count, pneumocystis pneumonia prophylaxis should be administered to all patients receiving daily chemotherapy while on radiotherapy.

Chemotherapy

According to National Comprehensive Cancer Network guidelines, patients with newly diagnosed MGMT-methylated glioblastoma, age 70 years or younger, should be treated with temozolomide and radiotherapy. Clinical trials have shown increased overall survival at 2 and 5 years on continued follow up in a group who received radiotherapy with concurrent daily temozolomide followed by six monthly cycles of adjuvant temozolomide. Results are similar in patients with age >60 and poor prognostic factors ⁹⁰. Trials were conducted with a combined regimen of temozolomide and lomustine with radiation therapy as an alternative option in MGMT-methylated glioblastoma, which resulted in inconclusive results ⁹¹.

Treatment is similar in MGMT-unmethylated glioblastoma, age 70 years or younger; however, these patients derive less benefit from temozolomide when compared to the methylated group. Standard therapy with temozolomide and radiotherapy is recommended if MGMT status is unknown due to benefit from temozolomide with tolerable side effect profile along with the lack of available alternatives for unmethylated tumors.

In patients with age 70 years or older with good performance status, temozolomide and radiotherapy are recommended, But a hypofractionated radiation course can be done rather than the standard course. Twelve cycles of adjuvant temozolomide are recommended with hypofractionated radiotherapy rather than six cycles in such patients ⁹². In patients with age 70 years or older with poor performance status, single modality, either temozolomide or radiotherapy, can be considered to avoid side effects and toxicities. In such cases, MGMT methylation status can be helpful in deciding between chemo and radiotherapy ⁹³.

No strong evidence exists for alternatives to temozolomide for MGMT- unmethylated glioblastomas, although trials have been conducted using a combination of bevacizumab/irinotecan in the past ⁹⁴.

Temozolomide is given orally daily during radiation therapy. Adjuvant treatment starts four weeks after radiotherapy, and it is given for six cycles, daily for five days in a 28-day cycle. Side effects include leucopenia, thrombocytopenia, hepatotoxicity, nausea, constipation, fatigue, etc. Regular complete blood count (CBC) should be done, and therapy should be held if absolute neutrophil count (ANC) falls below 1500/microL or platelets fall below 100,000/microL.

Prophylaxis for Pneumocystis pneumonia (PCP) should be given to all patients receiving concomitant chemoradiotherapy due to the high risk of CD4 T cell depletion by temozolomide.

Magnetic resonance imaging (MRI) with contrast is recommended within one month after completing radiotherapy and then frequently every two months during adjuvant temozolomide to assess the disease status. Further recommendations, according to National Comprehensive Cancer Network, includes MRI every two to four months for two to three years, and less frequently after that.

Treatment recommendation guidelines:

• Age> 70 –  radiotherapy plus concomitant therapy with temozolomide followed by adjuvant temozolomide with six cycles.
• Age< 65-70 –  hypofractionated radiotherapy plus concomitant therapy with temozolomide followed by adjuvant temozolomide with 12 cycles.

Targeted drug therapy

Targeted therapy is a type of cancer treatment that targets proteins that control how cancer cells grow, divide, and spread. As researchers learn more about the DNA changes and proteins that drive cancer, they are better able to design treatments that target these proteins. Targeted cancer drugs attack those abnormalities, causing the cancer cells to die. Bevacizumab (Avastin) targets the signals that glioblastoma cells send to the body that cause new blood vessels to form and deliver blood and nutrients to cancer cells. Bevacizumab may be an option if your glioblastoma recurs or doesn’t respond to other treatments ⁸⁴. Multiple studies of the humanized vascular endothelial growth factor (VEGF) antibody bevacizumab for glioblastoma have failed to demonstrate a survival benefit ⁹⁵. However, bevacizumab is often effective in reducing peritumoral edema and related clinical symptoms and signs ⁹⁶. Bevacizumab (Avastin) is approved in the United States and some other countries, but not in the European Union, for use in recurrent glioblastoma due to improvement in progression-free survival and reduction in corticosteroid use ⁹⁵. Continuation of bevacizumab post progression did not improve outcome in a small study ⁹⁷. Patients with recurrent glioblastoma should ideally be considered for clinical trials before receiving bevacizumab, as most trials exclude prior use of bevacizumab. Bevacizumab has also been proven to be effective in radiation-induced necrosis, although the doses used are lower than standard dosing for recurrent glioblastoma (typically 7.5 mg/kg every 3 week for a maximum of 4 treatments) ⁹⁸.

Electric-field therapy

The Optune device also known as the NovoTTF-100A System, uses low-intensity, intermediate-frequency, alternating electric fields (tumor- treating fields) to target dividing cells in glioblastoma multiforme while generally not harming normal cells ⁹⁹. The tumor-treating fields are generated via electrodes placed directly on the scalp. To target the tumor, array placement is based on the individual patient’s magnetic resonance imaging results.

Optune was initially approved in 2011 for use in glioblastoma multiforme that had recurred or progressed after treatment. In October 2015, the FDA expanded approval to include use of the device in conjunction with temozolomide chemotherapy in the first-line setting. Approval was based on an open-label, randomized phase 3 trial in 700 patients, in which median overall survival was 19.4 months with use of the device plus temozolomide, versus 16.6 months with chemotherapy only ⁹⁹.

In a randomized, open-label trial in 695 patients with glioblastoma, the addition of tumor-treating fields to treatment with temozolomide improved median progression-free survival from 4.0 months to 6.7 months (hazard ratio 0.63). Median overall survival improved from 16.0 months to 20.9 months (hazard ratio 0.63) ¹⁰⁰.

Corticosteroids

Corticosteroid drugs, preferably dexamethasone (in conjunction with gastric protection if used at high doses) are often given to reduce swelling around brain tumors ¹⁰¹. Dexamethasone alleviates neurologic deficits and signs of increased intracranial pressure such as headache and drowsiness. Low doses (eg, 4 mg/day given in 1–2 doses) are effective in most clinically symptomatic patients without signs of herniation ¹⁰². There is no need to give dexamethasone 4 times a day ¹⁰². Side effects of dexamethasone worsen with increased dose and duration of treatment ¹⁰³. There is also growing evidence that corticosteroids may have an adverse effect on patient outcome, so they should be avoided if patients are not symptomatic ¹⁰⁴. Patients on chronic corticosteroids (≥20 mg prednisone equivalents daily for ≥1 month) should be considered for prophylaxis for osteoporosis and pneumocystis jerovecii pneumonia ¹⁰⁵.

Anti-seizure drugs (anticonvulsants)

Seizures affect 23% of glioblastoma patients at presentation and an additional 20% later in the disease course ¹⁰⁶. While patients with seizures require anti-epileptic drugs (anticonvulsants), studies have not clearly shown a benefit of prolonged primary anti-epileptic drug prophylaxis in patients who have never had a seizure ¹⁰⁷. Current guidelines recommend tapering anti-epileptic drugs 1–2 weeks after surgery and avoiding long-term prophylaxis ¹⁰⁸. There is no role for primary perioperative prophylaxis (ie, in patients who have never had a seizure). A meta-analysis of 6 studies ¹⁰⁹, a Cochrane systematic review ¹¹⁰ and a subsequent randomized trial of phenytoin versus no prophylaxis ¹¹¹ have all shown no significant benefit from primary anti-epileptic drug prophylaxis. When anti-epileptic drugs are used, newer agents including levetiracetam and lacosamide are preferred over older drugs because of generally more favorable side effect profiles, reduced laboratory monitoring requirements, and lack of drug-drug interactions.110 Emerging data suggesting that neurons and glioma cells form synapses via AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors raises the possibility that anti-epileptic drugs that inhibit these receptors, such as perampanel, may be beneficial not only in controlling seizures, but also through possible antiglioma activity ¹¹². However, a prior trial with another glutamate inhibitor, talampanel, was ultimately interpreted to be negative ¹¹³.

Anticoagulants

Venous thromboembolism (venous blood clots) risk is high in the perioperative period and persists well beyond, with one-year incidence of approximately 20% ¹¹⁴, mandating a low threshold for pursuing diagnostic studies ¹¹⁵. Most ¹¹⁶, ¹¹⁷, though not all ¹¹⁸, studies suggest that the risk of precipitating intratumoral hemorrhage with anticoagulants is acceptably low, even in patients receiving bevacizumab ¹¹⁹. The preferred anticoagulant is not well studied in brain tumors; in systemic cancer, low molecular weight heparin (LMWH) is preferred over warfarin ¹²⁰. Direct oral anticoagulants (factor Xa and thrombin inhibitors) have been reported to be safe in patients with brain tumors ¹²¹. However, no randomized data are available for glioma patients and randomized trials on secondary prophylaxis of venous thromboembolism with direct oral anticoagulants enrolling cancer patients have generally shown a similar or slightly higher efficacy than low molecular weight heparin (LMWH) but with a slightly higher risk of bleeding ¹²².

A high incidence of recurrent venous thromboembolism with inferior vena cava (IVC) filters limits their use to patients with recent intracranial surgery, intratumoral hemorrhage, or absolute contraindications to anticoagulation ¹²³. Prophylaxis with anticoagulation outside of the perioperative setting has not been definitively studied, as the only trial addressing this issue was prematurely terminated for slow accrual ¹²⁴. A meta-analysis of pooled randomized clinical trial data indicated no survival benefit from anticoagulation in glioblastoma patients, but rather suggested that venous thromboembolism should be treated more vigorously in this patient population ¹²⁵.

Other symptomatic treatments

Cognitive deficits, personality changes, and mood disturbances are major comorbidities for glioblastoma patients ¹⁰¹. Before treatment, up to 91% of brain tumor patients have cognitive deficits, with only moderate correlation with cognitive complaints ¹²⁶. The frequent presence of fatigue and sleep disturbance contributes to cognitive impairment ¹²⁷. Medical treatments with acetylcholinesterase inhibitors (donepezil) or psychostimulants (methylphenidate, modafinil) to prevent cognitive decline and fatigue after radiation therapy in patients with brain tumors (<50% were glioblastoma) have been unsuccessful ¹²⁸. Although the 6-month prevalence of clinical depression is about 20% in brain tumor patients ¹²⁹, randomized studies on medical treatment are lacking.

Regular exercise ¹³⁰, adoption of a healthy diet, avoidance of hyperglycemia ¹³¹, early discussion of goals of care, and involvement of palliative care should be considered. Despite extensive interest in ketogenic diets and cannabinoids, there are currently no clinical data supporting their routine use.

Recurrent glioblastoma treatment

Glioblastoma patients invariably recur after a median interval of less than 7 months ¹³² and there is no clear standard-of-care salvage therapy (Figure 3). The National Comprehensive Cancer Network guidelines list clinical trials as the preferred option for eligible patients ¹³³. Surgery may have a role for symptomatic and/or large lesions. However, only patients who undergo complete resections have any survival benefit ¹³⁴. Other options include systemic therapy such as temozolomide rechallenge, nitrosoureas, bevacizumab, re-irradiation, and Tumor Treatment Fields (NovoTTF-100A system or Optune device in the US) ¹³⁵, none of which have been shown to prolong survival in randomized trials in this setting, or palliative care for patients with poor performance status.

Although other chemotherapeutic agents such as irinotecan, carboplatin, procarbazine, and etoposide are sometimes used for patients with recurrent glioblastomas, there are no data suggesting that they are beneficial ¹³⁶. A recent randomized phase 2 trial suggested that regorafenib, a VEGF receptor 2 and multikinase inhibitor, increased survival in patients with recurrent glioblastoma compared with lomustine ¹³⁷.

Repeat radiation therapy in the form of radiosurgery or hypofractionated radiotherapy (30–35 Gy in 5–15 fractions) is increasingly used for recurrent glioblastoma, although there is currently no definitive data regarding benefit ¹³⁸, ¹³⁹. A secondary analysis of the NRG Oncology/RTOG 0525 trial showed no significant survival benefit of re-irradiation over systemic therapy after tumor progression ¹⁴⁰. Preliminary results of the NRG phase 2 trial comparing bevacizumab alone versus bevacizumab with re-irradiation in patients with recurrent glioblastomas showed that the addition of re-irradiation improved progression-free survival (7.1 months with the combination vs 3.8 months with bevacizumab alone) but not overall survival ¹⁴¹.

Glioblastoma new treatment

Given the poor outcomes with current treatments, there is great interest in various experimental approaches under investigation ¹⁴².

Targeted Molecular (Precision) Therapies

Despite advances in understanding the molecular pathogenesis of glioblastoma, there has been only modest progress in developing effective targeted molecular therapies ¹⁴³. Challenges include the paucity of agents that effectively cross the blood-brain barrier (BBB) ¹⁴⁴, the relative lack of “easy” targets such as BRAFV600E mutations, redundant signaling pathways ¹⁴⁵ and tumor heterogeneity ¹⁴⁶.

The 2016 update of the WHO classification incorporated molecular parameters into the definition of certain brain tumors  ¹. Several of these markers are easily assessed by immunohistochemistry, including IDH1-R132H and histone H3 K27M, while other point mutations can be determined by sequencing. BRAFV600E mutation status, while challenging by immunohistochemistry is easily assessed by sequencing and has therapeutic implications for a subset of glioblastoma patients. For more comprehensive profiling, targeted NGS panels have proven to be useful, while some centers also have the capacity to perform whole exome sequencing or whole genome sequencing. Microsatellite instability can be readily assessed by either genome-wide or medium-sized panel approaches, and is relevant given the tumor-agnostic approval by the FDA for pembrolizumab for cancers with high microsatellite instability. Copy number variations—for example, the aforementioned chromosomal +7/−10 pattern—are relevant for glioma diagnosis and possibly treatment. Fusion detection, to identify a potentially relevant and druggable group of alterations (for example, fusions of neurotrophic-tropomyosin RTK [NTRK fusions]), requires specific coverage by either DNA-based approaches or alternatively mRNA-based analyses. Routine examination of these (and potentially additional) alterations will be critical if scientists are to make substantial steps forward for precision glioblastoma therapies ¹⁴⁷.

Examples of putative treatment-predictive biomarkers exist. The most often investigated biomarkers, high level EGFR amplification and EGFRvIII mutation, have been targeted with and without tumor pretesting, with the aim of suppressing pathway activation with EGFR inhibitors such as erlotinib ¹⁴⁸, targeting the heterogeneously expressed EGFRvIII neoantigen by vaccination with a peptide vaccine, rindopepimut ¹⁴⁹ or using the conformational change for specific binding of an antibody-drug conjugate, depatuxizumab mafodotin (ABT414) ¹⁵⁰, ¹⁵¹ without clinical activity ¹⁵². Targeting BRAFV600E mutations showed responses to monotherapy with Raf inhibitors such as vemurafenib ¹⁵³ or dual therapy with combined BRAF/MEK inhibition with trametinib and dabrafenib ¹⁵⁴, but these mutations are rare in glioblastoma except for epithelioid glioblastoma ¹⁵⁵, a somewhat controversial entity likely to be often confused with pleomorphic xanthoastrocytoma. Other potentially targetable mutations, such as NTRK fusions ¹⁵⁶, H3K27M mutations ¹⁵⁷ and FGFR mutations and FGFR3-TACC3 fusions ¹⁵⁸, are all uncommon in glioblastoma. Of note, mutations in the telomerase reverse transcriptase (TERT) promoter are found in up to 85% of glioblastomas ¹⁵⁹, although to date this mutation has been challenging to target.

The lack of success in targeted therapy trials in glioblastoma is likely due to tumor heterogeneity, lack of knowledge of the contribution of genetic alterations to tumor maintenance, targeting subclonal or unstable genetic alterations instead of stable and clonal oncogenic drivers, redundant signaling pathways, use of archival instead of freshly obtained recurrent tumor tissue for biomarker testing, insufficient assessment of drug brain tumor concentrations, failure of target inhibition, and development of rapid secondary resistance and clonal selection.

Currently, most therapeutic strategies and biomarkers are focused on single or multiple biological features that are differentially detected in patient groups responding to a given therapy. In several studies post-hoc exploratory analyses suggested subsets of patients that may have benefited from experimental treatments, but in the absence of validation, these remain only hypothesis generating. For example, the proneural subtype of glioblastoma defined by expression analyses ¹⁶⁰ or MRI features ¹⁶¹ may derive benefit from the addition of bevacizumab to standard treatment. Lower levels of carboxypeptidase G2 promoter methylation of cluster of differentiation (CD)95 ligand (CD95L) were correlated with improved overall survival with the CD95 inhibitory treatment asunercept (APG101) in combination with re-irradiation compared with re-irradiation alone ¹⁶². Also, based on a retrospective analysis, mammalian target of rapamycin (mTOR) Ser2448 phosphorylation may be a putative predictive biomarker of response to the mTOR inhibitor temsirolimus plus radiation in patients with newly diagnosed glioblastoma lacking MGMT promoter methylation ¹⁶³. Others have suggested PTEN loss predicts benefit from mTOR inhibitors ¹⁶⁴. Without preselection, mTOR inhibition is not only ineffective but may even confer a survival disadvantage compared with the standard of care. For example, the addition of a different mTOR inhibitor, everolimus, resulted in worse outcome in an unselected group of patients with newly diagnosed glioblastoma irrespective of MGMT status (Table 2) ¹⁶⁵.

Several clinical trials are based on well-defined molecular characteristics of the tumor, confirmation of adequate drug penetration and biological efficacy (eg, target engagement and modulation in neoadjuvant, “window-of-opportunity” surgery-based trials), as well as necessary retrospective validation of potential biomarkers (Table 3). Several large clinical trials are underway where prospectively assigned biomarkers will enrich predefined patient cohorts for potentially benefiting patients. The National Center for Tumor Diseases‒Heidelberg Neuro Master Match (N2M2) (NCT03158389), a trial of molecularly matched targeted therapies plus radiation therapy in patients with newly diagnosed glioblastoma without MGMT promoter methylation is currently ongoing ¹⁶⁶. Similarly, the National Cancer Institute MATCH trial, while designed mainly for extracranial solid tumors, does allow patients with glioblastoma if they meet the eligibility criteria. The Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial evaluating EGFR, mTOR/DNA-PK, and CDK4/6 inhibitors ¹⁶⁷ and the GBM Adaptive, Global, Innovative Learning Environment (AGILE) consortium ¹⁶⁸ are taking a different approach by enrolling patients into unselected cohorts with given therapies first, assessing potential biomarkers as the trial accrues and integrating this information via adaptive randomization processes to enrich specific arms that may be showing benefit with particular biomarkers (Table 3) ¹⁶⁸.

The extensive tumor heterogeneity in glioblastoma suggests that combination therapy may be more effective than treatment with single agents. However, combination studies to date have been associated with little activity and often significant toxicity, and increase the need for assessment of the targets in the tumor ¹⁴³. Potentially, combinations of more potent selective agents with less off-target effects may be better tolerated. To address the issues of heterogeneity and redundant signaling pathways, there is significant interest in exploiting synthetic lethality (targeting tumor stem cells) ¹⁶⁹ or common downstream pathways with agents such as marizomib, a proteasome inhibitor (NCT03345095), and selinexor, an exportin 1 inhibitor ¹⁷⁰.

Table 2. Selected completed trials with targeted molecular therapies

Molecular Target	Signaling Pathway	Therapy	Trial	Trial Concept (examples)	Trial Result
BRAFV600 mutation		Vemurafenib 153	NCT01524978	Basket trial with recurrent glioma arm	Objective response rate 25% overall; 3/6 glioblastoma had stable disease as best response
BRAFV600E mutation		Dabrafenib + Trematenib 155	NCT02034110	Phase II basket trial using novel Bayesian hierarchical statistical design	Objective response rate for glioblastoma 29%; 62% for low grade gliomas
EGFR amplification		Depatuxizumab mafodotin (ABT414) 150	NCT02573324 (Intellance 1)	Randomized phase III trial in newly diagnosed glioblastoma with EGFR amplification comparing radiation therapy + temozolomide ± depatuxizumab mafodotin	639 patients randomized Ocular toxicity common Depatuxizumab mafodotin median survival 18.9 Placebo: 18.7 Hazard ratio 1.02
EGFR amplification		Depatuxizumab mafodotin (Depatuxizumab mafodotin) (ABT414)206	NCT02343406 (Intellance 2)	Randomized phase II in recurrent glioblastoma comparing Depatuxizumab mafodotin, Depatuxizumab mafodotin + temozolomide, or temozolomide alone	260 patients 25–30% grade 3 or 4 Ocular toxicity Hazard ratio for the combination arm Depatuxizumab mafodotin+temozolomide compared with the temozolomide was 0.71 at initial analysis. On long-term follow-up, hazard ratio for the comparison of the depatuxizumab mafodotin+temozolomide compared with control was 0.66. Efficacy of depatuxizumab mafodotin monotherapy was comparable to that of temozolomide (hazard ratio = 1.04).
Exportin 1	Important for transport of tumor suppressor proteins and oncoprotein mRNA from nucleus to cytoplasm	Selinexor	NCT01986348	Multi-arm phase II trial in recurrent glioblastoma	Objective response rate 10% Progression-free survival at 6 months 19% 6 cycle progression-free survival (24 weeks) 30%
FGFR mutations and FGFR-TACC gene fusions	Highly oncogenic FGFR mutations and FGFR-TACC gene fusion that confers sensitivity to FGFR inhibitors	AZD4547	NCT02824133	Phase I/II study in patients recurrent glioma positive for FGFR fusion	Not available
FGFR mutations and FGFR-TACC gene fusions	Highly oncogenic FGFR mutations and FGFR-TACC gene fusion that confers sensitivity to FGFR inhibitors	Infigratinib (BGJ398) 171	NCT01975701	Phase II study in recurrent glioblastoma with FGFR1-TACC1, FGFR3-TACC3 fusion and/or activating mutation in FGFR1, 2 or 3	26 patients objective response rate 7.7% 4 patients disease control > 1 year (2 FGFR1 mutations, 1 FGFR3 mutation, 1 FGFR3-TACC3 fusion) Progression-free survival at 6 months 16%
mTOR		Everolimus 165	NCT01062399	Randomized phase II trial of radiotherapy+temozolomide ± everolimus in newly diagnosed glioblastoma	171 patients No difference in progression-free survival (median progression-free survival 8.2 months for everolimus vs 10.2 months for control) Overall survival for everolimus was inferior to that for control patients (median overall survival: 16.5 vs 21.2 months, respectively)
mTOR		Temsirolimus	NCT01019434	Randomized phase II of radiation therapy+temozolomide versus radiation therapy + temsirolimus in newly diagnosed unmethylated glioblastoma	111 patients randomized Not difference in 1 year survival (72.2% in temozolomide arm; 69.6% in the temsirolimus arm (hazard ratio 1.16). Phosphorylation of mTORSer2448 in tumor (hazard ratio 0.13), detected in 37.6%, associated with benefit from temsirolimus
Phosphatidylinositol 3-kinase (PI3K)	PIK3CA or PIK3R1 mutation, loss of PTEN activity through PTEN mutation, homozygous deletion or negative PTEN expression (<10% of tumor cells that stained positive), or positive phosphorylated AKTS473 (pAKTS473)	Buparlisib 172	NCT01339052	Multicenter, open-label, multi-arm, phase II trial in patients with PI3K pathway-activated glioblastoma at first or second recurrence	Objective response rate = 0 Progression-free survival at 6 months 8% Median progression-free survival 1.7 month
vascular endothelial growth factor		Bevacizumab 173	NCT0094382 (AVAGlio)	Phase III placebo-controlled trial comparing radiation therapy + temozolomide ± bevacizumab	921 patients randomized Median progression-free survival longer in the bevacizumab group than in the placebo group (10.6 months vs 6.2 months). Overall survival did not differ between groups.
vascular endothelial growth factor		Bevacizumab 174	NCT00884741 (RTOG 0825)	Phase III placebo-controlled trial comparing RT + temozolomide ± bevacizumab	637 patients randomized No difference in overall survival (bevacizumab median, 15.7 months, control 16.1 months (hazard ratio 1.13) progression-free survival was longer in the bevacizumab group (10.7 months vs 7.3 months; hazard ratio, 0.79)
vascular endothelial growth factor		Bevacizumab 95	NCT01290939 (EORTC 26101)	Phase III trial comparing lomustine to lomustine + bevacizumab in recurrent glioblastoma	437 patients randomized No survival advantage with addition of bevacizumab Median overall survival 9.1 months with lomustine compared with 8.6 months in combination group Progression-free survival 4.2 months with bevacizumab + lomustine compared with 1.5 month with lomustine alone
vascular endothelial growth factor receptors 1, 2, and 3 and PDGF receptors	No test yet required	Regorafenib 137	NCT02926222	Randomized phase II comparing regorafenib with lomustine in patients with relapsed glioblastoma (REGOMA):	7·4 months in the regorafenib group and 5·6 months in the lomustine group
vascular endothelial growth factorR2, cMET, AXL, RET	No testing required	Cabozantinib 175	NCT00704288	Single arm phase II in recurrent glioblastoma	220 patients Bevacizumab naive 14.5–17.6% objective response rate; progression-free survival at 6 months 22.3 to 27.6% Bevacizumab failure 4.3% objective response rate.
CD95/CD95ligand	Lower levels of methylation of the CpG2 in the promoter of the CD95 ligand	Asunercept 162	NCT01071837 NCT03152708	Re-irradiation ± asunercept in progressive glioblastoma CAN008 biomarker CD95 Ligand and CpG2 methylation in Chinese patients with glioblastoma	Progression-free survival at 6 months rates were 3.8% for reirradiation and 20.7% for reirradiation+APG101. Ongoing

Abbreviations: mTOR; mammalian target of rapamycin

[Source ⁴⁹ ]

Table 3. Selected ongoing trials with molecularly targeted treatments

Molecular Target	Therapy	Phase	Design	Tumor Type	Trial
mouse double minute 2	AMG-232	Phase 0/I	• P53 wildtype status • Phase 0/I to measure concentrations in tumor in patients with recurrent glioblastoma and of AMG 232 in combination with radiation therapy in patients with newly diagnosed glioblastoma and unmethylated MGMT promoter	Recurrent and newly diagnosed glioblastoma	NCT03107780
mTORC1/2	Sapanisertib (MLN0128)	Phase 0	• No selection • Phase 0 to evaluate tumor pharmacokinetics and pharmacodynamics effects	Recurrent glioblastoma	NCT02133183
CDK4/6	Abemaciclib	0/II	• Patients with activation of CDK4/6 pathway and intact retinoblastoma	Recurrent glioblastoma	NCT02981940
CDKs 1, 2, 7, and 9, JAK2 and FLT3	Zotiraciclib (TG02) with metronomic temozolomide	I/randomized phase II	• Phase I with metronomic temozolomide followed by randomized phase II comparing zoltiraciclib = temozolomide versus temozolomide	Recurrent grade III glioma and glioblastoma	NCT02942264
CDKs 1, 2, 7 and 9, JAK2 and FLT3	Zotiraciclib (TG02) with metronomic temozolomide	I	• Zotiraciclib + radiation therapy for unmethylated MGMT patients • Zotiraciclib with temozolomide for methylated MGMT patients • Zotiraciclib alone for recurrent patients	Newly diagnosed and recurrent grade III glioma and glioblastoma in elderly population	NCT03224104
H3K27M mutation	ONC201 (dopamine receptor D2 inhibitor and ClpP agonist) 176	II	• H3K27M mutated gliomas • Non H3K27M mutated midline glioblastoma	Recurrent H3K27M mutated gliomas and other glioblastoma	NCT02525692 NCT03295396
Interleukin-4 (IL-4) receptor	MDNA55	II	• Convection enhanced delivery of genetically engineered IL-4 linked to a modified version of the Pseudomonas aeruginosa exotoxin A	Recurrent glioblastoma	NCT02858895
hypoxia-inducible factor alpha	PTC2977	II	• No selection	Recurrent glioblastoma	NCT02974738
Proteasome	Marizomib	III	• No selection	Newly diagnosed glioblastoma	NCT03345095
			Platform Trials
Alk mouse double minute 2 sonic hedgehog CDK4/6 mTOR	Alectinib Idasanutlin Vismodegib Palbociclib Temsirolimus	Phase II	• Umbrella trial N2M2/NOA-20 • Alk expression • P53wild-type/mouse double minute 2 high • sonic hedgehog activation • CDK4/6 high or codeletion of CDKN2A/B • Phospho mTOR Ser 24448	Newly diagnosed glioblastoma without MGMT hypermethylation, targeted treatment according to molecular profile	NCT03158389
EGFR mTOR/DNA pharmacokinetics CDK4/6	Neratinib CC115 Abemaciclib	Bayesian adaptive randomized phase II platform trial	INSIGhT Agnostic (assessment post hoc)	Newly diagnosed unmethylated glioblastoma	NCT02977780
Agnostic (assessment post hoc)	Multiple regimens (regorafenib)	Bayesian adaptive randomized phase II/III platform trial	glioblastoma AGILE Multiple	Newly diagnosed and recurrent glioblastoma	NCT03970447

Abbreviations: mTOR; mammalian target of rapamycin

[Source ⁴⁹ ]

Viral therapy and gene therapy

There has been resurgent interest in oncolytic viruses and gene therapy in clinical trials for glioblastoma ¹⁷⁷. Oncolytic viruses are either natural viral strains or genetically engineered viruses designed to infect and/or replicate selectively in tumor cells ¹⁷⁸. Gene therapy instead utilizes viruses that have been rendered replication incompetent but deliver anticancer cDNAs. With either therapy there is an initial phase of direct cytotoxic activity caused by oncolytic virus replication or the gene therapy-delivered anticancer cDNA. This cytotoxicity may then induce a second phase of innate and adaptive antitumor immunity caused by released tumor antigens ¹⁷⁹. There is one oncolytic virus (talimogene laherparepvec) that has been FDA approved for melanoma ¹⁸⁰ and several gene therapys have been approved since 2017, such as voretigene neparvovec (Luxturna) for blindness and onasemnogene abeparvovec (Zolgensma) for spinal muscular atrophy.

For glioblastoma, several phase I clinical trials of both oncolytic viruses and gene therapys are in progress or have been completed, usually in the recurrent setting ¹⁸¹. In most, the treatment is delivered by intratumoral injection at the time of surgery. Currently there are several open gene therapy trials that include: (i) injection in the resected recurrent glioblastoma cavity of an adenoviral gene therapy vector that delivers an IL-12 cDNA whose transcription is activated by an oral agent, veledimex (NCT03636477)259; and (ii) injection into the resected newly diagnosed glioblastoma cavity of an adenoviral vector that delivers a thymidine kinase cDNA that leads to cytotoxicity when subjects take the oral drug, valacyclovir, combined with chemoradiation (NCT03576612) ¹⁸². Both trials also entail neoadjuvant or adjuvant immune checkpoint inhibition to counteract T-cell dysfunction. The latter trial is also being tested in pediatric brain tumors. Currently open oncolytic virus trials in patients with recurrent glioblastoma include: (i) stereotactic injection of an oncolytic herpes simplex virus type 1 (oHSV) that delivers an IL-12 cDNA (NCT02062827); (ii) stereotactic injection of an oHSV that has been engineered to replicate better in glioblastoma cells that express the stem cell marker, nestin (NCT03152318); and (iii) monthly injections of oHSV G47∆ ¹⁸³. There are also trials delivering oncolytic virus with stem cells: (i) intra-arterial delivery of allogeneic bone marrow‒derived human mesenchymal stem cells loaded with the oncolytic adenovirus DNX-2401 (BM-hMSCs-DNX2401) (NCT03896568); and (ii) injection of neural stem cells that deliver an oncolytic adenovirus into newly diagnosed glioblastoma (NCT03072134). A general conclusion is that both oncolytic virus and gene therapy treatments have been well tolerated. When post-tissue treatment is available, there has been evidence of increased infiltration of immune cells, including cytotoxic T cells that also may have upregulated inhibitory immune checkpoint signaling ¹⁸⁴.

More advanced trials (phase II and beyond) are also ongoing mostly for oncolytic viruses in the recurrent glioblastoma setting. These include: (i) convection-enhanced delivery of an engineered poliovirus (PVSRIPO; NCT02986178) ¹⁸⁵;  (ii) stereotactic injection of an oncolytic adenovirus with selectivity for glioblastoma cells driven by the p16/retinoblastoma (RB) pathway and integrin expression (tasadenoturev; DNX-2401) in combination with pembrolizumab (NCT02798406) ¹⁸⁶;  and (iii) intracavitary injection after glioblastoma resection of a retrovirus that delivers a cytosine deaminase cDNA that provides chemosensitivity to 5-fluorocytosine (Toca 511; NCT02414165) ¹⁸⁷. However, the phase III trial of Toca 511 was recently reported to show no survival benefit compared with standard of care in patients with recurrent glioblastoma ¹⁸⁸. A phase III trial of another viral therapy, ofranergene obadenovec (VB-111), which targets tumor endothelium, also failed to show a survival advantage in combination with bevacizumab compared with bevacizumab alone ¹⁸⁹, although it is possible that the simultaneous administration of bevacizumab may have impeded the effects of the virus ¹⁹⁰. Therefore, while there is currently optimism in the pursuit of novel concepts, this optimism must also be coupled with ongoing efforts to find molecular and immunologic variables and targets that may be associated with benefit.

Glioblastoma vaccines

Several experimental therapeutic vaccines have been developed over the past decades to treat glioblastoma multiforme. Dendritic cell vaccines have been able to modify the immune response in patients with malignant neoplasms and induce anti-tumor immunity ¹⁹¹. Recent advances in vaccination with dendritic cells have achieved encouraging results in clinical trials and may improve the survival of patients with glioblastoma multiforme ¹⁹¹. A recent double-blind, randomized phase II trial ¹⁹² evaluated the efficacy of the ICT-107 vaccine based on autologous dendritic cells loaded with six epitopes targeting glioblastoma multiforme-associated antigens: melanoma antigen gene 1, human epidermal growth factor receptor 2 (HER-2), absent in melanoma 2, tyrosi-nase-related protein-2, gp100 (also known as premelanosome protein) and interleukin-13 receptor subunit α-2 in patients with newly diagnosed glioblastoma multiforme, whose major histocompatibility complex serotype was human leukocyte antigen (HLA)-A1+ and/or HLA-A2+. The vaccine increased progression-free survival by 2.2 months but did not increase overall survival (17 months for the treatment group and 15 for the control group).

Modified polio vaccine therapy

The poliovirus receptor CD155 is broadly upregulated on the surface of malignant solid tumors, and a preliminary study of intratumoral infusion of a modified poliovirus vaccine has demonstrated benefit in some cases of recurrent malignant glioma. In a dose-finding and toxicity study, 61 patients with recurrent supratentorial WHO grade 4 malignant glioma received seven doses of a live attenuated poliovirus type 1 vaccine with its cognate internal ribosome entry site replaced with that of human rhinovirus type 2. The recombinant nonpathogenic polio–rhinovirus chimera was infused into the glioma via an implanted catheter ¹⁸⁵.

In contrast to overall survival rates in a historical control group, which declined steadily to 14% at 24 months and 4% at 36 months, overall survival in the study patients stabilized at 21% at 24 months, remaining at that rate through 36 months. Adverse events that affected more than 20% of the study patients in the dose-expansion phase included headache (52%), hemiparesis (50%), seizure (45%), dysphasia (28%), and cognitive disturbance (25%) ¹⁸⁵.

CAR T-cell therapy

CAR T-cell therapy is a type of immunotherapy. You might also hear it called a type of adoptive cell transfer. CAR T-cell therapy is a very complex and specialist treatment. With this treatment, a specialist collects and makes a small change to your T cells. After a few weeks, you have a drip containing these cells back into your bloodstream. The CAR T-cells then recognize and attack the cancer cells.

There is a growing interest in CAR T cells, and more recently, CAR-transduced natural killer cells. CAR T cells have been engineered to express CAR molecules on their surface, which allow them to recognize and bind to specific antigens on tumor cells, leading to target cell killing in an HLA-independent manner ¹⁹³. Although one patient with leptomeningeal spread of glioblastoma responded to treatment with CAR T cells against IL-13 receptor subunit alpha-2 ¹⁹⁴, the experience with CAR T cells to date for glioblastoma has been generally disappointing ¹⁹³. Current efforts are focused on developing next generation CAR T cells directed against multiple antigens, designing them to induce epitope spreading, combining them with checkpoint inhibitors to help overcome immunosuppression or with conventional therapies such as radiotherapy, and delivering them directly into the tumor ¹⁹⁵, ¹⁹⁶.

Other therapies

Overall, almost 100 therapies are under evaluation for glioblastomas. In addition to the ones listed above, other treatments include cytotoxic agents such as Val 083 (NCT02717962), BAL101553 (NCT03250299), and agents that may augment the activity of temozolomide, such as ibudilast (NCT03782415).

Glioblastoma prognosis

Although glioblastoma does not spread to other parts of the body, it is a very aggressive, grade 4 brain cancer that grows and spreads quickly within the brain and, thus, has a poor prognosis. At the present time scientists haven’t yet to find a cure for glioblastoma multiforme. In the mid-1990s, the median length of survival for glioblastoma was only 8–10 months, but it has almost doubled to 15–18 months now ¹⁹⁷, ¹⁹⁸ , ¹⁹⁹, ¹⁷⁴. The current standard glioblastoma multiforme treatment is effective and has resulted in more people living two, three, four years and longer. In addition, in the mid-1990s, essentially no patients with glioblastoma survived 5 years after their diagnosis; now 5.5% to 15% of patients survive 5 years post-diagnosis ²⁰⁰. Once glioblastomas recur, median overall survival is estimated to be 24–44 weeks ²⁰¹.

Various clinical factors are shown to affect survival glioblastoma like age, performance status, MGMT methylation status, and IDH1/2 mutation status. Young age, good performance status, MGMT methylation, IDH 1/2 mutant variety confers to have improved survival compared to their counterparts ²⁰².

Figure 4. Glioblastoma 5-year relative survival 

[Source ⁴⁹ ]

Glioblastoma life expectancy

Patients treated with optimal therapy, including surgical resection, radiation therapy, and chemotherapy, have a median survival of approximately 15–18 months, with fewer than 25% of patients surviving up to 2 years and fewer than 10% of patients surviving up to 5 years ¹⁴.

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