The NCCN Guidelines for CNS Cancers include recommendations for management of the following gliomas:9
Version 5.2020 © 2021 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-4
• Grade I: pilocytic astrocytoma, pleomorphic xanthoastrocytoma, ganglioglioma, and subependymal giant cell astrocytoma
• Grade II: diffuse astrocytomas and oligodendrogliomas
• Grade III: anaplastic astrocytoma and oligodendroglioma
• Grade IV: glioblastoma Molecular Profiling for Gliomas
Integrated histopathologic and molecular characterization of gliomas should be standard practice. Molecular/genetic characterization
complements standard histologic analysis, providing additional diagnostic and prognostic information that improves diagnostic accuracy and aids in treatment selection.
Updated Classification of Gliomas Based on Histology and Molecular Features
In 2016, the WHO classification for grade II–III gliomas was revised as follows: 1) oligodendrogliomas are now defined as tumors that have 1p19q codeletion and IDH mutation (unless molecular data are not available and cannot be obtained, in which case designation can be based on histology with appropriate caveats); 2) anaplastic gliomas were further subdivided according to IDH mutation status; 3) oligoastrocytoma is no longer a valid designation unless molecular data (1p19q codeletion and IDH mutation status) are not available and cannot be obtained.9 Such tumors should be described as “oligoastrocytoma, not otherwise specified (NOS)” to indicate that the characterization of the tumor is incomplete. Very rare cases of concurrent, spatially distinct oligodendroglioma (1p19q codeleted) and astrocytoma (1p19q intact) components in the same tumor may also be labeled oligoastrocytoma.9 It is important to note that correlations between the molecularly defined 2016 WHO categories and the histology-based 2007 WHO categories are limited and vary across studies.10-13 Thus, the
change from 2007 WHO to 2016 WHO reclassified a significant proportion of gliomas.
Multiple independent studies on gliomas have conducted genome-wide analyses evaluating an array of molecular features (eg, DNA copy number, DNA methylation, protein expression) in large populations of patients with grade II–IV tumors.12,14,15 Unsupervised clustering analyses, an unbiased method for identifying molecularly similar tumors, have been used to identify subgroups of gliomas with distinct molecular profiles.12,14,15 Remarkably, further analysis has shown that these molecular subgroups could be distinguished based on only a handful of molecular features, including mutation of IDH1/2 and 1p19q codeletion, biomarkers independently verified by many studies as hallmarks for distinguishing molecular subgroups in grade II–III gliomas.10-13,15-21 Using these markers alone, the majority of grade II–III tumors can be divided into three
molecular subtypes: 1) mutation of either IDH1 or IDH2 (IDH-mut) with 1p19q codeletion (1p19q codel); 2) IDH-mut with no 1p19q codeletion or with isolated deletion of 1p or 19q; and 3) no mutation of IDH1 or IDH2 (IDH wild type; IDH-wt).12 Multiple studies have shown that the 1p19q codeletion is strongly associated with IDH mutations, such that true whole-arm 1p19q codeletion in IDH-wt tumors is extremely rare.10,11,18,22,23 In a tumor that is equivocal, the presence of an IDH mutation indicates at least a grade II diffusely infiltrative glioma.24 Grade I non-infiltrative gliomas do not have IDH mutations.24
Other mutations commonly detected in gliomas can have diagnostic and prognostic value, such as those involving the histone chaperone protein, ATRX, which is most often found in grade II–III gliomas and secondary glioblastomas.25,26 ATRX mutation is robustly associated with IDH
mutations, and this combination is strongly suggestive of astrocytoma.27 In contrast, ATRX mutation is nearly always mutually exclusive with 1p19q codeletion. Therefore, a glioma that has loss of normal ATRX
Version 5.2020 © 2021 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-5 immunostaining is unlikely to be an oligodendroglioma. Mutations in the
promoter region of the telomerase reverse transcriptase (TERT) gene occur frequently in glioblastomas and oligodendrogliomas.28,29 TERT promoter mutations in gliomas are associated with 1p19q codeletion and IDH mutations in oligodendrogliomas.30 Interestingly, they are also highly characteristic of IDH-wt and ATRX wild-type glioblastomas, especially those that contain amplification of epidermal growth factor receptor (EGFR).28,29 H3K27M mutations in the histone-encoding H3F3A gene are mostly found in diffuse midline gliomas in both children and adults.31 Patients with these H3K27M mutated gliomas tend to have a very poor prognosis regardless of histologic appearance, so they are classified as WHO grade IV.30,31
Analyses of large databases have also suggested a number of other molecular markers as being potential characteristic/prognostic features of specific subgroups.11,13,15,18,22,27 Molecular features suggested as markers for subtyping grade II–III gliomas include mutations in NOTCH1, CIC, and FUBP1; mutation in TP53 and/or overexpression of aberrant TP53; PTEN loss or promoter methylation; amplification of EGFR; and chromosome 7 gain, chromosome 10 loss.10,12,13,19,30 Due to variability in results across studies, many of these molecular markers are not yet widely used to subclassify gliomas, although the 2020 version of the WHO classification of CNS tumors will include CDKN2A/B homozygous deletion as evidence of grade 4 status in IDH mutant astrocytomas, as indicated by a recent consensus statement.32
Prognostic Relevance of Molecular Subgroups in Glioma
Numerous large studies of patients with brain tumors have determined that, among grade II–III gliomas, 1p19q codeletion correlates with greatly improved progression-free survival (PFS) and overall survival
(OS).11,15,16,33-35 Likewise, the presence of an IDH mutation is a strong favorable prognostic marker for OS in grade II–III gliomas.12 Analyses
within single treatment arms showed that the IDH status is prognostic for outcome across a variety of postoperative adjuvant options. For example, in the NOA-04 phase III randomized trial in newly diagnosed anaplastic gliomas, IDH mutation was associated with improved PFS, longer time to treatment failure (TTF), and extended OS in each of the three treatment arms: standard RT (n = 160); combination therapy with procarbazine, lomustine, and vincristine (PCV; RT upon progression; n = 78); and temozolomide (TMZ; RT upon progression; n = 80).34
Multiple independent studies have shown that subdividing gliomas by molecular subtype, especially IDH1/2 and 1p19q status, yields greater prognostic separation than subdivision based on histology (as defined by WHO 2007). These include very large studies covering multiple grades and histology-based subtypes of gliomas,12,15,33 as well as smaller studies limited to 1 to 2 grades or histologic subtypes.11,36-38 Multiple studies have also shown that, among patients with grade II–III gliomas, the IDH-mut plus 1p19q-codeletion group has the best prognosis, followed by IDH-mut without 1p19q codeletion; the IDH-wt group has the worst prognosis.
11-13,33-35 Analyses within single treatment arms have confirmed this trend in prognosis across a variety of postoperative adjuvant treatment
options.11,34,35,38 TERT mutations in patients with high-grade IDH-wt glioma are associated with shorter OS, compared to IDH-wt tumors without a TERT mutation.13,29,39 However, a multivariate analysis of data from 291 patients with IDH-mut+1p19q-codeleted oligodendrogliomas showed that absence of a TERT mutation was associated with worse OS, compared to patients with TERT-mut oligodendrogliomas (HR, 2.72; 95% CI, 1.05–
7.04; P = .04).40
MGMT (O-6-methylguanine-DNA methyltransferase) is a DNA repair enzyme that can cause resistance to DNA-alkylating drugs.41 MGMT promoter methylation is associated with better survival outcomes in patients with high-grade glioma and is a predictive factor for response to
Version 5.2020 © 2021 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-6 treatment with alkylating chemotherapy such as TMZ or lomustine,30,42-44
even in older adult patients.45,46 Tumors with H3K27M mutations are far less likely to be MGMT promoter methylated31 and are associated with worse prognosis.47,48 Patients whose glioblastomas contain H3F3A G34 mutations, however, may have relatively higher rates of MGMT promoter methylation, and do not have a worse prognosis than other IDH-wt glioblastomas.48,49
Most pilocytic astrocytomas in pediatric patients contain BRAF fusions or, less commonly, BRAF V600E mutations, especially those arising in the posterior fossa; such tumors are rarely high grade.50 BRAF fusion is associated with better prognosis in pediatric low-grade astrocytoma.50-52 The likelihood of a BRAF fusion in a pilocytic astrocytoma decreases with age.50 The BRAF V600E mutation is present in most pleomorphic
xanthoastrocytomas, though it has also been found in some other pediatric low-grade gliomas, such as gangliogliomas and dysembryoplastic
neuroepithelial tumors,30,50,53 as well as a small proportion of glioblastomas (especially epithelioid glioblastoma).54 Retrospective studies have shown that BRAF V600E may be associated with increased risk of progression in pediatric low-grade gliomas,55 but one study found that this association was not quite statistically significant (N = 198; P = .07).52 Some studies have shown that tumors with a BRAF V600E mutation may respond to BRAF inhibitors such as vemurafenib,56-58 but ongoing trials will further clarify targeted treatment options in the presence of a BRAF fusion or V600E mutation (eg, NCT03224767, NCT03430947). BRAF fusion and/or mutation testing are clinically indicated in patients with low-grade glioma.
NCCN Molecular Testing Recommendations for Glioma
Recommendations for molecular testing of glioma tumors are provided in the Principles of Brain Tumor Pathology section in the algorithm. Based on studies showing that IDH status is associated with better prognosis in patients with grade II–III glioma,22,33,34,59 the panel recommends IDH
mutation testing in patients with glioma. Immunohistochemistry can detect the most common IDH mutation, which is IDH1 R132H. However,
sequencing must be done to detect the less common IDH1 mutations (eg, IDH1 R132C) and IDH2. This sequencing should be done in the proper clinical context (eg, younger patients with non-enhancing gliomas).
Patients with oligodendroglioma should also undergo 1p19q testing.
However, since 1p19q codeletion is strongly associated with IDH
mutation,22,23,60 1p19q testing is not necessary in tumors that are definitely IDH-wt, and tumors without an IDH mutation should not be regarded as 1p19q codeleted, even when results suggest otherwise. Mutation testing for ATRX and TERT are also recommended, given the diagnostic value of these mutations.25,27-29 Screening for H3K27M mutations (H3F3A and HIST1H3B sequencing preferred) and BRAF fusion and/or mutation testing may be carried out as clinically indicated.
Grade III–IV gliomas should undergo testing for MGMT promoter methylation status, since MGMT promoter methylated tumors typically respond better to alkylating chemotherapy, compared to unmethylated tumors.42,45,46,61 To date, there are no targeted agents that have shown improvement in OS in the treatment of glioblastoma. Nevertheless, molecular testing of glioblastomas is still encouraged by the panel, as patients with a detected driver mutation may be treated with a targeted therapy on a compassionate use basis, and these tests improve diagnostic accuracy and prognostic stratification. Detection of genetic or epigenetic alterations could also expand clinical trial options for a brain tumor patient.
Low-Grade Gliomas
Low-grade gliomas (ie, pilocytic and diffusely infiltrative astrocytomas, oligodendrogliomas) are a diverse group of relatively uncommon
malignancies classified as grade I and II under the WHO grading system.9 Low-grade gliomas comprise approximately 5% to 10% of all CNS
tumors.62 Seizure is a common symptom (81%) of low-grade gliomas, and
Version 5.2020 © 2021 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-7 is more frequently associated with oligodendrogliomas.63,64 The median
duration from onset of symptoms to diagnosis ranges from 6 to 17 months.
Grade I Gliomas
Diffuse astrocytomas are poorly circumscribed and invasive, and most gradually evolve into higher-grade astrocytomas. Although these were traditionally considered benign, they can behave aggressively and will undergo anaplastic transformation within 5 years in approximately half of patients.65,66 The most common non-infiltrative astrocytomas are pilocytic astrocytomas. Other grade I gliomas in which treatment recommendations are included in the NCCN Guidelines for CNS Cancers are pleomorphic xanthoastrocytoma, subependymal giant cell astrocytoma (SEGA), and ganglioglioma, though these grade I gliomas are uncommon. Pleomorphic xanthoastrocytomas are associated with favorable prognosis,67,68 though mitotic index is associated with survival outcomes.68,69 Gangliogliomas are commonly located in the temporal lobe, and the most significant predictors of survival are low tumor grade and younger age.70
SEGAs are typically located at the caudothalamic groove adjacent to the foramen of Monro. Though they are generally slow-growing and
histologically benign, they can also be associated with manifestations such as hydrocephalus, intracranial pressure, and seizures.71 SEGAs can be distinguished from subependymal nodules by their characteristic serial growth.72 These tumors occur in 5% to 20% of individuals with tuberous sclerosis complex (TSC).73-75
Treatment
Grade I gliomas are usually curable by surgery alone. Indication for treatment of SEGAs is based on development of new symptoms or radiologic evidence of tumor growth.72 Though surgery is sometimes a recommended option for SEGAs, many are in an area not amenable to resection, and recurrence may occur following resection.76,77 Surgery may pose risks because of the frequent location of SEGAs near the foramen of
Monro, but in specialized centers, morbidity is acceptable, and surgical mortality is extremely low.78
There is some evidence that BRAF inhibitors, as well as a BRAF/MEK inhibitor combination, may be used for treatment of low-grade gliomas that are BRAF mutated. The phase II VE-BASKET study showed that
vemurafenib was efficacious in BRAF-mutated low-grade gliomas, particularly PXA, with an overall response rate (ORR) of 42.9% (n = 7), median PFS of 5.7 months, and median OS not reached.58 Another phase II trial including 10 patients with low-grade glioma showed that
dabrafenib/trametinib was associated with an ORR of 56% (5 patients with a partial response and 4 patients with stable disease).79 Case reports have demonstrated clinical activity for the combination BRAF/MEK inhibitor dabrafenib/trametinib in patients with BRAF V600E mutant glioma.80,81 Reducing or stabilizing the volume of SEGAs through systemic therapy has been investigated. A phase III trial showed that 78 patients with SEGA and TSC who received everolimus, an mTOR inhibitor, had at least a 50%
reduction in tumor volume, compared to 39 patients who received a placebo (35% vs. 0%; P < .001), and 6-month PFS was 100% versus 86%, respectively (P < .001).82 Analyses from a long-term follow-up showed that median duration of response was not reached, with response duration ranging from 2.1 months to 31.1 months.83 Tumor volume
reduction rates of 30% and 50% were maintained in patients in the everolimus arm for more than 3 years. This regimen was generally well-tolerated, with the most frequently reported grade 3 or 4 adverse events being stomatitis (8%) and pneumonia (8%). Everolimus has also been investigated in a phase II trial including 58 patients with recurrent grade II gliomas, with a 6-month PFS rate of 84%.84 Medical therapy of SEGA, while effective, is a long-term commitment, unless it is being used short-term to facilitate surgical resection. Once mTOR inhibitor therapy is stopped, lesions typically recur, usually within several months, and
Version 5.2020 © 2021 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-8 eventually reach pretreatment volume. The lesions will continue to grow
unless therapy is reintroduced. Most patients tolerate long-term therapy with mTOR inhibitors quite well.85
NCCN Recommendations
When possible, maximal safe resection is recommended for grade I gliomas, and the actual extent of resection should be documented with a T2-weighted or FLAIR MRI scan within 48 hours after surgery. Patients may be observed following surgery. If incomplete resection or biopsy, or if surgery was not feasible, then RT may be considered if there is
significant tumor growth or if neurologic symptoms are present or
develop. A BRAF/MEK inhibitor combination may be used for patients with BRAF V600E mutant low-grade glioma. Treatment with an mTOR inhibitor (eg, everolimus) should be considered for patients with SEGA,82,83 though institutional expertise and patient preference should guide treatment decision-making for these rare tumors.72
Grade II Infiltrative Supratentorial Astrocytoma/Oligodendroglioma
Radiographically, low-grade oligodendrogliomas appear well demarcated, occasionally contain calcifications, and do not often enhance with contrast.
In histology, the typical “fried egg” appearance of these tumors is evident as a fixation artifact in paraffin but not in frozen sections. Grade II
oligodendrogliomas have a much better 5-year survival rate (82.7%) than diffuse astrocytomas (51.6%).86
Factors prognostic for PFS or OS in patients with grade II gliomas include age, tumor diameter, tumor crossing midline, neurologic status or PS prior to surgery, and the presence of certain molecular markers (see section above on Molecular Profiling for Gliomas).11,16,87-92 For example, IDH1/2 mutation is associated with a favorable prognosis in patients with grade II and III gliomas,12,13,34 supporting the emerging idea that molecular analysis should play a larger role in treatment decision-making, relative to
histopathology.64
Treatment Overview Surgery
Surgery remains an important diagnostic and therapeutic modality. The primary surgical goals are maximal safe resection to delay progression and improve survival, relief of symptoms, and provision of adequate tissue for a pathologic diagnosis and grading. Needle biopsies are often
performed when lesions are in deep or critical regions of the brain. Biopsy results can be misleading, because gliomas often have varying degrees of cellularity, mitoses, or necrosis from one region to another; thus, small samples can provide erroneous histologic grade or diagnosis.93,94
Surgical resection plays an important role in the management of low-grade gliomas. A systematic review showed that GTR was significantly
associated with decreased mortality and lower risk of disease progression up to 10 years after treatment, compared to STR.95 Because these tumors are relatively uncommon, published series generally include patients treated for decades, which introduces additional variables. For example, the completeness of surgical excision was based on the surgeon’s report in older studies. This approach is relatively unreliable when compared with assessment by modern postoperative imaging studies. Furthermore, many patients also received RT, and thus the net effect of the surgical procedure on outcome is difficult to evaluate. Two meta-analyses including studies of primary low-grade gliomas show that extent of resection is a significant prognostic factor for PFS and/or OS.96,97 Maximal safe resection may also delay or prevent malignant progression97-99 and recurrence.100 Patients who undergo an STR, open biopsy, or stereotactic biopsy are, therefore, considered to be at higher risk for progression. GTR is also associated with improved seizure control compared to STR.97
Biological considerations also favor an attempt at a complete excision of a low-grade glioma. First, the tumor may contain higher-grade foci, which may not be reflected in a small specimen. Second, complete excision may
Version 5.2020 © 2021 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-9 decrease the risk of future dedifferentiation to a more malignant tumor.101
Third, removal of a large tumor burden may enhance the benefit of RT. As a result of these considerations, the general recommendation for treating a low-grade glioma is to first attempt as complete an excision of tumor as possible (based on postsurgical MRI verification) without compromising function. However, for tumors that involve eloquent areas, a total removal may not be feasible, and an aggressive approach could result in
neurologic deficits. Residual tumor volume may also be a prognostic factor, with a randomized single institution study showing that the OS benefit of maximal safe resection was limited to patients with a residual tumor volume <15 cm3.102
Adjuvant Therapy
A large meta-analysis, including data from phase 3 trials (EORTC 22844 and 22845,103,104 and NCCTG 86-72-5190), confirmed that surgery followed by RT significantly improves PFS but not OS in patients with low-grade gliomas.105 Early versus late postoperative RT did not significantly affect OS, however, suggesting that observation is a reasonable option for some patients with newly diagnosed gliomas.104
Final results of a phase 3 randomized clinical trial, RTOG 9802, which assessed the efficacy of adjuvant RT versus RT followed by 6 cycles of PCV in patients with newly diagnosed supratentorial WHO grade II gliomas and at least one of two risk factors for disease progression (STR or age ≥40 years)106 showed significant improvements in both PFS and OS with the addition of PCV. 107 The median survival time increased from 7.8 years to 13.3 years (P = .02), and the 10-year survival rate increased from 41% to 62%. It is important to note, however, that roughly three-quarters of the study participants had a Karnofsky Performance Status (KPS) score of 90 to 100, and the median age was around 40 years.106 Exploratory analyses based on histologic subgroups showed a statistically significant improvement in OS for all subgroups except for patients with
astrocytoma.107 Given that the study participants treated with PCV after RT experienced a significantly higher incidence of grade 3 or 4 adverse
events (specifically neutropenia, gastrointestinal disorder, and
fatigue),106,107 PCV may be difficult to tolerate in patients who are older or with poor PS. A retrospective subgroup analysis suggests that the survival benefit with the addition of PCV was seen only in IDH-mut tumors; the IDH-wt subgroup did not appear to benefit from the chemotherapy.108 Combined treatment with RT plus TMZ is supported by a phase 2
multicenter trial (RTOG 0424) in patients with supratentorial WHO grade II tumors and additional risk factors (ie, age ≥40 years, astrocytoma, bi-hemispherical, tumor diameter ≥6 cm, neurologic function status >1).109 However, since the historical controls included patients treated in an earlier time period using different RT protocols, prospective controlled trials are needed to determine whether treatment with TMZ concurrently and following RT is as efficacious as PCV following radiation. There are currently no phase III data to support the use of RT and TMZ over RT and PCV for the treatment of patients with newly diagnosed, high-risk, low-grade glioma. The phase 3 randomized EORTC 22033-26033 trial showed that PFS is not significantly different for adjuvant RT versus dose-dense TMZ in patients with resected or biopsied supratentorial grade II glioma and more than one risk factor (N = 477).17 However, analyses of OS have not yet been reported for this trial.
Radiation Therapy
When RT is given to patients with low-grade gliomas, it is administered with restricted margins. A T2-weighted (occasionally enhanced T1) and/or FLAIR MRI scan is the best means for evaluating tumor extent, because these tumors enhance weakly or not at all. The clinical target volume (CTV) is defined by the FLAIR or T2-weighted tumor with a 1- to 2-cm margin. Every attempt should be made to decrease the RT dose outside the target volume. This can be achieved with 3-dimensional (3D) planning
Version 5.2020 © 2021 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-10 or intensity-modulated RT (IMRT), with improved target coverage and
normal brain/critical structure sparing often shown with IMRT.110,111 The recommended dosing for postoperative RT is based on results from two phase 3 randomized trials showing that higher dose RT had no significant effect on OS or time to progression,90,103 and on several retrospective analyses showing similar results.89,91,112 Because higher doses offer no clear advantages, the CNS Panel recommends lower-dose RT (45–54 Gy) for treatment of low-grade gliomas (grades I/II), including high-risk cases.
However, IDH-wt low-grade gliomas have similar survival only slightly better than IDH-wt glioblastomas.12 Therefore, an RT dose of 59.4 to 60 Gy may be considered for this subset of patients with low-grade glioma.
Preliminary data suggest that proton therapy could reduce the radiation dose to developing brain tissue and potentially diminish toxicities without compromising disease control.113
Recurrent or Progressive Disease
Though the survival impact is unclear, surgery for recurrent disease in patients with low-grade glioma may reduce symptoms, provide tissue for evaluation, and potentially allow for molecular characterization of the tumor.114-117 Maximal safe resection could play an important role for optimizing survival outcomes; a threshold value is unknown, but >90%
extent of resection is suggested.117 For patients without previous RT, results of the RTOG 9802 trial106,107 support use of chemotherapy with RT.
Data from phase II trials inform recommendations for chemotherapy treatment of patients with recurrent or progressive low-grade glioma.118-123 Patients should be enrolled in clinical trials evaluating systemic therapy options.
NCCN Recommendations
Primary and Adjuvant Treatment
For treatment recommendations for newly diagnosed grade II gliomas, the panel used the RTOG 9802106,107 criteria for determining if a patient is
considered to be at low or high risk for tumor progression: patients are categorized as being at low risk if they are 40 years or younger and underwent a GTR; high-risk patients are older than 40 years of age and/or underwent an STR. However, the panel acknowledges that other
prognostic factors have been used to guide adjuvant treatment choice in other studies of patients with low-grade glioma,124 such as tumor size, presence of neurologic deficits, loss of CDKN2A homozygous deletion, and the IDH mutation status of the tumor.17,87 If these other risk factors are considered, and treatment of a patient is warranted, then the panel
recommends that the patient be treated as high-risk.
Patients with low-risk and low-grade glioma may be observed following surgery. Close follow-up is essential as over half of these patients will develop tumor progression within 5 years.92 Following surgery, RT followed by PCV is a category 1 recommendation for patients with grade II glioma who are considered to be at high risk for tumor progression, based on the practice-changing results from the RTOG 9802 study,106,107 as discussed above. There is currently a lack of prospective randomized phase 3 data for the use of radiation and TMZ in patients with low-grade glioma, but interim data from the phase III CATNON trial illustrate that there is a benefit from adjuvant TMZ in patients with newly diagnosed 1p19q non-codeleted anaplastic gliomas.125 Therefore, RT followed by adjuvant TMZ is a category 2A option. Data from EORTC and NCIC studies, which included patients with glioblastoma, support RT with concurrent and adjuvant TMZ as an evidence-based regimen.126,127 Therefore, this is also a category 2A option. Because PCV is generally a more difficult chemotherapy regimen to tolerate than TMZ, it may be reasonable to treat an elderly patient or a patient with multiple
comorbidities with RT and TMZ instead of RT and PCV, but there are currently no data to show that doing so would result in similar
improvement in OS.