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Table of Contents
EDITORIAL
Year : 2021  |  Volume : 4  |  Issue : 1  |  Page : 2-4

Perspective on the current treatment strategies for glioma


Sun Yat-sen University Cancer Center, Guangzhou, Guangdong Province, China

Date of Submission08-Mar-2021
Date of Decision09-Mar-2021
Date of Acceptance10-Mar-2021
Date of Web Publication30-Mar-2021

Correspondence Address:
Dr. Zhong-ping Chen
Sun Yat-sen University Cancer Center, Guangzhou, Guangdong Province
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/glioma.glioma_2_21

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How to cite this article:
Chen Zp. Perspective on the current treatment strategies for glioma. Glioma 2021;4:2-4

How to cite this URL:
Chen Zp. Perspective on the current treatment strategies for glioma. Glioma [serial online] 2021 [cited 2022 Dec 8];4:2-4. Available from: http://www.jglioma.com/text.asp?2021/4/1/2/312464



Despite decades of research, gliomas remain a devastating disease with poor prognosis. The main strategy of treatment for gliomas consists of surgical resection, irradiation, and chemotherapy. Few glioma patients are able to achieve longtime survival, and the majority of patients continue to have unsatisfactory outcomes, even if receiving aggressive treatment. The best way to further advance glioma treatment and improve patient survival could start from understanding current treatment strategies.


  Some Low-Grade Gliomas Can Be Cured Top


In clinical practice, the WHO grade, tumor cell type, and tumor genotype of gliomas are important factors in determining treatment response. Although high-grade gliomas are often challenging to treat, patients with low-grade gliomas, such as pilocytic astrocytoma, ganglioglioma, pleomorphic xanthoastrocytoma, and subependymal giant cell astrocytoma, may be cured through complete tumor resection.[1] Oligodendrogliomas are another potentially curable category of gliomas, as they often show a relatively good response to irradiation and chemotherapy. The oligodendroglioma with 1p 19q LOH (loss of heterozygosity) showed almost 100% responsiveness to procarbazine + lomustine + vincristine (PCV) regimen, and similar results were observed with temozolomide.[2] Molecular genotype also has an important impact on the prognosis of glioma. For example, the IDH-mutant subtype of gliomas shows a comparatively good response to treatment.


  Surgery Alone Cannot Cure Infiltrative Gliomas Top


Since most gliomas grow in an infiltrative pattern, removing all tumor cells while avoiding functional brain tissue damage is impossible with surgery alone. The current surgical strategy for gliomas is maximal safe resection, i.e., remove tumor as much as possible, while at the same time preserving normal brain function.[3] Another challenge is the increasing evidence, suggesting that glioma cells may be present in the subventricular zone, which is usually far from the main tumor mass. This makes complete surgical resection impossible.[4] The remaining tumor cells (or glioma stem cells) will certainly regrow without adjuvant treatment after surgery.


  Radiotherapy is Not an Ideal Method for Glioma Treatment Top


Radiotherapy is a local form of treatment which attempts to kill infiltrating tumor cells in normal brain tissue which have not been removed by surgery.[5] Since glioma is insensitive to irradiation, even with dosages of 90 Gy, there is still 80%–90% local recurrence. According to the dose-effect irradiation to brain tissue, with radiation dosage over 72 Gy, 5% of cases will develop brain necrosis, while radiation dosage over 90 Gy will result in brain necrosis in 10% of cases. Therefore, the dose limitation of brain tissue prevents further radiation dosage increase for more effective killing of tumor cells. There are now several advanced irradiation technologies such as intensity-modulated radiation therapy, tomotherapy, and more recently particle (e.g., proton or carbon-ion) beam radiation therapy and heavy-ion radiotherapy. These newer modalities may improve radiation dose distribution while lowering adverse events but so far have not shown significant improvement in therapeutic efficacy.[6],[7] On the other hand, since subventricular zone involvement may be associated with distant recurrence of glioblastoma (GBM), therefore the use of local radiotherapy will be limited in this situation.


  The Benefits of Chemotherapy for Glioma are Still Relatively Limited Top


Since the 1970s, chemotherapy for glioma has involved from nitrosoureas to PCV and to temozolomide in more recent years. Evidence has shown definite improvement in clinical outcomes for glioma patients in general. The greatest success so far has been using PCV regimen, which showed almost 100% response in oligodendrogliomas with 1p 19q LOH.[8] However, cytotoxic chemotherapy for astrocytomas has not been so promising. In the EORTC-NCIC study for patients newly diagnosed with GBM, overall survival was increased about 2 months with the Stupp regimen, and the 5-year survival rate was only 9.8%. This means that it is still difficult for the majority of glioma patients to avoid tumor recurrence. Drug resistance, limitation of the blood–brain barrier, and toxicity of chemotherapeutic drugs are the main obstacles in glioma chemotherapy.[9]


  Tumor-Treating Fields Have Shown Benefit for Glioblastoma, but Uncertainties Remain Top


Tumor-treating field (TTF) is a unique noninvasive treatment modality that utilizes alternating electric fields of low intensity (1–3 V/cm) and intermediate frequency (100–300 kHz) to deliver therapy. Treatment effects have been assessed in patients with newly diagnosed and recurrent GBM in clinical trials and retrospective studies. While the results of these studies led to the Food and Drug Administration approval of TTF for both populations, a portion of the neuro-oncology and neurosurgery community remain skeptical of TTF. In randomized clinical trials, TTF improved survival for newly diagnosed GBM patients but not for patients with recurrent GBM. Although TTF has shown to exert a broad range of effects on tumor cells, including by disrupting a multitude of biological processes, including DNA repair, cell permeability, and immunological responses, confirmation with further studies is greatly needed. There are also concerns regarding study design, quality of life, and the cost of therapy.[10],[11]


  Molecular Target Therapy Could Be a Promise Strategy but Facing Many Problems Top


Recently, targeted therapies have shown significant benefit in numerous other cancer types with improvement in patient survival. However, although several promising markers have been identified in gliomas, therapies targeting these specific markers only be selectively tried. Clinical trials validating these markers have been promising but have yet to show a clear success in glioma patients. The problem is that glioma is a highly heterogeneous tumor, and the molecular profile in different areas of the tumor can vary significantly. Consequently, targeting one marker may work for only one region of the entire tumor. Using therapies that target a single marker, tumor cells can adjust to escape from the killing effects of the drug. Therapies that are directed against multiple targets would provide a greater chance of success, but much work is needed in this area.[12],[13]


  Immunotherapy Has Provided New Hope, but Many Challenges Remain Top


With the advancement in our understanding of the genetic basis and immune microenvironment of brain tumors, immunotherapy has become a promising approach for glioma treatment.[14] Immunotherapeutic approaches for glioma have been investigated for decades. Representative clinical trials have studied immune checkpoint inhibitors, CAR T-cells (chimeric antigen receptor-modified T cells), vaccines, and oncolytic viruses. However, to date, immunotherapies have shown little improvement in prognosis of patients with lethal malignant gliomas.[15] The relatively low response rate, the lack of validated predictive biomarkers, and the development of resistance to immunotherapies are the main challenges in treating patients with malignant gliomas. Gliomas have been treated as immunologically “cold” tumors and tend to have few mutations that could be targeted immunotherapeutically. Moreover, the genetic evolution of these tumors makes tumor populations extremely heterogeneous and therefore difficult to treat with a therapy targeted toward a single antigen. The standard care for this disease, radiation and chemotherapy, are both profoundly immunosuppressive and thwart many immunotherapeutic attempts. In addition, tumors in the brain seem to be able to promote bone marrow sequestration of the immune cells that could attack the tumor. Finally, attention also needs to be paid toward the unintended side effects of immunotherapies to the brain and systemic tissues. All these limitations will need to be addressed in order to achieve tumor control in immunotherapy-resistant gliomas. The development of such regimens requires a more detailed understanding of the interactions between a tumor and the host's immune system, as well as the mechanisms for immunotherapy resistance. Immunotherapy may prove to be a revolutionary treatment for gliomas, but there is still a road ahead of us.[16]



 
  References Top

1.
Schramm J, Blümcke I, Ostertag CB, Schlegel U, Simon M, Lutterbach J. Low-grade gliomas – Current concepts. Zentralbl Neurochir 2006;67:55-66.  Back to cited text no. 1
    
2.
Ruff MW, Buckner JC, Johnson DR, van den Bent MJ, Geurts M. Neuro-oncology clinical debate: PCV or temozolomide in combination with radiation for newly diagnosed high-grade oligodendroglioma. Neurooncol Pract 2019;6:17-21.  Back to cited text no. 2
    
3.
Vanderweyen DC, Theaud G, Sidhu J, Rheault F, Sarubbo S, Descoteaux M, et al. The role of diffusion tractography in refining glial tumor resection. Brain Struct Funct 2020;225:1413-36.  Back to cited text no. 3
    
4.
Lombard A, Digregorio M, Delcamp C, Rogister B, Piette C, Coppieters N. The subventricular zone, a hideout for adult and pediatric high-grade glioma stem cells. Front Oncol 2021;10:614930.  Back to cited text no. 4
    
5.
Gzell C, Back M, Wheeler H, Bailey D, Foote M. Radiotherapy in glioblastoma: The past, the present and the future. Clin Oncol (R Coll Radiol) 2017;29:15-25.  Back to cited text no. 5
    
6.
Combs SE. Proton and carbon ion therapy of intracranial gliomas. Prog Neurol Surg 2018;32:57-65.  Back to cited text no. 6
    
7.
Kong L, Lu JJ. Particle radiation therapy in the management of adult high-grade glioma: A narrative review. Glioma 2020;3:149-53.  Back to cited text no. 7
  [Full text]  
8.
Buckner JC, Shaw EG, Pugh SL, Chakravarti A, Gilbert MR, Barger GR, et al. Radiation plus procarbazine, CCNU, and vincristine in low-grade glioma. N Engl J Med 2016;374:1344-55.  Back to cited text no. 8
    
9.
Ferri A, Stagni V, Barilà D. Targeting the DNA damage response to overcome cancer drug resistance in glioblastoma. Int J Mol Sci 2020;21:4910.  Back to cited text no. 9
    
10.
Shah PP, White T, Khalafallah AM, Romo CG, Price C, Mukherjee D. A systematic review of tumor treating fields therapy for high-grade gliomas. J Neurooncol 2020;148:433-43.  Back to cited text no. 10
    
11.
Rominiyi O, Vanderlinden A, Clenton SJ, Bridgewater C, Al-Tamimi Y, Collis SJ. Tumour treating fields therapy for glioblastoma: Current advances and future directions. Br J Cancer 2021;124:697-709.  Back to cited text no. 11
    
12.
Delgado-López PD, Saiz-López P, Gargini R, Sola-Vendrell E, Tejada S. A comprehensive overview on the molecular biology of human glioma: What the clinician needs to know. Clin Transl Oncol 2020;22:1909-22.  Back to cited text no. 12
    
13.
Hahn WC, Bader JS, Braun TP, Califano A, Clemons PA, Druker BJ, et al. An expanded universe of cancer targets. Cell 2021;184:1142-55.  Back to cited text no. 13
    
14.
Lim M, Xia Y, Bettegowda C, Weller M. Current state of immunotherapy for glioblastoma. Nat Rev Clin Oncol 2018;15:422-42.  Back to cited text no. 14
    
15.
Reardon DA, Brandes AA, Omuro A, Mulholland P, Lim M, Wick A, et al. Effect of nivolumab vs bevacizumab in patients with recurrent glioblastoma: The checkmate 143 phase 3 randomized clinical trial. JAMA Oncol 2020;6:1003-10.  Back to cited text no. 15
    
16.
Adhikaree J, Moreno-Vicente J, Kaur AP, Jackson AM, Patel PM. Resistance mechanisms and barriers to successful immunotherapy for treating glioblastoma. Cells 2020;9:263.  Back to cited text no. 16
    




 

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