Low-Grade Gliomas

Etiology

There are no known causes of gliomas, and the risk factors favoring the development are poorly understood. Therapeutic irradiation is the only major environmental factor increasing the risk of all brain tumors, including low-grade gliomas.[5] Factors like a diet containing N-nitroso compounds, environmental carcinogens, and several occupations are responsible for sporadic mutations, e.g., TP53. Some hereditary mutations are frequent in gliomas.[6] Brain tumors present in various inherited tumor-predisposing syndromes like neurofibromatosis (NF), Li-Fraumeni cancer syndrome, Lynch syndrome, etc. These syndromes constitute a very small proportion of the overall glioma cases.

Epidemiology

The precise incidence of low-grade gliomas is a shifting target since adopting 2016 WHO CNS classification among tumor registries is just beginning. Based on the studies using the previous classification, the incidence of grade 2 oligodendrogliomas is 0.25, for astrocytomas is 0.51, and for mixed glioma is 0.20 per 100000 per year in the United States.[7] Low-grade gliomas occur more commonly in the younger age group between 20 and 40.[8] The peak incidence for oligodendrogliomas is 40 to 45 years, whereas for astrocytomas is 30 to 40 years. Low-grade gliomas are slightly more common in males.[7]

Pathophysiology

LGGs grow slowly and can be followed over the years without treatment unless they cause symptoms and grow. Multiple acquired genetic mutations are found in gliomas. Tumor suppressor protein 53 (p53), phosphatase and tensin homolog (PTEN), and epidermal growth factor receptor (EGFR) are involved in the pathogenesis of these tumors. p53 is the "guardian of the genome" and ensures the DNA is copied correctly; it destroys the cell if it is mutated. p53 usually mutates early in the disease, and other mutations can survive. EGFR normally stimulates cells to divide, but if it gets amplified, it stimulates cells to divide too much. Together these mutations cause uncontrollable cell division, a hallmark of cancer.[9] 

The most common presenting symptom in LGGs is a headache. Tumors are abnormal growths, and when they increase in size cause pressure effects in surroundings. The pathophysiology behind the headache is due to the increased pressure in the microvasculature due to obstruction, which leads to hydrocephalus. Other symptoms due to obstructive hydrocephalus are changes in vision, nausea, and vomiting.[1]

Histopathology

Atypia, anaplasia, microscopic proliferation, and necrosis are the histological features used to differentiate low-grade from high-grade tumors. Well-differentiated and hypercellular glia with nuclear atypia and rare mitotic activity are the histological features of LGGs. The type of tumor can be differentiated based on the appearance of cells, e.g., fried egg appearance and pleomorphic giant cells are present in oligodendrogliomas and astrocytomas, respectively. Therefore, histological classification is possible for these tumors.[10]

History and Physical

The presenting symptoms depend on the location of the tumor in the brain. For example, behavioral changes are present in frontal lobe tumors; receptive aphasia in temporal lobe mass and parietal lobe tumors can vary in presentation.[11] However, these tumors are relatively less common to present with focal neurological deficits such as unilateral weakness or aphasia. These tumors tend to infiltrate rather than destroy or compress the cortex, thus not causing any functional deficit. Cognitive dysfunction may develop over time and is mainly influenced by tumor location and size.[12]

The most common presenting symptoms in low-grade gliomas are headache and seizures. Seizures are especially common in oligodendrogliomas since these tend to invade the cortex. The seizure can be either partial/focal or sometimes generalized tonic-clonic type. The focal seizures may be unrecognized for a while before an actual diagnosis is concluded. As the tumor size increases, there is a rise in intracranial pressure. Headache manifests due to the increased pressure in the microvasculature and obstruction of the vessels. Other symptoms due to the raised intracranial pressure are changes in vision, nausea, and vomiting. It is important to note that asymptomatic patients are not uncommon, without any obstruction or compression symptoms.[1]

A comprehensive physical examination is necessary to check for any focal neurological deficits and other organ involvement, especially in genetic predisposition syndromes. Papilledema may be seen on fundoscopy.

Evaluation

Once the history and physical examination findings are determined to be concerning for a brain tumor, additional workup using radiographic diagnostic studies should be performed to understand the condition in more detail. The findings of the imaging studies vary according to the type and grade of the tumor.[11][13][14] After the radiological workup, surgery is typically indicated if large and causing neurological deficits and also to obtain a tissue sample for determining the diagnosis and classifying the tumor. The long-term outcomes depend on the type, grade, and molecular characteristics of the tumor, in addition to medical co-morbidities and the individual's age.

Radiological Evaluation

Computed Tomography (CT) Scan: CT scan is typically the initial study obtained due to the acute presentation of patients to the emergency department. On CT scans, the low-grade tumors are usually low-density in appearance. Over 95% of these tumors are located in the supratentorial compartment, mainly either the frontal or the temporal lobes. Calcification can be seen in about 20% of these tumors, particularly in oligodendrogliomas. Contrast enhancement is usually not seen, but when present is patchy in contrast to ring-enhancing typically seen in high-grade gliomas.

Magnetic Resonance Imaging (MRI) Brain: MRI is a more sensitive imaging study to delineate low-grade tumors and soft tissue in general compared to a CT scan. Low-grade gliomas appear hypointense on T1 and hyperintense on T2-fluid attenuated inversion recovery (FLAIR) sequences. Calcification can be evident on susceptibility-weighted imaging (SWI) sequence.[15] Low-grade tumors typically do not enhance and, when present, is patchy and not ring-enhancing. Since contrast enhancement is associated with a breach in the blood-brain barrier, its presence would favor and indicate a more aggressive or a higher-grade tumor.

Advanced Imaging Techniques: Functional MRI, diffusion MRI, perfusion MRI, MR spectroscopy, and positron emission tomography (PET) scan are more advanced diagnostic studies and add a modest value in diagnosing low-grade tumors. These tests are not routinely performed.[16] They help to identify changes in the tumor and its surrounding microenvironment to monitor the response to treatments and progression during the surveillance phase. In PET scans, the accumulation of [18F]-fluorodeoxyglucose can help to distinguish low-grade from high-grade tumors based on the uptake.[17] Other radiolabelled amino acids are also used for these scans.[18]

Neuro-pathological Diagnosis

After a decision to move forward with surgery or biopsy is made by the treating physician or tumor board/multidisciplinary team discussion, the tissue is obtained. The tissue is then subjected to histopathological examination to determine the diagnosis. This is considered the gold standard test to confirm the type of tumor. In addition, molecular markers are also tested to classify the tumor per the 2016 WHO CNS classification.

Histopathology: The main histopathological features that classify brain tumors include atypia, anaplasia, microscopic proliferation, and necrosis. Histologically, low-grade tumors are well-differentiated and demonstrate hypercellular glia with nuclear atypia and rare mitotic activity. An indicator of mitotic activity, the Ki-67 labeling index, is usually below 10% for low-grade gliomas. The appearance of the cells depends upon the type of tumor. Oligodendrogliomas tend to have a classic 'fried egg appearance' with clear, scant cytoplasm, isomorphic round nuclei, and fine delicate branching vessels, sometimes described as 'chicken wire vasculature.' Astrocytomas have pleomorphic giant cells with prominent cytoplasmic processes creating a fibrillary stroma. And these stains intensely with vimentin and glial fibrillary acidic protein (GFAP).[1][10] Oligoastrocytomas have mixed histology, either focally or diffusely distributed.

Molecular Neuropathology: A major restructuring in the WHO classification in 2016 resulted from the findings and understanding of molecular neuropathology of low-grade gliomas.[19] TP53 has been known to be present in most low-grade astrocytomas and rare to absent in oligodendrogliomas. It has also been well known that most of the oligodendrogliomas have co-deletion of the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q). Both these mutations (TP53 and 1p/19q co-deletion) are mutually exclusive in almost all low-grade gliomas.[20] The discovery of mutations of IDH, the gene coding for an enzyme in the Krebs cycle, and isocitrate dehydrogenase being present in over 75% of low-grade glioma has been a breakthrough.[21][22] 

Most are IDH1 mutations (R132H) and, less commonly, IDH2 mutations. These mutations lead to altered enzyme function, ultimately leading to the production of 2-hydroxyglutarate, which is an oncometabolite and has a broad range of effects on gene expression.[23] Thus from a molecular neuropathology perspective, low-grade gliomas may be classified into three categories: a) group with IDH mutation and 1p/19q co-deletion, which comprises oligodendrogliomas, b) group with IDH mutation and without 1p/19q co-deletion where most of these have TP53 mutations and ATRX mutations and comprise of astrocytomas, and c) group with neither IDH mutation nor 1p/19q co-deletion.

Thus, when a glioma is suspected on clinical presentation, imaging, and tissue obtained, it is strongly recommended to test for IDH mutation and 1p/19q co-deletion to have definitive tumor classification. In the 2016 WHO CNS classification, the diagnosis of oligoastrocytoma has been strongly discouraged since molecular studies can almost always aid in the classification of either oligodendroglioma or astrocytoma. Oligoastrocytomas can be diagnosed with a NOS (Not Otherwise Specified) designation and are indicated only when molecular studies are unavailable or not feasible.[2]

Treatment / Management

After presenting with clinical symptoms and imaging findings compatible with a low-grade glioma, the determination of surgical operability is typically considered first. Surgery is indicated in patients with a significant mass effect and neurological deficits secondary to the tumor, and the decision-making becomes obvious. The major challenge arises when the tumor is detected incidentally when an individual presents with a seizure or other neurological symptoms like headache, which is medically controlled and is otherwise asymptomatic.

Multiple factors need to be taken into consideration while making this decision, which includes the preference of the patient and prognostic factors like age, tumor size, and location. Adjuvant treatment with radiotherapy and chemotherapy may be considered in patients that have a high risk of recurrence based on age and extent of resection. In low-risk cases where observation is commonly chosen, serial imaging should be performed with a plan to revisit the decision appropriately based on follow-up studies.

Differential Diagnosis

Multiple conditions can clinically present similar to low-grade gliomas, so a long list of differential diagnoses must be considered carefully, as listed below.[24][25]

• Meningioma
• Primary CNS lymphoma
• Cerebral metastasis
• Spinal tuberculosis
• Brain abscess
• Cavernous malformation
• Cavernous sinus syndrome
• Intracranial hemorrhage
• Stroke
• Progressive multifocal leukoencephalopathy[26]
• Acute disseminated encephalomyelitis (ADEM)

Surgical Oncology

Surgical resection in eligible patients is the cornerstone of treatment with low-grade gliomas. Despite the lack of level 1 evidence, it serves as both a diagnostic and therapeutic modality. Sufficient tissue is obtained not only to confirm the diagnosis but also to perform molecular testing. Resection can relieve mass effects, hydrocephalus, and edema. Although never prospectively examined, the completeness of resection has been shown to impact overall and progression-free survival.[27] For patients with ≥90% resection of the tumor, the 5-year overall survival was 97% versus 76% for those <90%.[27] Based on the overall experience, most authorities in the field favor a maximal safe resection over biopsies.[28] Moreover, the diagnostic accuracy is improved with resection compared to needle biopsies.[29] Iatrogenic neurological deficits should be kept to a minimum. Steroids are typically administered pre-operatively and then tapered over several days postoperatively.

There are multiple techniques available to perform gross total resection (GTR) of the tumors and avoid neurological deficits in extended surgery or when tumors are not well demarcated. These include stereotactic neuro-navigation, intraoperative MRI, fluorescence-guided glioma surgery, and intraoperative functional mapping.[30][31][32][33]

Multiple surgical techniques exist that either maximize tumor resection or minimize morbidity. Intraoperative MRI (iMRI), developed in the 1990s, is one of the more established techniques for tumor identification and serves the goal of maximizing tumor resection through the use of real-time imaging.[34]. The technique provides real-time accuracy taking into account brain shifts from edema, loss of CSF, and tumor removal.[34] Randomized trials comparing iMRI to the more conventional microsurgery with neuro-navigation demonstrated a 96% complete tumor resection using iMRI compared to 68% with conventional techniques, although there was no difference in progression-free survival.[35] No additional surgical morbidity was discovered when using iMRI.

Other methods of tumor detection to maximize resection include heme precursor 5-aminolevulinic acid (5-ALA), which is synthesized into protoporphyrin IX (PpIX), which emits red light when excited by blue light.[34] This technique takes advantage of the difference in blood-brain barrier integrity that exists between infiltrating tumors and healthy brain tissue, as well as differential heme biosynthesis. Patients are given 5-ALA orally or intravenously and, after several hours, will accumulate PpIX, which can be identified during surgery in areas of residual tumor. Most of the prospective data for this technique is for high-grade gliomas, where it has shown a favorable improvement in progression-free survival and higher rates of tumor resection.[36] However, this technique has shown low detection levels in low-grade gliomas ranging from 0 to 35%.[37][38] Currently, this technique is not approved for a low-grade glioma, although new approaches to improve the detection rate are being investigated.[39]

Intraoperative functional mapping describes a multitude of techniques with the common goal of minimizing postoperative morbidity. The awake craniotomy for functional mapping is one such technique. Once the skin incision is complete and the bone flap removed, sedation is discontinued, and direct cortical or subcortical stimulation is then performed.[34] The direct stimulation of neurons is performed using a bipolar stimulation device. Language testing is then performed to look for areas of speech arrest, anomia, alexia, and dysarthria which are then identified in the surgical field. “Negative” functional mapping is the more common technique. A functional map is generated based on cortical stimulation that fails to produce a neurologic deficit. It allows for smaller craniotomies, shorter operative times, and few postoperative neurological deficits compared to the traditional “positive” mapping.[34]

Stereotactic neuro-navigation is commonly used in cranial surgery and allows for a 3-dimensional anatomic reconstruction using cross-sectional imaging such as CT or MRI. It is very useful in preoperative planning as it allows for the tailoring of craniotomies. However, the lack of real-time adjustments due to edema and CSF changes limits its usefulness and typically requires additional functional imaging. MRI diffusion tensor imaging (MRI-DTI) or Magnetoencephalography (MEG) are non-invasive functional mapping tools that can be utilized alongside traditional neuro-navigation. Randomized trials with standard neuro-navigation with or without MRI-DTI demonstrated approximately a 50% reduction in postoperative neurologic deficits (9.8% vs. 18.6%) using non-invasive functional imaging.[40].

LGGs can recur years to decades after initial definitive treatment. These patients may present with seizures, new neurologic deficits, or progression on follow-up imaging. Treatment management in this area is controversial, and the data remain retrospective. Re-resection can be considered when complete resection of the tumor is possible. The completeness of resection at primary treatment and re-resection influences overall survival.[41] The evidence does not suggest a decrement in overall survival with recurrent patients undergoing multiple resections. However, it must be emphasized that a diligent preoperative evaluation with adequate imaging is required to determine the probability of a successful complete resection while minimizing the risk of postoperative morbidity. Functional mapping or intra-operative molecular imaging can be used.

Complications as a result of surgical resection include seizures, epidural hematoma, cerebral abscess, wound infection, stroke, motor deficits, sensory deficits, speech deficits, partial blindness, and behavioral changes.[27][42].

To plan subsequent therapy, MRI is performed in the first 24 to 72 hours postoperatively. Observation is recommended to detect any neurologic deficits afterward.[34]

Radiation Oncology

Radiotherapy utilization in low-grade gliomas was prospectively examined in the mid-1980s in the non-believers’ trial, which evaluated the role of immediate radiotherapy after resection versus salvage.[43]  Five-year progression-free survival (PFS) was 55% vs. 35% in the salvage group without a survival benefit.[43]  In addition, a reduction in seizure activity (25% vs. 41%) was noted, along with no difference in malignant transformation. However, dose escalation trials have failed to show either progression-free or overall survival benefits.[44][45] 

The role of radiotherapy in the setting of low-grade glioma is confined to patients considered at high risk of progression despite surgery. The NCCN guidelines recommend that radiotherapy be offered in patients >40 years old or those with subtotal resection.[46] Several other prognostic factors have been gleaned from the Believers trial that can aid in the decision to offer adjuvant radiotherapy.[44] They include tumor size ≥6cm, age ≥40, tumor crossing midline, astrocytoma histology, and neurological deficits. Patients with three or more risk factors are considered high risk and may benefit from adjuvant radiotherapy.

For high-risk patients, radiotherapy is typically combined with chemotherapy.[46] RTOG 9802 examined the use of 6 cycles of PCV (procarbazine, lomustine, and vincristine) in high-risk WHO Grade II gliomas. There was a significant improvement in median survival (13.3 vs. 7.8 years) and 10-year progression-free survival (51% vs. 21%).[47] Sub-analysis revealed that the benefits of chemotherapy are confined to IDH-mutated gliomas. Other agents, such as temozolomide (TMZ), have been investigated. A Phase II trial using concurrent and adjuvant TMZ demonstrated a 5-year overall survival of 61%, with 54% experiencing a Grade 3-4 toxicity.[48] The ongoing CODEL trial, which includes high-risk WHO Grade II Gliomas and Grade III gliomas with 1p19q co-deletion, is a randomized prospective trial comparing PCV to TMZ with the use of radiotherapy in both arms (NCT00887146). There was a third TMZ alone arm that was closed prematurely due to the extremely high rates of progression.

The timing and sequencing may vary depending on the systemic agent. If PCV is planned, then radiotherapy is typically delivered before chemotherapy. If TMZ is being utilized, then radiotherapy is delivered concurrently.

Simulation Setup

The patient is typically placed in the supine position with head immobilization prior to CT simulation. This is usually accomplished with a thermoplastic head mask. Pre- and post-op MRI of the brain with and without contrast should be fused with the CT images to improve target delineation, including the tumor bed, gross residual disease, and residual edema.

Delivery

Typically, two modalities can be utilized in this setting: Intensity Modulated Radiation Therapy (IMRT) and Proton therapy. IMRT is the most common technique allowing for highly conformal treatment plans that, while leading to a low dose bath of radiation, can generally spare critical structures sufficiently to reduce the risk of long-term side effects. Proton therapy can be used in special circumstances, especially in children, to further reduce the dose to critical structures and hypothetically reduce the risk of long-term toxicity.

Dose and Dose Constraints

Doses typically range from 45-54Gy in 1.8-2.0Gy per fraction.[46][45] It should be noted, however, that doses higher than 45 have not demonstrated a progression-free survival or overall survival benefit.[44][45] Organs at risk include the lens, lacrimal gland, retina, optic nerve, optic chiasm, brain stem, spinal cord, pituitary gland, cochlea, and uninvolved brain tissue. Minimizing the dose to these structures, especially the CNS organs, is critical to reducing the risk of neurocognitive decline and radio necrosis. While specific protocols may vary in acceptable dose constraints, the QUANTEC constraints are acceptable to follow. The brainstem dose goal should be below 54 Gy, which will keep the rate of necrosis below 5%.[49] 

The optic nerve/chiasm should be kept under 55 Gy, which has a <3% risk of neuropathy.[49] Spinal cord doses of 50Gy or less carry a less than 1% risk of myelopathy.[49] Cochlea mean doses ≤45Gy generally have <30% risk of hearing loss.[49] Uninvolved brain doses should be <60Gy to keep the risk of symptomatic necrosis <3%. Lens doses are typically D<5-7Gy.[50] The dose to the retina should be <45-50Gy.[50] The pituitary dosing should be under 45Gy, but in younger patients, the dose should likely be under 30 Gy.[51]

Target Delineation

MRI imaging will be critical to target delineation in these patients. The pre and post-op MRI scans should be fused with the planning CT. Preoperative imaging can help delineate the tumor bed, while post-op imaging is useful for contouring any residual disease and edema. The gross target volume (GTV) is typically any residual disease based on the operative report or imaging. The clinical target volume includes the GTV, the tumor bed, and any post-operative edema on T2/FLAIR MRI sequence. A 1-1.5cm margin is typically added to make the CTV. A PTV margin of 0.5 to 0.7cm is also added.

Re-irradiation

One prospective study observing patients who have undergone a gross total resection of the low-grade glioma and younger than 40 years of age found that slightly over 50% have recurred within five years post-surgery.[52][44] Radiotherapy can be utilized in recurrent LGGs. It can be considered upfront therapy in patients where a gross total resection is not feasible or adjuvant therapy after a high-risk resection. Dosing and fractionation would be dictated by previous RT fields and the volume receiving the additional dose. SRS/SBRT or more fractionated approaches can be considered.

Medical Oncology

The number of systemic agents available for use in low-grade gliomas is quite limited. This is at least partly due to the blood-brain barrier, which prevents higher concentrations of these agents in the CNS. Targeted therapies also have a role in treating some of these malignancies.

Procarbazine, lomustine, and vincristine, typically delivered adjuvant after radiotherapy or surgery, is one of the original treatment regimens investigated prospectively. RTOG 9802 investigated the use of adjuvant PCV after radiotherapy in patients with high-risk low-grade gliomas.[47] While the initial reports did not show a survival benefit, the reports on longer-term follow-up demonstrated a significant increase in 10-year progression-free survival (21% vs. 51%) and overall survival (60% vs. 40%). On sub-analysis, the benefit appeared to be confined to IDH-mutated gliomas. The PCV regimen continues to be evaluated in prospective trials in more aggressive tumor types, such as in the CODEL trial (NCT00887146). The regimen is typically delivered over six cycles Procarbazine at a dose of 60mg/m2 orally per day on days 8-21 of each cycle, Lomustine at a dose of 110mg/m2 orally on day 1 of each cycle, and vincristine at a dose of 1.4mg/m2 (maximum dose of 2mg) administered intravenously on days 8 and 29 of each cycle.[53] Toxicities associated with this regimen include bone marrow suppression resulting in thrombocytopenia, neutropenia, and anemia, with 45% experiencing severe suppression. Hepatotoxicity, neurotoxicity, allergic drug reaction, nausea, and vomiting have also been documented in significant percentages of patients undergoing this treatment regimen.

Temozolomide (TMZ) is an oral alkylating agent that has been used in the treatment of both low- and high-grade gliomas. It typically alkylated guanine residues at the N-7 or O-6 positions. It can be delivered alone, in conjunction with radiotherapy, or as adjuvant treatment after radiotherapy. The efficacy of this medication is thought to be impacted by the expression or silencing O-6-methylguanine-DNA methyltransferase (MGMT) gene. When the gene is expressed in tumor cells, it removes methyl groups from the O-6 position, thus reversing the effect of the drug. Regardless, NCCN guidelines still recommend its use irrespective of MGMT methylation status.[46] RTOG 0424 was a Phase II trial that prospectively evaluated TMZ concurrently and adjuvantly with radiotherapy, which improved 3-year overall survival to 74% compared to 54% in historical controls.[48]

On further follow-up, the 5 and 10-year overall survival was 60.9% and 34.6%.[48] The drug is delivered at 75mg/m given with radiotherapy and 150mg/m post-radiation. The most common toxicity is myelosuppression, as well as nausea and vomiting.

Targeted therapies such as BRAF/MEK inhibitors may be appropriate in certain gliomas, such as pilocytic astrocytomas, pleomorphic xanthoastrocytoma (PXA), and ganglioneuromas. Patients that are incompletely resected or have progression with a BRAF V600E activating mutations may be eligible for Dabrafenib/trametinib or vemurafenib/cobimetinib. These drugs arrest cell growth by inhibiting B-Raf (dabrafenib and vemurafenib) and MEK (trametinib and cobimetinib), which are part of the Ras-Raf-MEK-ERK pathway that stimulates cell proliferation. For subependymal giant cell astrocytomas, an mTOR inhibitor such as everolimus may be considered.

In the setting of recurrent disease, systemic treatments for recurrent LGG can be considered alone, concurrent with radiotherapy, or adjuvantly. PCV, TMZ, or lomustine alone can be considered. PCV or TMZ can be considered after radiotherapy as well. Platinum-based therapies may also be used in cases of progression through other first-line treatments. The TAVAVEC trial investigating the combination of bevacizumab with TMZ in recurrent WHO Grade II and III gliomas failed to demonstrate any improvement in overall or progression-free survival. Another phase 3 trial is conducted to compare RT with adjuvant temozolomide versus RT with adjuvant PCV in anaplastic or low-grade co-deleted gliomas. (NCT00887146) Clinical trials targeting the mutant IDH protein are also underway.[54]

Regardless of the initial management, low-grade gliomas ultimately regrow. Increasing enhancement might develop, and when operated on, the tissue might have transformed into a high-grade glioma by histopathology. This phenomenon is called malignant transformation. Management of patients at this stage would be to treat the alternative treatment, which they did not receive previously.

Prognosis

A spectrum of outcomes is seen in patients with low-grade gliomas. Patient groups can be recognized with a median survival as low as two years to greater than 12 years, depending on the grade according to 2016 WHO CNS classification. A good understanding of the prognostic factors is thus critical in making a treatment decision and patient education in the overall management of these tumors.[55] The clinical prognostic factors include:

• Age: Younger patients do better compared to older patients, with some studies classifying the age of below and above 40 years being low and high risk, respectively
• Symptoms at presentation: Presenting symptoms like seizures are associated with a good prognosis as well, likely due to the earlier diagnosis of the condition leading to close monitoring - this could well be due to lead-time bias, while fixed neurological deficits are associated with a poor prognosis.
• Tumor size and area involved: Tumor size is also important, with larger tumors associated with a poor prognosis, and involvement of the corpus callosum is associated with adverse outcomes.

Molecular tests allow for a more refined estimation of prognosis. The presence of 1p/19q co-deletion is associated with a favorable diagnosis. One study showed that the median survival of 1p/19q co-deleted tumors (oligodendrogliomas) was 12 years compared to 8 years in non-co deleted gliomas.[55] IDH mutation is also associated with a favorable prognosis in most low-grade gliomas. A French study showed an OS of 11 years versus seven years in gliomas with and without IDH mutation in low-grade gliomas treated with temozolomide, indicating a favorable prognosis with chemosensitivity.[56]

Complications

Gliomas tend to grow and increase in size. If the decision is only to observe and leave the tumor unresected, the growth can lead to brain herniation and, ultimately, death. Even a smaller increase in the size of the tumor in a closed space like the cranium can cause a massive shift in intracranial pressure and downstream effects.

Several complications are associated with RT, and the severity depends on the duration of the treatment.

Radiation-induced Effects

Despite the advances in cranial radiotherapy delivery, the risk of acute and delayed side effects remains. The acute side effects include fatigue, headache, nausea, vomiting, dermatitis of the scalp, and hair loss. These symptoms can start within the first few days of treatment however are rarely severe enough to warrant a treatment break. Typically, these symptoms resolve in the weeks following treatment. Typically, the late toxicities are of more concern, especially in patients that are younger when they receive radiation. These late toxicities can appear anywhere from 3 months to several years after treatment. Potential late toxicities include cognitive decline, radiation necrosis, optic neuropathy, spinal cord myelopathy, hearing loss, cataracts, pituitary insufficiency, and radiation-induced secondary tumors. The ability to mitigate these toxicities varies.

Radiation necrosis (RN) is one of the more feared complications of radiation treatment. While it can occur as soon as three months after radiation treatment, it most commonly occurs 1-2 years post-treatment.[57] Common symptoms of RN include cognitive decline, focal neurologic deficits, and seizures. Patients may not have symptoms but only radiographic evidence. RN risk depends on the dose, fraction size, and volume irradiated. While the risk of RN appears to be independent of location, it does appear that certain areas are more susceptible to symptomatic RN than others. Partial brain doses of 60-72 Gy delivered in 2Gy/fraction results in a 1 to 5% risk of symptomatic necrosis.[57] 

It should be noted that there is no evidence of benefit for doses exceeding 60Gy in low-grade glioma; thus, the risk is still quite small. Twice daily radiotherapy or fraction sizes greater than 2Gy/fraction can increase this risk. It may be difficult to distinguish radiation necrosis from tumor progression or pseudoprogression. MRI of the brain with contrast may be the most useful imaging modality. Although imaging features alone are unreliable, they include rim enhancement, soap bubble appearance on T1 post-contrast imaging, and high signal on T2. These features alone only have a 25% positive predictive value, and additional studies will likely be warranted. MR spectroscopy of brain metabolites has been used to measure the choline-creatinine, or choline-n-acetyl aspartate ratios have a sensitivity and specificity of 94.1% and 100%, respectively when the ratio >1.71.[58]

MR perfusion is another method that examines the relative cerebral blood flow (rCBV) based on dynamic susceptibility-weighted MRI, but published data are inconsistent, and the values used vary by acquisition method.[58] PET/CT has also been suggested as a potential imaging modality as necrosis would be hypometabolic compared to surrounding brain tissue, but it has not been established as a reliable technique.[58] 

The first line of therapy for symptomatic radiation necrosis is corticosteroids with a long taper which results in a substantial reduction of inflammation but at the cost of Cushing-like features. In treatment-refractory cases, VEGF inhibitor bevacizumab may be used, and small studies have shown a 97% radiographic response to treatment with a 79% reduction in symptoms.[58] However, there is a risk of thrombosis and hemorrhage with bevacizumab.[58]  In patients with extensive necrosis and symptoms, surgical resection can reduce the mass effect of swelling and reduce symptoms. Hyperbaric oxygen may be another option, but the efficacy of this treatment is not well established.

Spinal cord myelopathy can range from pain, paresthesia, and decreased motor function to outright paralysis. The risk ranges from 1 to 10% with doses of conventionally fractionated RT ranging from 54-60Gy. Brainstem necrosis risk is <5% for patients given doses of 54Gy in 2Gy/fraction but can risk significantly in patients with doses exceeding 64Gy.

Hearing loss may occur in patients, especially if the tumor is near the cochlea, as could be expected with tumors in the temporal lobe. Mean cochlear doses of <45Gy have less than a 30% risk of sensorineural hearing loss (SNHL). Patient factors such as age, post-RT otitis media, and CSF shunts may increase the risk of SNHL.[59]

Radiation-induced optic neuropathy (RION) is characterized by acute monocular vision loss ranging from 3 months to 8 years post-treatment.[60] Up to 85% of patients can have visual acuity of 20/200 or worse.[60] The risk of optic neuropathy is <3%, with doses used in low-grade glioma. Hyper fractionation may help to increase the tolerance of the optic nerve/chiasm.[61]. Corticosteroids and/or hyperbaric oxygen have been used but with disappointing results.

Radiation-induced hypopituitarism (RIH) is a common long-term complication of head and neck radiotherapy. Symptoms vary based on the hormone deficiency that is produced. Commonly, pituitary insufficiency follows a specific temporal pattern with Growth hormone (GH) and Gonadotropin-releasing hormone (GnRH) deficiencies appearing first, followed later by adrenocorticotropic hormone (ACTH) and thyroid-releasing hormone (TRH) deficiency. Hyperprolactinemia may also develop due to the loss of inhibitory control from the anterior pituitary hormones. Interestingly, central diabetes insipidus is not regularly encountered. It usually presents in the first five years after treatment, but new deficiencies can appear over the patient’s lifetime.[62] The risk of hypopituitarism becomes appreciable when doses to the gland exceed 45Gy and is virtually guaranteed with doses exceeding 60Gy.[62] Long-term monitoring of hormone levels is appropriate in these patients. Treatment is typically centered on supplementing the hormone end product or exogenous stimulating hormone.

The lens of the eye is relatively radiosensitive with a conventional established threshold dose of 2Gy in a single fraction and 5 to 7Gy in a fractionated course. Recently this has become disputed as an excess risk compared to non-radiated groups persisted with doses lower than 2Gy. The latency period is inversely proportional to the lens dose, with an average of 2 to 3 years.[63] Over time, the posterior surface of the lens becomes opacified. The only definitive treatment is surgical correction.

Radiation-induced tumors can emerge as a result of cranial radiotherapy. It is mainly a concern in the pediatric population, but as cancer therapies improve, a growing cohort of patients may experience radiation-induced tumors. There was a recent large-scale retrospective cohort study of patients that received cranial radiotherapy for pituitary or craniopharyngiomas with over 20 years of follow-up. The patient received a median of 45 to 50.4Gy, similar to what would be prescribed to patients with low-grade gliomas.[64] The 20-year cumulative risk was 4% in radiated patients but 2.1% in non-radiated patients.[64] The vast majority of secondary tumors were benign (88%), with meningioma being the most common.[64]

Chemotherapy Induced Effects

There are various side effects experienced during chemotherapy treatment, as well. These include hair loss, constipation, flu-like symptoms, and CNS toxicity like weakness, loss of balance, headache, unsteadiness, drowsiness, or dizziness. Vincristine is associated with neuropathy. Bone marrow suppression with low blood counts is seen with lomustine.[65] Medications used for managing seizures and vasogenic edema are also associated with adverse effects that can impair the quality of life in these patients. In addition, anti-convulsant and radiation treatment are associated with cognitive changes that are difficult to differentiate from the decline secondary to the tumor growth itself.[66] Long-term side effects of steroids, typically used for managing vasogenic edema, should also be considered.[67]