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Evidence-based advances in glioma management

Samad, Muhammad A; Nathani, Karim R; Choudry, Usama K; Waqas, Muhammad; Khan, Saad A; Enam, Syed A

doi: 10.4103/ijssr.ijssr_2_18
Review Article

Glioma is primary brain tumors of the glial origin. Glioblastoma multiforme traditionally classified as Grade IV glial tumor carries the worst prognosis. Over the past decades, focus of the diagnosis and management has gradually shifted toward molecular and genetic profiling. This has been accompanied by advancement in radiology, radiation, and medical oncology. Despite significant progress in the individual disciplines, the overall prognosis has not increased significantly. There is consensus on the need of maximum safe resection for most of these tumors. Details of anatomy and white matter tracts obtained through preoperative imaging. These detailed radiological modalities allow the surgeons to plan a safe trajectory to the lesion, avoiding neurological complications. Five aminolevulinic acid and fluorescein guidance help increasing the extent of resection. Awake craniotomy with brain mapping has regained popularity for the safe resection of low-grade glioma, especially those located in eloquent areas. In this review article, we have discussed various aspect of glioma management including diagnosis and surgical resection.

Department of Medical College, The Aga Khan University, Karachi, Pakistan

Department of Medical College, The Aga Khan University, Karachi, Pakistan

Department of Surgery, Section of Neurosurgery, The Aga Khan University, Karachi, Pakistan

Department of Surgery, Section of Neurosurgery, The Aga Khan University, Karachi, Pakistan

Department of Surgery, Section of Neurosurgery, The Aga Khan University, Karachi, Pakistan

Department of Surgery, Section of Neurosurgery, The Aga Khan University, Karachi, Pakistan

Address for correspondence:Syed Enam, Department of Surgery, Section of Neurosurgery, The Aga Khan University, Karachi, Pakistan

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During the last few decades, the treatment options available and the survival of patients with brain glioma have not changed significantly, especially in comparison to other neoplasms, such as lung and breast cancer. 1 Despite the overall poor prognosis for malignant gliomas, incremental improvement has been noticed in survival of the patients due to advances in technology. 2 Over the last decade, the 3-year survival has increased from about 4% in 1999–2000 to 10% in 2009–2010. 3

WHO has classified astrocytomas from grade 1–4 depending on histological characteristics. Grade 1 and 2 are low-grade astrocytomas. Grade 1 astrocytomas exhibit slow growth and are benign in nature. Surgical excision for these tumors is curative in most cases; however, gross total resection (GTR) can sometimes be limited due to adhesions of tumor to the surrounding brain tissue. Grade 2 astrocytomas have greater likelihood of reoccurrence and progression over time, hence surgical excision with histopathological evaluation is very important. Grade 3 and 4 astrocytomas are high-grade gliomas, and surgery with GTR is the preferred approach, however, such as the Grades 1 and 2 astrocytoma, it depends on the location of the tumor. Resection of WHO Grade 3 and 4 astrocytoma is typically followed by chemotherapy and radiotherapy. 1 The 2016 central nervous system WHO introduced a restructured classification which incorporates new entities based on both histology and molecular features. Glioblastoma has been further classified into status of isocitrate dehydrogenase (IDH) mutation in tumor cells. Moreover, diffuse midline glioma, H3 K27M–mutant, and diffuse astrocytoma IDH-mutant were also added to the new classification. 4

Grade 4 astrocytoma, also called glioblastoma multiforme (GBM), is the most common primary intracranial tumor and is known to have the worst prognosis. GBM accounts for 50%–60% of all incident cases of gliomas. The incidence of GBM is 2–3 cases/100 000 people/year in Europe and North America. 5 The standard treatment involves maximal safe surgical resection followed the radiotherapy and chemotherapy. The extend of tumor resection directly effects survival, with more extensive resections providing better survival rates. 6 Hence, safe total resection followed by adjuvant chemoradiotherapy is the primary goal of treatment to provide patients the longest possible survival. 7

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Genetics in Glioma

Multiple genes have been associated with glioma. IDH1 mutations have been observed in more than 70% of low-grade glioma (LGG) and oligodendroglioma. 8 These are also present in 80% of secondary GBM, whereas in <5% of primary GBM. 9 IDH1 mutation has been common in young patients of GBM. 8 Other mutations include p53 mutation and 1p36/19q13 deletion, which are exclusive markers for astrocytoma and oligodendrogliomas, respectively. 10 These molecular parameters have facilitated the diagnosis of brain tumor subtypes with different clinical behavior and prognosis; they can even offer to be targets for future therapies.

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Radiological Advancements

Commonly used in clinical studies for supratentorial high-grade glioma, the Macdonald criteria, comprises of status of neurological deficits and use of corticosteroids. The criterion even assesses the measurement of the tumor lesion. Although widely in use, the criterion has several limitations. Two of the most important limitations are the limited role for nonenhancing tumor components and the poor modality for observation of treatment efficacy on follow-up. These limitations were addressed by the response assessment in neurooncology working group. They introduced a response assessment criterion for the clinical use of high-grade Gliomas in 2010. 11 They established individual criteria for use in case of high and LGG and brain metastasis.

In the past magnetic resonance imaging (MRI) only revealed the information regarding the anatomical location of the tumor and the disruption of blood–brain barrier. However, recent advancement in MRI sequences have led to invention of vascular imaging (perfusion/permeability), proton magnetic resonance spectroscopy (MRS), and diffusion imaging. These modalities provide information regarding cellular, metabolic, functional, hemodynamic, and cytoarchitectural characters of the lesion. 3 These techniques allowed better identification of the tumor margin, aid in tumor grading and also help in reducing surgical risk and assessing the response to therapy. 12

Diffusion-weighted and perfusion-weighted magnetic resonance imaging

Since its introduction in 1985, it has become an integral part of neuroimaging. 13 Diffusion-weighted imaging (DWI) involves measurement of the apparent diffusion coefficient (ADC) using the diffusion properties of water molecules in the tissue. Due to its heterogenic nature, different regions of the brain give different ADC values thus allowing the identification of regions with high cellularity. These regions are recorded with low ADC value. High-grade gliomas have higher cellularity as compared to LGGs leading to a significantly lower ADC value. 14 Provenzale et al. in a review suggested the role of ADC in predicting tumor grade. 15 Value of DWI in predicting pathology or grade; however, is still suggestive and not confirmatory.

Diffusion tensor imaging (DTI) and tractography are based on same principles as DWI and have revolutionized the glioma surgery. DTI helps provide a 3-dimensional structural image of the white matter (WM) tracts for analysis. This information is essential in selecting a safe trajectory to the lesion. 16 , 17 It has been shown to enhance safety by recognition of pyramidal tracts and optic radiation and increase the extent of resection of gliomas. 16 , 17 DTI has now been incorporated into the new generation neuronavigation systems. 18 , 19 With neuronavigation, it is possible to accurately localize, plan, and execute a trajectory which is safe to WM tracts. Use of this technology is on a steady increase.

It has been a challenge to differentiate between radiation necrosis and tumor recurrence. Both the conditions may present with similar features on conventional MRI. Newer sequences therefore, have been extensively looked at. In addition to DWI, perfusion-weighted imaging (PWI) and spectroscopy have been found useful in this regard. PWI measures relative cerebral blood volume (rCBV) of tissues hence regions of neovascularization are recorded with high rCBV value. In a meta-analysis of 13 studies, rCBV was significantly high in cases with tumor recurrence. They also discovered that rCBV (max) >4.2 can be used to predict tumor reoccurrence with 77.8% sensitivity and 94.4% specificity (P = 0.0001). However, biopsy remains the gold standard.

Other than their role in diagnosis and surgical resection, these advanced MRI modalities are also used for prognostication. According to a study, progression frees survival correlated with rCBV parameters (r = −0.54 to −0.56, P ≤ 0.009). This study also showed that rCBV (max) ≤3.8 can also be used as a predictor for 1-year survival with sensitivity of 93.7% and specificity of 72.7% (P =0.0002). 20 In future DWI, DTI and PWI will have an increasing role in the management of gliomas.


Diffusion weight MRI can also be used to record DTI. Using this DTI data, tractography techniques can be used to determine the trajectories of the WM pathways, as shown in Figure 1, allowing the reconstruction of peritumoral WM anatomy pre- and intra-operatively which aide in preoperative planning and intraoperating mapping of brain tumor. This allows neurosurgeons to resect tumor with minimal inference of WM pathways, hence, limiting the postoperative neurological deficits. However, the limitations to these techniques are biological causes such as edema in region surrounding the tumor, mass effect, and tract infiltration by the tumor cells as well as selection biases related to regions of interest or fractional anisotropy values (FA index). 21

Figure 1

Figure 1

A study was conducted to evaluate the efficiency of intraoperative DTI-based tractography in demarcating the corticospinal tract (CST). In this case, DTI was used to construct 40 CSTs. 22 The study revealed the DTI tractography was able to localize the CSTs with 100% sensitivity, 72% specificity, 78% positive predictive value, and 100% negative predictive value, when compared to direct electrical stimulation of subcortex which is the current gold standard.

However, DTI cannot resolve multiple crossing fibers and its results are effected by partial volume effects due to which more advance WM imaging techniques such as high-definition fiber tractography (HDFT) are gaining popularity. A study described five cases in which HDFT was used for the evaluation of perilesional WM tracks. 23 It showed that advanced WM imaging techniques are better in obtaining tractography data compared to conventional DTI, especially in the perilesional edematous regions. Hence, supporting that HDFT is a superior modality in WM imaging.

Magnetic resonance spectrometry

MRS works by providing the metabolic character of the brain glioma. Currently, 23 H MRS is the most widely used method, however, recently 15 P and 24 C MRS have also been used. 25 This technique allows preoperative determination of tumor differentiation, grading, and also helps in planning radiotherapy. Using the metabolic information regarding the tumor may allow greater resection and result in better neurological outcomes for glioma patients. 26

MR spectrometry can distinguish between low-grade and high-grade glioma. A study described the use of MRS-guided brain biopsy to locate the anaplastic foci within a LGG and also determine the correlation of MRS with tumor histology. MRS was used to guide the stereotactic biopsy (done at the maximum Choline/Creatine ratio) followed by tumor resection. The study discovered that the accuracy of MRS-guided biopsy was 84%. Moreover, it was revealed that differentiation between low-grade and high-grade gliomas can be done with sensitivity and specificity of 78%, using the Cho/NAA ratio of 0.9. 27

In a study, 29 patients with brain tumors underwent high-resolution (0.2–1 cc) 3D proton MRS imaging and MR imaging before undergoing surgery. This study compared the histological findings of the tumor biopsies to the preoperative measurement of metabolite levels using MRS. The study successfully demonstrated the use of 3D MRS imaging in determining the regions of cancer, hence, suggesting that MRS can be a valuable tool to guide surgical biopsies and focal therapies. 28

Intensity-Modulated radiation therapy

Use of adjuvant radiotherapy is a well-established method for managing brain tumors, however, 90% failures occur within the region of tumor irradiated. This suggests that the dose delivered by conventional therapy is not enough and there has been recent interest in delivering higher doses to specific but more aggressive regions of the tumor. This has led to development of intensity-modulated radiation therapy (IMRT). The use proton MRS imaging is an effective tool to determine more aggressive regions and target them as it has the ability to determine the biochemical, metabolic, and pathological changes in brain tissues. 29

The use of IMRT for gliomas provides dose distribution at the more correct angles and regions compared with conventional radiotherapy. Due to its focused target area, it offers better sparing of surrounding normal brain tissue. 30 Volumetric modulated arc therapy is new form of IMRT in which continuous modulation of the parameters allows radiotherapy to be delivered at a greater degree of freedom. 30

A study described use of hypofractionated stereotactic radiotherapy, which was delivered using IMRT (HS-IMRT), for recurrent GBM. Modalities such as 2 C-methionine positron emission tomography, computed tomography (CT), and MRI fusion were used to plan for the HS-IMRT. The median follow-up period was 12 months. The study revealed that the median overall survival time (OS) was 11 months from the beginning of the therapy. The study also reported 6-month survival rate of 71.4% and 1-year survival rate of 38.1%. Radiation necrosis requiring reoperation was noted in 4.8% of the patients. 24

Stereotactic radiosurgery

Developments in neuroradiology have not only been restricted to enhanced anatomical details but also now offer an advance therapeutic option. Stereotactic radiosurgery (SRS) uses stereotactic precise delivery of radiation beams from different directions to deliver high dose of radiation to the targeted lesion. This allows high-dose radiation to be delivered to a lesion with minimum acute or late radiation damage to normal adjacent tissues. 31 Gamma Knife™ is a type of SRS, which administers gamma rays from a Cobalt-60 source. Cyber Knife™ uses X-rays to destroy the lesion. Proton beam therapy is an uncommon form of SRS which uses proton beam, instead of radiation. It is available in North America only.

Literature expresses favorable outcomes with use of adjuvant SRS in case of glioma. Due to lack of prospective randomized control trials, the role of SRS in primary glioma treatment is still debatable. 31 A study was conducted to determine the efficacy and safety of gamma knife radiosurgery for the treatment of LGGs. 32 Forty-two procedures, performed on 39 patients with LGGs, were included in this study. Actuarial progression-free survival was at 1, 5, and 10 years were 74.9%, 52.8%, and 39.1%, while actuarial OS was 97.4%, 94.6%, and 91.8% at 9 months, 1 and 5 years, respectively. They controlled solid tumors in 69.2% of patients. Cystic enlargement occurred in 12.9% of patients. Moreover, this technique achieved volume reduction in 57.7% of cases with median volume reduction of 33.3%. The study confirmed that GKRS can be effectively used for controlling tumor growth as well as improving patients overall and progression-free survival in patients with LGGs.

In another study conducted, a total of 25 patients with pilocytic astrocytomas were treated using Gamma Knife™. 33 At 10 years following the procedure, OS rate of 96% and progression free survival rate of 80% was reported. A complete regression of tumor was observed in 10 patients (40%) whereas 10 patients (40%) had partial regression. The study also revealed that the target volume is an important prognostic factor for the patients (P = 0.037). Hence, the study also showed that radiosurgery can an alternative therapy to provide long-term control of pilocytic astrocytomas.

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Vascular endothelial growth factor (VEGF) is a possible target of antiangiogenic therapy in glioblastomas. Bevacizumab (Bev), which is a humanized anti-VEGF antibody, has shown improvement of functionality status and progression-free survival in case of recurrent glioblastoma. Literature has observed improved survival benefit with the use of bevacizumab along with SRS for recurrent high-grade glioma. However, prospective randomized clinical trials are still awaited. 31

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Surgical Techniques

Awake craniotomy

Awake craniotomy (AC) allows the surgeon to continuously monitor the neurological status of their patient while performing open brain surgery. This helps in early detection of interference with functional cortex and hence allowing the surgeon to perform maximal resection of the tumor without damaging the functional cortex and inducing neurological dysfunction. 34 The patient can retain adequate functional capacity, which may allow him to independently carry out his routine and even to go back to work.

A case series from Pakistan reported 16 cases of AC. 35 The authors reported the use of the Karnofsky performance status to assess the preoperative and postoperative functionality. The study revealed that there was a significant improvement in the score with preoperative score of 76 ± 10 and postoperative score of 96 ± 7 at discharge. They reported intraoperative complications in two patients, which were seizure and brain edema. The median operative time and median length of stay were176 min (interquartile range [IQR] 111–352) and 4 days (IQR 3–7), respectively. Hence, this study showed that AC can effectively maintain postoperative functionality patients undergoing glioma resection as well as resulted in a shorter hospital stay. This study shows that AC can be used effectively in developing countries as well.

Despite advancement in the method of surgery, severe neurological deficits may occur while performing an AC. A study reviewed 162 patients who underwent AC. 36 It revealed that 10 (6%) cases experienced severe neurological deficits due to anatomic or ischemic injury of subcortical pathways or internal capsule. The rest of the 152 patients were discharged with good outcomes. In another study, about half of the patients reported to experience certain degree of pain while undergoing AC. 37 Pain was mild and short lasting in most cases and did not hinder the procedure. However, pain was reported as moderate by 25% of the patients.

Extensive resection of brain tumors can lead to neurological deficits, and this has been a limitation in glioma surgery. However, recent data favors performing early surgery which has led to widespread use AC which allows intraoperative functional mapping hence reducing the incidence of neurological deficits. Hence, AC has revolutionized the management of low-grade glioma. 38 It even offers additional benefits of reduce number of ICU admissions, early discharge, and low-overall treatment cost. 34

Five-aminolevulinic acid fluorescein sodium

Fluorescence-guided brain tumor surgery is a recent advancement in glioma surgery. It was first introduced by Moore and is currently being used or is under active trail in many centers. The three most commonly used drugs are 5-aminolevulinic acid (5-ALA), fluorescein sodium, and indocyanine greens. Other stains such as tetracyclines, cresyl violet, cancer-selective alkylphosphocholine analogs, acridine orange, and acriflavine, have also been used for rapid tumor detection; however, limited studies are available for their experience. 39 Intraoperative photodynamic tumor visualization is achieved with use of 5-ALA and fluorescein sodium (Fl-Na) during the resection. 40 5-ALA fluoroscopy detects fluorescent protoporphyrin IX which accumulates in malignant glioma tissue, guiding the resection of the tumor. 41

A review of 105 articles evaluated the use of 5-ALA, fluorescein, indocyanine green, hypericin, 5-aminofluorescein-human serum albumin, endogenous fluorophores, and fluorescent agents. 42 It observed that among all the dyes used 5-ALA is the only fluorescent agent that has been verified by randomized control trails and has shown to improve the rate of GTR as well as progression-free survival in high-grade gliomas. It also revealed that fluorescein has only been studied in observational cohort studies and case series and lead to similar outcomes when used for florescence-guided surgery.

Another study reported the use of simultaneous staining with 5-ALA and Fi-Na during surgery to demarcate the boundary zone between the tumor and the normal brain parenchyma in patients planned to undergo GBM resection. The study reported that 5-ALA was better for detecting tumor cells in the boundary zone than was Fl-Na. However, both the stains failed to highlight some areas of glioblastoma, and tumor cells were found beyond the boundaries highlighted by either agent. 40

Another study studied the use fluorescence spectroscopy-based hand-held probe (HHF-probe) along with the fluorescence-guided resection surgical microscope (FGR-microscope) to detect the tumor and its boundaries. Eighteen operations were performed on 16 patients with suspected high-grade glioma. The study observed that HHF-probe was able to detect tumor after debulking using FGR microscopy, hence showing that HHF-probe is more sensitive than FGR-microscope. It also discovered that the HHF-probe when used in combination with the FGR-microscope was beneficial for when performing resection near the tumor margin. 43

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Many management techniques and options have emerged over the last few decades, with a primary focus to avoid postoperative neurological deficits and maximal safe resection to improve progression and OS. Further developments in radiological and surgical techniques are expected to improve the course of the disease.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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44. . .;:

    Glioma; glioma surgery; radiological advancements; radiosurgery; therapeutic radiology

    © 2018 President and Fellows of Harvard College