What are the advances in integrated clinical management of gliomas?

Glioma, i.e. tumor of neuroepithelial tissue origin, can occur in various parts of the brain tissue and is the most common primary intracranial tumor, accounting for about 50% of the tumors in the central nervous system. It is clinically characterized by high morbidity, recurrence, and mortality rates, and is one of the difficulties in neurosurgical treatment. Surgery combined with radiotherapy and chemotherapy is the standardized treatment plan for glioma. Although scholars at home and abroad have conducted a lot of research on immunotherapy, drug-targeted therapy and gene therapy for glioma, they have not yet achieved satisfactory efficacy. However, with the continuous application of new technologies and methods, some progress has been made in the clinical treatment of glioma. 1.The effect of surgical treatment for tumors in functional areas has been significantly improved. Surgical resection of diseased tissues is still the most important means of glioma treatment. Total resection/subtotal resection of the tumor can significantly prolong the survival period of patients; partial resection/biopsy can provide accurate pathological diagnosis and provide basis for further treatment, and at the same time, it can alleviate the symptoms of elevated intracranial pressure and improve the tolerance of patients to various auxiliary treatments after surgery. The surgical principle for non-functional zone tumors is total/subtotal resection of the tumor, but for functional zone tumors, the principle of their surgical treatment has been the focus of debate, mainly how to reduce the impact of surgery on the functional zone and maximize the preservation of the patient’s neurological function. In recent years, with the development of science and technology, and the application of new technology and equipment, the surgery of functional glioma has been transformed from pure anatomical mode to anatomical-functional mode, and has become a comprehensive and minimally invasive surgery of “anticipating in advance, grasping in operation, and resecting the tumor under the guidance of multiple localization and monitoring techniques”. In order to remove the tumor as much as possible on the basis of preserving the nerve function as much as possible, the efficacy of the surgery has been significantly improved. The new techniques adopted include: (1) preoperative functional imaging techniques to determine the functional anatomical regions and functional status of the brain, including functional magnetic resonance imaging (fMRI), diffusion tensor magnetic resonance imaging (DTI), magnetic resonance spectroscopic imaging (MRSI), etc.; (2) the development of surgical plans based on neuronavigation and “image-guided surgery (IGS)”; (3) the development of surgical plans based on neuronavigation; (4) the development of surgical plans based on neuronavigation; and (5) the development of surgical plans based on neuronavigation. Surgical planning; (3) the safe application of wake-up anesthesia technology during surgery; (4) intraoperative imaging technology to achieve real-time precise anatomical localization during surgery, including: intraoperative ultrasound, intraoperative magnetic resonance imaging (MRI); (5) intraoperative brain function localization represented by direct cortical electrical stimulation technology; (6) intraoperative fluorescence imaging and the use of fluorescence microscopy. With the deepening of research on the anatomical and functional aspects of the brain, it has been found that the localization of the anatomical and functional areas of the brain in the traditional sense is often inconsistent with the clinical situation, and the application of fMRI in the clinical setting confirms this result. Through fMRI scanning of a large number of patients, it was found that the functional areas of the brain were not only confined to one region, but in most cases were scattered in various lobes; at the same time, these functional areas could be compensated and displaced when the tumor occurred. This provides a solid foundation for us to remove more tumors while preserving neurological function during surgery. In addition, these techniques and methods mentioned above provide important help for us to further determine the functional zones during surgery and to understand the patient’s neurological status after tumor removal in time, which provides an important guarantee for more resections on the basis of preserving nerve function in surgery. Only a few hospitals in China can carry out this work due to the need for expensive imaging equipment, as well as the need for intraoperative wake-up anesthesia, intraoperative electrophysiological detection, and minimally invasive technology platforms. The hospital used these methods to surgically treat 12 patients with gliomas that involved functional brain areas and clearly showed corresponding symptoms. RESULTS: With the help of these techniques and methods, all of them were able to accurately locate the functional zones during the surgery. 8 cases (66.7%) had their tumors resected under the surgical microscope, 4 cases had their tumors subtotally resected, and all of them showed improvement in their original symptoms after the surgery, and only 1 case showed neurological dysfunction of the contralateral limb. It can be seen that preoperative fMRI functional zone localization and direct cortical electrical stimulation assisted by neuronavigation to locate the functional zone and tumor resection in the arousal state is a safe and effective method to deal with tumors involving the functional zone, which is worthy of further promotion. 2.Radiotherapy is an important adjuvant therapeutic measure The purpose of radiotherapy is to prevent and control the local recurrence of glioma, so the optimal mode of radiotherapy is to accurately irradiate the tumor area. With the emergence of small multileaf grating collimator and intensity modulation technology, three-dimensional conformal radiotherapy has become more and more accurate, so that a higher irradiation dose can be given to the tumor while reducing the damage to the brain tissue. In recent years, some hospitals/research institutes have also performed hyperfractionated radiotherapy, i.e., using a lower-than-usual daily dose, but with a longer total irradiation time and more than the usual number of radiation sessions to achieve a higher total dose (>60Gy), which results in more effective control of brain tumors without a significant increase in the number of long-term side effects. In addition, the use of radiosensitizers (e.g. BudR, IUdR) before/during radiotherapy can also make tumor cells more sensitive to radiotherapy. After the traditional radiotherapy has entered into the era of image-guided radiation therapy (IGRT), the formulation of radiation field has also been expanded with the advancement of diagnostic radiological equipment. In the past, it was believed that the radiation field should be the T2-weighted image of the tumor + peripheral 2 cm region, and with the increase in the application of PET/CT, some scholars of oncological radiotherapy have applied methionine-labeled isotopes to carry out radiotherapy with the high metabolic area as the radiation field after PET/CT. radiotherapy, the local radiotherapy control rate of their high-grade gliomas increased significantly. Interstitial radiotherapy, also known as brain parenchyma radiotherapy, intratumoral radiotherapy, implantation radiotherapy, etc., is the internal radiotherapy in which the radiation energy is directly implanted into the tumor, which can effectively control the growth of the tumor, prolong the life of the patient, and improve the therapeutic effect. If the brain stereotactic technology is used at the same time to permanently implant radioactive particles to treat brain tumors, it can avoid the dangers of hemorrhage, infection and damage to the important intracranial functional structures brought about by neurosurgical open craniocerebral surgery, and it is a new therapeutic approach to treat gliomas in microinvasive neurosurgery. Mesenchymal radiotherapy can be used as an adjuvant treatment before/after conventional external radiotherapy, and it can also be used as a treatment for recurrent glioma. 3.The emergence of new therapeutic drugs brings hope to chemotherapy Drug therapy plays an important role in further killing residual tumor cells, but early randomized trials of malignant glioma did not find that increased chemotherapy can significantly prolong the survival of patients. In recent years, the emergence of temozolomide, a novel alkylating agent with good CNS penetration, has sparked interest in chemotherapy for gliomas, and Stupp et al. reported in 2005 in the New England Journal of Medicine on the efficacy of a phase III trial of temozolomide (TMZ) in combination with simultaneous radiotherapy for the treatment of newly diagnosed GBM. The study showed that TMZ combined with concurrent radiotherapy followed by up to six cycles of adjuvant chemotherapy with TMZ prolonged survival. With the combined treatment modality, the two-year survival rate of patients increased from 10% to 26%. This is of epoch-making significance in the history of glioma chemotherapy. On top of this, the combination of intraoperative peri-tumor residual cavity patch of BCNU slow-release tablet Glidel Wafer increased the two-year survival rate of patients with glioblastoma multiforme to 39%. Surgery + intraoperative Glidel Wafer application + postoperative radiotherapy, synchronized TMZ chemotherapy + postoperative TMZ adjuvant chemotherapy are now adopted by the 2008 U.S. guidelines for the treatment of high-grade gliomas. Currently, research on TMZ has been carried out in at least five areas, including the application of TMZ to high-risk low-grade glioma population; research on TMZ resistance, which is currently believed to be the main resistance mechanism of TMZ is the high expression of MGMT, of which the change of the drug dosage density and the use of O6-benzylguanine (O6-BG) as a sensitizer to deplete MGMT are undergoing clinical trials. TMZ is currently undergoing clinical trials; TMZ for the treatment of brain metastases; the combination of TMZ with other cytotoxic or molecularly targeted drugs; and the combination of TMZ with tumor angiogenesis inhibiting drugs. It is believed that it can bring new hope to glioma patients in China. With the development of tumor immunology, molecular biology and other disciplines, immunotherapy, anti-angiogenesis therapy, gene therapy as the main content of biological therapy has gradually become the fourth treatment mode after surgery, radiotherapy and chemotherapy. In more than a decade, nearly 50 clinical trials of gene therapy for glioma have been conducted, but the gene therapy strategies that have received the most attention at present are the HSV-tk-GCV system; lysovirus (genetically engineered modified herpes simplex virus), of which the HSV-tk-GCV system has been promoted by the British pharmaceutical companies, and the current phase II clinical trials have been successful, and the gene therapy group [Surgery (with postoperative navigation) + The median survival time of gene therapy + postoperative radiotherapy] is 56% higher than that of the control group [surgery (applying postoperative navigation) + postoperative radiotherapy], and its efficacy is exciting, and it is currently undergoing phase III clinical trials in Europe. It is believed that it will enter clinical application in the near future. Molecularly targeted drug therapy for tumors is an exciting field in tumor therapeutics, such as non-small cell lung cancer and renal clear cell carcinoma, both of which have been selected for second-line drug therapy. Anti-angiogenic gene-targeted therapy is the most studied molecularly targeted therapy in gliomas. Bevacizumab (Avastin) is a new type of human anti-VEGF monoclonal antibody, which mainly plays a role in neutralizing VEGF and blocking its binding to VEGF receptor on endothelial cells, and it was found in 2007 that the combination of bevacizumab and chemotherapy drug irinotecan can increase the effect of radiotherapy for glioma, and it has already entered into the phase II clinical study. 5.Individualized treatment is an inevitable trend The evidence-based individualized comprehensive treatment of glioma is an inevitable trend. Neurosurgery is the mainstay of glioma treatment, combined with radiotherapy, chemotherapy and other related departments to formulate individualized treatment plans for different patients. Minimally invasive surgery should be used for patients with surgical indications, and the tumor should be removed as much as possible to reduce the tumor load under the premise of preserving neurological function; at the same time, histological diagnosis should be obtained, and radiotherapy, chemotherapy sensitivity test and gene expression test should be conducted to provide reference and create favorable conditions for further postoperative adjuvant therapy; the tumor’s sensitivity should be taken into account in the postoperative radiotherapy, and the tumor’s radiosensitivity should be taken into consideration, and whether there is any correlation between the tumor’s radiosensitivity and the tumor’s resistance to radiotherapy should be taken into consideration. gene expression associated with radiotherapy resistance. The development of postoperative chemotherapy regimen should be based on the results of in vitro drug sensitivity test and the expression of drug-resistant genes. Currently, most scholars consider the level of MGMT gene expression as an independent prognostic indicator, and patients with strong MGMT expression are significantly less susceptible to alkylating agents (including TMZ) than those with low MGMT expression, so how to treat patients with strong MGMT expression with chemotherapy is still a challenge faced by many neuro-oncologists. Glioma is a highly heterogeneous disease with complex mechanisms involving multiple factors and components, and it is impossible to envision a single therapy that can achieve the desired results. The treatment model of glioma should be multidisciplinary collaboration and gradually transition from empirical treatment to an individualized treatment model based on evidence-based medicine and molecular characteristics of tumors, i.e., evidence-based-normative-individualized comprehensive treatment. With the continuous progress of science and technology, through multidisciplinary collaboration and the complementary advantages and organic combination of multiple therapeutic methods, mankind will eventually realize the goal of long-term high-quality survival and even cure of glioma, especially high-grade glioma patients.