Glioblastoma is classified as a WHO grade 4 tumor and is one of the most aggressive tumors, with a 10-year survival rate of 0.71%1. Glioblastoma is the most common malignant primary brain tumor in adults and has the poorest 5-year survival rate of all tumor types occurring in humans2.
It is a tumor that originates from the glial cells of the brain and exhibits infiltrative growth. The mainstays of glioblastoma treatment are surgical resection, radiation therapy, and chemotherapy.
Glioblastomas can occur anywhere in the brain, but are particularly common in a supratentorial location and are extremely rare infratentorially. In principle, a distinction is made between primary and secondary glioblastomas. Primary glioblastoma develops directly from glial cells, whereas secondary glioblastoma develops from a low-grade glioma.
Epidemiology
In the United States, the incidence rate was 3.19 per 100,000 persons, with a mean age of 64 years, and it occurs approximately 1.6 times more frequently in men than in women3. The figures in Europe are approximately comparable to those in the United States. Glioblastomas are rare in children and adolescents, but can also occur in this age group. The mean age of children with a supratentorial glioblastoma is 12.7 years, and that of children with glioblastomas in the brainstem is 6.7 years4.
Symptoms
The symptoms leading to the initial diagnosis of glioblastoma vary considerably. For example, changes in behavior may occur and be noticed by family members. A 1957 study of 219 patients across all age groups demonstrated the most common symptoms that led patients to become symptomatic5, with headache being the most common symptom.
Symptom frequency
| Symptom | Present in (%) | Initial symptom in (%) | Main complaint in (%) |
|---|---|---|---|
| Headache | 86 | 37 | 35 |
| Mental changes | 47 | 7 | 3 |
| Nausea, vomiting | 45 | 0 | 1 |
| Motor deficit | 44 | 3 | 5 |
| Visual impairment | 39 | 5 | 2 |
| Impaired consciousness | 39 | 3 | 7 |
| Gait disturbance | 35 | 2 | 0 |
| Cranial nerve deficit | 35 | 4 | 1 |
| Personality change | 34 | 7 | 1 |
| Seizures | 32 | 16 | 10 |
| Aphasia | 32 | 5 | 4 |
| Sensory impairment | 23 | 4 | 1 |
| Table adapted from Frankel et al.6 |
Diagnosis
Glioblastoma can only be diagnosed on the basis of a tissue sample. Imaging cannot establish the diagnosis with certainty, as lymphoma often cannot be excluded on differential diagnosis. MRI is the gold standard in imaging and is also necessary for planning the surgical approach. On MRI, glioblastoma typically appears as a hypo- or isointense mass on the native T1 sequence, with variable contrast enhancement on postcontrast sequences, particularly at the margins. Contrast enhancement is usually seen at the edge of the necrotic tissue.
Resection vs. biopsy
The diagnosis of glioblastoma can only be established by histopathologic verification. Whenever possible, surgical treatment should be offered, as this has been shown to improve patient survival.
The main arguments against surgical resection are a poor Karnofsky Performance Status, very advanced patient age, or an eloquent tumor location7.
Surgical resection
Surgical resection of glioblastoma should always aim for complete resection of the contrast-enhancing tumor component. Complete resection of the contrast-enhancing component of glioblastoma (CRET) is associated with a higher survival rate8. To assess the extent of surgical resection, repeat MRI is typically performed within the first 48 hours after surgery. Delaying this postoperative imaging may make it impossible to reliably distinguish between postoperative blood products and tumor tissue; therefore, imaging should be performed within 48 hours after surgery.
Biopsy
The aim of a biopsy is to establish the diagnosis without removing a clinically relevant amount of tumor tissue. Biopsy should be considered in patients for whom surgical resection is not appropriate or not possible. Once a diagnosis of glioblastoma has been confirmed, a treatment plan using chemoradiation can be established without performing tumor resection.
Classification
The current classification of glioblastomas follows the 2016 WHO classification9, in which glioblastoma is classified as grade 4. According to the 2016 WHO classification, classification is based on both histopathologic features and defined molecular genetic markers. Four diagnostic biomarkers are currently used10:
IDH1/2
Isocitrate dehydrogenase (IDH) is an enzyme required for the citric acid cycle. If a mutation is present in the IDH1/2 gene, there is a survival advantage compared with the wild-type variant. IDH mutations are particularly common in patients with secondary glioblastoma11.
Postoperative treatment
The established treatment after the diagnosis and resection of glioblastoma is the so-called Stupp protocol, named after the Swiss physician Roger Stupp. It consists of combined chemoradiation. The Stupp protocol comprises fractionated radiation therapy totaling 60 Gy, delivered in 2-Gy fractions over 5 days per week for 6 weeks, with concomitant administration of 75mg Temozolomid per square meter of body surface area per day. After completion of radiation therapy, 6 cycles of chemotherapy with Temozolomid are administered at a dose of 150-200mg per square meter of body surface area for 5 days in a 28-day cycle12. Patients treated with combined chemoradiation demonstrated a clinically relevant and statistically significant survival benefit compared with patients receiving radiation therapy alone13.
Corticosteroids in the treatment of glioblastoma
Corticosteroids such as Dexamethason are frequently used in the treatment of glioblastoma. Tumors such as glioblastomas often cause vasogenic cerebral edema, which can have a mass effect and thus lead to neurologic deterioration in patients. Corticosteroids have a highly effective anti-edematous effect in vasogenic cerebral edema14. However, the use of Dexamethason should be well justified, as newer data suggest that although Dexamethason provides short-term symptom relief by reducing edema, it may have a negative effect on the outcomes of radiation therapy15.
Recurrence
Glioblastoma recurrence generally occurs at the site of the primary tumor. In fewer than 10% of cases, recurrence occurs at a site different from the original location16. Depending on the clinical condition, extent, and location of the recurrence, repeat surgical resection may be considered.
Survival time
Despite modern medicine, survival in patients with glioblastoma remains extremely poor. Patients without treatment have a mean survival of 3 months17.
Studies have shown that 80% tumor resection increases overall patient survival. Survival increases incrementally with further tumor resection between 80-100%18 19 20.
References
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Tamimi, Ahmad Faleh, and Malik Juweid. "Epidemiology and outcome of glioblastoma." Exon Publications (2017): 143-153. ↩ ↩
Dohrmann, George J., Jacqueline R. Farwell, and John T. Flannery. "Glioblastoma multiforme in children." Journal of neurosurgery 44.4 (1976): 442-448. ↩ ↩
Frankel, Saul A., and William J. German. "Glioblastoma multiforme: review of 219 cases with regard to natural history, pathology, diagnostic methods, and treatment." Journal of neurosurgery 15.5 (1958): 489-503. ↩ ↩ ↩ ↩
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SongTao, Qi, et al. "IDH mutations predict longer survival and response to temozolomide in secondary glioblastoma." Cancer science 103.2 (2012): 269-273. ↩ ↩
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Reulen, Hans J., Alexander Hadjidimos, and Kurt Schürmann. "The effect of dexamethasone on water and electrolyte content and on rCBF in perifocal brain edema in man." Steroids and brain edema. Springer, Berlin, Heidelberg, 1972. 239-252. ↩ ↩
Pitter, Kenneth L., et al. "Corticosteroids compromise survival in glioblastoma." Brain 139.5 (2016): 1458-1471. ↩ ↩
Choucair AK, Levin VA, Gutin PH, et al. Development of Multiple Lesions During Radiation Therapy and Chemotherapy. J Neurosurg. 1986;65:654-658. ↩ ↩
Malmostrom A, Gronberg BH, Marosi C, Stupp R, Frappaz D, Schultz H, et al. Temozolamide versus standard 6-week radiotherapy versus hypo fractionates radiotherapy in patients older than 60 years with glioblastoma. The Nordic randomized phase 3 trial. Lancet Oncol. 2012;13:916–26. ↩ ↩
Li, Yan Michael, et al. "The influence of maximum safe resection of glioblastoma on survival in 1229 patients: can we do better than gross-total resection?." Journal of neurosurgery 124.4 (2016): 977-988. ↩ ↩
Sanai, Nader, et al. "An extent of resection threshold for newly diagnosed glioblastomas." Journal of neurosurgery 115.1 (2011): 3-8 ↩ ↩
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