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A Literature Review on Glioblastoma with Special Reference to Surgical Approaches
A. Introduction
Glioblastoma or grade IV astrocytoma is the commonest and aggressive primary tumour in the brain. The term refers to the tumour of the glial cells and accounts for 52% of all brain tumour cases. Conventional chemotherapy or radiation therapies are ineffective due to the location of the tumour and also from the aspect of adverse effects on the brain. Surgical resection of the tumour is the most preferred intervention that shows a better prognosis. The literature review will reflect upon the overview and concerns of glioblastoma treatment options and pathogenesis of the disease. Moreover, it would portray the surgical options available for the management of glioblastomas.
B. Historical Perspective
The term was first introduced by Percival Bailey and Harvey Cushing in 1926. They speculated that tumour originates from precursors of glial cells or glioblasts. Further, they fine-tuned the term as “glioblastoma multiforme” which means the changed shape of glioblasts. Since necrosis and cysts handle the change in morphology of any cell, thus the term “multiforme” was introduced (Bleeker et al. 11-27).
C. Areas of Interests
Interests in the field of Glioblastoma attract both patients and clinicians. Patients want to get awareness in the detection of early symptoms and the risks of incurring Glioblastoma. On the other hand, clinicians are always in the search of newer possibilities in the management of Glioblastoma, apart from the traditional treatments of chemotherapy, surgery and radiotherapy (Hayden 278).

The field that interests both patients and physicians is the expected longevity of an individual after he or she is diagnosed with Glioblastoma. Finally, patients and clinicians are interested in the genesis of glioblastomas and targeted treatment options for managing glioblastomas.
a. Symptoms of glioblastomaThe most significant symptom is the progressive loss of memory, personality and increase in neurological deficit primarily due to the involvement of the disease in a temporal and frontal lobe of the cerebral cortex. The symptoms are associated with the locus of the tumour within the cortex and primarily remain asymptomatic till it reaches a specific size or metastasis. The other common symptoms are vomiting, headache, nausea, dementia and hemiparesis (Murray 118-127).
b. Expected Longevity and Epidemiology
The median survival time without treatment is around 4 and half months, while treatment with radiotherapy, chemotherapy or surgery may prolong the survival time to fifteen months or more(Ghebeh, Bakr & Dermin 1-2).. As such glioblastoma is very rare, with a prevalence of 3 cases per 100000 individuals. Around 50% patients die within one year. Patients die due to cerebral oedema or increased intracranial pressure (Molenaar 1-7).
c. Risk factors
Males are more prone to glioblastoma than females. Genetic predisposition is not an essential risk factor for the disease, as with other carcinomas. Smoking or consumption of excess meat has not been linked to the genesis of the disease till date. Alcohol consumption, infection with SV40 and HHV-6 viruses and cytomegalovirus has been linked to the aetiology of the disease. Moreover ionizing radiation and chemical exposure (like exposure to polyvinylchloride) has been linked to glioblastoma. In 2006, a report linked to brain cancer with lead exposure. Malaria and brain tumour has been closely correlated too (Murray 118-127). The concept is the transmission of viruses causing glioblastoma from the male anopheles mosquito to a human being. It is also speculated that immunosuppression associated malaria causes viruses to cause glioblastoma. Hypersensitivity reactions from drugs and certain environmental chemicals reactivate HHV-6 virus, causing glioblastoma (Bleeker 11-27).
d. Diagnostic Approaches
MRI or magnetic resonance imaging is used to diagnose glioblastomas. They appear as rings (lesions) within the cerebral cortex. However, such lesions are non-specific and can be due to abscesses, metastasis or multiple sclerosis (Smirniotipoulos et al 525-551). Stereotactic biopsy or craniotomy with tumour resection is the conclusive diagnosis (Showalter & Andrel 820-4). Further, an imaging of tumour blood flow by using perfusion MRI is another option to study the vascularity in glioma cells, which is an indication of disease progression and prognosis. Gliomas can be primary or secondary. Primary gliomas have a poor prognosis than secondary gliomas. Secondary gliomas are caused due a defect in IDH1 gene, which can be used a s a molecular marker in the diagnosis of the disease (Murray 118-127).
e. Challenges in Treatment
Glioblastomas are difficult to treat with conventional anti-cancer therapies since most chemotherapeutic agents fail to cross the blood brain barrier (Moviglia et al. 3-13). Moreover, the brain may get damaged by conventional therapies (Murray 118-127).
f. Current Treatment Options
Symptomatic therapy is ensured by anticonvulsants like phenytoin and corticosteroids like dexamethasone. Palliative therapy includes radiotherapy, chemotherapy or surgery. Resection of tumour through surgery is considered the best option. Chemotherapeutic agents like temozolomide and bevacizumab are used but with poor prognosis (Lawson et al. 2006).
g. Developments in Treatment Approaches
Genetically engineered stem cells used to target glioblastomas in mice has been successfully performed in 2014. In 2011, various clinical trials on Glioblastoma showed positive results (Murray 118-127).
h. Pathogenesis of GlioblastomaGlioblastoma is characterized by necrosis of glial cells surrounded by anaplastic cells that are profusely vascularised. The pathogenesis may be explained by:
Molecular alterations – Epidermal growth factor and its receptors are highly expressed in glial cells. The growth factor interacts with its receptors and stimulates the BAD-BCLX2 pathway. This activation leads to phosphorylation of BAD and hence it does not signal BCLX2 (which is the proapoptotic protein). Since the apoptotic pathway is not further stimulated, programmed cell death of the glial cells does not occur and leads to glioma. Other growth factors involved are the platelet-derived growth factor, NF-1 and PI3kinase pathway. The role of all these factors is to prevent the programmed cell death (Murray 118-127).
Up-regulation of ion channels- apart from molecular alterations glioma cells have a unique property to up-regulate potassium and chloride channels on its cell membrane. Entry of potassium and chloride creates the osmotic pull on water. The influx of water leads to the increase in a size of the cell providing increased surface area for vascularisation. Such actions help the glial cells to be alive and exhibit metastasis in surrounding tissues of the brain (Molenaar 1-7).
D. Nomenclature and Classification of GlioblastomasThe nomenclature of glioblastomas is based on recursive partitioning analysis that includes age of patient, likely survival period and treatment options available (Murray 118-127).
Category Age Karnofsky Performance Scale (KPS) Median Survival time
III <50 >90 17.1 months
IV >50 >70 11.2 months
V+VI >50 >70/<70 7.5 months
E. Review of Literature on Surgical Approaches
Principle: Surgical resection of glioblastoma cells are the most preferred options for treatment. Surgery reduces the glial cells from 1011 cells to 109 cells, with a net reduction of 99% of glial tissue. In fact, removal of 98% of the tumour cells has increased the life span of an individual significantly. Performing the surgery with a fluorescent dye aminolevulinic acid is very useful for precision and focused resection of tumour cells (Murat et al. 3015-24).
a. Category of Study: Evaluating success of surgical interventions in recurrent glioblastoma patients.
Study Objective: Impact of Repeated Surgery and Adjuvant therapies on survival time of patients with recurrent glioblastomaThe design of Study: Treatment arms were surgery alone, surgery with adjuvant therapy, adjuvant therapy alone and no treatment. The end point considered was overall survival time between recurrence and death/last follow-up. The adjuvant therapy was provided through temozolomide and radiation therapy.
Results: The overall survival time was not statistically significant between patients receiving total or partial resection of glioblastoma and with different adjuvant groups. However, major surgical morbidity at tumour recurrence occurred in 48% of operated patients.
Conclusion: The probability and risk of surgical morbidity must be carefully evaluated in patients with glioblastoma recurrence. If the risk of morbidity is high as per glioblastoma category, patients may be managed with adjuvant therapy alone (De Bonis et al 883-886).
b. Category of Study: Improvement of Reliability and Safety in Glioblastoma Surgery
Study design: Fluorescent guided the surgery (by using high dose fluorescein sodium 20mg/kg with excitation and barrier filters) in 10 glioblastoma patients were performed.
Results: The method helped to distinguish the details of invisible tumour and brain surface. It allowed determination of detailed assessment of positional relationships of tumour blood vessels and surrounding blood vessels. Since the staining was efficient focussed and precise microsurgery under a normal white light microscope was effectively performed.
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c. Category of Study: Is total surgery or partial surgery of glioblastoma needs to be performed?
Study Design: Meta-analysis approach was taken to evaluate various surgical studies on glioblastoma. Data were retrieved from the ALA-Glioma Study (fluorescence guided versus conventional surgery), BCNU wafer study (BCNU versus placebo).
Results: The medial survival time in the ALA study was 16.7 months and 11.8 months for complete and partial resections respectively, and the difference was statistically significant (p<0.0001). Patients in the BCNU study who had a greater than 90% resection of glial tumour cells, the medial survival time was 14.5 months versus 12.4 months in BCNU and placebo arm respectively and the difference was statistically significant (p<0.02). However when the resection of glial tumour cells was less than 90% there was no statistically significant difference between the medial survival time in BCNU arm versus placebo arm( 11.7 months versus 10.4 months respectively with p=0.98).
Conclusion: Complete resection or resection of glial cells at least above 90% increases the medial survival significantly over partial resections or resection of glial cells below 90%. In fact <90% resection of glial cells is as similar to placebo treatment (Stummer, van den Bent & Westphal 1211-1288).
d. Category of Study: Efficacy of Surgery in Adult and young glioblastoma patients.
Study Design: Retrospective study was done to evaluate overall survival in adult and young glioblastoma patients in Vorarlberg, Austria. 48 patients were evaluated with a median age of 62.5 years who underwent surgically proven glioblastoma surgery. Out of which 16 biopsies, 18 partial resections and 14 complete resections were noted. They were further administered post operative chemotherapy with temozolomide and radiation therapy.
Results: In younger patients the median survival time (16.9 months) was significantly more than the median survival time (7.7 months) of elderly patients( (p<0.005).The type of surgery significantly influenced outcomes in complete resection versus biopsy(p=0.06) in the younger group. However, the overall survival in elderly was not impacted by the type of resection performed.
Conclusion: Younger patients have better prognostic outcomes about medial survival time compared to elder patients. The study further indicated extent or type of surgery does not influence treatment outcomes in elderly patients suffering from glioblastoma (Missios 957-964).
e. Category of Study: Whether Cytoreductive Surgery is better than stereotactic surgery(biopsy)
Study design: There is a controversy about the type of surgery to be performed in patients with glioblastoma. Retrospective data was collected from 1986 and 1991 in patients who underwent stereotactic surgery with adjuvant radiation therapy versus patients who underwent cytoreductive surgery with adjuvant radiation therapy.
Results: The median survival time was 39.5 weeks in the cytoreductive surgery group versus 32 weeks in stereotactic surgery group; however the results were not statistically significant.
Conclusion: Decompression surgery along with radiotherapy should be performed for severe space occupying lesions of glial cells within the brain and especially if the patient does not have a predictive probability of increased neurodeficiency symptoms (Stummer et al 1211-1288).
f. Category of Study: Which is an efficient diagnostic technique to perform glioblastoma surgery?
Study Design: malignant brain tumours recur within 2 cm of the surgical area due to inadequate removal of metastatic cells. The study compared two diagnosis protocol based removal. One was with MRI-guided technology while the other was ALA- induced fluorescence microsurgery. Both the surgeries were performed by using Stealth Station image guidance system. Under the ALA- induced fluorescence imaging the size of the tumours were found to be higher than that with MRI done on the same tumours.
Conclusions: ALA- induced fluorescence imaging was more effective in revealing the size and morphology of the glioblastomas compared to MRI (Eljamel et al. 356-361).
F. Discussion and Conclusion
Glioblastomas impose a significant risk of morbidity and mortality in individuals whether young or elderly. The treatment and management of gliomas are difficult due to the diffuse location of lesions within the brain tissue. The prognosis is impacted owing to its location too. Since, the brain is a highly vascular tissue, carriage of oxygen and nutrients help the cancerous cells to exhibit failure of apoptosis and metastasis much faster compared to other tissues. Moreover, chemotherapeutic agents are not potent owing to their inability to cross the blood-brain barrier. The median survival time after diagnosis of glioblastoma is around 4 months to 2 years, depending upon treatment interventions. Surgery is an important intervention that improves the prognosis of survival time in these patients. Various results have indicated that complete resections of glial cells tumour should be preferred to partial or stereotactic removal o glial cells. The success of surgical intervention lies in the diagnostic technique used to visualize the tumours. ALA- induced fluorescence and High dose sodium induced fluorescence are more effective in revealing the size and morphology of the glioblastomas compared to conventional MRI. The risk of surgery should be taken after due consideration of the age and physical profile of the patients. Surgical interventions may be coupled to radiation or chemotherapeutic treatments. The extent of surgery should involve a resection of at least 90% of tumour cells to reflect a significant improvement in the median survival time of patients. The probability and risk of surgical morbidity must be carefully evaluated in patients with glioblastoma recurrence. If the risk of morbidity is high as per glioblastoma category, patients may be managed with adjuvant therapy alone.
Works Cited
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De Bonis, P, Florentino, A, Anile, C & Balducci,M. “The impact of repeated surgery and adjuvant therapy on survival for patients with recurrent glioblastoma”. Clinical Neurology and Neurosurgery 115.1(2011):883-886. Print
Eljamel, S, Petersen, M,Valentine, R & Buist, R. “Comparison of intraoperative fluorescence and MRI image guided neuronavigation in malignant brain tumours, a prospective controlled study”. Clinical Neuroscience, 10.4(2013):356-361.Print
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Hayden, E. (2010). “Genomics boosts brain-cancer work”. Nature, 463.7279 (2010):278. Print
Lawson, H,; Sampath, P, Bohan, E, Park, M.& Hussain. “Interstitial chemotherapy for malignant gliomas: The Johns Hopkins experience”. Journal of Neuro-Oncology 83.1(2006): 61–70.
 Murray, J. “Glioblastoma brain tumours: estimating the time from brain tumour initiation and resolution of a patient survival anomaly after similar treatment protocols”. Journal of Biological Dynamics 6(2012) :118-127
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Molenaar, R. “Ion Channels in Glioblastoma” ISRN Neurology (2011): 1–7.Print
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Murat, A.; Migliavacca, E.; Gorlia, T.; Lambiv, W. L.; Shay, T.; Hamou, M.-F.; De Tribolet, N.& Regli, L.”Stem Cell-Related ‘Self-Renewal’ Signature and High Epidermal Growth Factor Receptor Expression Associated with Resistance to Concomitant Chemoradiotherapy in Glioblastoma”.Journal of Clinical Oncology 26.8(2008): 3015–24.
Okuda, T, Yoshioka,H, & Kato,A.” Fluorescence-guided surgery for glioblastoma multiforme using high-dose fluorescein sodium with excitation and barrier filters”. J Clin Neurosci., 19.12(2012):1719-22. Print
Showalter, T& Andrel, J. “Multifocal Glioblastoma Multiforme: Prognostic Factors and Patterns of Progression”. International Journal of Radiation Oncology*Biology *Physics 69.3 (2007): 820–4.Print
Stummer,W, van den Bent,M &Westphal, M. “Cytoreductive surgery of glioblastoma as the key to successful adjuvant therapies: new arguments in an old discussion”. Acta Neurochirurgica 11.153(2011):1211-1218
Smirniotopoulos, J. G.; Murphy, F. M.; Rushing, E. J.; Rees, J. H.& Schroeder, J. W. “From the Archives of the AFIP: Patterns of Contrast Enhancement in the Brain and Meninges”. Radiographics 27.2(2008): 525–51.Print