|Year : 2020 | Volume
| Issue : 3 | Page : 119-125
Advancement of clinical therapeutic research on glioma: A narrative review
Fengping Li, Chao Ma, Chengshi Xu, Zhiyong Pan, Zhiqiang Li
Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province, China
|Date of Submission||27-May-2020|
|Date of Decision||18-Jun-2020|
|Date of Acceptance||14-Jul-2020|
|Date of Web Publication||17-Oct-2020|
Dr. Zhiqiang Li
Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Donghu Road 169#, Wuhan 430071, Hubei Province
Source of Support: None, Conflict of Interest: None
As theories evolve, the mechanism of glioma origination remains poorly understood. Understanding this mechanism promotes the clinical research on glioma therapeutic strategy and then improves the prognosis of patients with glioma. However, the overall survival of these patients is unsatisfactory. In the recent decade, a few novel therapies, such as tumor-treating fields and immunotherapy, have been introduced in clinic. Before they can be widely used, many key factors, including efficacy, safety, and benefit ratio, should be fully evaluated. Therefore, more clinical trials are required to corroborate the results and conclusions of basic research and improve the current treatment strategies. In this article, we searched relevant literature published in the past 5 years in PubMed and China National Knowledge Infrastructure and reviewed the advancements of clinical therapeutic research on glioma.
Keywords: Glioma, immunotherapy, radiochemotherapy, surgery, tumor-treating fields
|How to cite this article:|
Li F, Ma C, Xu C, Pan Z, Li Z. Advancement of clinical therapeutic research on glioma: A narrative review. Glioma 2020;3:119-25
| Introduction|| |
Gliomas are the leading primary malignant tumors of the central nervous system, with a morbidity of 7.3 cases per 100,000 people, comprising 85% of high-grade gliomas and 15% of low-grade gliomas. This condition can happen to both children and adults. Its incidence and prognosis are closely linked to race, gender, and other patient-related factors. In general, the first-line treatment for removing gliomas is surgery. Nevertheless, often, gliomas have already spread in the brain when diagnosed; thus, the recurrence rate remains high. To improve the patient's overall survival and progression-free survival (PFS), and to reduce the recurrence rate, physicians are trying to administer a combination of radiotherapy and chemotherapy, such as short-term radiotherapy and temozolomide, after surgery., However, considering that gliomas are highly invasive and heterogeneous and those glioma stem cells are resistant to various treatment options, the prognosis is generally extremely poor, as mainly manifested in cognitive function decline., With numerous studies that are currently conducted, malignancy-related glioma-specific molecules have been increasingly discovered;,, hence, treatment schemes that are designed according to a series of molecular markers, including some drugs and the novel designing of the radiotherapy model, are essential to improve the survival rate of patients with gliomas. Research on the proliferation mechanism of glioma cells proposed that tumor-treating fields (TTF), diet therapy, and some other strategies improves the quality of postoperative recovery of patients to a greater extent., This review starts from various angles and discusses the practical effects and future directions of development concerning glioma treatment options.
| Database Search Strategy|| |
We searched PubMed and China National Knowledge Infrastructure to identify multiple relevant studies published in the past 5 years. The terms included “glioma,” “glioblastoma,” “therapy,” “surgery,” “radiotherapy,” “chemotherapy,” and “tumor-treating fields.” More than 100 studies were found and some of them served as references. Some important reference data were listed for our thesis argument. We also simultaneously combined the authors' experience to review on the latest glioma treatment methods.
| Surgical Removal|| |
In clinical practice, high-grade gliomas, diffuse low-grade gliomas, and recurrent gliomas are commonly treated by surgery. Maximum tumor resection is performed and is classified into gross-total resection, subtotal resection, partial resection, and biopsy. Identifying the extent of resection in each individual is generally difficult because the excision extension is closely related to the postoperative recovery of patients. Each resection grade indicates a different prognosis. Compared with subtotal resection, gross-total resection can prolong the overall survival rate and PFS. To effectively prevent postoperative permanent dysfunction, physicians routinely use auxiliary techniques such as intraoperative awakening and intraoperative brain function positioning, which aid in analyzing the impact of the resection site on the patient's sensory and motor functions., These techniques integrate a fluorescence-guided surgery, which can decrease tumor recurrence rate and prolong patient survival compared with white-light surgery. A highly sensitive monoamine oxidase-A-specific probe-F1, which was recently designed by Fang et al., can clearly detect the boundary of the gliomas and paracancerous tissue with the aid of two-photon fluorescence microscopy, making F1 a hot spot with a broad prospect of application. In resecting high-grade gliomas, the imaging agent 5-aminolevulinic acid hydrochloride is frequently used to guide surgeons in performing accurate resection under a blue light. In a previous systematic analysis, 5-aminolevulinic acid hydrochloride can reduce the incomplete resection rate (level of evidence, low). In addition, the cost and benefit of this agent are satisfactory for patients. In analyzing the blood perfusion status and grade of gliomas in real time, physicians can employ various ultrasound-based imaging techniques, such as B-mode, Doppler (power, color, and spectral), contrast-enhanced ultrasound, and elastosonography, intraoperatively to determine the maximum resection range.
However, glioma resection surgery involves certain risks. It has a positive impact on complex attention, language, learning and memory tasks, and continuous follow-up improvement immediately after the operation, as indicated in a meta-analysis of 313 patients. Furthermore, the patients' attention, language fluency, object naming, and other neurocognitive functions are remarkably improved by the intraoperative awakening, but the patient's executive function has declined and even has a long-term downward trend. Hence, surgery is not always the first treatment choice, depending on glioma type. Known for its extreme aggressiveness, diffuse intrinsic pontine glioma can spread to almost every important functional area of the brain. From the clinical viewpoint, selecting different surgical timing and operative duration does not remarkably improve the patient's overall survival. To maximize the benefit of surgery to patients, researchers continually develop technology and improve the surgical procedures. As proposed by Li et al., a surgery guided by positron emission technology and optical dual-mode images can more sensitively locate the tumor for a more accurate removal; postoperatively, patients demonstrate an extended PFS, with no new neurological damage. In a clinical study by Schneider et al., lobectomy was used for temporal glioblastoma, resulting in a marked improvement of the patient's Karnofsky Performance Score, PFS, and overall survival compared with total resection.
| Radiochemotherapy|| |
For some solid tumors such as gliomas, radiochemotherapy is often an integral part of the standard treatment plan proposed by clinical guidelines. However, some clinical problems, such as myelosuppression, chemoradiotherapy resistance, and toxicity to normal cells, have been observed., In radiotherapy, a certain dose of radiation is released, consequently breaking the double-strand DNA of tumor cells and then destroying the cell cycle. The formed DNA fragments can also induce apoptosis. Furthermore, 5-Iodo-2′-deoxyuridine can increase radiotherapy sensitivity. However, considering the activation of the DNA repair system, the presence of glioma stem cells, and the increase in regulatory T cells with immunosuppressive effects caused by irradiation, cancer cells can escape death and continue the malignant proliferation, resulting in radioresistance., The main chemotherapy drug currently used for newly diagnosed and recurrent gliomas is temozolomide. This drug can traverse the blood–brain barrier and invade the cerebrospinal fluid, thereby considering as a highly effective antitumor alkylating agent. Under the physiological pH state of the systemic circulation, temozolomide is rapidly transformed into the active product 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC), which plays a cytotoxic role through the mismatch repair of methylated adducts. To increase the rate of drug passing through the blood–brain barrier, scientists have tried to inhibit and even destruct the blood–brain barrier components, as guided by focused ultrasound with drug administration, to achieve superior results; as a result, the local concentration of temozolomide in the brain significantly increases., Similar to other cytotoxic drugs, temozolomide can cause several adverse events, such as nausea, vomiting, and hematological reactions (myelosuppression). To reduce the incidence of adverse reactions and fully exert the antitumor effect of radiochemotherapy in patients with gliomas, physicians generally employ short-term radiotherapy combined with chemotherapy.
Some scholars have conducted numerous clinical studies to analyze the effect of radiochemotherapy on glioma prognosis. For instance, compared with radiotherapy alone, short-term radiotherapy combined with temozolomide administration prolonged patient's overall survival, decreasing the mortality risk by 33% (9.3 months vs. 7.6 months; hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.56–0.80; P < 0.001). Chemotherapeutic drugs must reach an effective concentration in glioma cells to effectively exert the antitumor effect. These drugs can be efficiently guided to the target area through the barrier with the help of imaging analysis of the blood–brain barrier. To analyze the impact of radiotherapy and chemotherapy individually and radiochemotherapy on patients, researchers have conducted numerous basic experiments and clinical trials. In a randomized open-label phase-three intergroup study, the investigators randomly divided 477 patients into the radiotherapy group (n = 240) and the chemotherapy group (temozolomide, n = 237), with a median follow-up of 48 months. Although the median PFS of the radiotherapy group was longer than that of the chemotherapy group (unadjusted HR, 1.16; 95% CI, 0.9–1.5; P = 0.22), PFS remained to be not significantly different between the two groups. Conversely, in a clinical trial involving 251 eligible patients, the patient's 10-year PFS (21% vs. 51%) and overall survival (13.3 years vs. 7.8 years; HR, 0.59; P = 0.003) could be significantly improved in radiochemotherapy (mebendazole and cyclohexyl-nitrosourea) compared with those in radiotherapy alone, consistent with the results of other previous studies., In recent years, owing to the rapid advancement of biopharmaceutical technology, various monoclonal antibody types, such as the recombinant humanized monoclonal antibody bevacizumab, have been developed as anticancer drugs; bevacizumab can combine to vascular endothelial growth factor and inhibit the growth of blood vessels and the metastasis of various tumors.,, Together with temozolomide, this drug is often used to treat recurrent glioma, but clinical studies have confirmed that bevacizumab and temozolomide combination has no significant difference in improving the overall survival compared with temozolomide alone. In contrast, bevacizumab may have a higher incidence of adverse reactions, such as hematological toxicity, neurological disorders, fatigue, and even treatment-related death. To evaluate bevacizumab pretreatment in patients with glioma, the researchers selected a different set of representative radiophenotype markers according to pretreatment baseline MRI. By analyzing these markers, the overall survival and PFS after using bevacizumab could be substantially stratified. Therefore, when formulating a plan for patients with glioma, the benefits and damages should be comprehensively considered, and the drug or radiation dose should be carefully selected to maximize the survival benefit of the patients.
| Immuno- and Bio-Therapy|| |
The treatment options and prognosis of gliomas in children and adults are considerably different. Various molecular pathologic bases determine the differences in their treatment approaches, which must be considered when planning for treatment., In a meta-analysis of more than 1000 cases of high-grade and diffuse intrinsic pontine gliomas in children by Mackay et al., molecular changes mainly occurred in H3F3A (H3.3) and HIST1H3B (H3.1), including 67 cases of H3.3G34R/V (n = 63 G34R and n = 4 G34V), 316 cases of H3.3K27M, and 66 cases of H3.1/3.2K27M (n = 62 HIST1H3B, n = 2 HIST1H3C, and n = 2 HIST2H3C), and adult gliomas are distinguished by IDH1 and other molecular markers. The mutant IDH1 can promote the glioma progression in vivo, triggering seizures, and other nervous system syndromes., Therefore, in the past few years, scientists focused more on oncolytic virus. By modifying the E1A virus gene, Delta-24-RGD (DNX-2401) can selectively bind to glioma cells to promote chronic inflammatory cell activities, such as CD8+ T lymphocyte infiltration, and other immune reactions., Tejada et al. initially used adenovirus DNX-2401 to treat an 8-year-old child with diffuse intrinsic pontine glioma; in the first few weeks, the patient well tolerated the injection of viral particles in situ during pathological biopsy, and radiation therapy could be performed after 2 weeks.
A human immune system consists of a class of receptors that can inhibit the activation and differentiation of T lymphocytes. T lymphocytes lose its ability to induce cytotoxicity. Normally, T lymphocytes have a protective effect on normal human cells and protect the body from autoimmune diseases. Inhibited T lymphocytes are regarded as the immune checkpoint. However, cunning cancer cells also use these immune checkpoints to evade recognition and poisoning by the immune system and proceed to unlimited proliferation of such immune checkpoints, including programmed death-1 (PD-1), programmed cell death ligand 1, and cytotoxic T lymphocyte-associated antigen-4. The high expression of these molecules is often closely associated with patient survival. According to this principle, scientists have designed various monoclonal antibody types to block the relevant immune checkpoint pathways and adequately inhibit tumor cell proliferation. The resulting immune checkpoint blockade therapy has helped millions of patients suffering from cancer.,, Unfortunately, the use of inhibitors can result in resistance of tumor cells to treatment. Crafty cancer cells can counteract the pharmacological effects of monoclonal antibodies by producing exosomes expressing immune checkpoints. Compared with chemotherapy, these inhibitors can significantly improve patients' overall survival and PFS, with a lower incidence of side effects. However, with the widespread use, rare but serious, or even life-threatening adverse events occur in patients. For instance, a 66-year-old patient with lung adenocarcinoma using an anti-PD-1 monoclonal antibody developed myositis–myasthenia gravis overlap syndrome complicated with myasthenia crisis and myocarditis. Therefore, the patient's reaction should be closely observed, and symptomatic treatment of serious complications should be performed immediately.
The impact of immune checkpoint inhibitors on the tumor microenvironment is extremely complex. These inhibitors can be used to treat various cancers because they can remodel the myeloid and lymphatic cavity, activate the differentiation of the mononuclear/macrophage system in the tumor, and restore the activity of cell subpopulations, such as antitumor T cells. However, these inhibitors are hindered by the blood–brain barrier and immunosuppressive microenvironment; thus, sufficient drugs cannot reach the target area to exert their efficacy. Inspired by the theory that oncolytic viruses can efficiently cross the barrier and specifically bind to glioma cells, some scholars used the heoncolytic herpes simplex virus expressing PD-1 monoclonal antibody to examine the effect of combining these two agents on glioma, which can acquire a lasting memory immune response in a glioblastoma mouse model without any toxicity to normal neurons., With the advantages of specific binding to glioma cells and few side effects, oncolytic viruses can be combined with drugs such as temozolomide and monoclonal antibodies to effectively inhibit tumor cell proliferation, suggesting a great potential clinical research value.
| Tumor-Treating Fields|| |
TTF is a new type of cancer therapy; however, its anticancer mechanism has remained poorly understood, and the clinical efficacy requires further investigation. TTF uses a low-density, specific frequency electric field to function on the chromosome-related proteins of cancer cells to stimulate the erroneous separation of chromosomes; as a result, double-stranded DNA breaks, which in turn affects cell proliferation, and even induces apoptosis. The antitumor effect is closely associated with the specific absorption rate of the cells to the electric field, the frequency of the electric field, and the commutation time., TTF can also induce a high expression of autophagy genes, thereby inhibiting tumor cell proliferation. TTF efficacy is affected by various physical factors and the patient's constitution. To obtain an individualized treatment plan, physicians can use electric field-volume histograms and specific absorption rate-volume histograms to analyze various relevant factors and apply them clinically. TTF can stimulate the body's antitumor immune effect and activate the macrophages by triggering the nuclear factor κB and mitogen-activated protein kinase pathways. Moreover, TTF can effectively inhibit the malignant proliferation of glioma cells and has a great clinical potential; hence, it should be considered to be added to the standard treatment plan for patients with glioma.
To analyze the effect of TTF combined with radiotherapy on cancer prognosis, Karanam et al. used non-small cell lung cancer cell lines and found that TTF has radiation sensitization. The reason is that TTF after radiotherapy can delay DNA damage repair after the irradiation of cancer cells.,,, In addition, the electric field array of TTF does not affect the coverage of the target tumor by the rays. Similarly, when combined with TTF and baseline temozolomide, tumor growth and neovascularization were inhibited, as revealed in early MRI analysis after treatment. A clinical study involving 695 patients with glioblastoma who had completed initial radiochemotherapy confirmed that the median PFS of the group that received temozolomide combined with TTF was 6.7 months compared with 4 months in the group receiving only temozolomide chemotherapy; the difference was significant. Furthermore, the daily life ability and cognitive function of patients in the combined treatment group have been remarkably improved. In addition, the side effects caused by the electric field-related treatment may only be skin itching without headache, insomnia, and other adverse reactions; thus, the patient can tolerate well to TTF., However, the cost-effectiveness of using TTF is not relatively high. In a 3-health-state Markov model, the researchers analyzed the relationship between life-years gained using TTF and the corresponding cost, and they found that the benefit was extremely minimal (mainly because of the high cost of the device) and cannot be applied as the first-line treatment. Moreover, certain requirements are needed for the duration for the patient to wear the electric field device. The duration is usually superior to 18 h and every 24 h, bringing inconvenience to the patient's daily life. Therefore, further research is needed to further simplify the treatment equipment and improve the penetration rate in patients.
| Summary|| |
Glioma, especially glioblastoma, greatly abbreviates the survival time of patients, with an extremely low quality of life. Although the maximum extent and safe surgical resection and radiochemotherapy are standard treatment options, glioma cannot significantly improve patient's quality of life. Another complicated problem is the rehabilitation of patients after treatment. Selecting treatment strategies is still tremendously challenging. Related research is still ongoing with the development of oncolytic viruses, TTF, and other treatments. Through the combined use of surgery, short-term radiotherapy, temozolomide, and TTF to a certain extent, the overall survival and PFS of patients can be prolonged, and the occurrence of adverse events may be reduced. At the same time, health-care professionals must also be alert to the occurrence of fatal complications related to immune checkpoint inhibitors. Furthermore, formulating prevention and emergency schemes in advance is essential as well. The result of basic research and clinical trials do not always have a high degree of consistency., Therefore, these two types of studies should be closely combined and complement each other, so that the feasibility, safety, and clinical efficacy of the treatment plan can be fully evaluated to better serve patients with glioma.
Financial support and sponsorship
This work was supported by the Medical Science Advancement Program of Wuhan University of China (No. TFJC2018003, to ZL) and the National Health Commission of China (No. 2018ZX-07S-011, to ZL).
Conflicts of interest
There are no conflicts of interest.
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