High Grade Glioma Surgery – Clinical Aspects and Prognosis

Introduction: High grade gliomas (HGG) are a group of tumors with infiltrative nature in general. Surgery is the first step in their treatment. It can be beneficial in two aspects: firstly, in establishing normal intracranial pressure and, secondly, in reducing the tumour volume. The choice of method depends on the location of the lesion, the expected grade of malignancy, and the general condition of the patient. Despite constant development of neuro-oncology and microsurgical techniques, the 5-year survival rate in patients with HGG remains less than 10% and the median survival is still less than 2 years. Aim: At present, there is no final therapeutic “segment” to provide a better outcome than the complex treatment of HGG. Moreover, the treatment’s relative efficacy and recurrence of these tumours carry an additional problem. The aim of this study was to estimate the overall survival of patients with HGG operated in our clinic and compare it with literature data. Materials and methods: One hundred twenty-one cranial operations for HGG were reviewed (conducted between 2014 and 2019). Summary characteristics of the various parameters were presented in respect to the radical nature of the operative intervention using Kaplan-Meier analysis and chi square tests. All patients were followed up at regular check-ups. Results: HGGs were 103 or 85.12% of all gliomas operated for the 2014-2019 period. The most common cases were in the 51 to 60 age group. The cases in men were twice as common. The most common localization of the neoplasm is in the temporal region (36.36%) and the rarest was found in the occipital region (3.30%). It was estimated that our operated patients with HGG had 12.23 months overall survival. Gross total resected patients had a median survival (OS) of 14.53 months, while subtotal resected patients had a median survival (OS) of 10.44 months. It is estimated 7.97 months free tumor survival period (time to relapse FTS) for our operated patients with HGG. Gross total resected patients had a median FTS of 10.88 months, while subtotal resected patients had median FTS of 5.70 months. We noticed permanent new neurological deficit (NND) in 20 patients (19.45%) operated with GTR, and in 5 patients (4.85%) operated with STR. Conclusions: Median survival OS, free tumor survival period FTS and new neurological deficit NND were statistically significant (p<0.05) with extent of resection – GTR or STR in our study. Maximal safe radical (total) or supratotal resection is preferred in treating HGG.


INTRODUCTION
High grade gliomas (HGG) are a group of tumors with infiltrative nature in general. Traditionally, they have been divided into primary and secondary (arising de novo (90%) and developed from a pre-existing lower grade tumor (10%)). High grade gliomas account for 15% of all intracranial neoplasms and approximately 50% of all astrocytomas. HGGs can arise anywhere within the brain; they have a predilection for the subcortical white matter and deep grey matter of the cerebral hemispheres, particularly the temporal lobe. They have a tendency to undergo cystic degeneration with resultant intratumoural necrosis and hemorrhages. The vast majority of HGGs are sporadic. Rarely, they are related to prior radiation exposure (radiation-induced GBM). Surgery can be beneficial in two aspects of HGGs treatment: to establish the normal intracranial pressure and to reduce the tumour volume. The choice of method depends on the location of the lesion, the expected grade of malignancy/infiltration, and the general condition of the patient. Despite constant development of neuro-oncology and microsurgical techniques, the 5-year survival rate in patients with high grade gliomas remains less than 10% and the median survival is still less than 2 years. 1,2 However, patients with extensive resection and adjunctive therapy such as radiation and temozolamide (TMZ) chemotherapy show a longer survival. 3 Accumulated knowledge of the glioblastoma significant molecular, immunohistochemical and gene heterogeneity, make prognostic expectations less enthusiastic. 4

AIM
At present, there is no final therapeutic "segment" to provide a better outcome than the complex treatment of HGG. Moreover, the treatment relative efficacy and recurrence of these tumors present some additional problems. The aim of this study was to estimate the overall survival of patients with HGG operated in our clinic and compare it with literature data.

MATERIALS AND METHODS
Operative surgery reports from 2014 to 2019 were reviewed. One hundred twenty-one cranial operations for HGG were reviewed. All craniotomies were planned by using four methods: craniometric points, CT scans/topograms, MRI scans/topograms, and intraoperative real-time ultrasonography. 5 Summary characteristics of the various parameters were presented in respect to the radical nature of the operative intervention using Kaplan-Meier analysis and chi square tests. All patients were followed up at regular checkups (1 month, 3 month, 1 st year, 2 nd year, 3 rd year) estimating the clinical status.

RESULTS
HGGs were 103 or 85.12% of all gliomas operated for the study period. The most common cases are in the 51 to 60 age group. The cases in men were twice as common. In 64.46% of cases, the patient's condition was assessed by 90 points on the Karnofsky scale. Classic clinical presentation was presented in all cases. The most common localization of the neoplasm was in the temporal region (36.36%) and the rarest one was in the occipital region (3.30%). Infratentorial localization was identified in 1.66% of cases. Eloquent brain areas were affected by 60.33% of neoplasms, 36.36% of tumours were >6 cm in their largest diameter. Twelve (09.91%) reoperations were performed (see Table 1 and 2).

DISCUSSION
HGG surgical resection appears to be vital. A cause for future recurrences is the existence of viable tumor cells over and above the enhancing tumor margins. This suggests why surgical resection is more useful as part of multimodal treatment. 6,7 The impact of HGG surgery is a constant debate among neurosurgeons. The infiltrative nature of HGG makes unimaginable the curative resection. The recurrence delay and prolonging the OS is likely due to a wider margin resection coupled with adjuvant therapy. 1,2, 7 Stummer et al. described the influence on the survival using 5-aminolevulinic acid (ALA) in HGG tumor surgery. 8 The authors reported for comparison of cytoreductive surgery using 5-ALA (n=161) versus conventional white light microscopy (n=161). The researchers concluded that surgical resection using 5-ALA facilitates more complete resections of contrast-enhancing tumour.
Lacroix et al. 9 described 416 patients operated for glioblastoma over a 6-year period. Pre-and post-operative assessment of tumour volume was done using computer image analyses. The authors reported 5 independent predictors of survival: age, KPS, extent of tumor resection, and the amount of necrosis and enhancement on preoperative MRI studies. Resection of 98% or more of the tumor was associated with significant survival advantage [(13 months versus 8.8 months median survival in patients operated with gross total resection (98% or greater)] and less than 98% resection respectively (p=0.02)). This study supports the concept of aggressive cytoreductive surgery as part of the management of high grade gliomas.
Maximal safe tumour resection is the correct surgical treatment of glioblastomas and other HGG gliomas. Technological development in the OR is improved by neuronavigation, awake craniotomy and supratotal resection by fluorescence microscopy (not applied in the clinic). [10][11][12][13][14][15][16][17] However, no extremely significant improvement in the OS through the use of these technologies has been achieved. HGG reoperation has also been debated in the neurosurgical society and there are many studies showing improvement of survival with re-resection. 18,19 Surgical resection of glioblastoma and other HGGs recidivisms should be seriously considered in terms of quality of life and median survival. Chemotherapy with bevacizumab (inhibits angiogenesis) is the only widely accepted non-surgical treatment for recurrent gliomas. 15 HGG treatment is a complex strategy including: surgical tumor resection, radiation therapy, chemotherapy (temozolamide, bevacizumab) and other investigational therapies.
TTF or tumor treating fields (FDA-approved 2015) -Increase 2-year survival from 29% (radiotherapy + TMZ) to 43% in patients treated with TTF in satisfactory postoperative status. Other methods and therapies remain unclear or are still unproven. 3 Our results (following the country's comprehensive treatment algorithm for this pathology) are poorer in terms of postoperative survival as reported in highly specialized neuro-oncology centres in America and Europe (24-months median survival). 1,12,13,16 Post-operative survival of at least 24 months with a high quality of life reaches 58% of the patients operated in San Francisco. 1,2 It is clear that effective methods for the treatment of HGG will be more likely to be found in the scientific laboratories than in ORs. Unfortunately, the biological and molecular HGG heterogeneity (even in the same tumour) is a significant barrier for effective therapies. 20 The ultimate goal of surgery remains the radical (under fluoroscopic microscopy -supratotal) resection and the preservation of brain functions at the same time. Any neurological deficit postoperatively leads to an undesirable risk/benefit ratio for the patient. [12][13][14] Molecular biology and immunology have found molecular markers (MGMT, methyl-guanine-methyl-transferase gene, docking receptors) that are of prognostic significance, thus making conventional histological diagnosis inadequate today. More aggressive treatment is needed to improve the median survival for glioblastoma and other HGGs. More efforts are still needed to provide hope for patients, though it is not clear how to achieve this.

CONCLUSION
Maximal safe radical (total) or supratotal resection is preferred in treating HGG. In our study, the extent of the tumour resection is a statistically significant advantage that influences the median survival, free tumor survival period, and new neurological deficit. After 30 years of researching, the prognosis for HGG patients is still disappointing. New and original approaches originating from scientific laboratories are needed. It seems reasonable to start with a proposal for all patients to be included in clinical trials.  . This percentage could be reduced by using neuronavigation, awake craniotomy and supratotal resection by fluorescence microscopy (not applied in the clinic).