Glioblastoma multiforme

Glioblastoma multiforme (GBM), also known as grade 4 astrocytoma, is the most common and aggressive type of primary brain tumor, accounting for 52% of all primary brain tumor cases and 20% of all intracranial tumors. Despite being the most prevalent form of primary brain tumor, GBM's occur at only 2-3 cases per 100,000 people in Europe and North America.

 Treatment can involve chemotherapy, radiotherapy and surgery, all of which are acknowledged as palliative measures, meaning that they do not provide a cure. The five year survival rate of the disease has remained unchanged over the past 30 years and stands at less than three percent. Even with complete surgical resection of the tumor, combined with the best available treatment, the survival rate for GBM remains very low.

Causes

 Almost all cases of GBM are sporadic, without a familial predilection, although chromosomal aberrations such as PTEN mutation, MDM2 mutation, and p53 mutation are commonly seen in these tumors. Growth factor aberrant signaling associated with EGFR, and PDGF are also seen.

  Pathogenesis

 Glioblastoma multiformes are characterized by the presence of small areas of necrotizing tissue that is surrounded by highly anaplastic cells. This characteristic differentiates the tumor from Grade 3 astrocytomas, which do not have necrotic tissue regions. Although glioblastoma multiforme can be formed from lower grade astrocytomas, post-mortem autopsies have revealed that most glioblastoma multiformes are not caused by previous lesions in the brain

 Unlike oligodendrogliomas, glioblastoma multiformes can form in either the gray matter or white matter of the brain, but most GBM arises from the deep white matter and quickly infiltrate the brain, often becoming very large before producing symptoms. The tumor may extend to the meningeal or ventricular wall, leading to the high protein content of cerebrospinal fluid (CSF) (> 100 mg/dL), as well as an occasional pleocytosis of 10 to 100 cells, mostly lymphocytes. Malignant cells carried in the CSF may spread to the spinal cord or cause meningeal gliomatosis. However, metastasis of GBM beyond the central nervous system is extremely rare. About 50% of GBM occupy more than one lobe of a hemisphere or are bilateral. Tumors of this type usually arise from the cerebrum and may exhibit the classic infiltrate across the corpus callosum, producing a butterfly (bilateral) glioma.

 The tumor may take on a variety of appearances, depending on the amount of hemorrhage, necrosis, or its age. A CT scan will usually show a nonhomogeneous mass with a hypointense center and a variable ring of enhancement surrounded by edema. Part of a lateral ventricle is usually deformed and both lateral and third ventricles may be displaced.

  Symptoms

 Although common symptoms of the disease include seizure, nausea and vomiting, headache, and hemiparesis, the single most prevalent symptom is a progressive memory, personality, or neurological deficit due to temporal and frontal lobe involvement. The kind of symptoms produced depends highly on the location of the tumor, more so than on its pathological properties. The tumor can start producing symptoms quickly but occasionally is asymptomatic until it reaches an enormous size.  

 Diagnosis

 Diagnosis of a suspected GBM on CT or MRI should rest on a stereotactic biopsy or by a craniotomy, which can, at the same time, remove as much tumor as possible. Although the entire tumor can never be removed theoretically due to its multicentricity and diffuse character, partial resection ("debulking") can still prolong survival slightly.

Treatment 

Treatment of primary brain tumors and brain metastases consists of both symptomatic and palliative therapies.

  Symptomatic therapy

 Supportive treatment focuses on relieving symptoms and improving the patient’s neurologic function. The primary supportive agents are anticonvulsants and corticosteroids.

     * Anticonvulsants are administered to the ~25% of patients who have a seizure. Prospective studies have failed to show the efficacy for prophylactic anticonvulsants. Those receiving phenytoin concurrent with radiation may have serious skin reactions such as erythema multiforme and Stevens-Johnson syndrome.

    * Corticosteroids, usually dexamethasone given 4 to 10 mg every 4 to 6 h, can reduce peritumoral edema (through rearrangement of the blood-brain barrier), diminishing mass effect and lowering intracranial pressure, with a decrease in headache or drowsiness.

  Palliative therapy

 Palliative treatment usually is done to achieve a longer survival time, albeit only a slight increase [see below]. It includes surgery, radiation therapy, and chemotherapy.

 A maximally feasible resection with maximal tumor-free margins ("debulking") is usually performed along with external beam radiation and chemotherapy. Total cranial irradiation (4500 cGy) with a boosted dose (1500 to 2000 cGy) at the site of the tumor, can increase survival by 5 months [see below]. The addition of the chemotherapeutic agent carmustine alone increases survival slightly. Most oncologists prefer a combination chemotherapy consisting of procarbazine, lomustine, and vincristine (PCV regimen). Another combination includes carboplatin and cisplatin. Their efficacy is limited, and toxicity, particularly with the PCV regimen, can be considerable. Despite initial studies suggesting the superiority of PCV over BiCNU, there are now clear data demonstrating no benefit of PCV over BiCNU in either glioblastoma or anaplastic astrocytoma patients. Brachytherapy (implantation of radioactive beads or needles) and high-dose focus radiotherapy (stereotactic radiosurgery) have not shown to increase survival times. 

In a large phase III trial, implantation of BiCNU-impregnated wafers - trade name Gliadel Wafers- at the time of primary resection, improved median survival to 13.9 months, compared with only 11.6 months for placebo wafers (P = .03), in newly diagnosed patients with malignant glioma. Despite initial treatment, virtually all malignant gliomas recur. At relapse, patients may benefit from re-resection, focal radiotherapy techniques (such as radiosurgery), and different chemotherapeutic agents. Depending upon which chemotherapeutic agent was used at initial treatment, temozolomide, procarbazine, or a nitrosourea would be a reasonable conventional choice at recurrence. Clinical trials employing signal transduction inhibitors, epidermal growth factor receptor inhibitors, or antiangiogenic agents may also be available at tumor relapse.