Glioblastoma multiforme medical therapy
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Marjan Khan M.B.B.S.[2]
Overview
The predominant therapy for glioblastoma multiforme is surgical resection. Adjunctive chemotherapy and radiation may be required. Supportive therapy for glioblastoma multiforme includes anticonvulsants and corticosteroids. Cytotoxic therapy for GBM has evolved due to the approval of temozolomide which is an alkylating agent for newly diagnosed GBM. Active agents include also the nitrosureas which include carmustine and lomustine, platinum agents, etoposide, irinotecan and PCV combination.
Medical Therapy
- The predominant therapy for glioblastoma multiforme is surgical resection. Adjunctive chemotherapy and radiation may be required.[1][2][3]
- Cytotoxic therapy for GBM has evolved due to the approval of temozolomide which is an alkylating agent.
- Active agents include also the nitrosureas that include carmustine (BCNU) and lomustine (CCNU), platinum agents, etoposide, irinotecan and PCV combination.
- Temozolomide is a newer oral alkylating agent that has excellent penetration into the central nervous system.
- Temozolomide has 96-100% bioavailability and promotes the methylation of the O6 position on guanine.
- Temozolomide can be effective for recurrent GBM while its efficacy can be increased with metronomic rather than standard schedule as well as with high average daily dose (>100 mg/m2).
- The nitrosureas, carmustine (1,2 bis[2-chloreoethyl]-1-nitrosurea BCNU) and lomustine (CCNU), are two alkylating drugs used in the treatment of GBM.
- Carmustine biodegradable wafers (Gliadel) are an implantable depot form of BCNU that are placed in the cavity that is formed after resection of newly diagnosed or recurrent tumor.
Radiotherapy
- Radiotherapy has been used in conjunction with surgery as early as 1979.
- Radiation therapy induces severe DNA damage causing the cells to undergo apoptosis due to double-strand breaks.
- Post-operative radiotherapy is recommended among all patients who develop glioblastoma multiforme.
- Adjuvant radiotherapy can reduce the tumor size to 107 cells.
- Radiotherapy may not cure the cancer, but can control the tumor and delay recurrence.
- Targeted three-dimensional conformal radiotherapy is preferred to whole brain radiotherapy.
- Total radiation dose of 5,000-6,000 cGy has been found to be optimal for treatment.[2]
- Resistance to radiotherapy can be problematic in GBM as EGFRvIII confers cellular resistance to such treatment options by upregulating the DNA double-stranded break repair machinery.
- Gamma knife monotherapy in a GBM mouse xenografts model increased survival.
- Quick identification of recurrence would allow for gamma knife treatment while the tumor remains volumetrically small.
Chemotherapy
- Chemotherapy is indicated as adjuvant therapy for glioblastoma multiforme.[3]
- Temozolomide (Temodar) is the preferred drug for the treatment of glioblastoma multiforme.[3]
- Irinotecan, etoposide and cisplatin have been used in the treatment of GBM demonstrating modest efficacy as adjuvant chemotherapy.
- Other chemotherapeutic drugs that may be used for the treatment of glioblastoma multiforme include:
Resistance to chemotherapy and radiotherapy
- Many GBMs have intrinsic or acquired resistance to chemotherapy.
- MGMT gene promoter methylation is an important mechanism of resistance to temozolomide treatment in GBM.
- Methylation of MGMT is found in 30–60% of GBM cases and is associated with a favorable outcome if treated with alkylating agents.
- There is evidence that glioma stem cells contribute to GBM chemoresistance.
- Stem cells from highly chemotherapy resistant grade IV gliomas show expression of multidrug resistance protein-1 (MRP1) transporters and grade II gliomas show expression of P-glycoprotein
Monoclonal antibodies
- Monoclonal antibodies recognize cell surface receptors and ligands and prevent receptor signaling through the disruption of receptor–ligand interactions and downstream receptor activation.
- FDA approved bevacizumab which is a antibody against vascular endothelial growth factor (VEGF).
- Systemic injection of bevacizumab aims to block the response to VEGF and thus prevent neovascularization of the tumor and consequently decrease its size.
- Recent data show that bevacizumab in combination with the standard treatment did not improve overall patient survival compared to standard treatment alone.
- Bevacizumab is still considered one of the best new treatments for GBM due to the relatively limited added toxicity compared to standard treatment of care.
- AMG595 specifically targets EGFRvIII and is currently being tested in phase I clinical trials.
- AMG595 is a non-cleavable linker immunoconjugate between a human monoclonal antibody directed against EGFRvIII and the cytotoxic agent mertansine.
Supportive treatment
Supportive therapy for glioblastoma multiforme includes anticonvulsants and corticosteroids, which focuses on relieving symptoms and improving the patient’s neurologic function.
- Anticonvulsants are administered to the patients who have a seizure. Phenytoin given concurrently with radiation may have serious skin reactions such as erythema multiforme and Stevens-Johnson syndrome.
- Corticosteroids, usually dexamethasone given 4-10 mg every 4-6 h, can reduce peritumoral edema, diminish mass effect, and lower intracranial pressure with a decrease in headache or drowsiness.
References
- ↑ Treatment of glioblastoma multiforme. Dr Dylan Kurda and Dr Frank Gaillard et al. Radiopaedia 2015. http://radiopaedia.org/articles/glioblastoma
- ↑ 2.0 2.1 Barani IJ, Larson DA (2015). "Radiation therapy of glioblastoma". Cancer Treat Res. 163: 49–73. doi:10.1007/978-3-319-12048-5_4. PMID 25468225.
- ↑ 3.0 3.1 3.2 Minniti G, Muni R, Lanzetta G, Marchetti P, Enrici RM (2009). "Chemotherapy for glioblastoma: current treatment and future perspectives for cytotoxic and targeted agents". Anticancer Res. 29 (12): 5171–84. PMID 20044633.