Primary central nervous system tumors: clinical guidelines

Applies toadults2025 editionC70.0, C70.1, C70.9, C71.0…

Clinical guidelines of the Russian Ministry of Health, adults. 2025 edition, ICD-10 codes: C70.0, C70.1, C70.9, C71.0….

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Brief for Practice

WhiteCoat Pro editorial summary of the guideline text, 2025 edition. Each item links to the original section — verify against it before prescribing.

Primary CNS tumors are a heterogeneous group of neoplasms originating from the brain and spinal cord tissues and their meninges. Treatment strategy is determined primarily by the integrative morphological and molecular diagnosis, tumor location, extent, and the patient's functional status; treatment is planned by a multidisciplinary tumor board.

Key points

TNM staging and anatomical-topographic characteristics are not used for primary CNS tumors. Key parameters are the histological diagnosis and WHO grade 1–4. → in text
The diagnosis must be integrative: histological type, grade, significant molecular features, tumor location and extent, as well as history of prior treatment. → in text
For most tumors, the primary imaging modality is contrast-enhanced brain MRI; if there is a risk of leptomeningeal dissemination, the entire contrast-enhanced spinal cord is also imaged. → in text
Treatment strategy may include surgery, radiation therapy, and systemic antineoplastic therapy; the choice is determined by histological type, molecular markers, patient age, and treatment response. → in text
Post-treatment contrast-enhanced brain MRI is performed every 3 months for the first 2 years, then every 6 months; tumor response is assessed using RANO criteria. For certain tumors, spinal cord MRI is additionally performed. → in text
Treatment strategy is determined by a tumor board involving a neurosurgeon, oncologist, and radiation oncologist; a neurologist, endocrinologist, ophthalmologist, and other specialists are engaged when necessary. → in text

Diagnostics

Take complaints and medical history, assess neurological and somatic status, and evaluate functional status using the Karnofsky performance scale. Level of Evidence C, Grade of Recommendation 5. → in text
Perform brain MRI without and with contrast in T1, T2, T2-FLAIR, and post-contrast T1 sequences, in three planes or with thin axial slices. Level of Evidence C, Grade of Recommendation 5. → in text
In medulloblastoma, pineoblastoma, primary CNS germ cell tumor, and other conditions with a risk of leptomeningeal dissemination, perform contrast-enhanced MRI of the brain and entire spinal cord; post-surgery, if the study was not performed previously, MRI is conducted no earlier than 2–3 weeks later. → in text
Obtain a complete blood count, blood chemistry panel, and coagulogram. For pineal or sellar/chiasmatic region tumors, determine alpha-fetoprotein, β-hCG, and LDH. Level of Evidence C, Grade of Recommendation 5. → in text
Perform electroencephalography in patients with CNS tumors and a history of seizures. Level of Evidence C, Grade of Recommendation 5. → in text
Confirm the diagnosis by examining biopsy or surgical specimens using histology and immunohistochemistry. Level of Evidence C, Grade of Recommendation 5. → in text
If surgical resection is impossible or inappropriate, or if primary CNS lymphoma is suspected, stereotactic or open biopsy is performed. Level of Evidence C, Grade of Recommendation 5. → in text
For integrative classification and prognostic refinement, test for IDH1/2, MGMT methylation, and 1p/19q co-deletion whenever possible. Level of Evidence C, Grade of Recommendation 5. → in text
When technically feasible, additionally assess molecular genetic characteristics, including ATRX, TERT, and BRAF, depending on the clinical situation. → in text

Treatment

Surgery or biopsy is performed in a specialized neurosurgical facility with experience in neuro-oncological interventions; the goal of resection is to maximally reduce tumor volume, decrease mass effect, and obtain material for diagnosis. Neurophysiological monitoring is used when the tumor is close to motor areas, nerve tracts, and cranial nerves. Level of Evidence C, Grade of Recommendation 5. → in text
To increase the radicality of resection, neuronavigation, intraoperative ultrasound flowmetry, and 5-aminolevulinic acid fluorescence-guided surgery are used. Level of Evidence B, Grade of Recommendation 2. → in text
In grade 3–4 malignant tumors, radiation therapy is initiated up to 6 weeks post-surgery; for grade 3–4 diffuse gliomas, a fractionation of 1.8–2.0 Gy per fraction to a total dose of 59.4–60 Gy is typically used. Level of Evidence C, Grade of Recommendation 5. → in text
In glioblastoma and grade 4 astrocytoma, the preferred postoperative regimen is chemoradiotherapy with temozolomide 75 mg/m² daily during radiation therapy (30 fractions of 2 Gy), followed by 6–12 cycles of temozolomide 150–200 mg/m² on days 1–5 every 28 days. Level of Evidence C, Grade of Recommendation 5. → in text
For adult low-grade diffuse gliomas, radiation therapy is administered at 1.8–2.0 Gy per fraction to a total dose of 50.4–54 Gy. For grade 3 gliomas, the PCV regimen may be used: lomustine 100 mg/m² on day 1, vincristine 1.4 mg/m² on days 1 and 8, procarbazine 70 mg/m² on days 8–21, every 6 weeks. Level of Evidence C, Grade of Recommendation 5. → in text
In primary CNS lymphoma, high-dose methotrexate 3.5–8 g/m² is used as first-line therapy in patients aged 65 years or younger, with a Karnofsky score >50 and preserved liver and kidney function; treatment is administered in an inpatient setting with monitoring of blood drug concentrations. Level of Evidence C, Grade of Recommendation 5. → in text
In the presence of a clinically significant increase in β-hCG (≥5 times the upper limit of normal) or AFP (>2 times the upper limit of normal), treatment for a primary CNS germ cell tumor is initiated with chemotherapy without histological verification. For pure germinoma, cisplatin + etoposide is used, followed by irradiation of the ventricular system to a total dose of 24 Gy in the absence of evidence of spinal leptomeningeal metastasis. Level of Evidence C, Grade of Recommendation 5. → in text
For neurological symptoms caused by intracranial hypertension, mass effect, or hydrocephalus, prescribe the minimum effective dose of dexamethasone (0.5–4 mg) with gradual tapering after symptom regression. If lymphoma is suspected, glucocorticoids should not be administered prior to morphological verification, except in cases of life-threatening edema or brain shift. Level of Evidence C, Grade of Recommendation 5. → in text

When to refer and how to monitor

If neurological symptoms characteristic of a brain or spinal cord tumor are present, refer the patient to a neurologist and/or for contrast-enhanced MRI; if a space-occupying lesion is identified, refer to a neurosurgeon. → in text
If a space-occupying lesion along with clinical manifestations is directly life-threatening, the patient is hospitalized for neurosurgical treatment. → in text
Emergency or urgent hospitalization is indicated for tumor complications or complications of surgical, radiation, or drug therapy requiring specialized care. → in text
Elective hospitalization is necessary for complex interventional diagnostic procedures or antineoplastic treatment requiring round-the-clock or day-patient monitoring. → in text
Consultation at an outpatient oncological care center or primary oncology office must take place no later than 5 working days after the referral is issued; if it is impossible to provide the required scope of care, the patient is referred to other specialized medical organizations, including federal centers. → in text

Frequently asked questions

Should a primary CNS tumor be staged using TNM?

No. TNM and separate anatomical-topographic staging are not used; prognosis and treatment are primarily determined by the morphological diagnosis and grade. → in text

When is total spinal cord MRI necessary?

It is mandatory for tumors with a risk of leptomeningeal dissemination, including medulloblastoma, pineoblastoma, primary CNS germ cell tumors, as well as spinal cord tumors. In ependymoma, the brain is additionally evaluated to rule out a primary cerebral lesion and metastases. → in text

Can a diagnosis be made without a biopsy?

In selected cases, yes: when typical clinical and neuroimaging features of certain lesions are present, or when a biopsy in an eloquent area, severe patient condition, or marked vascularization carries a high risk of disability or death. For most tumors, the diagnosis is confirmed by examining surgical or biopsy material. → in text

Should anticonvulsants be prescribed prophylactically?

No, prophylactic anticonvulsant therapy is not recommended for patients without seizures. In the presence of seizures, including a history thereof, a neurological consultation is required to prescribe or adjust treatment. → in text

How frequently should a patient be monitored post-treatment?

Brain MRI without and with contrast is performed every 3 months for the first 2 years, then every 6 months; for certain tumors or upon the appearance of neurological symptoms, spinal cord MRI is added. Response is evaluated using RANO criteria. → in text

Status: Applied · approved by the Scientific and Practical Council of the Russian Ministry of Health
Database ID: 585, edition 2 (ID 585_2)
Publication date: May 29, 2025
Age category: adults
ICD-10 codes: C70.0 C70.1 C70.9 C71.0 C71.1 C71.2 C71.3 C71.4 C71.5 C71.6 C71.7 C71.8 C71.9 C72.0 C72.1 C72.2 C72.3 C72.4 C72.5 C72.8 C72.9 D18.0 D18.1 D32.0 D32.1 D32.9 D33 D42.0 D42.1 D42.9 D43.0 D43.1 D43.2 D43.3 D43.4 D43.7 D43.9 D48.2
Specialties: Oncology Neurosurgery
Developers: Russian Association of Neurosurgeons
Association of Oncologists of Russia
All-Russian Public Organization «Russian Society of Clinical Oncology»
Official text: Russian Ministry of Health Rubricator — 585_2

List of Abbreviations

GTV (Gross Tumor Volume)

IDH – isocitrate dehydrogenase

MGMT – O6-methylguanine-DNA methyltransferase

TNM – (abbreviation for tumor, nodus, and metastasis) international classification of malignant tumor stages

PTV (Planning Tumor Volume)

RANO – Response Assessment criteria in Neuro-Oncology

RTOG – Radiation Therapy Oncology Group

WHO – World Health Organization

IV bol. – intravenous, bolus

IV inf. – intravenous infusion Gy – Gray

CTV (Clinical Tumor Volume)

CT – computed tomography

mg/m²– milligrams per square meter

ICD-10 – International Classification of Diseases 10th Revision

MRI – magnetic resonance imaging

PCT – polychemotherapy

PET/CT – positron emission tomography combined with computed tomography

RCT – randomized controlled trial

SFD – single focal dose

TFD – total focal dose

SRT – stereotactic radiotherapy

STB – stereotactic biopsy of brain tumor.

US – ultrasound examination

Terms and Definitions

ECOG (Eastern Cooperative Oncology Group) – a 5-grade scale for assessing the general condition of a cancer patient before, during, and after treatment (recommended by the Eastern Cooperative Oncology Group).

Adjuvant chemotherapy – a type of chemotherapy administered after tumor removal.

Boost – additional irradiation of the tumor or tumor bed.

Immunohistochemical examination – a microscopic tissue examination method that provides the most specific identification of target substances and is based on treating sections with labeled specific antibodies against the target substance (antigen).

Antineoplastic drug therapy – administration of drugs orally, subcutaneously, intravenously, or intramuscularly, aimed at a systemic antitumor effect.

Palliative care – treatment aimed at improving the quality of life of patients by providing maximum comfort and support at the final stage of an oncological disease.

Supportive care – treatment aimed at reducing the adverse effects of primary treatment (chemotherapy, targeted therapy, radiation therapy). Maintenance therapy aims to maintain a positive response to primary treatment.

Stereotactic radiotherapy – a variant of external beam radiation therapy using stereotactic navigation methods, ensuring precision delivery of the maximum dose of ionizing radiation to a well-defined target in the minimum possible number of fractions. The dose of ionizing radiation during stereotactic radiotherapy is limited by the risk of post-radiation complications. Stereotactic radiotherapy can be delivered in radiosurgery mode, when the radiation dose is administered in a single fraction, and in hypofractionation mode, when the radiation dose is administered in several (usually 2 to 7) fractions.

Target (measurable) brain lesion – defined as an area of contrast enhancement that can be accurately measured in at least one dimension with a greatest diameter of not less than 10 mm, visualized on two or more axial slices (with a scan increment of 1.5–2 mm) with a perpendicular measurement in the plane of at least 5 mm

Neoadjuvant chemotherapy – a type of chemotherapy administered immediately before surgical removal of the primary tumor to improve surgery/radiation therapy outcomes and prevent metastasis formation.

Prehabilitation – rehabilitation from the moment of diagnosis until the start of treatment (surgery/chemotherapy/radiation therapy).

Targeted therapy – a type of anticancer therapy that blocks the growth of cancer cells by interfering with the mechanism of action of specific target molecules necessary for carcinogenesis and tumor growth.

BRAF – an oncogene encoding B-Raf serine/threonine kinase.

MEK – mitogen-activated protein kinase kinase gene.

Gliomas are a collective term that combines all diffuse astrocytic and oligodendroglial gliomas, as well as other types – so-called circumscribed gliomas – pilocytic astrocytoma, subependymal giant cell astrocytoma, astroblastoma, and other tumors originating from glial cells. The WHO classifications introduced the concept of grade, which determines the malignancy grade of a glioma. According to the 5th edition of the WHO Classification of CNS Tumors (2021), grades are designated by Arabic numerals from 1 to 4.

Traditionally, low-grade gliomas (grades 1–2) (well-differentiated gliomas, including astrocytoma, oligodendroglioma, as well as rare tumor types – pleomorphic xanthoastrocytoma, subependymal giant cell astrocytoma, pilocytic astrocytoma) and malignant gliomas (grades 3–4) (anaplastic astrocytoma, anaplastic oligodendroglioma, glioblastoma) are distinguished. Grade 1 gliomas are rare in adults: gangliocytoma, dysembryoplastic neuroepithelial tumor, multinodular and vacuolated neuronal tumor, dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease). The 2021 WHO classification abandons the term "anaplastic" and recommends naming the tumor "Astrocytoma, Grade 2, 3, or 4" or "Oligodendroglioma, Grade 2 or 3", respectively.

Astrocytoma is a tumor developing from the astrocytic component of glia and represented by astrocytes. It can be localized in the cerebral hemispheres, cerebellum, as well as in the brainstem and spinal cord. In grade 2–4 gliomas, the presence of IDH (1,2) mutations is of great importance: it determines the probability of the tumor responding to first-line treatment (radiation therapy and alkylating agents), as well as the prognosis of the disease. Astrocytomas with wild-type IDH-1, -2 genes are now considered glioblastomas. Among grade 4 astrocytomas, glioblastoma "wild type (wt)" (no IDH mutations detected) and grade 4 astrocytoma with a detected IDH (1,2) mutation are distinguished. Glioblastoma wt arises and develops as a primary tumor over several months. Grade 4 astrocytoma with an IDH mutation develops from grade 2–3 astrocytomas with an IDH mutation (previously called "secondary glioblastoma").

Oligodendroglioma and oligoastrocytoma are tumors consisting predominantly of oligodendrocytes. In the 2016 World Health Organization (WHO) classification, it was decided to abandon the term "oligoastrocytoma". Mandatory conditions for the diagnosis of oligodendroglioma are the presence of the IDH-1(2) mutation and 1p/19q co-deletion (as well as the ATRX mutation). Grade 2 oligodendroglioma and grade 3 anaplastic oligodendroglioma are distinguished.

Pleomorphic xanthoastrocytoma on magnetic resonance imaging (MRI) is typically a cystic, well-demarcated tumor from the surrounding brain tissue, localized in the subcortical region of the cerebral hemispheres, the solid part of which intensely enhances with contrast and is located asymmetrically relative to the cyst. Pleomorphic xanthoastrocytoma Grade 2 is more common, but the 2021 WHO classification also introduced the concept of "anaplastic pleomorphic xanthoastrocytoma Grade 3" – an aggressive, malignant tumor requiring intensive adjuvant treatment – radiation therapy, chemotherapy, targeted therapy. In more than half of the cases, the BRAF (V600E) mutation is found in pleomorphic xanthoastrocytoma, which determines the indications for targeted therapy.

Subependymal giant cell astrocytoma (SEGA) is most often a manifestation of tuberous sclerosis (Bourneville disease). On MRI, it presents as a solid tumor, often blocking one or both foramina of Monro, hypointense on T1-weighted images, and showing intense contrast enhancement. Computed tomography (CT) typically reveals symmetric calcifications in the projection of the thalami. The standard treatment for these tumors is optimal ( gross total) resection. In some cases, SEGA metastasizes along the arachnoid membranes of the brain and spinal cord. In disseminated SEGA, targeted therapy with everolimus** (acting via blockade of HIF/VEGF receptors) is of major clinical significance.

Pilocytic astrocytoma – in the classic variant, according to magnetic resonance (MR) characteristics, it is a hypointense tumor on T1-weighted and hyperintense on T2-weighted images, usually well and uniformly enhancing with contrast media, often with a cystic component. It is commonly found in childhood and young adults, but can be detected at any age. Usually, this tumor manifests only locally, but it can also present with an aggressive course – a tendency toward local invasion and recurrence, and dissemination along the leptomeninges of the brain and spinal cord. A rare variant of malignant pilocytic astrocytoma is malignant glioma with piloid features (9421/3).

Gliomatosis cerebri is a diffuse glial tumor involvement of brain structures (affecting more than 3 anatomical regions of the cerebral hemispheres, typically crossing the corpus callosum and showing periventricular spread). This concept was removed from the WHO morphological classification of CNS tumors starting with the 2016 edition, but as a clinical variant, this term deserves attention because it significantly limits treatment options—ruling out tumor resection and, as a rule, local radiation therapy.

Brainstem gliomas. At different levels of the brainstem, glial tumors with varying anatomical-morphological characteristics and clinical manifestations are encountered. Some of these tumors (e.g., tectal plate glioma) are benign and may not progress without treatment throughout a patient's life. Others (e.g., malignant pontine gliomas with the K27 mutation in H3F3A, HIST1H3B, and/or HIST1H3C genes), by contrast, are characterized by an aggressive clinical course with limited options for specialized care for such patients.

Spinal cord gliomas. As a rule, diffuse intramedullary tumors affecting various levels of the spinal cord require specific approaches to surgery and external beam radiation therapy for central nervous system and brain involvement (RT). Separate clinical guidelines are dedicated to the treatment of intramedullary tumors.

Meningiomas are tumors originating from the arachnoid cap cells of the brain. Meningiomas are the most common primary CNS tumor. Most frequently, meningiomas are localized in the cranial vault area (convexity meningiomas), the superior sagittal sinus (parasagittal meningiomas), and the sphenoid wings. Less commonly, meningiomas occur in other compartments of the skull base—the olfactory groove (cribriform plate region), the tuberculum sellae region, the posterior cranial fossa, the cerebellar tentorium, the lateral ventricles, and the optic nerve sheath. In approximately 6% of cases, meningiomas are located in the spinal canal.

Ependymomas are rare tumors arising from the ependyma of the brain or spinal cord, occurring with approximately equal frequency in children and adults. In the brain, ependymomas are more frequently located within the ventricular system. Extraventricular ependymomas are identified less often. Another group consists of spinal cord ependymomas, which grow intradurally (often projected along an expanded central canal). Frequently, these tumors are fairly well demarcated from the surrounding brain tissue and, as they grow, cause expansion of the corresponding parts of the ventricular system (or the central canal of the spinal cord, respectively). In approximately half of the cases, CT and MRI reveal signs of small calcifications. On MRI, they show strong, predominantly heterogeneous contrast enhancement. The 2021 WHO classification abandons the term "anaplastic" and recommends designating the tumor as "ependymoma grade 2 or grade 3," respectively.

Primary central nervous system (CNS) lymphoma is a relatively rare CNS tumor (accounting for approximately 2% of all primary and 5–7% of all primary malignant CNS tumors), classified according to oncohematological classifications among rare forms of non-Hodgkin extranodal lymphomas. Morphologically, in more than 90% of cases, it is represented by diffuse large B-cell lymphoma, B-cell variant. A distinction is made between CNS lymphomas in immunocompetent patients and immunocompromised patients (HIV-associated lymphomas, post-transplant lymphomas, lymphomas in patients with other forms of immunodeficiency). In approximately 15–20% of patients with primary CNS lymphoma, vitreous or retinal involvement is detected.

Primary CNS germ cell tumors are a rare group of primary CNS tumors (0.9% of all primary CNS tumors), occurring predominantly in children and young adults (median age around 18 years) with a male predominance (7:1 ratio). Histologically, all variants of these tumors are identical to analogous seminomatous and non-seminomatous testicular and ovarian tumors. The most common locations for primary CNS germ cell tumors are the pineal region and the chiasmatic-sellar region (especially in children), which determines the corresponding symptoms: occlusive hydrocephalus syndrome and oculomotor disorders, as well as visual and hormonal disturbances. Bifocal localization (simultaneously in the pineal and chiasmatic-sellar regions) combined with diabetes insipidus is a pathognomonic syndrome complex of primary CNS germinoma.

Germ cell tumors are divided into germinoma (the term "pure" germinoma is also well established) and non-germinomatous germ cell tumors. All patients undergo blood tests for β-hCG and AFP in plasma and, according to indications, in cerebrospinal fluid). In patients with "pure" germinoma, these markers do not exceed normal values (sensitive criteria are considered to be: for AFP, a plasma or CSF level greater than 25 ng/mL; for hCG, greater than 50 IU/L) [78].

In accordance with the 2021 WHO morphological classification of CNS tumors, the following morphological types of primary CNS germ cell tumors are distinguished:

- Germinoma (9064/3)

- Embryonal carcinoma (9070/3)

- Yolk sac tumor (9071/3)

- Choriocarcinoma (9100/3)

- Mature teratoma (9080/0)

- Immature teratoma (9080/3)

- Teratoma with somatic-type malignancy (9084/3)

- Mixed germ cell tumor (9085/3)

The treatment of CNS germ cell tumors includes chemotherapy (CT) and external beam radiation therapy for central nervous system and brain involvement (RT) (see Fig. 10, 11 of the addendum). Radiotherapy should be performed using modern equipment with linear accelerators and 3D planning, or on proton therapy accelerators. Radiotherapy options include:

External beam radiation therapy for central nervous system and brain involvement,
External beam precision radiation therapy with stereotactic targeting on a focused linear accelerator for central nervous system and brain involvement,
External beam gamma therapy for central nervous system and brain involvement,
External beam radiation therapy with individual shaping or fixing devices for central nervous system and brain involvement,
Stereotactic external beam radiation therapy using neutron, proton, and heavy ion beams for central nervous system and brain involvement.

In the case of a diagnosis of "pure" primary CNS germinoma, the treatment protocol includes chemotherapy regimens (#cisplatin** + #etoposide**, or #carboplatin** + #etoposide**) (see section 3.3). After every 2 cycles, treatment efficacy is evaluated by performing contrast-enhanced MRI of the brain and spinal cord (one segment); after 4 cycles, radiation therapy is administered involving whole ventricular irradiation at a daily dose (FDD) of 1.8–2.0 Gy up to a total dose (TDD) of 24 Gy, with an additional boost up to 45 Gy in the presence of residual tumor. Treatment for non-germinomatous germ cell tumors should be initiated with chemotherapy using the #cisplatin** + #etoposide** + #ifosfamide** regimen (see section 3.3) monitored by tumor marker levels in blood plasma and contrast-enhanced MRI of the brain and spinal cord (one segment). After 3 treatment cycles, efficacy is evaluated and, if a residual tumor is present, the option of surgical resection is discussed. Subsequently, RT is administered in the form of craniospinal irradiation at a daily dose of 1.8–2.0 Gy up to a total dose of 35 Gy and, if necessary, an additional tumor boost up to 45–55 Gy.

Pituitary adenoma, or according to the 2021 WHO Classification of CNS Tumors – pituitary adenoma/pituitary neuroendocrine tumor (PitNET) – is a tumor characterized by clonal neoplastic proliferation of hormone-producing cells of the anterior pituitary gland. Notably, its ICD-O code is 8272/3. This code appears in the 2021 WHO Classification of Endocrine and Neuroendocrine Tumors and the 2021 WHO Classification of CNS Tumors. It is known that some pituitary adenomas/PitNETs may exhibit aggressive clinical behavior, rapid growth, and early recurrence despite multimodal treatment. Reliable prognostic and predictive markers have not been identified to date. The grade is also not currently defined.

Adamantinomatous craniopharyngioma, WHO Grade 1, is a cystic-solid squamous epithelial tumor typically localized in the chiasmatic-sellar and hypothalamic region and characterized by a mutation in the CTNNB1 gene.

Papillary craniopharyngioma, WHO Grade 1, is a solid or partially cystic non-keratinizing squamous epithelial tumor that most frequently develops in the infundibular region of the floor of the third ventricle and is characterized by a mutation in the BRAF gene.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

The term "primary CNS tumors" combines tumors that vary in histological structure, malignancy, and clinical course, but share a common origin from the tissues making up the CNS and its meninges.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

In 5% of patients with CNS tumors, the development of the disease may be associated with known hereditary syndromes (neurofibromatosis type I and II, and several others), and all of them, with the exception of Turcot syndrome, demonstrate an autosomal dominant inheritance pattern. In the vast majority of cases, primary CNS tumors occur sporadically.

Most gliomas are characterized by a diffuse growth pattern with invasion into surrounding normal brain tissue. Depending on their malignancy, gliomas can develop over years without manifesting any symptoms (e.g., oligodendroglioma), or conversely, appear and progress within several months (e.g., glioblastoma). Some primary CNS tumors are associated with dysembriogenetic processes (e.g., medulloblastoma, primary CNS germ cell tumors, craniopharyngioma, etc.).

1.3 Epidemiology of the Disease or Condition

Gliomas are the most common type of primary malignant brain tumors and other CNS tumors, accounting for 80.8% of all malignant brain tumors and other CNS tumors. According to CBTRUS [1] (Central Brain Tumor Registry of the United States), between 2014 and 2018, the incidence rate of primary malignant brain and CNS tumors was 7.06 per 100,000 population. In the Russian Federation, according to A.D. Kaprin et al. [2], the incidence of malignant tumors of the brain and other parts of the CNS among both sexes in 2020 was 5.75 per 100,000 population.

According to CBTRUS [1], primary CNS tumors are predominantly meningiomas (40.8%, with less than 1% being malignant meningiomas) and gliomas (26.7%, with glioblastoma accounting for 14.2% of all primary brain tumors). Pituitary tumors account for 17.2%, and acoustic neuromas (vestibular schwannomas) for 8.1% [1].

According to CBTRUS [1] 2021 data, primary malignant brain and CNS tumors consist of glioblastomas (50.9%), diffuse and anaplastic astrocytomas (11.2%), oligodendrogliomas (4.5%), ependymal tumors (3.0%), lymphomas (6.8%), and other histologies.

1.4 Features of Coding the Disease or Condition

C70.0 Malignant neoplasm of cerebral meninges

C70.1 Malignant neoplasm of spinal meninges

C70.9 Malignant neoplasm of meninges, unspecified

C71.0 Malignant neoplasm of cerebrum, except lobes and ventricles

C71.1 Malignant neoplasm of frontal lobe

C71.2 Malignant neoplasm of temporal lobe

C71.3 Malignant neoplasm of parietal lobe

C71.4 Malignant neoplasm of occipital lobe

C71.5 Malignant neoplasm of cerebral ventricle

C71.6 Malignant neoplasm of cerebellum

C71.7 Malignant neoplasm of brain stem

C71.8 Malignant neoplasm of brain overlapping lesion

C71.9 Malignant neoplasm of brain, unspecified

C72.0 Malignant neoplasm of spinal cord

C72.1 Malignant neoplasm of cauda equina

C72.2 Malignant neoplasm of olfactory nerve

C72.3 Malignant neoplasm of optic nerve

C72.4 Malignant neoplasm of acoustic nerve

C72.5 Malignant neoplasm of other and unspecified cranial nerves

C72.8 Malignant neoplasm of brain and other parts of central nervous system overlapping lesion

C72.9 Malignant neoplasm of central nervous system, unspecified

D18.0 Hemangioma of any site

D18.1 Lymphangioma of any site

D32.0 Benign neoplasm of cerebral meninges

D32.1 Benign neoplasm of spinal meninges

D32.9 Benign neoplasm of meninges, unspecified

D33 Benign neoplasm of brain and other parts of central nervous system

D33.0 Benign neoplasm of brain, supratentorial

D33.1 Benign neoplasm of brain, infratentorial

D33.2 Benign neoplasm of brain, unspecified

D33.3 Benign neoplasm of cranial nerves

D33.4 Benign neoplasm of spinal cord

D33.7 Benign neoplasm of other specified parts of central nervous system

D33.9 Benign neoplasm of central nervous system, unspecified

D42 Neoplasm of uncertain or unknown behavior of meninges

D42.0 Neoplasm of uncertain or unknown behavior of cerebral meninges

D42.1 Neoplasm of uncertain or unknown behavior of spinal meninges

D42.9 Neoplasm of uncertain or unknown behavior of meninges, unspecified

D43 Neoplasm of uncertain or unknown behavior of brain and central nervous system

D43.0 Neoplasm of uncertain or unknown behavior of brain, supratentorial: cerebral ventricle, cerebrum, frontal lobe, occipital lobe, parietal lobe, temporal lobe

D43.1 Neoplasm of uncertain or unknown behavior of brain, infratentorial: brain stem, cerebellum, fourth ventricle

D43.2 Neoplasm of uncertain or unknown behavior of brain, unspecified

D43.3 Neoplasm of uncertain or unknown behavior of cranial nerves

D43.4 Neoplasm of uncertain or unknown behavior of spinal cord

D43.7 Neoplasm of uncertain or unknown behavior of other parts of central nervous system

D43.9 Neoplasm of uncertain or unknown behavior of central nervous system, unspecified (Central nervous system NOS)

D48 Neoplasm of uncertain or unknown behavior of other and unspecified sites

D48.2 Neoplasm of uncertain or unknown behavior of peripheral nerves and autonomic nervous system

Coding of primary CNS tumors according to ICD-10 should be carried out in accordance with the ICD code in the classification.

1.5 Classification of the disease or condition

Currently, molecular parameters have been added as biomarkers in the classification of CNS tumors. The 2021 WHO Classification of Tumors of the Central Nervous System [47, 49] malignant gliomas are presented in Table 1.

Table 1. Classification of tumors of the brain and CNS from 2021 [47, 49]

Gliomas, glioneuronal tumors, and neuronal tumors	Grade	Molecular features
Adult-type diffuse gliomas
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted	2, 3	IDH1, IDH2, 1p/19q, TERT promoter, CIC, FUBP1, NOTCH1
Astrocytoma, IDH-mutant	2, 3, 4	IDH1, IDH2, ATRX, TP53, CDKN2A/B
Glioblastoma, IDH-wildtype	4	IDH-wildtype, TERT promoter, chromosomes 7/10, EGFR
Pediatric-type high-grade diffuse gliomas
Diffuse hemispheric glioma, H3 G34-mutant	4	H3G34, TP53, ATRX
Diffuse midline glioma, H3 K27-altered	4	H3K27, TP53, ACVR1, PDGFRA, EGFR, EZHIP
Pediatric-type diffuse high-grade glioma, H3-wildtype and IDH-wildtype	4	IDH-wildtype, H3-wildtype, PDGFRA, MYCN, EGFR (methylome)
Infant-type hemispheric glioma		NTRK, ALK, ROS, MET family
Circumscribed astrocytic gliomas
High-grade astrocytoma with pilocytic astrocytoma features		BRAF, NF1, ATRX, CDKN2A/B (methylome)
Pleomorphic xanthoastrocytoma with anaplastic features	3	BRAF, CDKN2A/B
High-grade neuroepithelial tumor of the CNS with MN1 alteration		MN1

Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, WHO grade 3 is defined by two genotypic features: isocitrate dehydrogenase (IDH) mutation, as well as co-deletion of the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q), accompanied by microvascular proliferation and necrosis foci. It has been reported that the 1p/19q co-deletion is present in approximately 60–90% of histopathologically diagnosed oligodendrogliomas and in 30–50% of oligoastrocytomas. Besides its diagnostic value, the 1p/19q co-deletion is also associated with a better response to radiation therapy and alkylating chemotherapy, as well as a longer progression-free and overall survival.

Astrocytoma, IDH-mutant, WHO grade 2 is a diffusely infiltrative astrocytic glioma with an IDH1 or IDH2 mutation that is well-differentiated and lacks histological features of anoplasia. Mitotic activity is absent or low. Microvascular proliferation, necrosis, and homozygous CDKN2A/B deletions are absent.

Astrocytoma, IDH-mutant, WHO grade 3 is a diffusely infiltrative astrocytic glioma with an IDH1 or IDH2 mutation that exhibits focal anaplasia and significant mitotic activity. Microvascular proliferation, necrosis, and homozygous CDKN2A/B deletions are absent.

Astrocytoma, IDH-mutant, WHO grade 4 is a diffusely infiltrative astrocytic glioma with an IDH1 or IDH2 mutation, with microvascular proliferation, necrosis, homozygous CDKN2A/B deletion, or any combination of these features. Previously, such tumors were referred to as "secondary glioblastomas".

Glioblastoma, WHO grade 4 is an IDH-wildtype diffuse astrocytic glioma with microvascular proliferation, necrosis, or one or more of the following molecular features of glioblastoma: TERT promoter mutation, EGFR gene amplification, or +7/−10 chromosome copy number changes.

Diffuse midline glioma, H3 K27-altered was included in the 2016 classification, but, as mentioned above, its name was changed to reflect the fact that other alterations (e.g., EZHIP protein overexpression) can define this entity in addition to the previously recognized H3 K27 mutation.

The remaining 3 are newly recognized types.

Diffuse hemispheric glioma, H3 G34-mutant is a diffuse IDH-wildtype cerebral hemispheric glioma with a missense mutation in the H3F3A gene, replacing glycine with arginine or valine at position 34 of histone H3.3. The tumor is most commonly found in children and young adults and is located in the cerebral hemispheres. The histological picture typically presents as a diffusely infiltrating glioma with astrocytic differentiation and signs of anaplasia, including mitotic activity, microvascular proliferation, and/or necrosis.

Pediatric-type diffuse high-grade glioma H3-wildtype and IDH-wildtype is identified by wild-type histone H3 and wild-type IDH1/2 genes, and, as with many other CNS tumor types, requires molecular characterization and integration of histopathological and molecular data for diagnostic purposes.

Infant-type hemispheric glioma is a new type of high-grade glioma that occurs in newborns and infants and has a distinct molecular profile with gene fusions of ALK, ROS1, NTRK1/2/3, or MET. It should be noted that the term "glioblastoma" is no longer used for pediatric-type neoplasms.

High-grade astrocytoma with pilocytic astrocytoma features. An astrocytoma with histological features of anaplasia alongside pilocytic histology and frequent MAPK pathway gene alterations, combined with homozygous CDKN2A/B deletion and loss of nuclear ATRX expression (indicating a mutation), as well as a distinct DNA methylation pattern.

Pleomorphic xanthoastrocytoma with anaplastic features consists of spindle cells and multinucleated giant cells; they also contain large lipid droplets and a high number of reticulin fibers, making them resemble fibrous xanthomas with foci of necrosis and/or ≥5 mitoses per high-power field. The median time to progression is about 20 months, with a 1-year progression-free survival rate of 57% according to Rutkowski M.J. et al. [49].

High-grade neuroepithelial tumor of the CNS with MN1. alteration Most tumors in the methylation class "high-grade neuroepithelial tumor of the CNS with MN1 alteration" display a histological appearance consistent with astroblastoma, while the morphology of some does not correspond to astroblastoma.

According to the 2021 classification, the tumor is called "astroblastoma, MN1-altered"; the classification does not recommend using the term "High-grade neuroepithelial tumor of the CNS with MN1 alteration", and there is no histological debate. Diagnosing it is challenging.

1.5.2. Staging

TNM classification is not applied to primary CNS tumors. Staging based on anatomical and topographical characteristics is not used either. The determining factor for both treatment tactics and disease prognosis is the morphological (histological) diagnosis. For primary CNS tumors, one of the most important classification criteria is the morphological diagnosis, specifically the tumor grade (grade 1–4 in accordance with the 2021 WHO classification) [3, 6]. According to the WHO classification, 4 malignancy grades are distinguished: grade 1 – no malignancy criteria, grade 2 – one malignancy criterion (nuclear atypia), grade 3 – two malignancy criteria (nuclear atypia and mitoses), and grade 4 – 3 or 4 malignancy criteria (nuclear atypia, mitoses, endothelial proliferation, necrosis).

Depending on the location of the tumor in the CNS, the following are distinguished:

Infratentorial tumors

1. Cerebellum, fourth ventricle (medulloblastoma, astrocytoma, ependymoma, choroid plexus tumors, ATRT, etc.).

2. Brainstem, pons (astrocytoma, glioblastoma, embryonal tumor, etc.).

Supratentorial tumors

1. Chiasmal and thalamic tumors (astrocytoma, craniopharyngioma, CNS germ cell tumors, etc.).

2. Midbrain, third ventricle, pineal region (pineal gland tumors, CNS germ cell tumors, astrocytoma, ependymoma, pineoblastoma, etc.).

3. Hemispheric tumors (astrocytoma, glioblastoma, ependymoma, embryonal tumor, ependymoma, oligodendroglioma, ATRT, neuroblastoma, ganglioneuroblastoma, etc.).

Spinal cord tumors

1. Intramedullary (astrocytoma, ependymoma, embryonal tumor, etc.).

2. Extramedullary: intra- and extradural (neuroblastoma, Ewing sarcoma, etc.).

1.6 Clinical presentation of the disease or condition

The clinical presentation of primary CNS tumors is heterogeneous and determined by both the nature of the tumor and its location and extent. The neurological examination is pivotal in evaluating the clinical symptoms of patients with CNS tumors.

1. General cerebral symptoms:

- headaches;

- hypertension-hydrocephalus syndrome.

2. Focal neurological symptoms:

- deficit/hypofunction symptoms – movement disorders, cranial nerve dysfunctions, sensory disturbances, mental disorders, speech and writing disorders, memory impairments, etc.; seizure disorder.

3. Endocrine disorders (mainly in patients with pituitary tumors, craniopharyngioma, primary CNS germ cell tumors, etc.) [4].

Based on their clinical course, the development of CNS tumors can be divided into symptomatic and asymptomatic (when no clinical manifestations are detected for a long time). Symptoms of the disease may manifest acutely as an epileptiform syndrome or an occlusive-hydrocephalic attack, or as a result of hemorrhage into the tumor, or with a gradual increase in focal and/or general cerebral symptoms [5].

A number of primary brain tumors (embryonic tumors, ependymal, and germ cell tumors) metastasize to other parts of the CNS. Neurological disorders in metastasis sometimes mask the symptoms of the primary tumor. Clinical symptoms of spinal cord tumors include back pain (in 50% of cases), resistance to trunk flexion, paravertebral muscle spasm, spinal deformity (progressive scoliosis), gait disturbance, decreased reflexes in the upper extremities and increased reflexes in the lower extremities, sensory disturbances depending on the level of the lesion, a positive Babinski sign, and dysfunction of the bladder and/or anal sphincters. Symptoms of spinal cord compression worsen in the supine position and improve in the sitting position.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Differential diagnosis of primary CNS tumors is recommended to be performed based on brain MRI with contrast enhancement in T1 non-contrast, T2, T2-FLAIR, and T1 contrast-enhanced modes either in 3 projections or using thin slices in the axial projection (SPGR mode) (A05.23.009; A05.23.009.001) and/or spinal cord magnetic resonance perfusion (one section) (A05.23.009.012), distinguishing them from non-neoplastic CNS diseases, such as hemorrhage in the setting of arterial or arteriovenous malformation, pseudotumoral forms of demyelinating processes, and inflammatory processes (brain abscess, toxoplasmosis, etc.) [72, 79]. In addition, primary and metastatic CNS tumors should be differentiated. Modern capabilities of contrast-enhanced brain MRI and contrast-enhanced spinal cord MRI allow for a high degree of reliability in both differential diagnosis with other diseases and clarifying the nature of the primary CNS tumor.

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

The standard diagnostic workup for patients with primary CNS tumors is brain MRI with contrast enhancement in T1 non-contrast, T2, T2-FLAIR, and T1 contrast-enhanced modes either in 3 projections or using thin slices in the axial projection (SPGR mode) (A05.23.009; A05.23.009.001). These techniques provide maximum diagnostic information about the localization, size, and structure of the tumor, and its relationship with important anatomical regions of the brain and major blood vessels. On MRI, the main sign of tumor growth is a mass effect leading to displacement and compression of intracerebral structures and impaired cerebrospinal fluid dynamics. Furthermore, contrast-enhanced brain MRI and contrast-enhanced spinal cord MRI (one section) make it possible to evaluate the pattern of tumor growth, tumor structure, presence of calcification zones, hemorrhages, necrosis, and the degree of contrast enhancement. A number of CNS lesions, such as schwannomas and meningiomas, have typical clinical and neuroimaging characteristics that allow a diagnosis to be established without a biopsy. For tumors with a high probability of dissemination along the brain and spinal meninges (medulloblastoma, pineoblastoma, primary CNS germ cell tumors, all spinal cord tumors), it is mandatory to perform spinal cord MRI (cervical, thoracic, and lumbosacral regions) and contrast-enhanced spinal cord MRI (cervical, thoracic, and lumbosacral regions) in sagittal and frontal projections, and additionally in the axial projection in the area of detected tumor lesions (A05.23.009.001; A05.23.009; A05.23.009.010; A05.23.009.011). For spinal cord ependymomas, it is recommended to perform a brain MRI to rule out a primary brain ependymoma with spinal cord metastases or multiple primary ependymomas [70-72].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Magnetic resonance semiotics of primary CNS tumors is highly variable and makes it possible both to differentiate neoplastic and non-neoplastic processes and to suggest a particular histological diagnosis. In addition to these standard examination methods, brain computed tomography (CT) and brain CT with intravenous contrast enhancement (A06.23.004.006; A06.23.004), computed tomography angiography of cerebral vessels (A06.12.056) and/or magnetic resonance angiography of intracranial vessels (A05.23.009.008), MR tractography (A05.30.016), functional brain magnetic resonance imaging (fMRI) (A05.23.009.002) with determination of motor areas and/or speech cortical centers, brain computed tomography perfusion (A06.23.004.001) and/or brain magnetic resonance perfusion (A05.23.009.002), and spinal cord magnetic resonance perfusion (one section) (A05.23.009.012) may be performed according to indications. Another important additional examination method is positron emission tomography combined with brain computed tomography (PET/CT) (A07.23.008; A07.23.008.001), positron emission tomography combined with computed tomography using tumorotropic radiopharmaceuticals (A07.30.043), and positron emission tomography combined with computed tomography using tumorotropic radiopharmaceuticals with contrast enhancement (A07.30.043.001).

In cases where brain MRI, contrast-enhanced brain MRI, spinal cord MRI, and contrast-enhanced spinal cord MRI (A05.23.009.001; A05.23.009; A05.23.009.010; A05.23.009.011) cannot be performed, it is necessary to perform brain CT, brain CT with and without intravenous contrast enhancement (A06.23.004.006; A06.23.004), or spine computed tomography (one section) (A06.03.058), and/or spine computed tomography with intravenous contrast enhancement (one section) (A06.03.058.003), and/or spine computed tomography with multiplanar and three-dimensional reconstruction (A06.03.058.001), and/or spiral spine computed tomography [6].

The main criterion for diagnosing a CNS tumor is the pathomorphological examination report of biopsy (surgical) material from central nervous system and brain tissues using immunohistochemical methods (A08.23.002.001), and/or pathomorphological examination of biopsy (surgical) material from central nervous system and brain tissues using histobacterioscopic methods (A08.23.002.002), and/or pathomorphological examination of biopsy (surgical) material from central nervous system and brain tissues using histochemical methods (A08.23.002.003), and/or pathomorphological examination of biopsy (surgical) material from central nervous system and brain tissues (A08.23.002). Histological features depend on the origin of the tumor (astrocytic, ependymal, embryonic, pineal, meningeal tumors, etc.). Features of high-grade gliomas predominantly include cellular atypia and polymorphism, pronounced mitotic activity, closely packed cellular elements, vascular endothelial proliferation, zones of hemorrhage and necrosis, and changes in the extracellular matrix. The microscopic picture of medulloblastomas largely depends on the histological variant of the tumor and is driven by the low degree of differentiation of cellular elements and high mitotic activity inherent in other embryonic tumors. Therefore, immunophenotyping of biological material to detect non-hematopoietic markers (IPT) (A12.30.012.004) or genomic profiling of the studied pathomorphological material is of great importance for differential diagnosis.

Molecular genetic testing is necessary to establish a correct pathomorphological diagnosis in accordance with the requirements of the WHO classification of CNS tumors (2021); it complements light microscopy and immunohistochemical data [3, 47]. Determining the molecular genetic characteristics of a tumor allows for a more precise classification of its subgroup, especially when neoplasms share a similar histological picture, helps predict the disease course, and in some cases may influence the choice of therapy [3, 47, 50, 51].

If technically feasible, the following molecular genetic characteristics should be evaluated (optional):

Molecular genetic testing for mutations in the IDH1 gene in biopsy (surgical) material (code A27.30.051); Molecular genetic testing for mutations in the IDH2 gene in biopsy (surgical) material (code A27.30.052). The IDH mutation is characteristic of grade 2 and 3 gliomas and secondary grade 4 glioblastomas. It helps to differentiate glioblastomas from grade 2 and 3 gliomas [51]. Grade 1 gliomas do not harbor IDH1/2 mutations; the detection of these mutations indicates the presence of a diffuse glioma and makes it possible to rule out the diagnosis of a circumscribed tumor. IDH mutations are associated with MGMT gene methylation; accordingly, tumors carrying this mutation have a better prognosis and response to external beam radiation therapy for central nervous system and brain lesions; external beam precision stereotactic image-guided radiation therapy using a focused linear accelerator for central nervous system and brain lesions; external beam gamma therapy for central nervous system and brain lesions; external beam radiation therapy for central nervous system and brain lesions using individual shaping or fixing devices; stereotactic external beam radiation therapy using neutron, proton, and heavy ion beams for central nervous system and brain lesions, and alkylating agents [53].
Determination of MGMT gene methylation in biopsy (surgical) material (A27.30.057) of O6-methylguanine-DNA methyltransferase (MGMT). MGMT is an enzyme responsible for DNA repair induced by alkylating agents and/or radiation therapy [54]. Methylation of the MGMT promoter is accompanied by increased sensitivity to alkylating agents and external beam radiation therapy for central nervous system and brain lesions; external beam precision stereotactic image-guided radiation therapy on a focused linear accelerator for central nervous system and brain lesions; external beam gamma therapy for central nervous system and brain lesions; external beam radiation therapy for central nervous system and brain lesions using individual shaping or fixing devices; external beam radiation therapy for central nervous system and brain lesions using stereotactic neutron, proton, and heavy ion beams; such tumors have a better prognosis. Chemoradiotherapy (CRT) with temozolomide** (L01AX03) is less effective in patients with tumors lacking MGMT promoter methylation [55].
Molecular genetic testing for 1p/19q co-deletion in biopsy (surgical) material. One of the most important tests in the diagnosis of oligodendroglial tumors. The diagnosis of oligodendroglioma can be established if the tumor harbors the 1p/19q co-deletion [56]. The 1p and 19q co-deletion confirms a relatively favorable prognosis and is a predictor of a good response to alkylating agent therapy and CRT with alkylating agents [57, 58].
ATRX mutation. Testing for the ATRX mutation is strongly recommended, but not strictly mandatory. The ATRX gene encodes a chromatin-regulating protein. Loss of protein function due to this mutation leads to alternative lengthening of telomeres. Determination is possible using immunohistochemistry (IHC) (loss of immunohistochemical staining indicates the presence of mutant ATRX protein). The ATRX mutation correlates with the presence of IDH1/2 and TP53 mutations, while being mutually exclusive with the 1p/19q co-deletion [59].
TERT mutation. Testing for the TERT mutation is possible, but not strictly mandatory. TERT encodes the catalytic activity of telomerase, an enzyme responsible for maintaining telomere length in dividing cells. The mutation is determined by sequencing the promoter region [60]. The presence of the TERT mutation and the absence of IDH1/2 mutations are associated with worse survival rates.
Molecular genetic testing for mutations in the BRAF gene in biopsy (surgical) material. The activating BRAF mutation is found in 60-80% of grade 2-3 pleomorphic xanthoastrocytomas, 30% of dysembryoplastic neuroepithelial tumors, 20% of grade 1 gangliogliomas, and 5% of grade 1 pilocytic astrocytomas [61, 62]. Sporadically, the BRAF mutation is also found in other diffuse gliomas [63, 64].
BRAF:KIAA1549 fusion. Main histological variants: pilocytic astrocytoma, pilomyxoid astrocytoma. Most frequent localization: chiasiasmatic-sellar region, cerebellum, brainstem.

Comments: The diagnosis is established based on: neuroimaging data (presence of a CNS focal lesion) and the results of pathomorphological examination of biopsy (surgical) material.

However, in some cases, when the tumor process is localized in functionally important areas of the CNS, or due to the patient's severe general condition or marked vascularization, histological verification may be associated with a high risk of disability or death. In such situations, the diagnosis can be established based on clinical and radiological data.

2.1 Complaints and Anamnesis

In patients with CNS tumors, it is recommended to collect complaints and medical history, assess neurological and somatic status, as well as functional status using the Karnofsky performance scale (Appendix G2. Patient condition severity assessment scale) [67, 70, 71, 72, 79].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

2.2 Physical Examination

It is recommended for all patients with suspected CNS tumors to undergo a clinical examination, including a general physical examination and assessment of the patient's condition [70, 71, 72].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

2.3 Laboratory Diagnostics

Patients with CNS tumors are recommended to undergo a complete blood count (CBC) with differential to detect blood parameter abnormalities and ensure their subsequent correction [5, 7, 19].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Patients with CNS tumors are recommended to undergo a general general-medical blood biochemistry panel (testing blood urea, creatinine, total protein, albumin, total bilirubin, alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase activities) to detect relevant blood parameter abnormalities and ensure their subsequent correction [5, 7, 19].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Patients with CNS tumors are recommended to undergo a screening hemostasis test (coagulogram) (B03.005.006) to identify corresponding disorders by evaluating hemostatic parameters [5, 7, 19].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

When a pineal and/or chiasmatic-sellar region tumor is detected, patients are recommended to undergo blood tumor marker testing – serum alpha-fetoprotein (AFP) level, serum human chorionic gonadotropin (free beta-subunit) level (β-hCG), and blood lactate dehydrogenase activity [8, 9, 19]. Since non-germinomatous germ cell tumors of the CNS are characterized by elevated blood plasma tumor markers (AFP and/or β-hCG), patients with suspected tumors of this type are recommended to undergo blood tests for these markers for differential diagnosis [9].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

To refine the prognosis, patients with diffuse gliomas are additionally recommended (as an option) to undergo molecular genetic testing for mutations in the IDH1 and IDH2 genes in biopsy (surgical) material, determination of MGMT gene methylation in biopsy (surgical) material, and molecular genetic testing for 1p/19q translocation in biopsy (surgical) material [8, 10].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

To refine the prognosis in medulloblastomas, it is advisable to determine the molecular-genetic subtypes of the tumor (WNT, SHH, Group 3 (C), Group 4 (D)) [8, 10, 79].

2.4 Instrumental Diagnostics

Patients with CNS tumors are recommended to undergo brain MRI without and with contrast in 3 projections using standard sequences (T1, T2, T2-FLAIR, T1 + contrast) to assess brain tissue status [6, 8].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Patients with CNS tumors localized in functionally important areas are recommended to undergo functional MRI of the motor and speech areas of the brain, as well as magnetic resonance (MR) studies – MR angiography of intracranial vessels (A05.23.009.008), MR tractography (A05.30.016), functional MRI of the brain (fMRI) (A05.23.009.002) with identification of motor zones and/or speech cortical centers, and brain and spinal cord MR perfusion (single region) (A05.23.009.003; A05.23.009.012) [8, 11].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

In suspected CNS tumors with a risk of leptomeningeal dissemination (medulloblastoma, pineoblastoma, primary CNS germ cell tumors, etc.), it is recommended to perform brain MRI, contrast-enhanced brain MRI, spinal cord MRI, and contrast-enhanced spinal cord MRI in sagittal and coronal projections, with additional axial projection in the area of identified tumor lesions (A05.23.009.001; A05.23.009; A05.23.009.010; A05.23.009.011) [6, 8].

Comment: Magnetic resonance imaging of the brain, contrast-enhanced magnetic resonance imaging of the brain, magnetic resonance imaging of the spinal cord, and contrast-enhanced magnetic resonance imaging of the spinal cord (A05.23.009.001; A05.23.009; A05.23.009.010; A05.23.009.011), if not performed before surgery, should expediently be performed no earlier than 2–3 weeks after surgery to avoid postsurgical artifacts.

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

In patients with CNS tumors, to assess tumor metabolic activity, as well as repeatedly during treatment and follow-up to evaluate the dynamics of metabolic activity in addition to brain (and/or spinal cord) MRI, positron emission tomography (PET) is recommended: brain PET/CT, including with contrast enhancement (A07.23.008; A07.23.008.001), and brain PET/CT with tumor-tropic radiopharmaceuticals, including with contrast enhancement (A07.30.043; A07.30.043.001) [6, 8].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

In patients with CNS tumors, brain CT is recommended in addition to MRI in cases of bone tumors for better visualization of bone structures. When indicated, it is necessary to perform computed tomography perfusion of the brain (A06.23.004.001) and/or magnetic resonance perfusion of the brain or magnetic resonance perfusion of the spinal cord (A05.23.009.003; A05.23.009.012), computed tomography angiography of one anatomical region (A06.12.050), and/or magnetic resonance angiography of intracranial vessels (A05.23.009.008) [4, 6, 8].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

In patients with CNS tumors and a history of seizures, electroencephalography is recommended to assess the electrophysiological state of the cerebral cortex [4].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

In patients over 18 years of age with CNS tumors, to prepare for surgical intervention, ultrasound duplex scanning of lower extremity vessels (arteries and veins) (A04.12.002.001) is recommended to assess their patency and rule out thrombosis [7, 19].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

In patients with CNS tumors, to prepare for surgical intervention, targeted chest radiography (A06.09.007.001), complex ultrasound of the abdominal organs, and ECG (and echocardiography, as indicated) are recommended [8].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

In patients with CNS tumors, tumor biopsy (stereotactic brain tumor biopsy, open brain tumor biopsy) followed by pathomorphological examination of the biopsy (surgical) material using immunohistochemical methods is recommended in cases where surgical removal is impossible or inappropriate, as well as in suspected primary CNS lymphoma [12].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

2.5 Other Procedures

In patients with CNS tumors, pathomorphological examination of the biopsy (surgical) material of central nervous system and brain tissues using immunohistochemical methods (A08.23.002.001), and/or pathomorphological examination using histobacterioscopic methods (A08.23.002.002), and/or pathomorphological examination using histochemical methods (A08.23.002.003), and/or pathomorphological examination of the biopsy (surgical) material of central nervous system and brain tissues (A08.23.002) is recommended [70, 71, 72].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

In patients with CNS tumors, to clarify the morphological diagnosis and enable potential additional studies, review of histological preparations in the pathomorphological department of an oncological institution, a federal neurosurgical institution, or a reference center is recommended [8, 13].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

In patients with CNS tumors, an initial consultation (examination) by an oncologist (B01.027.001) (at a specialized medical institution, outpatient cancer care center, primary oncology office, or primary oncology department) is recommended to determine treatment tactics and further patient routing [8].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

In patients with CNS tumors, an initial consultation (examination) by a neurosurgeon (B01.024.001) (at a specialized neurosurgical center or department with experience in treating neuro-oncological patients) is recommended to determine treatment tactics and assess the feasibility of surgical treatment [13].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

In patients with CNS tumors, a multidisciplinary team meeting involving an oncologist, neurosurgeon, and radiation therapist is recommended to determine treatment tactics [7, 13].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

In suspected tumors of the sellar-chiasmal region, an initial consultation (examination) by an endocrinologist (B01.058.001) is recommended to determine and correct any endocrinological disorders associated with the tumor process [70, 71, 72, 79].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

In patients with CNS tumors, an initial consultation (examination) by an ophthalmologist (B01.029.001) is recommended to check for oculomotor and visual disorders, as well as to assess signs of intracranial hypertension on funduscopy [7, 13].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Formulation of diagnosis and drafting the treatment plan

The diagnosis is formulated in accordance with the 2021 WHO Classification of CNS Tumors and includes the name of the tumor along with its grade.

The diagnosis must be integrative (standard), including:

histological structure;
grade according to the 2021 WHO Classification of CNS Tumors; molecular information recommended by WHO classifications for the given tumor type (e.g., for gliomas: IDH-1/2, 1p/19q codeletion, or "NOS" tumor, or "NEC" tumor);
indication of the localization and extent of the tumor process;
indication of previously administered therapeutic measures.

The treatment plan is drawn up by a multidisciplinary oncology team involving neurosurgeons, oncologists, radiation therapists, and, if necessary, an initial consultation (examination, review) by a radiologist and specialists in other related fields (neurologist, ophthalmologist, otorhinolaryngologist, etc.). The basis for specifying the treatment plan is the established diagnosis of a CNS tumor – see above (recommendation):

neuroimaging data according to the criteria of localization and histological structure [6];
patient age;
general somatic status;
presence of comorbidities.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

Principles of treatment for malignant CNS tumors:

1. Multidisciplinary approach;

2. Combined modality treatment: surgery, radiation therapy, and chemotherapy;

3. Protocol-based therapy – standardized treatment regimens depending on the histological variant of the tumor, patient age, molecular markers, and treatment response.

Standard therapeutic procedures for patients with primary CNS tumors currently include surgery, radiotherapy, and systemic antineoplastic therapy. During the treatment process, its efficacy must be regularly monitored: Magnetic resonance imaging of the brain, Magnetic resonance imaging of the brain with contrast enhancement, and/or Magnetic resonance imaging of the spinal cord, Magnetic resonance imaging of the spinal cord with contrast enhancement (A05.23.009.001; A05.23.009; A05.23.009.010; A05.23.009.011) [13]. The frequency of performance depends on the histological diagnosis and the stage of treatment. Tumor dynamics are evaluated according to the RANO criteria (see Appendix G1).

3.1. Surgical treatment

Surgical resection is performed to achieve the maximum possible reduction in tumor volume in order to relieve intracranial hypertension, reduce neurological deficits, and obtain a sufficient amount of morphological material.

For surgical treatment or biopsy, the patient must be admitted to a specialized neurosurgical facility with experience in neuro-oncological surgeries. A mandatory prerequisite for CNS tumor surgery is the use of a neurosurgical microscope.

The surgical approach is performed via craniotomy (A16.23.022) in the projection of the planned surgical intervention. In certain cases (localization in the posterior cranial fossa, pronounced symptoms of intracranial hypertension with the risk of brain herniation), decompressive craniectomy is permitted.

For surgeries in anatomical proximity to the motor areas of the cortex or motor pathways, as well as in the projection areas of cranial nerve nuclei and along the course of cranial nerves in patients with CNS tumors, microsurgical removal of cerebral hemisphere neoplasms using neurophysiological monitoring (A16.23.024.003) and intraoperative electrophysiological study of the brain and spinal cord (A10.23.001) is recommended [11].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

To increase the radicality of microsurgical removal of brain neoplasms (A16.23.024), the use of neuronavigation systems, intraoperative ultrasound flowmetry, and intraoperative fluorescence diagnostics of tumor spread using aminolevulinic acid is recommended [11, 14–16].

GCR BLEL 2Grade of Recommendation – B (Level of Evidence – 2)

In the postoperative period following tumor removal, patients with CNS tumors are recommended to undergo brain computed tomography (CT) and contrast-enhanced brain computed tomography (A06.23.004.006; A06.23.004) and/or spinal computed tomography (one segment) (A06.03.058) and/or intravenous contrast-enhanced spinal computed tomography (one segment) (A06.03.058.003) and/or spinal computed tomography with multiplanar and three-dimensional reconstruction (A06.03.058.001) and/or spiral spinal computed tomography and/or brain magnetic resonance imaging, contrast-enhanced brain magnetic resonance imaging, and/or spinal magnetic resonance imaging, contrast-enhanced spinal magnetic resonance imaging (A05.23.009.001; A05.23.009; A05.23.009.010; A05.23.009.011) or within 24–72 hours (A06.23.004.006; A06.23.004; A05.23.009; A05.23.009.001) [8, 19, 79].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

In patients with cerebral gliomatosis, verification of the diagnosis by stereotactic needle biopsy or open tumor biopsy is recommended, as the choice of treatment strategy may depend on the histological diagnosis (e.g., for oligodendroglial tumors, molecular genetic testing for 1p/19q chromosomal translocation in the biopsy/surgical specimen is usually indicated, and if detected, chemotherapy based on nitrosourea derivatives L01AD is prescribed) [8].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Comment: depending on the clinical situation, neuroimaging data, morphological examination, immunohistochemical and molecular genetic markers, and expert consensus, 3 approaches may be considered: observation (if the patient has no clinical symptoms of the disease), chemotherapy (see section 3.3), and external beam radiation therapy for central nervous system and brain lesions; stereotactically guided precision external beam radiation therapy using a focused linear accelerator for central nervous system and brain lesions; external beam gamma therapy for central nervous system and brain lesions; external beam radiation therapy for central nervous system and brain lesions using individualized shaping or immobilization devices; stereotactic external beam radiation therapy using neutron, proton, and heavy ion beams for central nervous system and brain lesions.

In certain clinical situations, antineoplastic drug therapy and/or radiotherapy may be planned based on neuroimaging data and the clinical picture by decision of a multidisciplinary board involving neurosurgeons, oncologists, radiation therapists, and, if necessary, specialists from related fields (radiologists, neurologists, ophthalmologists, etc.) [7, 8, 19].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

For nodular brainstem tumors, exophytic growth patterns, and MRI signs of complete or partial demarcation from brainstem structures (e.g., pilocytic astrocytoma), microsurgical removal of brain neoplasms (A16.23.024) or stereotactic brain tumor biopsy (A16.23.023.001) is recommended [8, 19].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

In case of a diffuse growth pattern of brainstem tumors (e.g., diffuse pontine glioma – "diffuse pontine glioma"), the feasibility of stereotactic brain tumor biopsy A16.23.023.001 should be considered, followed by the recommended use of external beam radiation therapy for central nervous system and brain lesions; stereotactically guided precision external beam radiation therapy using a focused linear accelerator for central nervous system and brain lesions; external beam gamma therapy for central nervous system and brain lesions; external beam radiation therapy for central nervous system and brain lesions using individualized shaping or immobilization devices; stereotactic external beam radiation therapy using neutron, proton, and heavy ion beams for central nervous system and brain lesions) and antineoplastic drug therapy without mandatory verification [8, 17].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

In tectal plate gliomas, after resolution of hydrocephalus, patients are recommended to have a follow-up appointment (examination, consultation) with a neurosurgeon and brain magnetic resonance imaging, contrast-enhanced brain magnetic resonance imaging (A05.23.009; A05.23.009.001, B01.024.002) (in case of tumor progression, the issue of resection followed by radiotherapy is considered) [8, 17].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

In ependymoma, patients are recommended microsurgical removal of brain neoplasms (A16.23.024) [10].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Comment: Chemotherapy may be used in cases of ependymoma recurrence (see Fig. 5). Chemotherapy regimens for ependymomas are specified in Section 3.3.

Upon establishing the histological diagnosis of ependymoma or anaplastic ependymoma, patients are recommended to undergo Magnetic Resonance Imaging of the brain, Magnetic Resonance Imaging of the brain with contrast enhancement, Magnetic Resonance Imaging of the spinal cord, and Magnetic Resonance Imaging of the spinal cord with contrast enhancement (A05.23.009.001; A05.23.009; A05.23.009.010; A05.23.009.011) (in order to determine the radicality of surgery and detect potential spinal metastases), as well as cytological examination of cerebrospinal fluid cells (A08.23.007) (optional) [10]. If cytological examination of cerebrospinal fluid cells (A08.23.007) was not performed before surgery, it must be performed 2 weeks after surgery.

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

As the method of choice for establishing the diagnosis of CNS lymphoma, patients are recommended stereotactic biopsy [8].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

If a clinically significant elevation of one or both markers is detected (β-hCG – from 5 times the upper limit of normal, AFP – more than 2 times the upper limit of normal), treatment for a patient with a primary CNS germ cell tumor is recommended to be initiated with chemotherapy without histological verification of the tumor [18, 78].

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

For primary (pure) CNS germinoma, patients are recommended to undergo chemotherapy with a #cisplatin** + #etoposide** regimen (see Section 3.3) followed by irradiation of the cerebral ventricular system (external beam radiation therapy for central nervous system and brain lesions using individual shaping or fixation devices A07.23.001.003) with a total focal dose (TFD) of 24 Gy (in the absence of data indicating leptomeningeal dissemination) [18, 78].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

In lesions of the chiasro-sellar region, patients with CNS tumors are recommended to undergo dynamic blood testing for thyroid-stimulating hormone (TSH) (A09.05.065), blood testing for total triiodothyronine (T3) (A09.05.060), blood serum testing for free thyroxine (FT4) (A09.05.063), blood testing for free cortisol (A09.05.136), blood testing for prolactin (A09.05.087), blood testing for insulin-like growth factor I (A09.05.204), blood serum testing for follicle-stimulating hormone (A09.05.132), blood serum testing for luteinizing hormone (A09.05.131), blood testing for total estradiol in women (A09.05.154), blood testing for total testosterone in men (A09.05.078), and determination of anti-pituitary hormone antibodies in the blood (A12.06.032) with the involvement of an endocrinologist [18, 78].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

For subependymal giant cell astrocytoma, patients are recommended to undergo microsurgical removal of brain neoplasms (A16.23.024) [8, 71].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Patients with subependymal giant cell astrocytoma with diffuse involvement are recommended treatment with everolimus** [19, 71].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Patients with pilocytic astrocytoma are recommended to undergo microsurgical removal of brain neoplasms (A16.23.024) (provided the tumor is resectable), accompanied by contrast-enhanced brain MRI and non-contrast brain MRI in T1 non-contrast, T2, T2-FLAIR, and T1 contrast-enhanced modes either in 3 projections or as thin slices in the axial projection (in SPGR mode) (A05.23.009; A05.23.009.001) in the postoperative period to assess the radicality of the surgery [8, 71].

Comment: in case of radical microsurgical removal of brain neoplasms (A16.23.024), the patient is indicated for observation; in case of residual tumor, radiotherapy is indicated.

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

3.2. Radiation therapy (radiotherapy)

Teletherapy or radiotherapy methods are a core component of treatment for the majority of patients with CNS tumors. It is preferable to use a radiosurgical treatment system; a radiosurgical system with accessories, a radiotherapy system with accessories, a stereotactic radiosurgical system with MRI guidance, a linear accelerator-based radiosurgical system, a neurosurgical radiotherapy system with accessories, and a proton therapy system.

Radiotherapy is used as an independent treatment method or following microsurgical removal of brain neoplasms (A16.23.024) or stereotactic brain tumor biopsy (A16.23.023.001), in the event of tumor recurrence/continued growth. External beam radiation therapy for central nervous system and brain lesions; external beam precision radiation therapy with stereotactic guidance on a linear accelerator with focusing for central nervous system and brain lesions; external beam gamma therapy for central nervous system and brain lesions; external beam radiation therapy for central nervous system and brain lesions using individual shaping or fixing devices; external beam radiation therapy for central nervous system and brain lesions using stereotactic techniques with neutron, proton, and heavy ion beams) may be delivered both to the tumor region (to the residual tumor or tumor bed) and along potential pathways of metastasis (e.g., craniospinal irradiation (CSI) in the treatment of medulloblastoma), as well as boost therapy (additional irradiation of the tumor/tumor bed). The optimal RT technique is the use of conformal irradiation techniques, which allows for the safest possible delivery of the dose to the tumor region with the minimum possible radiation load to healthy tissues, taking into account the tolerance of adjacent structures.

When planning irradiation for patients with CNS tumors, computed tomography (CT) topometric planning (A06.30.009) is performed, and where possible, an individual fixation device—a thermoplastic mask—is used.

Patients with small tumors (up to 3 cm in maximal dimension) with clear borders located outside critical structures (gliomas [pilocytic astrocytomas, ependymomas], meningiomas, schwannomas, paragangliomas, pituitary adenomas, craniopharyngiomas, etc.) may undergo radiosurgical treatment (single-fraction and/or hypofractionation) using stereotactic techniques. If technically feasible and equipment for fractionated stereotactic irradiation is available, radiosurgical treatment of tumors greater than 3 cm in maximal dimension is possible [12, 13].

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

For patients undergoing treatment for malignant tumors (grades 3–4), it is recommended to initiate RT within up to 6 weeks after surgery, in some cases combining it with systemic antineoplastic drug therapy [19, 22] (see Section 3.3).

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

When planning RT to clarify the margins of the residual tumor, patients are recommended to use contrast-enhanced brain MRI data, as well as positron emission tomography (PET) to detect inflammatory foci when necessary (A07.30.034), PET combined with CT (PET/CT [A07.23.008; A07.23.008.001]) of the brain, including with contrast administration, and PET/CT with tumor-tropic radiopharmaceuticals, including with contrast enhancement (A07.30.043; A07.30.043.001). The gross tumor volume (GTV) and clinical target volume (CTV) are determined by the type and grade of malignancy of the tumor. The margin for the planning target volume (PTV) is determined in accordance with the characteristics of the device, fixation system, and navigation system [32].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

During the first follow-up (within 1–1.5 months) after RT for glioma, the phenomenon of pseudoprogression may be observed: an increase in the contrast-enhanced portion of the tumor in the absence of increasing neurological symptoms and with stable doses of systemic corticosteroids (H02). In this case, a contrast-enhanced brain MRI in T1 non-contrast, T2, T2-FLAIR, and T1 contrast-enhanced modes either in 3 projections or as thin slices in the axial projection (in SPGR mode) (A05.23.009; A05.23.009.001) is recommended in 1–3 months (totaling 2–3 months after the completion of RT) to definitively assess disease dynamics [19, 33].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Patients with large and/or diffusely growing tumors of various histological origins (primarily grades 1–4 gliomas, meningiomas, schwannomas, etc.), as well as when irradiating potential pathways of tumor metastasis (medulloblastomas, germinomas, anaplastic ependymomas, etc.), are recommended a hypofractionation regimen with a fraction dose (FD) of 3 Gy or more, which can be used in medical institutions with experience in using this RT technique (optional) [8, 31].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

In patients with a Karnofsky performance scale score of 60 or lower or of advanced age (over 70 years), it is recommended to perform RT using a hypofractionation regimen: FD 3.4 Gy, total dose (TD) 34 Gy; FD 2.67 Gy, TD 40.05 Gy; or FD 5 Gy, TD 25 Gy, which can be applied in medical institutions with experience in this RT technique [8, 31, 46, 71]. See Appendix G3 [74, 75], Appendix G4 [68].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Comments: for better differentiation of postoperative changes and more precise determination of the removed tumor bed, in some cases it is advisable to use preoperative X-ray/CT/MRI scans when defining the target [33]. Depending on the localization, tumor volume, involvement of critical brain structures, and prior courses of RT, it is possible to reduce margins and the radiation dose to reduce the risk of radiation reactions and the development of neurological deficits [34]. In the case of a recurrent course or aggressive tumor behavior, dose escalation relative to recommended values is possible [34]. Following RT, delayed post-radiation reactions and brain injuries may occur, including the development of radiation necrosis. To differentiate between post-radiation complications and tumor recurrence, it is advisable to use additional imaging modalities alongside contrast-enhanced brain MRI: positron emission tomography (PET) to detect inflammatory foci (A07.30.034), PET combined with CT (PET/CT) of the brain, including with contrast administration (A07.23.008; A07.23.008.001), and PET/CT with tumor-tropic radiopharmaceuticals, including with contrast enhancement (A07.30.043; A07.30.043.001); contrast-enhanced brain MRI in T1 non-contrast, T2, T2-FLAIR, and T1 contrast-enhanced modes either in 3 projections or as thin slices in the axial projection (in SPGR mode) (A05.23.009; A05.23.009.001); magnetic resonance perfusion of the brain and/or spinal cord (A05.23.009.003; A05.23.009.012), brain CT perfusion (A06.23.004.001); MR tractography (A05.30.016). For the treatment of clinically significant post-radiation complications, steroid therapy and/or the prescription of #bevacizumab** may be used [8, 26, 27, 71, 72].

Treatment of Ependymomas

In patients with ependymoma when metastasis is detected (based on pre-/postoperative brain and spinal MRI: brain magnetic resonance imaging, contrast-enhanced brain magnetic resonance imaging, spinal magnetic resonance imaging, contrast-enhanced spinal magnetic resonance imaging [A05.23.009.001; A05.23.009; A05.23.009.010; A05.23.009.011]), CSI is recommended with a total dose of 36.0 Gy and a fraction dose of 1.8 Gy [70, 71, 72].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Comments: Prophylactic craniospinal irradiation or whole-brain irradiation (external beam radiation therapy for central nervous system and brain lesions; stereotactic external beam precision radiotherapy using a focused linear accelerator for central nervous system and brain lesions; external beam gamma therapy for central nervous system and brain lesions; external beam radiation therapy for central nervous system and brain lesions using individual shaping or fixing devices; stereotactic external beam radiation therapy for central nervous system and brain lesions using neutron, proton, and heavy ion beams) does not improve survival compared to local radiation therapy and is indicated for patients with proven CNS spread [65].

For spinal ependymoma with incomplete tumor resection, RT is administered up to a total dose (TD) of 45.0 Gy. For the primary intracranial focus, a TD of 54–59.4 Gy is recommended [70,71,72, 8, 10].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Treatment of germinomas (germ cell tumors) and non-germinomatous germ cell tumors

Treatment of "pure" germinomas

In the treatment of "pure" germinomas, irradiation of the ventricular system (external beam radiation therapy for central nervous system and brain lesions; stereotactic external beam precision radiotherapy using a focused linear accelerator for central nervous system and brain lesions; external beam gamma therapy for central nervous system and brain lesions; external beam radiation therapy for central nervous system and brain lesions using individual shaping or fixing devices; stereotactic external beam radiation therapy for central nervous system and brain lesions using neutron, proton, and heavy ion beams) is recommended [9, 78,79].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Comments: if 3D conformal radiotherapy is not available, whole-brain irradiation is indicated (external beam radiation therapy for central nervous system and brain lesions (A07.23.001); stereotactic external beam precision radiotherapy using a focused linear accelerator for central nervous system and brain lesions (A07.23.001.001); external beam gamma therapy for central nervous system and brain lesions (A07.23.001.002); external beam radiation therapy for central nervous system and brain lesions using individual shaping or fixing devices (A07.23.001.003); stereotactic external beam radiation therapy for central nervous system and brain lesions using neutron, proton, and heavy ion beams (A07.23.001.004)).

Following platinum-based polychemotherapy for disease control, irradiation of the ventricular system (external beam radiation therapy for central nervous system and brain lesions (A07.23.001); stereotactic external beam precision radiotherapy using a focused linear accelerator for central nervous system and brain lesions (A07.23.001.001); external beam radiation therapy for central nervous system and brain lesions using individual shaping or fixing devices (A07.23.001.003); stereotactic external beam radiation therapy for central nervous system and brain lesions using neutron, proton, and heavy ion beams (A07.23.001.004)) at a dose of 21.6–25.5 Gy is recommended, with irradiation of the tumor bed in some cases at a dose of 30–40 Gy (in the presence of residual tumor) [9], with a boost in some cases to the residual tumor and metastasis areas (if visualized on brain MRI, contrast-enhanced brain MRI, spinal MRI, contrast-enhanced spinal MRI (A05.23.009.001; A05.23.009; A05.23.009.010; A05.23.009.011) after completion of the craniospinal irradiation course) up to a TD of 30–45 Gy [18, 78].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Comments: GTV = ventricular system + tumor bed,

CTV = GTV + 5 mm,

Fraction dose = 1.8–2.0 Gy, TD = 24.0 Gy.

Treatment of bifocal "pure" germinomas

In the presence of bifocal germinomas involving the pineal and chiasmatic-sellar regions (without signs of dissemination), treatment may be initiated with chemotherapy (and/or RT) without histological verification (optional). Irradiation of the ventricular system (A07.23.001.001 stereotactic external beam precision radiotherapy using a focused linear accelerator for central nervous system and brain lesions; A07.23.001 external beam radiation therapy for central nervous system and brain lesions; A07.23.001.002 external beam gamma therapy for central nervous system and brain lesions; A07.23.001.003 external beam radiation therapy for central nervous system and brain lesions using individual shaping or fixing devices; A07.23.002 external beam radiation therapy for spine and spinal cord lesions) is performed with a fraction dose of 1.8–2.0 Gy, TD of 24.0 Gy, in some cases with or without a local boost up to a TD of 40.0 Gy [78,79].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Treatment of recurrent "pure" germinomas

Patients with recurrent pure germinomas are recommended to undergo surgical treatment, local irradiation or whole-CNS irradiation, and polychemotherapy including high-dose chemotherapy with autologous hematopoietic stem cell transplantation [18, 78].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Treatment of non-germinomatous germ cell tumors of the CNS

Patients with non-germinomatous germ cell tumors of the CNS are recommended to receive platinum-based polychemotherapy, RT (craniospinal irradiation 24–35 Gy, local 40–56 Gy), as well as microsurgical removal of brain neoplasms (A16.23.024) [18].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Treatment of mature teratomas

As the primary treatment method for mature teratomas, the maximum possible microsurgical removal of brain neoplasms is recommended [8, 22, 78].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Comments: adjuvant treatment is not required after gross total resection. For partial resection, stereotactic RT techniques and radiosurgery are used.

Treatment of diffuse low-grade gliomas in adults: oligodendroglioma WHO grade 2 (IDH mutation, 1p/19q codeletion), WHO grade 2 astrocytoma (IDH mutation)

The irradiation volume is recommended to include the residual tumor and/or tumor bed (the following MRI sequences are recommended for defining irradiation volumes: T1 with contrast enhancement, T2-FLAIR). CTV includes GTV + 0.5 cm (contrast-enhanced brain MRI in T1 non-contrast, T2, T2-FLAIR, and T1 with contrast either in 3 planes or thin slices in axial plane (SPGR) (A05.23.009; A05.23.009.001)). For small PTV volumes (≤3 mm), 1–3 daily image-guidance sessions are recommended.
For diffuse low-grade gliomas in adults: oligodendroglioma WHO grade 2 (IDH mutation, 1p/19q codeletion), WHO grade 2 astrocytoma (IDH mutation), radiation therapy with a fraction dose of 1.8–2.0 Gy up to a TD of 50.4–54.0 Gy is recommended [8, 22].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Patients with high-grade diffuse glioma (glioblastoma, oligodendroglioma WHO grade 3 (IDH mutation, 1p/19q codeletion), astrocytoma WHO grade 3 or 4 with IDH mutation) for tumor growth control are indicated for external beam radiation therapy for central nervous system and brain lesions, stereotactic external beam precision radiotherapy using a focused linear accelerator for central nervous system and brain lesions, external beam gamma therapy for central nervous system and brain lesions, external beam radiation therapy for central nervous system and brain lesions using individual shaping or fixing devices, stereotactic external beam radiation therapy for central nervous system and brain lesions using neutron, proton, and heavy ion beams (A07.23.001, A07.23.001.001, A07.23.001.002, A07.23.001.003, A07.23.001.004).

It is recommended to include the residual tumor and/or tumor bed in the GTV. CTV = GTV + 1.0–2.0 cm (the following brain MRI modes must be used: brain MRI with contrast T1 without contrast, T2, T2-FLAIR, T1 with contrast either in 3 projections or in thin slices in the axial projection (in SPGR mode) (A05.23.009; A05.23.009.001)). A PTV margin of 3–5 mm is added to the CTV. When using a PTV (≤3 mm), daily setup verification is recommended. If at the first stage of treatment the edema, evaluated using T2/FLAIR (A05.23.009; A05.23.009.001), is included in the irradiation volume, then at the second stage of treatment (boost), the field sizes are reduced. The boost target volume generally covers only the residual tumor and the resection cavity. There is a range of acceptable CTV values [31, 71].
Radiation therapy with a fractional dose (FD) of 1.8–2.0 Gy up to a total dose (TD) of 59.4–60 Gy is recommended.
In cases of a large tumor volume, tumor spread to the brainstem or spinal cord involvement, or grade 3 astrocytoma, a reduced dose of FD 1.8 Gy, TD 54–55.8 Gy or FD 1.9 Gy, TD 57 Gy is recommended [31, 71].
For patients with a widespread brain tumor and pronounced perifocal edema, an irradiation dose of FD 2 Gy, TD 46 Gy or FD 1.8 Gy, TD 45–50.4 Gy at the first stage is recommended. At the second stage, FD 2 Gy, TD 14 Gy or FD 1.8 Gy, TD 9–14.4 Gy. [31, 71].
For patients with a Karnofsky performance scale score of 60 or lower and/or elderly patients (over 70 years old), the following fractionation regimens are recommended: FD 3.4 Gy, TD 34 Gy; FD 2.67 Gy, TD 40.05 Gy; FD 5 Gy, TD 25 Gy. The use of the above fractionation regimen may be considered for elderly (over 70 years) and/or frail patients (Karnofsky score of 60 or lower) with small tumors for whom a longer course of treatment would be intolerable [31, 71, 70, 71, 72].
Patients with diffuse gliomas grade 3–4 are indicated for external beam radiotherapy concomitantly with temozolomide** administration on irradiation days [22, 70, 71, 72] (see section 3.3); patients with WHO grade 3 oligodendroglioma (IDH-mutant, 1p/19q codeleted) may receive radiotherapy alone (without temozolomide**) followed by chemotherapy (see section 3.3) [72]

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Treatment of medulloblastomas.

For patients aged 18 years and older, it is recommended:

for standard risk – craniospinal irradiation (CSI) with FD of 1.6–2.0 Gy up to a TD of 23.4 Gy. A boost is delivered to the tumor bed with an FD of 1.8–2.0 Gy up to a TD of 54.0–55.8 Gy. If adjuvant chemotherapy is not used, it is recommended to apply CSI doses of FD 1.8–2.0 Gy, TD 30–36 Gy, with a boost delivered to the tumor bed at an FD of 1.8–2.0 Gy up to a TD of 54.0–55.8 Gy [70, 71, 72];
for high risk – CSI with an FD of 1.6–2.0 Gy up to a TD of 36.0 Gy. A boost is delivered to the tumor bed with an FD of 1.8–2.0 Gy up to a TD of 54.0–55.8 Gy [70, 71, 72].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

For patients with diffuse pontine/midbrain/brainstem gliomas, stereotactic irradiation techniques are recommended for tumor control, with a recommended TD of 54 Gy in 30 fractions. The CTV includes the visible tumor + brainstem + 0.5–1.0 cm [70, 71, 72, 79].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Treatment of meningiomas

In all cases (grade 1–3 meningiomas), the GTV includes the contrast-enhancing part of the tumor and hyperostotic changes. Inclusion of the "dural tail" in the GTV is decided on an individual basis. For grade 2 meningioma, the resection cavity may be included in the GTV. For grade 3 meningioma, the resection cavity must be included in the GTV [34, 35].

For grade 1 meningiomas, GTV = CTV. The optimal CTV margin for grade 2 meningiomas is 0.5–2 cm. For grade 3 meningiomas, CTV = GTV + 2–3 cm [34, 35, 71].

In patients with grade 1 meningioma, radiation therapy with FD 1.8–2.0 Gy up to TD 50–54 Gy; FD 7.5 Gy up to TD 22.5 Gy; FD 5.5 Gy up to TD 27.5 Gy; or radiosurgical treatment (single fraction) of 14–16 Gy is recommended. If the tumor is located close to critical organs and structures, a dose reduction to 50–50.4 Gy is recommended [35, 36, 71].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

In patients with grade 2 meningioma, radiation therapy with FD 1.8–2.0 Gy up to TD 54.0–60.0 Gy is recommended; radiosurgical and hypofractionated irradiation with dose escalation (single fraction of 16–20 Gy, 5 fractions to a TD of 27.5–30 Gy) are also recommended [35, 36, 71].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

In patients with grade 3 meningioma, radiation therapy with FD 1.8–2.0 Gy up to TD 59.4–60.0 Gy (total maximum doses of 66–70 Gy) is recommended; radiosurgical and hypofractionated approaches (single fraction of 16–20 Gy, 5 fractions to a TD of 27.5–30 Gy) are also possible [35, 36, 71].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Treatment of lymphomas

Patients receiving systemic therapy are generally not prescribed whole-brain radiation therapy. For whole-brain irradiation, doses of FD 1.8 Gy, TD 23.4 Gy are recommended
In case of a partial response to treatment or if chemotherapy is unfeasible, a patient with primary CNS lymphoma is recommended to undergo whole-brain radiotherapy at an FD of 1.8–2.0 Gy, TD 23.4–36.0 Gy, followed by contrast-enhanced brain MRI (A05.23.009; A05.23.009.001) and, if necessary, the addition of a boost to bioequivalent doses of TD 45.0 Gy to the persisting contrast-enhancing lesion (see Fig. 7, 8) [70, 71, 72]
For patients in whom systemic therapy is unfeasible, whole-brain radiotherapy at an FD of 1.8–2.0 Gy, TD 24.0–36.0 Gy with the addition of a boost to bioequivalent doses of TD 45.0 Gy is recommended [70, 71, 72].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Primary spinal cord tumors.

Recommended fraction doses (FSD) of 1.8 Gy up to a total dose (TD) of 45–54 Gy.
For spinal tumors below the medullary conus, bioequivalent doses are recommended up to 60 Gy.
It is recommended to use CTV margins of 1–2 cm superiorly and inferiorly. A PTV margin of 3–5 mm is added to the CTV. When using a PTV (≤3 mm), daily image guidance for patient setup is recommended.
In certain cases, radiosurgery or hypofractionated SRS/SBRT may be recommended for spinal tumors such as hemangioblastoma, while respecting dose constraints for critical organs and spinal cord structures.
Proton therapy may also be recommended in the treatment of primary spinal cord tumors to reduce radiation exposure to surrounding normal tissues, the spinal cord, and nerve roots. [70, 71, 72].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

3.3. Antineoplastic drug therapy

Indications and selection of systemic antineoplastic therapy regimens depend on the histological diagnosis: glial tumors, medulloblastoma, primary CNS lymphoma, primary CNS germ cell tumors, parenchymal tumors of the pineal gland (pineoblastoma and pineocytoma with intermediate differentiation), choroid plexus carcinoma, etc. [19].

Main systemic antineoplastic therapy regimens for primary CNS tumors

Gliomas

It is recommended to administer chemotherapy for gliomas using one of the following regimens depending on the clinical situation and the patient's condition:

- PCV: Lomustine** (CCNU) 100 mg/m² – day 1 + #Vincristine** 1.4 mg/m² – days 1, 8 + Procarbazine** 70 mg/m² – days 8–21, every 6 weeks (standard regimen for grade 3) [8, 71];

- PC: Lomustine** (CCNU) 70–100 mg/m² – day 1 + Procarbazine** 60 mg/m² – days 1–14, every 6 weeks [8, 71];

- #Lomustine** (CCNU) 110 mg/m² – day 1; every 6 weeks [25, 71];

- Temozolomide** 5/23: 150–200 mg/m² – days 1–5, every 28 days (standard regimen for grades 3–4) [8, 71];

- Temozolomide** as part of concurrent chemoradiotherapy 75 mg/m² – daily throughout the RT course (standard regimen for grades 3–4) [22, 71];

- #Temozolomide** 150 mg/m² – days 1–5 + #Carboplatin** (#Carboplatin** AUC 3), every 4 weeks [8, 71, 72];

- Temozolomide** 150 mg/m² – days 1–5 + #Cisplatin** 20 mg/m² – days 1–5 [71, 72];

- #Temozolomide** 7/7: 75–150 mg/m² – course days 1–8 and 15–22, every 28 days [76, 85];

- Temozolomide** 150–200 mg/m² – days 1–5 + #Bevacizumab** 5–10 mg/kg – days 1, 15; every 4 weeks [71, 72];

- Temozolomide** 150–200 mg/m² – days 1–5 + #Bevacizumab** 5–10 mg/kg – days 1, 15; every 4 weeks in patients with unresectable gliomas, diffuse brainstem gliomas, disseminated diffuse intramedullary gliomas [71, 83, 84]

- #Bevacizumab** 5–10 mg/kg – days 1, 15; every 4 weeks in patients with unresectable gliomas, diffuse brainstem gliomas, disseminated diffuse intramedullary gliomas [71, 83, 84]

- Bevacizumab** 10 mg/kg every 2 weeks + #Carboplatin** AUC 4–6 every 4 weeks [86];

- #Bevacizumab** 5 mg/kg every 2 weeks + #Etoposide** 80 mg/m² days 1–5 every 3–4 weeks [71, 72];

- #Bevacizumab** 5 mg/kg every 2 weeks concurrently with radiation therapy (see Section 3.2) in patients with extensive unresectable grade 3–4 gliomas or with large residual tumor after resection of grade 3–4 gliomas with prominent perifocal edema [80]

- #Dabrafenib** 150 mg twice daily daily + #Trametinib** 2 mg once daily daily (tumors with a detected BRAF mutation) [71, 72];

- #Vemurafenib** 960 mg twice daily daily + #Cobimetinib** 60 mg days 1-21 every 28 days (tumors with a detected BRAF mutation) [71, 72].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

It is recommended for recurrent gliomas to administer chemotherapy using one of the following regimens depending on the clinical situation and the patient's condition:

- #Bevacizumab** 5-10 mg/kg – days 1, 15 + Irinotecan** 125-200 mg/m² – days 1, 15, every 28 days [26, 71, 72];

- #Bevacizumab** 5-10 mg/kg – days 1, 15, 29 + Lomustine** 90 mg/m² – day 1, every 6 weeks [25, 2, 71];

- #Bevacizumab** 10 mg/kg – days 1, 15, 29 + Carmustine** 80 mg/m² – day 1 IV infusion, every 6 weeks [88];

- #Bevacizumab** 5-10 mg/kg – days 1, 15 + #Lomustine** 40 mg/m² – days 1, 8, 15, 22, every 6 weeks [71, 72];

- #Bevacizumab** 5-10 mg/kg – days 1, 15, every 28 days [71, 72];

- Temozolomide** 150-200 mg/m² – days 1-5 + #bevacizumab** 5-10 mg/kg – days 1, 15, every 4 weeks [71, 72];

- #Bevacizumab** 5-10 mg/kg every 2 weeks concurrently with radiotherapy (see section 3.2) in patients with grade 3-4 recurrent gliomas with significant perifocal edema [48, 71, 81].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Comments: if the V600 BRAF mutation is present in the tumor, the issue of targeted therapy is decided by an oncology board and/or medical committee.

It is recommended for primary central nervous system lymphoma to administer chemotherapy using one of the following regimens depending on the clinical situation and the patient's condition:

- #Methotrexate** 3-8 g/m² – day 1, every 3 weeks; administered in an inpatient setting of a hematology or chemotherapy department ± Rituximab** 375 mg/m², every 3 weeks [8, 28, 71]

Comment: this treatment is possible only in an inpatient setting in a hematology department or a chemotherapy inpatient unit with recommended monitoring of blood methotrexate** levels after its administration;

- #Temozolomide** 150 mg/m² – days 1-5; every 28 days + rituximab** 375 mg/m², every 3 weeks [72];

- #Temozolomide** 150-200 mg/m² – days 1-5, every 28 days [72].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

It is recommended for primary central nervous system germ cell tumors to administer chemotherapy in the following regimen:

- #Cisplatin** + #Etoposide** (see below) every 21-28 days [13, 78].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

It is recommended for primary non-seminomatous central nervous system germ cell tumors to administer chemotherapy using one of the following regimens depending on the clinical situation and the patient's condition:

- #Cisplatin** 25 mg/m² – days 1-4 + #Etoposide** 80 mg/m² – days 1-4, every 21 days [13, 18, 78];

- #Cisplatin** 20 mg/m² days 1-5 + #Etoposide** 80 mg/m² – days 1-5 + #Ifosfamide** 1500 mg/m² (+mesna**) IV on days 1, 3, 5, every 3-4 weeks [13, 18, 78];

- #Cisplatin** 20 mg/m² days 1-4 + #Etoposide** 80 mg/m² – days 1-4 + #Cyclophosphamide** 600 mg/m² – day 4, every 4-6 weeks, for a total of 6 treatment courses [13, 18, 78].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).

It is recommended for medulloblastoma, pineoblastoma, and pineocytoma with intermediate differentiation to administer chemotherapy in the following regimen:

- #Cisplatin** 25 mg/m² – days 1-4 + #Etoposide** 80 mg/m² – days 1-4 + #Cyclophosphamide** 600 mg/m² – day 4, every 4-6 weeks, for a total of 6 treatment courses [8, 71].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

It is recommended for recurrent anaplastic meningioma (or aggressive behavior of other morphological types of meningiomas, in patients with aggressive recurrent tumor behavior with rapid growth of tumor nodes and the emergence of new tumor foci that have progressed after courses of radiotherapy, and in patients with schwannomatosis) – as an option:

- #Bevacizumab** 5 mg/kg + #Sunitinib** 50 mg weeks 1-4, 2 weeks off [71];

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

- #Octreotide** 30 mg intramuscularly every 28 days + #Everolimus** 10 mg daily [71, 89]

GIB CLOE 4Grade of Recommendation – C (Level of Evidence – 4)

It is recommended upon the development of post-radiation reactions and radiation necrosis (following radiation treatment administered via standard fractionation, hypofractionation, or radiosurgery regimens):

- #Bevacizumab** 7.5 mg/kg – every 3 weeks. [80]

GIB CLOE 4Grade of Recommendation – C (Level of Evidence – 4)

3.3.1. Methods for selecting chemotherapy regimens

For patients with glioblastoma and grade 4 astrocytoma (WHO, 2021), the recommended postoperative treatment regimen of choice is chemoradiotherapy with temozolomide**: chemoradiotherapy with daily temozolomide** (75 mg/m²) (throughout the entire course of radiotherapy – 30 fractions of 2 Gy per fraction) followed by 6-12 courses of temozolomide** 150-200 mg/m² on a 5/23 schedule (see section 3.3) [71, 72].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Patients with anaplastic astrocytoma are recommended either radiotherapy followed by courses of antineoplastic drug therapy in the PCV regimen or as monotherapy (lomustine**, temozolomide**), or chemoradiotherapy with temozolomide** (see section 3.3) [18, 22–24, 71, 72].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

In the presence of 1p/19q codeletion (± IDH-1/2 mutation) in patients with anaplastic oligodendroglioma in the postoperative period, both radiotherapy and chemotherapy (PCV or temozolomide** monotherapy on a 5/23 schedule) are recommended [8, 71, 72]. See section 3.3

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Comment: chemotherapy and radiotherapy are administered sequentially. Chemotherapy is equally effective both before and after radiotherapy. In case of a complete response to chemotherapy in such patients, radiotherapy may be deferred as a reserve treatment option in case of recurrence (see Fig. 3).

For patients older than 60 years and/or with a Karnofsky Performance Scale (KPS) score of 60% (Appendix G2. Patient Condition Severity Assessment Scale) or lower with grade 3-4 gliomas, radiotherapy may be administered in a hypofractionated regimen (10 fractions up to a total dose of 34 Gy, 15 fractions up to a total dose of 40 Gy, 15 fractions up to a total dose of 45 Gy, 20 fractions up to a total dose of 50 Gy), or temozolomide** monotherapy on a 5/23 schedule is prescribed [8, 43–45, 71, 72].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Comment: The administration of radiotherapy and/or antineoplastic drug therapy to patients with a low performance status and/or signs of intracranial hypertension, or extensive tumor spread is decided on an individual basis.

It is recommended to discuss patients with glioma recurrence at an oncology board (multidisciplinary team) to select the treatment method (indications for surgery/radiotherapy/antineoplastic drug therapy) with the participation of a neurosurgeon, oncologist, radiation therapist, radiologist, and physicians of other necessary related specialties [7, 19, 71].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Comments: Methods for treating patients with glioma recurrences include repeat surgery, systemic antineoplastic drug therapy, re-irradiation, and palliative care (see Fig. 1). For small local recurrences, radiosurgery or hypofractionated radiotherapy may be used.

As antineoplastic drug therapy in a patient with glioblastoma recurrences after the 1st line of treatment (chemoradiotherapy with temozolomide**), the administration of regimens incorporating #bevacizumab** is recommended (see section 3.3) [71, 72].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

As antineoplastic drug therapy in a patient with grade 3 recurrent anaplastic astrocytic and oligodendroglial tumors, the administration of temozolomide** is recommended (if it has not been used previously or if it was used, but there was a sufficiently long (at least 6 months) disease control without treatment) (see Fig. 2, 3) [19, 24, 25, 71].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Comment: Nitrosourea derivatives may also be offered if they have not been used previously. For oligodendroglial and anaplastic astrocytic tumors, the strategy depends on the previously used treatment regimen. If radiotherapy was used, chemotherapy is administered in the PCV regimen; if radiotherapy and PCV chemotherapy were used, preference is given to temozolomide** chemotherapy. In the case of primary treatment with PCV chemotherapy alone, radiotherapy may be performed.

For pleomorphic xanthoastrocytoma, tumor removal without adjuvant therapy is recommended provided that a radical surgery is achieved according to follow-up contrast-enhanced brain MRI and delayed MRI (at 3 months) [8, 71, 72].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Comment: if a BRAF mutation is detected in the event of tumor recurrence or a large residual tumor, the issue of targeted therapy with RAF and MEK inhibitors may be considered by the oncology board and medical committee.

In primary central nervous system lymphoma, tumor removal for the purpose of diagnosis verification is recommended in cases where the tumor is located in brain areas hazardous for stereotactic biopsy (e.g., cerebellopontine angle, fourth ventricle, small tumor in the projection of the third ventricle, etc.) or to resolve life-threatening conditions caused by a large tumor volume
In patients with primary CNS lymphoma, first-line treatment is recommended to be chemotherapy based on high-dose #methotrexate** (3.5-8 g/m², see section 3.3) for patients aged no older than 65 years, with Karnofsky Performance Status (KPS) >50 (Appendix G2. Patient severity assessment scale), and preserved hepatic and renal function (see Fig. 6, 7) [72].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Comment: This treatment is only possible in an inpatient setting within a hematology department or an inpatient chemotherapy unit, with recommended monitoring of blood #methotrexate** levels after its administration (blood drug level testing A09.05.035.

Patients with primary CNS lymphoma in the 1st line may also receive intra-arterial chemotherapy under conditions of temporary blood-brain barrier opening (optional) [29].

GIB CLOE 4Grade of Recommendation – C (Level of Evidence – 4)

For elderly patients and/or those with poor performance status (ECOG 60 and below), the following first-line treatment is recommended: #Temozolomide** 150 mg/m² – days 1–5; every 28 days + rituximab** 375 mg/m², every 3 weeks [72];
- #Temozolomide** 150–200 mg/m² – days 1–5, every 28 days [72] followed by treatment response assessment after 2 cycles and a repeated multidisciplinary oncology team review (optional) [90, 91] (see section 3.3).

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Treatment of a patient with primary CNS lymphoma is recommended to be carried out under the supervision of an oncologist or hematologist (see Fig. 6, 7) [8, 29, 72].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

In children with medulloblastomas, it is recommended to achieve the maximum possible resection of the cerebellar and fourth ventricle neoplasm using microsurgical techniques (A16.23.062.001) [10, 20, 30, 71, 72].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

In patients with CNS tumors presenting with hydrocephalus but without signs of obstructive syndrome, shunting procedures prior to tumor removal are not recommended. If signs of increased intracranial pressure persist after tumor resection, ventriculoperitoneostomy is recommended [20, 21, 79].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

3.4. Palliative and supportive care

Supportive care in patients with primary CNS tumors is provided in accordance with the practical guidelines of the Russian Society of Clinical Oncology (RUSSCO) [72].

Palliative and symptomatic therapy is recommended in patients with primary CNS tumors and/or widespread leptomeningeal disease in the presence of a poor overall survival prognosis [70, 71, 72].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

The principles of prevention and treatment of anemia in patients with primary CNS tumors correspond to the principles outlined in the clinical guidelines "Anemia in Malignant Neoplasms", available in the Russian Ministry of Health's clinical guidelines registry https://cr.minzdrav.gov.ru.
The principles of treatment and prevention of nausea and vomiting in patients with primary CNS tumors correspond to the principles outlined in the methodological guidelines "Prevention and Treatment of Nausea and Vomiting" (Authors: Vladimirova L.Yu., Gladkov O.A., Koroleva I.A. et al., DOI: https://doi.org/10.18027/2224-5057-2024-14-3s2-2-02, https://rosoncoweb.ru/standarts/?chapter=nausea_vomiting).
The principles of prevention and treatment of infectious complications and febrile neutropenia in patients with primary CNS tumors correspond to the principles outlined in the methodological guidelines "Treatment of Infectious Complications of Febrile Neutropenia and Administration of Colony-Stimulating Factors" (Authors: Sakaeva D.D., Orlova R.V., Shabaeva M.M., DOI: 10.18027/2224-5057-2024-14-3s2-2-04, https://rosoncoweb.ru/standarts/?chapter=febrile_neutropenia).
The principles of prevention and treatment of hepatotoxicity in patients with primary CNS tumors correspond to the principles outlined in the methodological guidelines "Management of Hepatotoxicity" (Authors: Tkachenko P.E., Ivashkin V.T., Maevskaya M.V., DOI: 10.18027/2224-5057-2024-14-3s2-2-05, https://rosoncoweb.ru/standarts/?chapter=hepatotoxicity).
The principles of prevention and treatment of cardiovascular complications in patients with primary CNS tumors correspond to the principles outlined in the methodological guidelines "Practical Guidelines for the Management of Cardiovascular Toxicity of Antineoplastic Drug Therapy" (Authors: Vitsenya M.V., Ageev F.T., Orlova R.V., Poltavskaya M.G., Potievskaya V.I., DOI: https://doi.org/10.18027/2224-5057-2024-14-3s2-2-06, https://rosoncoweb.ru/standarts/?chapter=cardiovascular_toxicity).
The principles of prevention and treatment of skin complications in patients with primary CNS tumors correspond toয়নের principles outlined in the methodological guidelines "Practical Guidelines for the Medical Treatment of Dermatological Reactions in Patients Receiving Antineoplastic Drug Therapy" (Authors: Koroleva I.A., Bolotina L.V., Gladkov O.A., Gorbunova V.A., Kogonia L.M., Kruglova L.S., Orlova E.V., Orlova R.V., DOI: 10.18027/2224-5057-2024-14-3s2-2-07, https://rosoncoweb.ru/standarts/?chapter=dermatological_reactions).
The principles of prevention and treatment of nephrotoxicity in patients with primary CNS tumors correspond to the principles outlined in the methodological guidelines "Practical Guidelines for the Management of Nephrotoxicity of Antineoplastic Drugs" (Authors: Gromova E.G., Biryukova L.S., Dzhumabaeva B.T., Kurmukov I.A., Somonova O.V., DOI: 10.18027/2224-5057-2024-14-3s2-2-11, https://rosoncoweb.ru/standarts/?chapter=nephrotoxicity).
The principles of prevention and treatment of thromboembolic complications in patients with primary CNS tumors correspond to the principles outlined in the methodological guidelines "Practical Guidelines for the Prevention and Treatment of Thromboembolic Complications in Cancer Patients" (Authors: Somonova O.V., Antukh E.A., Vardanyan A.V., Gromova E.V., Dolgushin B.I., Elizarova A.L., Sakaeva D.D., Selchuk V.Yu., Tryakin A.A., Cherkasov V.A., https://rosoncoweb.ru/standarts/RUSSCO/2024/2024-2-12.pdf, https://rosoncoweb.ru/standarts/?chapter=thromboembolism).
The principles of prevention and treatment of the consequences of drug extravasation in patients with primary CNS tumors correspond to the principles outlined in the methodological guidelines "Guidelines for the Treatment of Consequences of Antineoplastic Drug Extravasation" (Author: Buydenok Yu.V., Obukhova O.A., DOI: 10.18027/2224-5057-2024-14-3s2-2-13, https://rosoncoweb.ru/standarts/?chapter=extravasation_antitumor_drugs).
The principles of prevention and treatment of immune-mediated adverse events in patients with primary CNS tumors correspond to the principles outlined in getDateTime the methodological guidelines "Practical Guidelines for the Management of Immune-Mediated Adverse Events" (Authors: Novik A.V., Protsenko S.A., Ballyuzek M.F., Vasiliev D.A., Zhukova N.V., Maslova D.A., Nosov D.A., Petenko N.N., Semenova A.I., Kharkevich G.Yu., Yudin D.I., DOI: 10.18027/2224-5057-2024-14-3s2-2-15, https://rosoncoweb.ru/standarts/?chapter=immunerelated_adverse_events).

3.5. Steroid and anti-edematous therapy

The goal of steroid therapy is the temporary alleviation of clinical symptoms associated with mass effect due to perifocal edema.

In the presence of neurological symptoms caused by intracranial hypertension, mass effect, or hydrocephalus, steroid therapy is recommended for patients with primary CNS tumors at doses corresponding to the severity of these symptoms [71, 72]. See Appendix G5 [69]

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Comments: corticosteroid therapy doses depend on the severity of symptoms. The minimum required dose is selected (dexamethasone** 0.5–4 mg (H02AB02)). After symptom regression, a gradual dosage reduction is necessary, and in the absence of symptom recurrence, complete discontinuation [41].

In case of suspected lymphoma, the use of glucocorticoids (H02AB) is not recommended prior to morphological verification, except in situations where cerebral edema and dislocation threaten the patient's life [72].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Patients with extensive edema with/without mass effect should be prescribed steroids at least 24 hours prior to the initiation of radiotherapy.

To prevent gastrointestinal ulcers/bleeding, patients taking NSAIDs or antithrombotic agents are indicated for H2-receptor blockers and/or proton pump inhibitors

Comments: Dexamethasone** doses are tapered gradually over 2 weeks or more, based on individual clinical symptom dynamics and taking into account potential complications of steroid therapy.

Reducing/discontinuing the dexamethasone** dosage prior to surgical removal and/or radiation therapy is inexpedient.

Systemic corticosteroids are prescribed and administered in 1-2 doses, orally or intramuscularly, in accordance with the circadian rhythm, with maximum doses in the morning and the last dose no later than 4:00 PM - 5:00 PM.

It is recommended to prescribe #bevacizumab** in patients with primary CNS tumors presenting with neurological symptoms caused by extensive brain edema or radionecrosis following radiation therapy that are refractory to standard anti-edema therapy [70, 71].

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

Comments: #bevacizumab** is prescribed as a means to correct post-radiation changes. The use of #bevacizumab** therapy should be considered in patients: with contraindications to steroid therapy; with radionecrosis and local recurrence (according to positron emission tomography (PET) to detect inflammatory foci (A07.30.034), PET combined with brain CT (PET/CT), including with contrast agent administration (A07.23.008; A07.23.008.001), PET/CT with tumor-tropic radiopharmaceuticals, including with contrast enhancement (A07.30.043; A07.30.043.001)) in the previously irradiated lesion to optimize the volume of re-irradiation.

The dose of #bevacizumab** is 5 mg/kg of body weight every 2 weeks or 7.5 mg/kg at 3-week intervals, continued until symptom regression or radiological improvement (usually 4 administrations) [25, 26, 27, 70, 71, 72].

3.6. Anticonvulsant therapy

If patients have a seizure disorder (including a history thereof), it is recommended to consult a neurologist for the prescription/adjustment of anticonvulsant therapy [70, 71].

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

Comments: in patients without a seizure disorder, prophylactic anticonvulsant therapy is not recommended.

3.7. Diet therapy.

Organization of therapeutic nutrition for patients with primary CNS tumors during inpatient treatment in medical organizations is carried out in accordance with the orders of the Russian Ministry of Health No. 330 dated August 5, 2003, "On measures to improve therapeutic nutrition in medical and preventive institutions of the Russian Federation", No. 395n dated June 21, 2013, "On approval of therapeutic nutrition standards", and No. 1008n dated September 23, 2020, "On approval of the procedure for providing patients with therapeutic nutrition". Appendix A3

The principles of nutritional support in patients with primary CNS tumors comply with the principles outlined in the methodological guidelines "Practical recommendations for nutritional support in cancer patients" (Authors: Sytov A. V., Zuzov S. A., Kukosh M. Yu., Leiderman I. N., Obukhova O. A., Potapov A. L., Khoteev A. Zh., DOI: 10.18027/2224-5057-2024-14-3s2-2-08, https://rosoncoweb.ru/standarts/?chapter=nutritional_support).

4. Medical Rehabilitation and Sanatorium-Resort Treatment

It is advisable to carry out rehabilitation measures to restore neurological functions in accordance with the clinical guidelines for the provision of medical care to patients with a primary tumor.

Currently, there are no clinical trials involving patients with primary CNS tumors for most types of medical rehabilitation. Available data from systematic reviews indicate that various types of medical rehabilitation accelerate functional recovery, reduce hospital stay duration after surgery, and lower the rate of complications and mortality in patients with malignant tumors. Rehabilitation measures in patients with primary CNS tumors are carried out after local treatment (medical rehabilitation services for a patient who has undergone surgery for a malignant neoplasm, medical rehabilitation services for a patient who has undergone chemotherapy, medical rehabilitation services for a patient who has undergone radiation therapy). The scope of rehabilitation measures is determined by the severity of the neurological deficit and is carried out in specialized medical rehabilitation departments according to general principles of rehabilitating patients with neurological pathology, taking into account the type and characteristics of the disease.

4.1. Principles of psychological rehabilitation of patients with primary CNS tumors.

It is recommended to inform patients about the disease, psychological reactions; areas of responsibility during the treatment process; methods of communication with relatives and medical staff; ways to obtain additional information about their disease or condition; and methods of obtaining social support, which leads to improved quality of life and disease outcomes [71, 73].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Educational events and psychological support are recommended (self-diagnosis of pathological psychological reactions; coping mechanisms for stress; monitoring the mutual influence of psychological reactions and physical condition), which can be considered as the primary mechanism for transforming stressful events into personal experience, promoting social and psychological adaptation under the conditions of disease and treatment [71, 73].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

It is advisable to conduct targeted psychotherapeutic interventions for psychological reactions associated with metastatic brain lesions (astheno-anxious-depressive reactions, narcissistic reactions, etc.); this leads to a reduction in anxiety and health-related disorders, and also brings about positive changes in coping with the disease [71, 73].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

5. Prevention and Dispensary Observation

It is recommended that after treatment for a primary CNS tumor, the patient undergoes follow-up examinations for the timely detection of disease recurrence, including brain MRI with and without contrast (A05.23.009; A05.23.009.001) at the following intervals: every 3 months for the first 2 years, and every 6 months thereafter. For certain pathologies, spinal MRI and contrast-enhanced spinal MRI (A05.23.009.010; A05.23.009.011) are also indicated, or when neurological symptoms appear [10, 19, 71].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Patients with brain tumors are recommended to have their MRI data evaluated in accordance with the RANO treatment response criteria (see Appendix G1) [8, 13, 19].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).

It is recommended that patients with primary non-germinomatous germ cell tumors also undergo monitoring of tumor markers (AFP, hCG) [8, 13, 19]. See Section 2.3

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).

Algorithms for the treatment of primary brain tumors according to various histological groups are given in Appendix B.

6. Organization of Medical Care

Medical care, except for medical care provided as part of clinical trials, in accordance with Federal Law No. 323-FZ dated November 21, 2011 (as amended on May 25, 2019) "On the fundamentals of protecting the health of citizens in the Russian Federation", is organized and provided:

1) in accordance with the regulations on the organization of medical care by types of medical care, approved by the authorized federal executive body;

2) in accordance with the procedure for the provision of medical care in the profile "oncology", mandatory for implementation throughout the Russian Federation by all medical organizations;

3) based on these clinical guidelines;

4) taking into account the standards of medical care approved by the authorized federal executive body.

Primary specialized health care is provided by an oncologist and other medical specialists at an outpatient oncological care center or in a primary oncological office, primary oncological department, or outpatient department of an oncological dispensary.

If an oncological disease is suspected or detected in a patient, general practitioners, district general practitioners, general practice physicians (family physicians), specialist physicians, and mid-level medical personnel shall refer the patient in the established manner for consultation at an outpatient oncological care center, a primary oncological office, or the outpatient department of an oncological dispensary (oncological hospital) for the provision of primary specialized health care.

When neurological symptoms characteristic of a brain/spinal cord tumor are detected in a patient, they are referred to a neurologist and/or for a contrast-enhanced MRI of the brain and/or spinal cord. If signs of a space-occupying lesion in the brain/spinal cord are detected, the patient is referred for a neurosurgical consultation to determine further management tactics. In cases where brain/spinal cord imaging data do not rule out metastatic brain disease, the patient is referred to an outpatient oncology center for a primary oncological workup. If the detected space-occupying lesion in the brain/spinal cord, together with clinical manifestations, poses an immediate threat to life, the patient is hospitalized for neurosurgical treatment in accordance with the procedure for providing care in the "neurosurgery" specialty.

A consultation at an outpatient oncology center, a primary oncology office, or a primary oncology department of a medical organization must be held no later than 5 working days from the date the referral for consultation is issued. The oncologist at the outpatient oncology center (or, in the absence of an outpatient oncology center, the oncologist at the primary oncology office or the polyclinic department of the oncology dispensary/oncology hospital) arranges for the acquisition of biopsy (surgical) material and organizes other diagnostic tests necessary to establish a diagnosis, including the extent of the oncological process and the stage of the disease.

Upon detecting signs of an oncological disease in the brain/spinal cord, the patient is referred to a neurosurgical department/institution, where the decision on surgical tactics is made in accordance with the procedure for providing medical care in the "neurosurgery" specialty.

The timeframe for performing pathological anatomical examinations necessary for the histological verification of a malignant neoplasm shall not exceed 15 working days from the date of receipt of the biopsy (surgical) material at the department of pathological anatomy (pathology bureau).

The timeframes for diagnostic instrumental and laboratory examinations in case of suspected oncological disease shall not exceed the timeframes established in the state guarantee program for the free provision of medical care to citizens, approved by the Government of the Russian Federation.

The oncologist of the outpatient oncological care center (primary oncological office, primary oncological department) shall refer the patient to an oncological dispensary or medical organizations providing medical care to patients with oncological diseases to clarify the diagnosis (if the oncologist of the outpatient oncological care center, primary oncological office, or primary oncological department is unable to establish the diagnosis, including the extent of the oncological process and the stage of the disease) and to receive specialized, including high-tech, medical care.

For oncological diseases included in categories C00–C97, D00–D09, D21, D31–D33, and D35–D48 of the International Statistical Classification of Diseases and Related Health Problems, 10th Revision (hereinafter referred to respectively as oncological diseases, ICD-10), as well as in cases of suspected oncological diseases, the oncologist of the oncology dispensary (oncology hospital) or other medical organization providing medical care to cancer patients shall organize a consultation or a medical board (consilium), including via telemedicine technologies, at federal state budgetary institutions subordinate to the Russian Ministry of Health that provide medical care (hereinafter referred to as national medical research centers for the purposes of this Procedure).

In complex clinical cases to clarify the diagnosis (in the event that a diagnosis cannot be established, including the extent of the oncological process and the stage of the disease) for the purpose of evaluation, interpretation, and description of the results, the oncologist shall arrange for the referral of: digital images obtained from pathological anatomical studies to the fourth group pathological anatomical bureau (department) (reference center) via information interaction, including the use of telemedicine technologies for remote interaction between medical workers; digital images obtained from diagnostic imaging methods to the remote diagnostic imaging consultation center via information interaction, including the use of telemedicine technologies for remote interaction between medical workers; biopsy (surgical) material for re-examination involving pathological anatomical, immunohistochemical, and molecular genetic studies: to the fourth group pathological anatomical bureau (department) (reference center), as well as to molecular genetic laboratories for molecular genetic testing.

Treatment tactics are determined by a medical board (consilium) of physicians, including oncologists, a radiation oncologist, and a neurosurgeon (for nervous system tumors) of a medical organization that includes departments of surgical methods for the treatment of malignant neoplasms, systemic antineoplastic therapy, and radiation therapy (hereinafter referred to as the oncological consilium), including an oncological consilium conducted using telemedicine technologies, with the involvement of other specialist physicians if necessary.

Dispanserization (follow-up) by an oncologist for a patient with a diagnosed oncological disease is established and carried out in accordance with the procedure for follow-up of adults with oncological diseases.

For record-keeping purposes, information about a newly diagnosed case of an oncological disease shall be sent within 3 working days by the oncologist of the medical organization where the respective diagnosis was established to the oncological dispensary or the organization of the subject of the Russian Federation performing the function of registering patients with newly diagnosed malignant neoplasms, including via the Unified State Health Information System.

Specialized, including high-tech, medical care in medical organizations providing medical care to adult patients with oncological diseases is provided based on medical indications provided for by the regulations on the organization of specialized, including high-tech, medical care. Specialized medical care, excluding high-tech care, in medical organizations subordinate to federal executive authorities is provided based on medical indications stipulated in paragraph 5 of the procedure for referring patients to medical organizations and other organizations subordinate to federal executive authorities for the provision of specialized (excluding high-tech) medical care, provided in the appendix to the regulations on the organization of the provision of specialized, including high-tech, medical care.

Waiting times for the provision of specialized (excluding high-tech) medical care must not exceed the timeframes established in the program of state guarantees of free medical care for citizens, approved by the Government of the Russian Federation.

If a patient with an oncological disease has medical indications for medical rehabilitation, the oncologist arranges for it to be provided in accordance with the procedure for organizing adult medical rehabilitation.

If a patient with an oncological disease has medical indications for sanatorium-resort treatment, the oncologist arranges for it in accordance with the procedure for organizing sanatorium-resort treatment.

Palliative medical care for a patient with oncological diseases is provided in accordance with the provision on organizing the provision of palliative medical care, including the procedure for interaction between medical organizations, social service organizations, public associations, and other non-profit organizations operating in the field of health protection.

If an oncological disease is suspected and/or detected in a patient during the provision of emergency medical care, the patient is transferred or referred to medical organizations providing medical care to patients with oncological diseases to determine management tactics and the need for additional other methods of specialized antitumor treatment.

6.1. Indications for emergency or urgent hospitalization in a medical organization are:

1) the presence of complications in patients with primary central nervous system (CNS) tumors requiring emergency and urgent specialized medical care;

2) the presence of treatment complications (surgical, radiation, drug, etc.) in patients with primary CNS tumors requiring emergency and urgent medical care.

6.2. Indications for planned hospitalization in a medical organization are:

1) the need to perform complex interventional diagnostic medical procedures requiring subsequent monitoring in an inpatient or day-hospital setting;

2) the presence of indications for specialized antitumor treatment (surgery, radiation therapy, drug therapy) requiring monitoring in an inpatient or day hospital setting.

6.3. Indications for discharging a patient from a medical organization are:

completion of a treatment course or one of the stages of specialized, including high-tech, medical care in an inpatient or day care setting in the absence of treatment complications requiring drug correction and/or medical interventions in a hospital setting (inpatient or day care);
documented refusal of the patient or their legal representative from specialized, including high-tech, medical care in an inpatient or day care setting.
the need to transfer the patient to another medical organization of the appropriate medical profile. The conclusion regarding the feasibility of transferring the patient to a specialized medical organization shall be made after a preliminary consultation based on the provided medical documents and/or preliminary examination data by specialists of the receiving medical organization.

6.4. Medical procedures that can be provided within the framework of primary specialized medical care (i.e., on an outpatient basis) under the supervision of an oncologist:

organization of consultations with specialized medical specialists;
administration of steroid therapy if indicated;
referral for CT, MRI, PET if indicated.

6.5. Indications for referring a patient to another medical organization

When receiving medical care under the state program of free healthcare guarantees for citizens, a citizen has the right to choose a medical organization in the manner approved by the authorized federal executive body, and to choose a physician taking into account the physician's consent. Specifics of choosing a medical organization by citizens residing in closed administrative-territorial entities, in territories with physical, chemical, and biological health-hazard factors included in the relevant list, as well as by employees of organizations included in the list of organizations in certain industries with particularly hazardous working conditions, are established by the Government of the Russian Federation.

If the medical organization lacks the capability to provide the recommended scope of medical care to patients with metastatic brain lesions, it is recommended to utilize the referral system to other medical organizations, including outside the constituent entity of the Russian Federation, and to federal centers with appropriate equipment and personnel;

Clinical guidelines do not encompass the entire diversity of real-world clinical practice and cover only the most frequent and typical clinical situations. If a practicing physician or medical organization encounters a clinical situation not adequately reflected in these clinical guidelines, it is recommended to use the telemedicine consultation system or referral to federal and national medical research centers to refine the treatment strategy;

Identification of clinical situations or exacerbation of concomitant pathology unrelated to the profile of the oncology facility that hinders the implementation of this treatment stage (e.g., acute myocardial infarction, acute cerebrovascular accident, need for neurosurgical treatment, etc.) requires referral to specialized medical organizations.

7. Additional Information

Patients with primary CNS tumors represent a heterogeneous group with diverse clinical and biological tumor characteristics and overall survival rates. Therefore, it is important to consider various clinical factors influencing the prognosis of patients with primary CNS tumors prior to making treatment decisions. The concept of a "prognostic factor" is defined as a clinical situation that can be used to assess the probability of recovery or the likelihood of disease recurrence (Use of Recursive Partitioning Analysis in Clinical Trials and Meta-Analysis of Randomized Clinical Trials, 1990-2016). Numerous studies, albeit retrospective in nature, have identified various prognostic factors and enabled the development of different prognostic tools (scales) for predicting overall survival in patients with primary CNS tumors. Currently, the optimal prognostic scale is the RPA classification, which allows for assessing patients' overall survival prognosis depending on a number of factors that vary among patients with different types of primary CNS tumors. (Appendix G1. RPA Classification) [15].

Criteria for Evaluating the Quality of Medical Care

	Quality criteria	Performance assessment (yes/no)
1	Contrast-enhanced magnetic resonance imaging (MRI) of the brain performed (at diagnosis)	yes/no
2	Neurosurgical intervention performed on a patient capable of tolerating surgery with a resectable CNS tumor	yes/no
3	Pathological anatomical examination of biopsy (surgical) material performed	yes/no
4	Multidisciplinary oncological team meeting held comprising a neurosurgeon, oncologist, and radiation oncologist	yes/no
5	Systemic anti-tumor therapy and/or chemoradiotherapy and/or external beam radiotherapy and/or surgical treatment administered (according to medical indications and in the absence of contraindications)	yes/no

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Appendix A1. Working Group Composition

"Diagnostics Block"

Grinevich V.N., Candidate of Medical Sciences, Head of the Pathological Anatomy Department, Moscow City Oncology Hospital No. 62 of the Moscow Healthcare Department.

Pronin I.N., Doctor of Medical Sciences, Professor, Academician of the Russian Academy of Sciences, Deputy Director for Research, National Medical Research Center for Neurosurgery named after Academician N.N. Burdenko of the Russian Ministry of Health.

Ryzhova M.V., Doctor of Medical Sciences, Head of the Pathological Anatomy Department, National Medical Research Center for Neurosurgery named after Academician N.N. Burdenko of the Russian Ministry of Health.

"Surgical Block"

Usachev D.Yu., Doctor of Medical Sciences, Professor, Academician of the Russian Academy of Sciences, Director, National Medical Research Center for Neurosurgery named after Academician N.N. Burdenko of the Russian Ministry of Health.

Krylov V.V., Doctor of Medical Sciences, Professor, Academician of the Russian Academy of Sciences, Chief freelance neurosurgeon of the Russian Ministry of Health.

Bekyashev A.Kh., Doctor of Medical Sciences, Head of the Neurosurgery Department, National Medical Research Center for Oncology named after N.N. Blokhin of the Russian Ministry of Health.

Gorelyshev S.K., Doctor of Medical Sciences, Professor, Head of Neurosurgical Department 1, National Medical Research Center for Neurosurgery named after Academician N.N. Burdenko of the Russian Ministry of Health.

Grin A.A., Doctor of Medical Sciences, Professor, Chief freelance neurosurgeon of Moscow.

Evzikov G.Yu., Doctor of Medical Sciences, Head of the Neurosurgical Department, Clinic of Nervous Diseases, I.M. Sechenov First Moscow State Medical University

Zaitsev A.M., Candidate of Medical Sciences, Head of the Neurosurgical Department, P.A. Herzen Moscow Oncology Research Institute, a branch of the National Medical Research Center for Radiology of the Russian Ministry of Health.

Konovalov N.A., Doctor of Medical Sciences, Professor, Corresponding Member of the Russian Academy of Sciences, Deputy Director, National Medical Research Center for Neurosurgery named after Academician N.N. Burdenko of the Russian Ministry of Health.

Rostorguev E.E., Candidate of Medical Sciences, Head of the Neuro-Oncology Department, Rostov Research Institute of Oncology of the Russian Ministry of Health.

Ulitin A.Yu., Doctor of Medical Sciences, Professor, Chief freelance neurosurgeon of St. Petersburg.

"Radiotherapy Block"

Izmaylov T.R., Doctor of Medical Sciences, Head of the Radiotherapy Department, National Pirogov Medical Surgical Center of the Russian Ministry of Health.

Vinogradova Yu.N., Doctor of Medical Sciences, Head of the Department of Radiation and Combined Treatment Methods, A.M. Granov Russian Research Center of Radiology and Surgical Technologies of the Russian Ministry of Health.

Golanov A.V., Doctor of Medical Sciences, Corresponding Member of the Russian Academy of Sciences, Head of the Radiology and Radiosurgery Department, National Medical Research Center for Neurosurgery named after Academician N.N. Burdenko of the Russian Ministry of Health.

Gulidov I.A., Doctor of Medical Sciences, Head of the Radiotherapy Department, A.F. Tsyb Medical Radiological Research Center, a branch of the National Medical Research Center for Radiology of the Russian Ministry of Health.

Datsenko P.V., Doctor of Medical Sciences, Head of the Neuroradiology Department within the Radiotherapy Division, P.A. Herzen Moscow Oncology Research Institute, a branch of the National Medical Research Center for Radiology of the Russian Ministry of Health.

Novikov S.N., Doctor of Medical Sciences, Head of Radiotherapy, N.P. Napalkov National Medical Research Center of Oncology of the Russian Ministry of Health.

Trunin Yu.Yu., Doctor of Medical Sciences, Leading Researcher, Radiology and Radiosurgery Department, National Medical Research Center for Neurosurgery named after Academician N.N. Burdenko of the Russian Ministry of Health.

"Antineoplastic Drug Therapy Block"

Kobyakov G.L., Doctor of Medical Sciences, Deputy Chief Physician for Oncology, National Medical Research Center for Neurosurgery named after Academician N.N. Burdenko of the Russian Ministry of Health.

Absalyamova O.V., Candidate of Medical Sciences, Head of the Day Hospital, National Medical Research Center for Neurosurgery named after Academician N.N. Burdenko of the Russian Ministry of Health.

Naskhletashvili D.R., Candidate of Medical Sciences, Senior Researcher, National Medical Research Center for Oncology named after N.N. Blokhin of the Russian Ministry of Health.

Smolin A.V., Candidate of Medical Sciences, Head of the Radiological Center, Main Military Clinical Hospital named after Academician N.N. Burdenko of the Russian Ministry of Defense.

Fedenko A.A., Head of the Department of Drug Treatment of Tumors, P.A. Herzen Moscow Oncology Research Institute, a branch of the National Medical Research Center for Radiology of the Russian Ministry of Health.

"Healthcare Organization Block"

Tanyashin S.V., Doctor of Medical Sciences, Professor, Lecturer at the Department of Neurosurgery with Neuroscience Courses, National Medical Research Center for Neurosurgery named after Academician N.N. Burdenko of the Russian Ministry of Health.

Ivanov S.A., Doctor of Medical Sciences, Professor, Corresponding Member of the Russian Academy of Sciences, Honored Doctor of the Russian Federation, Director of the A.F. Tsyb Medical Radiological Research Center, a branch of the National Medical Research Center for Radiology of the Russian Ministry of Health, Chief freelance oncologist of the Central Federal District of the Russian Ministry of Health.

Gevorkyan T.G., Deputy Director for the Implementation of Federal Projects, National Medical Research Center for Oncology named after N.N. Blokhin of the Russian Ministry of Health.

Nevolskikh A.A., Doctor of Medical Sciences, Deputy Director for Clinical Work, A.F. Tsyb Medical Radiological Research Center, a branch of the National Medical Research Center for Radiology of the Russian Ministry of Health.

Khailova Zh.V., Candidate of Medical Sciences, Deputy Director for Organizational and Methodological Work, A.F. Tsyb Medical Radiological Research Center, a branch of the National Medical Research Center for Radiology of the Russian Ministry of Health.

Komarov Yu.I., Candidate of Medical Sciences, Deputy Director for Organizational and Methodological Work, N.P. Napalkov National Medical Research Center of Oncology of the Russian Ministry of Health.

No conflicts of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1) Oncologists;

2) Surgeons;

3) Radiologists;

4) Radiation oncologists;

5) Neurosurgeons;

6) Medical university students, residents, and postgraduate students.

Methods used for evidence collection/selection: electronic database search; analysis of current scientific developments on the problem of brain tumors in Russia and abroad; synthesis of the practical experience of Russian and foreign

specialists.

Table A1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

LoE	Definition
1	Systematic reviews of studies with reference standard control or systematic reviews of randomized clinical trials with meta-analysis
2	Individual studies with reference standard control or individual randomized controlled trials and systematic reviews of studies of any design, except randomized controlled trials, with meta-analysis
3	Studies without consecutive reference standard control or studies with a reference standard not independent of the test method, or non-randomized comparative studies, including cohort studies
4	Non-comparative studies, case report
5	Only justification of mechanism of action or expert opinion is available

Table A2. Levels of Evidence (LoE) grading scale for methods of prevention, treatment, and medical rehabilitation, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitative interventions)

LoE	Definition
1	Systematic review of RCTs incorporating meta-analysis
2	Individual RCTs and systematic reviews of studies of any design except RCTs incorporating meta-analysis
3	Non-randomized comparative studies, including cohort studies
4	Non-comparative studies, case reports or case series, case-control studies
5	Only justification of the mechanism of action of the intervention (preclinical studies) or expert opinion is available

Table A3. Grades of Recommendation (GoR) grading scale for methods of prevention, diagnostics, treatment, and medical rehabilitation, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitative interventions)

GoR	Definition
A	Strong recommendation (all considered efficacy criteria (outcomes) are important, all studies are of high or acceptable methodological quality, and their conclusions on the outcomes of interest are consistent)
B	Conditional recommendation (not all considered efficacy criteria (outcomes) are important, not all studies are of high or acceptable methodological quality, and/or their conclusions on the outcomes of interest are inconsistent)
C	Weak recommendation (lack of adequate quality evidence (all considered efficacy criteria (outcomes) are unimportant, all studies are of low methodological quality, and their conclusions on the outcomes of interest are inconsistent)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

These clinical guidelines have been developed taking into account the following regulatory and legal documents:

Federal Law No. 323-FZ "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation", Moscow, 2013.
Nomenclature of Medical Services (New Edition). Approved by Order of the Ministry of Health and Social Development of the Russian Federation No. 804n dated October 13, 2017.
Order of the Russian Ministry of Health No. 931n dated November 15, 2012, "On Approval of the Procedure for Providing Medical Care to Adult Patients in the Profile 'Neurosurgery'."
Order of the Ministry of Health of the Russian Federation No. 203N dated May 10, 2017, "On Approval of Criteria for Assessing the Quality of Medical Care."
Order of the Ministry of Health of the Russian Federation No. 116n dated February 19, 2021, "On Approval of the Procedure for Providing Medical Care to Adult Patients with Oncological Diseases" (Registered on April 1, 2021, No. 62964).
Decree of the Government of the Russian Federation No. 1180-r dated May 16, 2022, "On Approval of the List of Diseases or Conditions (Groups of Diseases or Conditions) under Which the Use of a Medicinal Product Is Permitted in Accordance with Indicators (Characteristics) of the Medicinal Product Not Specified in Its Instructions for Use."
Order of the Ministry of Health of the Russian Federation No. 330 dated August 5, 2003, "On Measures to Improve Medical Nutrition in Healthcare Institutions of the Russian Federation."
Order of the Ministry of Health of the Russian Federation No. 395n dated June 21, 2013, "On approval of therapeutic nutrition standards".
Order of the Ministry of Health of the Russian Federation No. 1008n dated September 23, 2020, "On Approval of the Procedure for Supplying Patients with Clinical Nutrition."

Type of care.

Diagnostic and therapeutic measures for patients with primary CNS tumors can be either elective or emergent. Urgent measures are performed in the event of hypertension-hydrocephalus syndrome, signs of brain herniation, or hemorrhage into the tumor.

Conditions for providing medical services.

Diagnostic measures at the stage of diagnosis and during the observation period or between treatment stages, as well as preoperative examinations, including laboratory tests, are performed on an outpatient basis. Surgical treatment is performed in a specialized neurosurgical inpatient facility equipped with a neurosurgical operating room in accordance with Order of the Russian Ministry of Health No. 931n dated November 15, 2012, "On Approval of the Procedure for Providing Medical Care to Adult Patients in the Profile 'Neurosurgery'," and having experience and specialists in performing the type of surgical operations in question.

Radiotherapy can be performed in both round-the-clock and day inpatient settings (Order of the Ministry of Health of the Russian Federation No. 116n dated February 19, 2021, "On Approval of the Procedure for Providing Medical Care to Adult Patients with Oncological Diseases" (Registered on April 1, 2021, No. 62964))

Current instructions for the medicinal products mentioned in these clinical guidelines can be found on the website grls.rosminzdrav.ru

Appendix B. Physician Action Algorithms

Fig. 1. Treatment algorithm for grade 2-4 diffuse gliomas (Part 1)

Fig. 2.Treatment algorithm for diffuse gliomas (part 2)

Fig. 3.Treatment algorithm for malignant gliomas (part 3)

Fig. 4. Treatment regimen for ependymomas

Fig. 5. Treatment regimen for ependymoma recurrence

Fig. 6. Diagnostic scheme for primary CNS lymphoma

Fig. 7.Treatment regimen for primary CNS lymphoma

Fig. 8.Treatment regimen for relapsed primary CNS lymphoma

Fig. 9. Treatment regimen for primary CNS germ cell tumors (I)

Fig. 10.Treatment regimen for primary CNS germ cell tumors (II)

Fig. 11.Treatment regimen for adult patients with medulloblastoma and malignant pineal parenchyma tumors (pineoblastoma, pineal parenchymal tumor of intermediate differentiation)

RANO criteria for assessing treatment efficacy in CNS tumors

The efficacy of treatment for CNS tumors is evaluated using the RANO scale (Appendix G1. RANO Scale).

Complete response:

- regression of all measurable and non-measurable contrast-enhancing lesions; stable or decreasing non-enhancing lesions on T2/FLAIR sequences; absence of corticosteroid therapy;

- neurological status: improvement or stabilization.

Partial response:

- decrease in the sum of perpendicular diameters of all measurable lesions by ≥50%; absence of progression of non-measurable lesions;

- stable or decreasing non-enhancing lesions on T2/FLAIR; stable or decreasing corticosteroid doses;

- neurological status: improvement or stabilization.

Disease progression:

- increase of ≥25% in the sum of perpendicular diameters of all measurable lesions; significant increase in non-enhancing lesions on T2-FLAIR;

- appearance of new lesions;

- stable or increasing corticosteroid doses; worsening of neurological symptoms.

All other cases are considered disease stabilization.

Appendix C. Patient Information

In case of complications, it is recommended to contact an oncologist, radiation oncologist, or surgeon.
If neurological symptoms persist after treatment, you should consult your attending physician. To prevent the development of new brain metastases, examinations should be performed according to the attending physician's recommendations.
If nausea (vomiting) occurs, consultation with the attending physician is required to potentially adjust anti-edema therapy. Discontinuation (or cessation) of steroid therapy is only possible after consulting the attending physician.
During treatment and follow-up, it is advisable to limit alcohol consumption and smoking. If body temperature rises to 38°C or higher, contact the attending physician to determine appropriate treatment.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. RANO criteria for evaluating response to CNS tumor treatment

Russian name: RANO criteria for evaluating treatment efficacy in CNS tumors.

Original name: Response assessment in neuro-oncology criteria.

Source (official developer website, validation publication): Quant, E.C., Wen, P.Y. Response Assessment in Neuro-Oncology. Curr Oncol Rep 2010;13(1):50–6 [66].

Type: rating scale.

Purpose: evaluation of treatment efficacy in CNS tumors.

Content: criteria for evaluating treatment efficacy in CNS tumors according to RANO (Response Assessment in Neuro-Oncology international working group).

Criteria	Complete response	Partial response	Stable disease	Disease progression
T1-WI + contrast enhancement	No	≥50%	<50%, but >25%	<25%
T2-WI/FLAIR	Stabilization/decrease	Stabilization/decrease	Stabilization/decrease	Increase
New lesion	No	No	No	May be
Corticosteroids	No	Stabilization/decrease	Stabilization/decrease	Not assessed
Clinical presentation	Stabilization/improvement	Stabilization/improvement	Stabilization/improvement	Worsening
Criteria	All	All	All	Any

Key (interpretation): provided in the content.

Appendix G2. WHO/ECOG performance status scale

Russian name: WHO/ECOG performance status scale.

Original title: The Eastern Cooperative Oncology Group/World Health Organization Performance Status (ECOG/WHO PS).

Source (official developer website, publication with validation): https://ecogacrin.org/resources/ecog-performance-status.

Original publication: Oken M.M., Creech R.H., Tormey D.C., Horton J., Davis T.E., McFadden E.T., Carbone P.P. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5(6):649−55 [67].

Type: rating scale.

Purpose: to describe the patient's level of functioning in terms of their ability to care for themselves, daily activities, and physical abilities (walking, work, etc.).

Content (template):

Score	Description
0	The patient is fully active, able to perform all activities as before the disease (90-100% on the Karnofsky scale)
1	Patient is unable to perform any heavy work, but is able to carry out light or sedentary work (e.g., light housework or office work) (70-80% on the Karnofsky scale)
2	Ambulatory and capable of self-care, but unable to carry out any work activities; up and about more than 50% of waking hours
3	The patient is capable only of limited self-care, spending more than 50% of waking hours in a chair or bed (30-40% on the Karnofsky scale)
4	Disabled, completely unable to self-care, confined to a chair or bed (10-20% on the Karnofsky scale)
5	Dead

Scoring key (interpretation): provided within the scale itself.

Appendix G3. RPA classification (RTOG)

RPA (RTOG) classification [74, 75]

RPA class	Age, years	Karnofsky index	Description	Median survival, months
I	<50	–	Anaplastic astrocytoma, normal mental status	58,6
II	≥50	70-100	Anaplastic astrocytoma, symptom duration >3 months	37,4
III	<50	–	Anaplastic astrocytoma, abnormal mental status	17,9
RPA class	Age, years	Karnofsky performance scale	Description	Median survival, months
IV	<50	90-100	Glioblastoma	11,1
	<50	<90	Glioblastoma
	≥50	70-100	Anaplastic astrocytoma, symptom duration <3 months
	≥50	70-100	Glioblastoma (partial or total resection), functional neurological status
V	≥50	70-100	Glioblastoma (partial or total resection), non-functional neurological status	8,9
	≥50	70-100	Glioblastoma, biopsy, radiation dose >54 Gy
	≥50	<70	Glioblastoma, normal mental status
VI	≥50	<70	Glioblastoma, abnormal mental status, radiation dose <54 Gy	4,6

Appendix G4. Karnofsky Performance Scale [68]

Russian name: Karnofsky scale.

Original name (if applicable): Karnofsky Performance Status.

Source (official developer website, validation publication): Karnofsky D.A., Burchenal J.H. The clinical evaluation of chemotherapeutic agents in cancer. In: MacLeod C. (ed.). Evaluation of chemotherapeutic agents. New York: Columbia University Press; 1949:191–205 [68].

Type: rating scale.

Purpose: to describe the patient's level of functioning in terms of their ability to care for themselves, daily activities, and physical abilities (walking, work, etc.).

Content (template):

Score	Karnofsky Performance Scale
100	Normal activity, no complaints
90	Able to carry on normal activity; minor signs or symptoms of disease
80	Normal activity with effort; some symptoms or signs of disease
70	Cares for self, unable to carry on normal activity or to do active work
60	Requires occasional assistance, but is able to care for most of their personal needs
50	Requires considerable assistance and frequent medical care
40	Disabled; requires special care and assistance
30	Severely disabled; hospital admission is indicated although death not imminent
20	Very sick; hospital admission and active supportive care necessary
10	Moribund
0	Dead

Scoring key (interpretation): provided within the scale itself.

Appendix G5. Visual Analogue Scale for pain assessment

Russian name: Visual Analog Scale for pain assessment.

Original title: Visual Analog Scale for Pain (VAS Pain).

Source (official developer website, validation publication): Hawker G.A., Mian S., Kendzerska T., French M. Measures of adult pain: Visual Analog Scale for Pain (VAS Pain), Numeric Rating Scale for Pain (NRS Pain), McGill Pain Questionnaire (MPQ), Short-Form McGill Pain Questionnaire (SF-MPQ), Chronic Pain Grade Scale (CPGS), Short Form-36 Bodily Pain Scale (SF-36 BPS), and Measure of Intermittent and Constant Osteoarthritis Pain (ICOAP). Arthritis Care Res (Hoboken) 2011;63(Suppl 11):S240–52 [69].

Type: rating scale.

Purpose: designed for quantitative assessment of pain syndrome taking into account the patient's subjective sensations and selection of analgesic therapy.

Content (template):

"Rate your pain severity on the scale, where 0 is no pain and 10 is the most severe, unbearable pain."

Instructions: the patient is asked to mark the severity of pain on a 10-centimeter line from 0 to 10.

Key: 1-3 points – mild pain; 4-7 points – moderate pain; 8 or more points – severe pain.

Scales and calculators from this guideline

Karnofsky Performance Scale (KPS)Percentage scale for self-care and work capacity ECOG / WHO (Performance Status)Scale for assessing the general condition of cancer patients VAS for Pain (Visual Analog Scale)Assessment of pain intensity using a 10-point visual analog scale

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