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Combined treatment strategies for high-grade gliomas

Combined treatment strategies for high-grade gliomas. This article reviews the research progress of radiotherapy in the treatment of high-grade gliomas.

How to treat high-grade glioma?

With the in-depth understanding of the pathogenesis of high-grade gliomas, a variety of comprehensive treatment methods have been formed: radiotherapy combined with chemotherapy, molecular targeted therapy, immunotherapy, and tumor treatment field (TTFields) combined with chemotherapy. These emerging treatment options can show better anti-tumor activity and improve survival rates.

This article reviews the research progress of radiotherapy in the treatment of high-grade gliomas.

Radiotherapy combined with chemotherapy

Chemotherapy can reduce the size of the lesion, improve local blood circulation, and increase radiosensitivity. Chemotherapeutic drugs have cell cycle specific cytotoxic effects on s-phase cells, and simultaneous RT and chemotherapy have complementary effects on cell killing.

The most commonly used chemotherapy drug in the treatment of high-grade gliomas is oral temozolomide, which is widely distributed throughout the body without passing through the liver.

It easily locates on brain tumor cells after crossing the blood-brain barrier, and acts on all cells at all stages of the cell cycle. In addition, oral absorption is rapid, and the incidence of side effects is low.

DNA repair enzyme o6-methylguanine-DNA methyltransferase (MGMT) inhibits the killing of tumor cells by temozolomide. Methylation of the MGMT promoter silences the gene in cancer, so the cell no longer produces MGMT.

This phenomenon is related to tumor regression and prolonging OS and disease-free survival. The basic treatment plan is to give temozolomide for 6 weeks of radiotherapy at the same time, and then for 6 months of adjuvant temozolomide treatment.

However, because temozolomide is quite tolerable and there is no effective second-line therapy, up to 12 courses of treatment are now allowed.

In our previous research, we concluded that radiotherapy plus chemotherapy is quite toxic. In addition, radiotherapy can lead to secondary gliomas, so other researchers also believe that combination therapy is a potential way to treat radiation-induced gliomas.

Molecular targeted drugs combined with radiotherapy

At present, because glioma is resistant to radiotherapy and chemotherapy, the recurrence rate is high, and the treatment effect is not ideal. In order to overcome the limitations of these treatments, people began to study molecular targeted drugs combined with radiotherapy and chemotherapy. Molecular targeted drugs activate specific molecular signal transduction pathways to effectively kill tumors.

Molecular targeted therapies include vascular endothelial growth factor (VEGF) inhibitors and epidermal growth factor receptor (EGFR) inhibitors combined with radiotherapy. Its signal transduction pathway can activate cell apoptosis, inhibit cell cycle or block blood vessel growth. Bevacizumab is a common molecular targeted drug; it is a humanized anti-VEGF monoclonal antibody that can activate VEGF downstream pathways (RAS-RAF-MAPK, etc.) through protein phosphorylation. Bevacizumab is currently approved for the treatment of patients with recurrent high-grade gliomas, but not as part of the pre-program for newly diagnosed high-grade gliomas.

Gefitinib is an effective small molecule inhibitor of EGFR tyrosine kinase. Schwer et al. used SRT combined with gefitinib to treat recurrent high-grade gliomas. They reported that the 36 Gray dose of three sites was well tolerated, and gefitinib was 250 mg daily. Aflecept is a recombinant fusion protein of the extracellular domain of VEGF. It has high affinity and can also remove VEGF. Groot et al. evaluated its therapeutic effect on patients with recurrent high-grade glioma. They found that afolicept monotherapy was not as effective as bevacizumab and was moderately toxic.

Immunotherapy

Nowadays, immunotherapy is being applied to a wider range of diseases, and research has deepened our understanding of how immunotherapy is applied. The immune system can protect the host and suppress the tumor microenvironment.

Immunotherapy uses the host immune system to induce an anti-tumor response to eliminate tumors. RT releases tumor antigens and regulates immune pathways, leading to an increase in tumor antigen concentration and the major histocompatibility complex (MHC) on the surface of tumor cells, triggering tumor-specific cytotoxic T cells, and ultimately leading to the immunogenic death of tumor cells. The main target of T cell receptors is the MHC that carries tumor antigens.

MHC I participates in antigen recognition through CD8+ cytotoxic T lymphocytes (ctl), while MHC II participates in antigen recognition through CD4+ Th cells.

Electric Field Therapy (TTFields)

Electric field therapy is an anti-splitting treatment that uses a low-intensity, medium-frequency (200khz) alternating electric field (18 hours/day) and uses four insulated sensor arrays to be placed directly on the skin around the tumor. This treatment acts on cells in the middle and late stages of mitosis (G1/S or G2/M) through dipole redistribution, hindering the orderly arrangement and positioning of tubulin, disrupting the normal assembly of spindle microtubules, and leading to centromeres Break, destroy the organelle structure. The result is an overall decrease in cell proliferation, followed by apoptosis, which is strongly affected by p53 mutations. TTFields act on several molecular targets/pathways to affect Ca2+ and electrical signals.

When using TTFields, clinicians should adjust the sensor array layout according to the specific position of the tumor to increase the field strength and achieve the best tumor cutting effect. Different TTFields intensities have different results on PFS and OS in patients with high-grade glioma.

Many clinical trials have compared TTFields plus temozolomide with temozolomide alone, and some trials have added lomustine to the treatment regimen. Stupp et al. used TTFields plus temozolomide or temozolomide alone to treat patients with high-grade glioma. They found that the median OS was 20.9 months and 16.0 months, respectively.

The addition of TTFields to standard temozolomide therapy can improve the survival of patients with high-grade gliomas, except for skin itching, and has no negative impact on health-related quality of life.

In addition, Lazaridis and others believe that TTFields combined with lomustine and temozolomide is superior to TTFields combined with temozolomide monotherapy in the treatment of patients with high-grade glioma.

This analysis suggests for the first time that the combination of TTFields/lomustine/temozolomide is safe and feasible. Lu et al. compared the PFS and OS of the two treatment strategies and found that the combination of TTFields, temozolomide, bevacizumab and irinotecan may be more effective than the combination of TTFields and bevacizumab in the PFS and OS of patients with high-grade glioma. OS improvement plays a more important role.

In short, TTFields combined with chemotherapy can prolong PFS and OS, so it is a new treatment model for patients with newly diagnosed or relapsed high-grade glioma.

(source:internet, reference only)

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