GLIOBLASTOMA ACCORDING TO THE LITERATURE

 

CONTACT N.H. TO LEARN MORE ABOUT ALTERNATIVES TO THE CURRENT PRACTICE OF DIAGNOSING AND TREATING BRAIN CANCER.

 

Introduction

Glioblastoma multiforme (GBM) is a rapidly fast-growing tumor that develops in specialized supporting star-shaped cells (astrocytes and oligodendrocytes) of the brain and spinal cord called the glial cells. According to the World Health Organization (WHO), glioblastoma is considered to be the most common primary brain neoplasm (WHO, 2007). GBM is also often referred to as a grade IV astrocytoma, due to its aggressive and invasive nature. 

 

This devastating brain cancer has a high mortality rate with death typically occurring within the first 15 months after diagnosis in the majority of individuals (Bleeker. FE, 2012). These high grade tumors are also largely resistant to therapy and thus correspond to a poor overall prognosis.

 

Primary vs secondary glioblastoma

Glioblastomas have traditionally been subcategorized into primary and secondary tumors, depending upon their occurrence and the nature of the present mutation.

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Primary glioblastoma multiforme

Primary glioblastomas are tumors that arise de-novo, that is in the absence of a prior lesion such as a low-grade astrocytoma. These, however, account for almost 90% of all GBM and are more aggressive than secondary glioblastoma. Primary glioblastomas are usually more common in the elder patient population.

 

Secondary glioblastoma multiforme

Secondary glioblastomas, in contrast to primary Glioblastoma multiforme, are relatively uncommon and account for approximately 10% of all glioblastomas. These tumors arise from pre-existing low-grade astrocytomas and tend to be less aggressive, in comparison to their counterparts (Alifieris C, 2015). These lesions are more commonly observed in younger individuals and interestingly have a higher predilection for the more frontal parts of the brain. 

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Incidence

According to the National Cancer Institute, glioblastoma multiforme has an incidence of 2-3/100,000 adults per year (Dolecek TA, 2012). Overall GBM accounts for 52% of all primary brain tumors. An estimated 14,000, glioblastoma cases are diagnosed each year in the United States alone.

 

Etiology 

The exact cause behind the occurrence of glioblastoma multiforme remains unknown. Multiple pieces of literature propose genetic susceptibility such as association with rare inherited tumor syndromes, like neurofibromatosis type1 (NF1) and Li-Fraumeni syndrome, turcot syndrome, Ollier disease, and Maffucci's syndrome, etc. A vast majority of cases are also identified to be sporadically occurring due to mutations. 

 

Other inconclusively proven causes include prior head trauma, exposure to N-nitroso compounds, occupational toxins, smoking, pesticide exposure, and radiation, etc. Some literature also links glioblastoma to be associated with certain viruses such as SV40, HHV-6, and cytomegalovirus (Crawford JR, 2009) (Vilchez RA, 2003).

 

Epidemiology

Glioblastoma multiforme can occur at any age, however, its peak incidence is documented to be between 65-75 years of age. The disease also demonstrates a slight male predominance of a 3:2 male to female ratio. An ethnic variation is also documented with a greater frequency reported in Caucasians than others.

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Sign & Symptoms of GBM

Glioblastoma multiforme can manifest as a variety of signs and symptoms that depend upon the location of the brain tissue involved. Typically the clinical history of patients with GBM is short, being less than three months in more than 50% of the patients. Some common presenting signs and symptoms may include

 

• The gradually progressive neurological deficits, such as motor weakness, hemiparesis, sensory loss, visual loss, aphasia, etc.

• Generalized symptoms of increased intracranial pressure, including persistent headaches, double or blurred vision, nausea, vomiting, and cognitive impairment,

• New-onset seizures,

• Loss of appetite

• Rarely, less than two percent of patients present with intratumoral hemorrhage and may demonstrate acute stroke-like signs and symptoms.

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Diagnostic Strategies GBM

Multiple invasive and noninvasive techniques are employed to make a diagnosis of glioblastoma multiforme. These include:

 

Neurological exam

The first most clinical exam that is typically carried out once the patient is suspected to have any neurological complaint. This involves an examination of basic neurological functions such as vision, hearing, smell, motor and sensory skills, balance and coordination, and reflexes assessment. This usually gives a rough clue to the practitioner about the suspected location of the pathology. 

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Computed Tomography (CT or CAT scan)

CT Scan aids in identifying and localizing the site, size, and shape of the lesion.

 

Magnetic Resonance Imaging (MRI)

MRI is a more advanced and relatively more precise imaging technique that helps in accurately localizing the lesions for carrying out biopsies and surgical resection. 

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Magnetic resonance spectroscopy (MRS)

It helps detect the tumor’s chemical profile, which further aids in dictating management. 

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Positron Emission Tomography (PET scan)

is especially helpful in the detection of recurrences and metastatic tumor lesions in different parts of the body.  

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Biopsy

In the majority of cases a biopsy of the suspected lesion is required to make a conclusive diagnosis of glioblastoma multiforme. The biopsied sample is also sent for immunohistochemistry to determine the exact nature of the cancerous cell and to assess and predict their response to different cytotoxic drugs.

 

These investigations also aid in guarding the tumor, however, in most instances, a complete staging of the GBM is neither practical nor possible. This is because these tumors usually have ill-defined margins, that invade the surrounding tissue and involve the white matter of the brain.

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Treatment of GBM

Unfortunately, no current treatment regimes are proposed to be curative. On the other hand, without any therapeutic intervention, the mean survival is documented to be around three months only. Therefore, typically a combination of treatment modalities are employed to manage glioblastoma multiforme. These include surgical removal of the tumor, followed by radiation and chemotherapy. 

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Surgery

Surgical resection remains the mainstay of treatment of GBM, where the primary goal is to remove the maximum mass of the tumor without compromising the healthy brain tissue. This primarily attempts to preserve if possible the normal neurological functions such as the motor skills of walking, talking, and other voluntary muscle movements. Unfortunately, in the majority of cases, the GBM is infiltrating in nature, invading the surrounding vital brain tissue, making complete removal of tumor mass extremely unlikely. The reason why additional treatment modalities are offered is adjuvant to surgery.

 

Surgery, thus, mostly aids in the reduction of tumor mass, commonly referred to as the Debulking surgery, and decreases the intracranial pressure. These two combined improvements are known to prolong the survival rate and enhance the quality of remaining life in some individuals.

 

A triple combination of surgical resection along with chemo-radiotherapy has also shown to significantly increase long-term survival. Such a similar study conducted in 2009, (Sonoda et al.) followed 123 patients diagnosed with GBM that were initially treated by maximum tumor resection, followed by radiation therapy and then intravenous injection of cytotoxic agents. Following these treatment regimes, the authors found a long-term survival rate of 14.6%, which was substantially higher than surgical resection alone.

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Radiotherapy

Radiotherapy is mostly initiated post-surgery, or as the first line in advanced and/or inoperable cases. The primary objective of radiotherapy is to eliminate the remaining cancerous cells post-surgery that was difficult to remove due to their infiltrating nature. It is to bear in mind that although radiotherapy is more targeted therapy than surgery, it still damages the healthy tissue surrounding the tumor mass. 

 

However, after every treatment session the healthy tissue repairs, unlike the tumor mass. Typically a total of ten to thirty radiotherapy sessions are required, depending upon the nature of the tumor mass. Studies report the employment of radiotherapy to improve survival outcomes especially when conducted in adjuvant to surgery.

 

Multiple pieces of literature demonstrate clear survival advantages with postoperative radiation therapy (RT) of doses up to 5,000-6,000 cGy. However, further dose-escalation attempts beyond 6,000 cGy have shown to increase toxicity without imparting any additional survival benefit. This has led to the introduction of agents that serve as radiosensitizers and increase the efficacy of the radiation therapy without promoting radiotoxicity (Barani IJ, 2015). 

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Chemotherapy

Chemotherapy involves the administration of cytotoxic drugs that are designed to kill cancerous cells only. These include Temozolomide(Temodar) which is currently regarded as the standard chemotherapy agent for GBM (Hart MG, 2013). it was documented that the survival among patients increased with the introduction of temozolomide from 8.1 to 9.7 months (Dolecek TA, 2012). This drug is administered in six-twelve cycles post-radiation. In some instances, thin disks like preparation of the cytotoxic drugs are also directly administered in the tumor mass during surgery. 

 

The main objective of chemotherapy is long-term control over tumor mass, however, it is reported to impart this effect in only 20% of individuals. Other targeted drug therapy include newer anti-angiogenesis e.g. bevacizumab. Multiple pieces of retrospective studies published document response rates of bevacizumab to be 25% to 74%, and progression-free survival for six months (PFS6) rates of 32% to 64% (Norden AD, 2008). This PFS6 rate is superior to the 21% PFS6 rate reported for temozolomide. 

 

The studies also document bevacizumab therapy to cause rapid reductions in intracranial edema, which is believed to facilitate in decreasing the dose or overall eliminating the need of corticosteroid use. The drug was also found to have a relatively safe side effect profile with a very low risk of intracranial hemorrhage. Hypertension, fatigue, thromboembolic events, and delayed wound-healing were few complications that were reported as bevacizumab toxicities (Narayana A, 2009).

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New advances

As priorly discussed the current treatment strategies are unfortunately able to produce long-term remission in GBM tumors thus multiple advances are under clinical trials as alternatives. These include highly focused radiation therapy, gene therapy, and immunotherapy, etc. Some specialized oncology centers also use radiosurgery where high focus radiation is delivered to the tumor while low intensity in the surrounding tissue. This modality is typically used in selective cases of tumor recurrences. 

 

Another interventional modality includes Tumor treating fields (TTF) therapy that employs electrical fields to disrupt the tumor cell multiplication. This is an FDA-approved therapy that can be employed in both newly diagnosed and recurrent cases of glioblastoma. A three-phased randomized clinical trial conducted in 2015, followed a combination of alternating electric field therapy plus temozolomide in newly diagnosed glioblastoma cases. The study found a significant improvement in 3-month progression-free survival and a 5-month improvement in overall survival when the combination therapy was compared to temozolomide therapy alone (Stupp R, 2015).

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Supportive (palliative) care

The majority of patients of GBM require specialized medical care, that is directed towards relief of symptoms due to the incurable nature of their disease. This includes pain relieving strategies and assistance in managing daily routines etc, that sometimes are also offered along with the aggressive treatment regimens. 

 

The aid of high-dose steroids may also be employed to reduce swelling and decrease symptoms associated with high intracranial pressure (Young RM, 2015).

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Survival Rates of GBM

Despite advancement in treatment options, unfortunately, the prognosis of glioblastoma multiforme remains poor, with an average documented survival between 12-16 months. Individuals that survive up to three years or more of the initial diagnosis are thus referred to as long-term survivors.

 

Factors that negatively impact the prognosis of the disease include; deep location of the lesion, extreme age, and low pre-diagnosis functional status of the patients, etc.

 

 

References

Alifieris C, Trafalis DT. Glioblastoma multiforme: Pathogenesis and treatment. Pharmacology & therapeutics. 2015 Aug 1;152:63-82.

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Barani IJ, Larson DA. Radiation therapy of glioblastoma. Current understanding and treatment of gliomas. 2015:49-73.

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Bleeker FE, Molenaar RJ, Leenstra S. Recent advances in the molecular understanding of glioblastoma. Journal of neuro-oncology. 2012 May;108(1):11-27

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Crawford JR, Santi MR, Thorarinsdottir HK, Cornelison R, Rushing EJ, Zhang H, Yao K, Jacobson S, MacDonald TJ. Detection of human herpesvirus-6 variants in pediatric brain tumors: association of viral antigen in low-grade gliomas. Journal of clinical virology. 2009 Sep 1;46(1):37-42.

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Dolecek TA, Propp JM, Stroup NE, Kruchko C. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005–2009. Neuro-oncology. 2012 Nov 1;14(suppl_5):v1-49.

Grossman SA, Batara JF. Current management of glioblastoma multiforme. seminars in oncology 2004 Oct 1 (Vol. 31, No. 5, pp. 635-644). WB Saunders.

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Hart MG, Garside R, Rogers G, Stein K, Grant R. Temozolomide for high-grade glioma. Cochrane Database of Systematic Reviews. 2013(4).

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Krex D, Klink B, Hartmann C, Von Deimling A, Pietsch T, Simon M, Sabel M, Steinbach JP, Heese O, Reifenberger G, Weller M. Long-term survival with glioblastoma multiforme. Brain. 2007 Oct 1;130(10):2596-606.

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Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P. 2007 WHO classification of tumors of the central nervous system. Acta neuropathologica. 2007 Aug 1;114(2):97-109.

 

Mann J, Ramakrishna R, Magge R, Wernicke AG. Advances in radiotherapy for glioblastoma. Frontiers in neurology. 2018 Jan 15;8:748.

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Narayana A, Kelly P, Golfinos J, Parker E, Johnson G, Knopp E, Zagzag D, Fischer I, Raza S, Medabalmi P, Eagan P. Antiangiogenic therapy using bevacizumab in recurrent high-grade glioma: impact on local control and patient survival. Journal of neurosurgery. 2009 Jan 1;110(1):173-80.

 

Naydenov E, Tzekov C, Minkin K, Nachev S, Romansky K, Bussarsky V. Long-term survival with primary glioblastoma multiforme: a clinical study in Bulgarian patients. Case reports in oncology. 2011;4(1):1-1.

 

Norden AD, Young GS, Setayesh K, Muzikansky A, Klufas R, Ross GL, Ciampa AS, Ebbeling LG, Levy B, Drappatz J, Kesari S. Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. Neurology. 2008 Mar 4;70(10):779-87.

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Roth JG, Elvidge AR. Glioblastoma multiforme: a clinical survey. Journal of neurosurgery. 1960 Jul 1;17(4):736-50.

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Smith JS, Jenkins RB. Genetic alterations in adult diffuse glioma: occurrence, significance, and prognostic implications. Front Biosci. 2000 Jan 1;5(1):213-31.

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Sonoda Y, Kumabe T, Watanabe M, Nakazato Y, Inoue T, Kanamori M, Tominaga T. Long-term survivors of glioblastoma: clinical features and molecular analysis. Acta neurochirurgica. 2009 Nov;151(11):1349-58.

 

Stupp R, Taillibert S, Kanner AA, Kesari S, Steinberg DM, Toms SA, Taylor LP, Lieberman F, Silvani A, Fink KL, Barnett GH. Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma: a randomized clinical trial. Jama. 2015 Dec 15;314(23):2535-43.

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