Astrocytoma, a type of glioma (neuroglial cell tumor), is neuroepithelial in origin and arises from the astrocytes present in the brain and spinal cord. Astrocytomas are highly common in the brain but can also occur in the spinal cord. The World Health Organization (WHO) has classified astrocytomas into four distinct grades based on their histology (constituent cell type), which also correlates to the level of their malignancy (aggressiveness of the cancer), prognosis (treatment outcome), period of overall survival (OS), and progression free survival (PFS). The etiology (cause) of astrocytoma is unknown. It may present as a primary brain tumor or may arise from metastasis (spread of cancer from one part of the body to other). There is no evidence for a definitive premalignant (precancerous) or an attributable precursor lesion or stage for astrocytoma.
The earliest recognized stage of an infiltrating (encroachment on adjacent healthy tissue) astrocytoma is WHO Grade II or Diffuse Astrocytoma. The regional effects caused by astrocytoma are due to compression, invasion, and destruction of surrounding healthy brain tissue by the tumor. The major focal damage brought about by a growing astrocytoma are arterial (of the arteries) and venous (of the veins) hypoxia (low oxygen saturation), shortage of cellular nutrients and release of abnormal cell mediators (significant biochemical molecules that participate in cell-to-cell communication) that disrupt the neural tissue. The neural effects are due to disruption of healthy nerve transmission and structural damage of neurons. The secondary effects comprise a raised intracranial pressure (ICP – pressure in and around the tissues of the brain) and extracellular fluid volume (ECF – the fluid present around and in between cells in the body tissue) in the central nervous system (CNS). Astrocytoma can be either asymptomatic (usually in the early stages) or symptomatic. The generalized clinical signs include headache, nausea, and vomiting, while the focal signs (which are due to regional brain tissue damage) comprise defects in vision, hearing, and speech. High-grade astrocytomas (WHO Grades III and IV) show rapid progression of symptoms (within a few weeks). Headache from CNS tumors are mostly tension type, bifrontal (both sides of the forehead), constant and dull. Low-grade astrocytomas typically present with seizures. The obstruction and accumulation of ECF leads to an increase in the ICP. The classic triad of increased ICP presents with headache, nausea, and papilledema (swelling in the nerve of the eye). For example, signs of raised ICP in infants comprise an enlarged head with prominent scalp veins. The typical signs of a brain tumor include mental confusion, learning impairment, disturbed vision, seizures, and ataxia (poor muscular control). Astrocytoma is often associated with other diseases such as Li-Fraumeni syndrome (Tp53 syndrome), Turcot-Lynch syndrome (DNS mismatch repair loss), Neurofibromatosis (NF) type 1 & 2, and Tuberous Sclerosis Complex (TSC).
There are several biomarkers (biochemical molecules/biologic traits, characteristic/indicative of a particular process/condition) that mark tumorigenesis (process of tumor generation) and/or indicate early malignancy in astrocytoma. There is neither a known cause, nor an established prevention strategy for astrocytoma. Early diagnosis, a lower histologic grade, and better clinical performance at diagnosis, are good prognostic indicators. With the exception of blood tests, radiography (magnetic resonance imaging ‘MRI’ and to a lesser extent computer tomography ‘CT’), are routinely employed in diagnosis and treatment planning. Histology (microscopic study of tissue structure), however, is the gold standard to accurately define the grade and type of astrocytoma. The treatment regimen is dictated by the grade of malignancy, anatomic site, age, and general condition of the patient. Low-grade tumors require less aggressive intervention than high-grade tumors, the latter which necessitates a rigorous intervention. The treatment may comprise active surveillance only, maximal safe surgical resection followed by active surveillance, and/or fractionated radiotherapy, and chemotherapy. Supportive or adjunctive therapy serves to alleviate the clinical symptoms of tumor and adverse effects of the conventional treatment methods. A multidisciplinary approach is crucial for planning and execution of the treatment. The team of doctors includes a neurosurgeon, a radiation oncologist, a medical oncologist, and a neurologist. Post treatment close monitoring is mandatory for all astrocytomas.
Surgery can either be a conventional craniotomy or stereotactic (3D imaging-guided) craniotomy which is performed for two reasons – maximal debulking of tumor, and to obtain a biopsy specimen. The extent of resection (EOR) of tumor relates positively to the length of progression free survival (PFS) and overall survival (OS) of the patient. Low grade astrocytomas are routinely treated by supratotal (beyond the tumor boundaries) resection. Additionally, a ventriculoperitoneal (VP) shunt or an external ventricular drain (EVD) may be used to drain out excess ECF and lower the raised ICP. External radiotherapy techniques employed in the treatment of astrocytoma encompass Conformal Radiotherapy, Intensity Modulated Radiation Therapy (IMRT), and Stereotactic Radiotherapy. The advanced radiotherapy techniques which include Proton Radiotherapy, and Carbon Ion Radiotherapy (CIRT) have the advantage of better tissue penetration and cause less collateral damage to the surrounding healthy brain tissue. Chemotherapy can be systemic (oral or parenteral/intravenous administration of drug), intrathecal (drug is placed directly into the cerebrospinal fluid ‘CSF’) or regional (drug is inserted into an organ or a body cavity). The drugs commonly used in treating malignant astrocytoma are Carmustine/BCNU, Lomustine/CCNU, and Nimustine/ACNU. In addition, combination regimens of various drugs, including microtubule inhibitors, topoisomerase inhibitors, organometallics (carboplatin and cisplatin), temozolomide, angiogenesis inhibitors (angiostatin and endostatin), and signal transduction inhibitors such as tamoxifen are being utilized as part of the chemo-oncologist’s armamentarium.
Immunology based cancer therapies are beginning to receive attention as alternatives to the foregoing treatment options. Many of these new therapies are still undergoing clinical trials. These novel treatments include gene therapy, wherein a therapeutic genetic substance (DNA/RNA) is administered directly into the tumor cell via a nanoparticle or an oncolytic immunogenic virus (special tumor-destructor virus); dendritic cell vaccine therapy that utilizes a vaccine made from antigens (Ag) and antigen presenting cells (APC) against the mutant IDH enzyme; and Pd-1/Pd-L1 Pathway (tumor-initiated cellular pathways hamper the human body’s natural immunity to resist/fight cancer) inhibitors. The FDA approved anti-PD-1 antibodies are Nivolumab, Pembrolizumab, and Cemiplimab, and the FDA approved anti-PD-L1 antibodies are Atezolizumab, Aduvumab, and Duravulumab.
The current focus of research on this disease is the development of targeted therapy based on the molecular pathophysiology (the process of disease progression) of astrocytoma. The identification of specific biomarkers for each astrocytoma type guides the development of precisely tailored (personal medicine also translational medicine) therapeutic strategies that can minimize the systemic toxicity (adverse effects of a treatment procedure) and overcome the disadvantages of conventional cancer therapies. High-grade astrocytomas have a significant negative impact on the health-related quality of life (HRQL) post-treatment, especially when recurrent, while the low-grade tumors are associated with a relatively better HRQL. Therapy or counseling has proved successful in enhancing or maintaining HRQL in patients with astrocytoma, even though it cannot significantly improve their long-term survival.
Written by Manasa Tata, M.D.S. (Rhenix LifeSciences) & Lawrence D. Jones, Ph.D. (CureScience)