I. Preface
The “Expert Consensus on the Diagnosis and Treatment of Malignant Gliomas of the Central Nervous System in China” has been well received since its publication in October 2009. In order to meet the needs of clinicians and patients, in September 2011, the writing group changed the name of “Consensus” to “Guidelines” and added the following contents: hairy cell astrocytic glioma, embryonic dysplastic neuroepithelioma, ganglioneuroma, ganglioglioma, and WHO grade II glioma (e.g., diffuse cell glioma). The following are added: hairy cell astrocytic glioma, embryonal dysplastic neuroepithelioma, ganglioneuroma, ganglioglioma, WHO grade II glioma (e.g. diffuse astrocytoma, oligodendroglioma, and ventricular meningioma), WHO grade III and IV gliomatosis, medulloblastoma, and supratentorial neuroectodermal tumor. Neuropathologists, neuroimaging specialists, and rehabilitation specialists were added to the list of authors. The procedure for writing the “consensus” was maintained: 1) multidisciplinary experts proposed the problem and scope to be addressed by the “guideline”. 2) information experts searched the literature for evidence according to the problem, with emphasis on Chinese literature in addition to foreign literature. 3) the experts of the writing team read the literature and classified it according to the five levels of evidence-based medicine. According to the five levels of evidence-based medical classification, randomized control studies “CONSORT” and guidelines “AGREE” procedure, multiple people consult on a certain issue, assess the quality of evidence in the literature, reach a recommendation level, and combine the Chinese national situation and actual situation, and write a recommendation. The recommendations are written in the light of the Chinese situation. The final draft is coordinated and finalized by the writing team leader.
Overview and principles of management
Glioma is the most common primary intracranial tumor and is classified as grade I-IV in the WHO (2007) classification of central nervous system tumors. Low-grade gliomas (WHO grade I-II) commonly include hairy cell astrocytoma, pleomorphic yellow astrocytoma and ventricular giant cell astrocytoma. There are also mixed glial neuronal tumors, such as ganglioglioma and embryonic dysplastic neuroepithelial tumors. In the past 30 years, the incidence of malignant brain tumors has been increasing year by year. According to the U.S. Brain Tumor Registry, malignant gliomas account for approximately 70% of primary malignant brain tumors. Among the malignant gliomas, mesenchymal astrocytoma (WHO grade III) and glioblastoma multiforme (GBM, WHO grade IV) are the most common, with GBM accounting for approximately 50% of all gliomas.
The pathogenesis of gliomas is unknown, and the two risk factors identified so far are exposure to high doses of ionizing radiation and genetic mutations in genes with high epistasis associated with rare syndromes. Therefore, hot topics of research on glioma pathogenesis include heterozygous deletions of alleles and genetic variants of genes, DNA mismatch repair, disruption of cellular signaling pathways (e.g., epidermal growth factor receptor and platelet-derived growth factor pathways), mutations in PI3K/Akt/PTEN, Ras and P53/RB1 pathways, and tumor stem cells.
The clinical manifestations of glioma include increased intracranial pressure (e.g., headache, nausea and vomiting, personality and consciousness changes) and neurological abnormalities (e.g., seizures, motor and/or sensory deficits). The initial imaging diagnosis of glioma relies mainly on magnetic resonance imaging (MRI) and computed tomography (CT) scans. Magnetic resonance spectroscopy (MRS), positron emission tomography (PET) and single photon emission tomography (SPECT) are helpful in distinguishing tumor recurrence from radiation necrosis. Ultimately, tumor specimens need to be obtained by tumor resection or biopsy and a definitive pathological diagnosis made. Morphologic changes are the basis of pathologic diagnosis. Molecular biological markers are important for determining molecular subtypes, individualized treatment and clinical prognosis, such as glial fibrillary acidic protein, isocitrate dehydrogenase 1 and Ki-67 antigen (level I evidence).
The treatment of glioma is a combination of surgery, radiotherapy and chemotherapy. Surgery advocates safe and maximal removal of the tumor (level II evidence). Radiotherapy kills or inhibits residual tumor cells and prolongs survival (Level II evidence). Several new radiotherapy techniques have improved the effectiveness of radiotherapy. Temozolomide (TMZ) applied in parallel with radiotherapy for 6 more courses after surgery has become the standard of care for newly diagnosed GBM and significantly improves patient survival (level I evidence). Endogenous O6-methylguanine-DNA methyltransferase (MGMT) methylation levels and chromosome 1p/19q heterozygosity deletion can be used as predictors of chemotherapy sensitivity and good prognosis in GBM and oligodendroglioma, respectively (level II evidence). Those with isocitrate dehydrogenase 1 mutations have a better prognosis than wild type (level I evidence).
There has been some progress in neuroimaging and treatment of glioma, but the prognosis of glioma is not yet satisfactory. The treatment of glioma requires multidisciplinary cooperation among neurosurgery, radiotherapy, oncology, pathology and rehabilitation, following evidence-based medical evidence, individualized and comprehensive treatment, standardization and optimization of treatment protocols, with the aim of achieving maximum therapeutic benefit, prolonging progression-free survival and overall survival of patients, and improving the quality of survival.
III. Diagnostic imaging
It is strongly recommended that the imaging diagnosis of glioma should be based on MRI scan with enhancement and CT as a supplement. MRI scan with enhancement and special features such as magnetic resonance spectroscopy (MRS) can not only differentiate glioma from non-tumor lesions, but also help to grade glioma, clarify the extent of glioma invasion, and help tumor stereotactic biopsy area selection, and facilitate glioma resection and prognostic assessment (level III evidence).
Low-grade gliomas usually show slightly low signal in T1W, slightly high signal in T2W and FLAIR on plain MRI, and mostly non-enhanced or mildly heterogeneous enhancement on enhanced scans; solid parts of hairy cell astrocytoma, hairy cell mucinous astrocytoma and pleomorphic yellow astrocytoma are often significantly enhanced; adjacent meninges of pleomorphic yellow astrocytoma are often involved and significantly enhanced, and about 70% of them may show “The MRI of nodular cell tumor and nodular glioma cystic part is low in T1W and high in T2W; the solid part is slightly low in T1W and slightly high in T2W, and the T1W enhancement shows different degrees of enhancement. Ventricular meningioma shows moderate heterogeneous enhancement. About 80% of oligodendrogliomas show nodular, patchy or clustered calcifications. CT examination is useful for detecting calcifications in the tumor, which is very helpful for preoperative qualitative diagnosis. MRI scan of high-grade glioma is usually a mixed-signal lesion with iso- or low-signal T1W and heterogeneous high-signal T2W. The tumor often spreads along the white matter fiber bundles, and MRI enhancement scan shows nodular or irregular “wreath-like” enhancement. Glioma is mostly non-enhancing or slightly plaque-like strengthening. The majority of medulloblastomas are clearly and uniformly enhancing, but a few are moderately enhancing, while PNET is not uniformly enhancing and has irregular “ring-like” enhancement.
MRI special features (MRS, DWI, DTI, PWI and BOLD), PET and SPECT are recommended for differential diagnosis, preoperative evaluation, outcome evaluation and postoperative follow-up.
IV. Pathological diagnosis and molecular biological markers
Pathological diagnosis and grading of glioma is strongly recommended in strict accordance with WHO (2007) classification of central nervous system tumors. In order to cooperate with the treatment, efficacy observation and prognosis judgment of glioma patients, molecular biological markers of glioma are performed as appropriate: detection of IDH1 gene mutation and chromosome 1p/19q heterozygous deletion in low-grade glioma is important for clinical prognosis judgment (Class I evidence). Gliomas characterized by differentiation to astrocytes and 60%-70% of oligodendroglial cell tumors are positive for glial fibrillary acidic protein (Level I evidence). Oligodendrocyte-specific nuclear transcription factors are useful in identifying oligodendroglial tumors from gliomas of astrocyte origin. Epidermal growth factor receptor amplification and its variant III mutation are valuable for the diagnosis of primary GBM. Ki-67 proliferation index is closely related to the degree of tumor differentiation, infiltration or metastasis and prognosis, and is one of the important reference indicators for determining tumor prognosis (level I evidence). Neuron-specific nuclear proteins are important for determining the neuronal component in tumors, and are mainly used for the diagnosis and differential diagnosis of glial neuronal tumors and neuroblastomas.
Based on molecular biological markers related to signaling pathways, medulloblastoma can be classified into several molecular subtypes, such as Wnt, Shh and non-Wnt/Shh types. This typing is important for clinical development of optimal treatment plans and determination of prognosis (Level II evidence).
Seven principles of glioma grading are strongly recommended (level I evidence): tumor cell density; pleomorphism or atypia of tumor cells, including hypodifferentiated and undifferentiated components; high heterogeneity or atypia of tumor cell nuclei, with the presence of multinuclei and meganuclei; high nuclear fission activity; vascular endothelial cell hyperplasia (appearing as glomeruloid vascular hyperplasia); necrosis (pseudoganglionic necrosis) and elevated Ki-67 proliferation index. Because of the heterogeneous features within the glioma, the pathological diagnosis of glioma should be made on obtaining the maximum extent of tumor tissue specimens.
V. Surgical treatment
Maximum safe resection of the tumor is strongly recommended as the basic principle of surgery (Class II evidence). Safety is defined as postoperative neurological status > KPS > 70 points. For those who cannot safely resect the tumor completely, partial tumor resection, craniotomy biopsy or stereotactic (or under navigation) puncture biopsy can be used as appropriate to clarify the histopathological diagnosis of the tumor. The extent of tumor resection is associated with patient survival time, sensitivity to radiotherapy and chemotherapy, etc. (Level I evidence).
It is strongly recommended that maximum safe tumor resection should be sought for gliomas confined to the lobes of the brain (Class II evidence). Based on the swollen, infiltrative growth pattern and blood supply characteristics of gliomas, microscopic neurosurgical techniques are recommended to make anatomical resection along the white matter fiber bundle course of the tumor margin with the cerebral sulcus and cerebral gyrus as the boundary to obtain maximum tumor resection with minimal tissue and neurological function damage and a clear histopathological diagnosis. For malignant glioma and gliomatosis with diffuse infiltrative growth in the dominant hemisphere, lesions invading bilateral hemispheres, elderly patients (>65 years old), poor preoperative neurological status (KPS <70), deep intracerebral or brainstem sites, partial tumor resection, cranial biopsy or stereotactic (or under navigation) puncture biopsy is recommended as appropriate. Partial tumor resection offers a higher survival advantage than biopsy alone. Biopsy is mainly used for lesions that are adjacent to functional areas or deep in location and cannot be removed clinically. Biopsy mainly includes stereotactic (or under navigation) biopsy and open surgical biopsy. Stereotactic (or guided) biopsy is indicated for lesions that are more deeply located, whereas craniotomy is indicated for lesions that are superficially located or close to/in the functional cortex or brainstem.
A review of MRI <72 h after surgery is strongly recommended to assess the extent of glioma resection using quantitative volumetric analysis of preoperative and postoperative imaging. For high-grade malignant gliomas, T1W-enhanced MRI is currently recognized as the "gold standard"; for low-grade malignant gliomas, T2W or FLAIR is recommended, and for units that do not have access to MRI, CT scan and enhancement are recommended <72 h after surgery.
Conventional neuronavigation, functional neuronavigation, intraoperative neurophysiological monitoring techniques (e.g., cortical functional localization and subcortical stimulation of nerve conduction bundle localization), and intraoperative MRI real-time image neuronavigation (level II evidence) are recommended. Fluoroscopy-guided microsurgery, intraoperative ultrasound imaging for real-time localization, preoperative and intraoperative DTI to clarify the spatial anatomical relationship between the tumor and the peripheral nerve bundles, and preoperative and intraoperative BOLD-functional MRI for cortical functional localization may be recommended.
VI. Radiotherapy
6-10 MV external radiation with conventional segmentation (1.8-2.0 Gy/dose, 5 times/week) is strongly recommended; stereotactic radiotherapy and stereotactic/inter-tissue brachytherapy are not recommended as the initial postoperative treatment modality (Class II evidence); the application of 3D conformal radiotherapy or intensity-modulated radiotherapy is recommended; the target area should be outlined with reference to the preoperative and postoperative imaging data, with MR as the primary The target area should be outlined with reference to preoperative and postoperative imaging data, with MR as the main basis, supplemented by functional MRI and PET-CT results, and CT/MR image fusion is recommended for treatment planning design in units with conditions.
The incidence of pseudo-progression of glioma after TMZ synchronized radiotherapy increases and the time of pseudo-progression appears earlier, which is difficult to distinguish from recurrence and radiation necrosis, and can be identified with the help of MRS, PET/CT or biopsy.
High-grade gliomas (including GBM, mesenchymal astrocytoma, mesenchymal oligodendroglioma and mesenchymal oligodendroglioma): Radiotherapy is recommended to be started as early as possible after surgery – the standard dose of local tumor irradiation is 60 Gy. GTV is the residual tumor and/or operative cavity shown on postoperative MRI T1-enhanced images. CTV1 is the GTV For GBM, simultaneous TMZ radiotherapy followed by 6 courses of TMZ adjuvant chemotherapy is highly recommended (see GBM chemotherapy).
Gliomatosis: localized tumor irradiation at 50-60 Gy or whole brain irradiation at 40-45 Gy. GTV is the area of abnormal signal on MRI FLAIR or T2-weighted images. CTV is the area of abnormal signal on MRI FLAIR or T2-weighted images + 2-3 cm of external radiation.
Low-grade glioma: It is recommended that those with complete tumor resection can be observed regularly if the prognostic factors are low-risk (≤2 points); if the prognostic factors are high-risk (3~5 points), early radiotherapy should be given. Early radiotherapy is recommended for those with residual tumor after surgery. gTV is an area of abnormal signal on MRI FLAIR or T2-weighted images. cTV is GTV or/and 1~2 cm of outgrowth of the surgical cavity margin. 45~54 Gy of total dose and 1.8~2.0 Gy of fractionated dose are strongly recommended for low-grade glioma (Class I evidence).
Ventricular meningioma: observation is recommended for surgical total resection; postoperative whole-brain radiotherapy for partially resected or mesenchymal ventricular meningioma; spinal cord irradiation may be withheld if spinal cord MRI and cerebrospinal fluid exfoliation cytology are negative, and total spinal cord irradiation should be added if one of the above tests is positive. The GTV is the anatomical area of preoperative tumor invasion and the area of postoperative MRI signal abnormality; CTV is the area of GTV outgrowth of 1~2 cm. Gy, with fractionated doses of 1.8~2 Gy.
Medulloblastoma: In addition to <72 h postoperative brain-enhanced MRI, spinal cord-enhanced MRI is recommended 2-3 weeks postoperatively or before radiation therapy, and cerebral fluid cytology should be done >2 weeks postoperatively if necessary. Patients should be treated separately according to the risk of recurrence (general risk group and high risk group). Whole brain total spinal cord irradiation (CSI) + posterior cranial fossa thrust General risk group: CSI dose 30-36 Gy, posterior cranial fossa thrust to 55.8 Gy; or CS I dose 23.4 Gy, posterior cranial fossa thrust to 55.8 Gy, simultaneous chemotherapy with VCR and combined chemotherapy after radiotherapy; High risk group: CSI dose 36 Gy, posterior cranial fossa thrust to 55.8 Gy, combined chemotherapy after radiotherapy.
In younger children younger than 3 years old, chemotherapy is usually the main adjuvant treatment and conventional radiotherapy is not recommended.
VII. Chemotherapy
High-grade glioma: Simultaneous postoperative TMZ radiotherapy with oral TMZ 75 mg/m2 for 42 days is strongly recommended for patients with newly diagnosed GBM. Four weeks after the end of radiotherapy, TMZ treatment with 150 mg/m2 for 5 consecutive days, 28 days as a course of treatment, and if well tolerated by the patient, the dose is increased to 200 mg/m2 for 6 courses of chemotherapy in subsequent chemotherapy (level I evidence). ACNU (or other alkylating agents BCNU, CCNU) in combination with VM26 regimen may also be used, depending on the circumstances (Level I evidence). For patients with newly diagnosed mesenchymal glioma, radiotherapy combined with TMZ (same as GBM) or nitrosoureas such as ACNU or PCV regimens (lomustine + methylbenzylhydrazine + vincristine) is recommended. Testing for MGMT promoter region methylation status, isocitrate dehydrogenase 1/2 mutations, and 1p/19q deficiency (level II evidence) is recommended for patients with high-grade gliomas in units where available.
Low-grade gliomas: for those with total resection, those without high-risk factors can be observed; radiotherapy and chemotherapy are recommended for those with high-risk factors. Radiotherapy and chemotherapy are recommended for those with residual. TMZ is recommended as the chemotherapy drug of choice for adjuvant treatment of low-grade glioma. Recommend testing for 1p19q deletion in patients with low-grade glioma in units where available; chemotherapy may be administered first in cases of combined deletion (Class II evidence). Those with isocitrate dehydrogenase 1 mutations have a better prognosis than wild type (level I evidence).
Pediatric gliomas: postoperative chemotherapy is recommended for patients with low-grade gliomas, especially in infants and children who cannot be treated with radiotherapy; the main regimens are vincristine + carboplatin, 6-thioguanine + procarbazine + lomustine + vincristine (TPCV regimen), low-dose cisplatin + etoposide and TMZ. for patients with high-grade gliomas, PCV regimen chemotherapy (vincristine, CCNU and prednisone) is recommended. Methylation of the MGMT promoter region is recommended for testing prior to chemotherapy for pediatric gliomas in units where available.
Ventricular meningioma and mesenchymal ventricular meningioma: Chemotherapy for adult patients with primary ventricular meningioma is controversial and evidence-based medical studies are lacking. Chemotherapy is recommended for recurrences. In patients with mesenchymal ventricular meningioma, chemotherapy may be administered after surgery and radiation therapy. The main regimens of chemotherapy include platinum-based combination chemotherapy and etoposide and nitrosourea chemotherapy.
Medulloblastoma: For children at average risk, chemotherapy is recommended after surgery and radiotherapy (but not as a substitute for radiotherapy) with a combination chemotherapy regimen of vincristine + cisplatin + CCNU or vincristine + cisplatin + cyclophosphamide or vincristine + VP16 + carboplatin (cyclophosphamide). The recommended chemotherapy regimen after surgery and radiotherapy for children assessed as high risk is: vincristine + cisplatin + CCNU combination chemotherapy. Postoperative chemotherapy alone is recommended for patients <3 years of age, and high-dose shock chemotherapy may delay or avoid the immediate and long-term complications associated with postoperative radiotherapy in infants and children. For adult patients, after surgery and radiotherapy, the commonly used chemotherapy regimens are CCNU, vincristine and prednisone.
VIII. Treatment and follow-up of recurrent tumors
The treatment of recurrent tumor should be considered according to the site of recurrence, tumor size, intracranial pressure, patient’s general condition and previous treatment. If the patient is in good general condition, surgical treatment is recommended for local recurrent tumor with obvious occupying effect. For patients who are not suitable for reoperation, radiation therapy and/or chemotherapy may be recommended; if those who have received previous radiation therapy are not suitable for reirradiation therapy, chemotherapy is recommended. For patients with high-grade glioma who have not received TMZ chemotherapy in their first treatment, the standard TMZ chemotherapy regimen is still recommended after recurrence. TMZ dose-intensity regimens, TMZ in combination with platinum drugs, and irinotecan in combination with bevacizumab may be recommended for the treatment of recurrent high-grade glioma. Patients with recurrent high-grade glioma may be recommended for various investigational therapies including molecularly targeted therapies, gene therapy, and immunotherapy.
A basic clinical review of the patient is strongly recommended, including general condition, cognitive and psychiatric status, neurological signs and physical examination, necessary laboratory tests, and imaging review. During follow-up, tumor-induced or treatment-related signs and symptoms should be monitored and managed, including the use of steroid hormones and their side effects, the use of antiepileptic drugs and their side effects, and the immediate and long-term side effects of radiotherapy and chemotherapy.
There is no high-level evidence of evidence-based medicine to determine the duration and interval of follow-up. Generally, low-grade gliomas should be followed up every 3-6 months for 5 years; thereafter, they should be followed up at least once a year. High-grade gliomas should be followed up 2-6 weeks after the end of radiotherapy, and then every 1-3 months for 2-3 years, and then the follow-up interval can be extended appropriately. Doctors should also individualize the follow-up interval according to the histopathology of the tumor, the degree of resection and tumor residual, whether new symptoms appear, whether the patient participated in clinical trials, the patient’s compliance and health status.
Rehabilitation treatment
Dysfunction caused by central nervous system glioma includes coma, pain, epilepsy, motor dysfunction, sensory dysfunction, depression, anxiety, speech and swallowing dysfunction, cognitive impairment, visual impairment, psychiatric impairment, dysbiosis, decreased ability to perform activities of daily living, decreased ability to participate in society and low life satisfaction. Rehabilitation therapy is necessary and important to effectively improve patients’ function and quality of survival. It is recommended to use internationally used functional assessment instruments, scales and techniques for the assessment of functional impairment. The rehabilitation treatment methods are mainly integrated treatment with individualized programs, including recommended physical therapy (Level II evidence), occupational therapy (Level II evidence), strongly recommended speech therapy, cognitive impairment therapy (Level I evidence), rehabilitation engineering, anti-spasticity therapy, rehabilitation nursing, nutritional support, recreational therapy, analgesia, psychotherapy and Chinese traditional medicine treatment, and can be combined with related pharmacological treatment.
It is highly recommended that the three-level rehabilitation treatment model for central nervous disorders, which is currently being promoted in China, can be applied to the rehabilitation of patients with glioma. “Primary rehabilitation” refers to the early rehabilitation treatment in the emergency room or neurosurgery department of the hospital; “secondary rehabilitation” refers to the rehabilitation treatment in the rehabilitation ward or rehabilitation center; “tertiary rehabilitation ” refers to continued rehabilitation in the community or at home (Level I evidence).