Secondary malignant neoplasm of the brain and cerebral meninges: clinical guidelines

List of Abbreviations

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

WHO – World Health Organization

IV bol. – intravenous, bolus

IV inf. – intravenous infusion

Gy – Gray

CT – computed tomography

mg/m² – milligrams per square meter

BM – brain metastases

ICD-10 – International Classification of Diseases 10th Revision

MRI – magnetic resonance imaging

SCLC – small cell lung cancer

NSCLC – non-small cell lung cancer

WBRT – whole-brain radiotherapy

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

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).

PD1 – programmed cell death protein 1.

PD-1 inhibitor – a monoclonal antibody that blocks the interaction between programmed cell death protein 1 (PD-1) and its ligands.

Boost – additional irradiation of the tumor or the resection cavity.

Distant metastases – the appearance of new metastatic lesions in the brain, typically outside the area of prior local treatment.

Single brain metastasis – the presence of a single metastatic lesion in the brain.

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.

Local recurrences – the development of a relapse (or continued growth) within the area of previously irradiated or resected metastatic lesions.

Multiple metastatic disease – a count of 5 or more lesions in the brain.

Limited metastatic disease – a count of 4 or fewer lesions in the brain.

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.

Solitary brain metastasis – the presence of a single metastatic lesion in the brain with no other manifestations of distant metastasis of the tumor process.

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

Stereotactic radiotherapy – a form of external beam radiotherapy 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, where the radiation dose is delivered in a single fraction, and in hypofractionated mode, where the radiation dose is delivered 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 longest diameter of not less than 10 mm, visualized on two or more axial slices (with a scan increment of 1.5–2 mm) and a perpendicular short-axis dimension in the measurement plane of not less than 5 mm.

Non-target (non-measurable) brain lesion – lesions with a longest diameter of less than 10 mm, or lesions whose boundaries cannot be determined, metastases to the dura mater and leptomeninges, and metastases to the skull bones. The cystic component of a lesion or the resection cavity of a brain metastasis should not be measured to determine response.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Brain metastases represent a heterogeneous group of intracranial neoplasms uniting tumors of diverse origin, histological structure, clinical course, and treatment outcomes resulting from hematogenous metastasis of extracranial malignant tumors.

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

The brain metastasis cascade involves several stages. Initially, metastatic cells detach from the primary tumor site. To reach the CNS, tumor cells must survive in the systemic circulation, penetrate the brain parenchyma, and survive in the CNS microenvironment. This is facilitated by immunosuppressive mechanisms underlying the entire metastatic process, as evading immunological recognition and maintaining an immunosuppressive environment in the CNS are important for tumor cell survival [10].

The most critical steps of the metastatic cascade have been established in brain metastasis models, including: arrest of tumor cells at vessel bifurcations, perivascular growth, vessel co-option, and angiogenesis, which promotes macrometastasis formation. Thus, detachment of cells from the primary tumor, invasion of the surrounding stroma and basement membrane, intravasation of cancer cells, extravasation, disruption of the blood-brain barrier (BBB), invasion, and colonization of the CNS are the main stages of brain tumor metastasis [8].

The microenvironment, consisting of tumor cells and resident CNS cells, promotes metastatic growth, regulates tumor progression, and determines response to therapy. Emerging evidence suggests that tumor cells are capable of inducing the formation of a specialized environment primed for metastatic dissemination, survival, and proliferation of tumor cells, termed the «pre-metastatic niche» [16].

Tumor stem cells are present in metastases, contributing to treatment resistance and a propensity for recurrence. Stem cells reside in the perivascular niche, promoting tumor cell growth and proliferation.

Vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) signaling pathways are involved in angiogenesis and represent potential targets for anti-angiogenic therapy. Furthermore, vessel co-option may also contribute to tumor recurrence by facilitating the migration of cancer cells beyond the tumor [12; 14].

Metastatic brain tumors are also capable of expressing epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) under the influence of multigenic transcription factors and growth factor signaling. A better understanding of the pathways involved in EMT/MET may enable the development of targeted therapy to slow tumor progression and inhibit the dissemination of metastatic cells [8].

1.3 Epidemiology of the Disease or Condition

Annual incidence rates of metastatic brain involvement in non-metastatic and metastatic forms of oncological diseases are respectively:

• In lung cancer: small cell lung cancer 15.8% and 23.5%; squamous cell carcinoma 5.3% and 15.9%; adenocarcinoma 14.4% and 26.8%; non-small cell (other) 12.8% and 25.6%.

• In lung cancer, the frequency of brain metastasis depends on the molecular and genetic characteristics of the tumor, amounting to: EGFR mutations – 15%-20%; KRAS G12C mutations 10%-12%; ALK translocations 4%-5%.

• In melanoma: 0.6% and 28.2%;

• In breast cancer: HR+/HER2− subtype – 0.22% and 5.5%; HR+/HER2+ subtype – 0.6% and 7.9%; HR−/HER2+ subtype – 1.1% and 11.5%; triple-negative subtype – 0.7% and 11.4%;

• In renal cell carcinoma: 1.5% and 10.9%;

• In seminoma: 0.9% and 7.6%;

• In esophageal cancer: 1.7% and 5.3%;

Taking into account cumulative survival, brain metastases develop during the course of the disease in 40% of patients with melanoma and in 30% of patients with generalized breast cancer. [9]

1.4 Features of Coding the Disease or Condition

C79.3 – Secondary malignant neoplasm of brain and cerebral meninges

1.5 Classification of the disease or condition

Depending on the number of lesions in the brain, they are classified as: single – one lesion in the brain (or solitary – one lesion in the brain and no other manifestations of distant metastatic tumor disease); oligometastatic brain involvement – several lesions; multiple metastases.

1.6 Clinical presentation of the disease or condition

The clinical presentation of patients with brain metastases varies depending on a number of factors, including the type of primary tumor, whether metastatic brain involvement was detected via screening, or on brain MRI in the event of neurological symptoms.

Neurological symptoms are observed in 60-75% of patients with brain metastases: neurological deficit – 20%-75%, headache – 25%-57%, seizure syndrome – 10-20%, nausea/vomiting (5%), and drowsiness (5%). In 20-40% of patients with brain metastases, 4 or more tumor lesions are detected upon initial diagnosis. Metastatic involvement of the brainstem occurs in 10% of patients [9].

2. Diagnostics, medical indications and contraindications for diagnostic methods

• A patient with metastatic brain involvement is recommended to undergo clinical and instrumental examinations aimed at establishing the diagnosis, assessing the functional status and the extent of the tumor process, followed by determining the patient care algorithm in accordance with the clinical guidelines for malignant neoplasms of primary localizations [18].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

Comments: The diagnosis is established based on: neuroimaging data (presence of focal metastatic brain lesions and results of pathomorphological examination of biopsy (surgical) material from the primary tumor focus, extracranial metastasis, or metastatic lesion in the brain)

2.1 Complaints and Anamnesis

Comments: headache, nausea, vomiting, and dizziness are the most common symptoms in patients with metastatic brain involvement. These symptoms typically reflect elevated intracranial pressure and displacement of brain structures (generalized cerebral symptoms).

Sensory disturbances, memory impairment, motor disorders (paresis and paralysis), visual and hearing impairments, and epileptic seizures are determined by the localization of the metastatic lesion in various brain structures (focal symptoms).

Multiple metastatic lesions in the brain are often accompanied by coordination disorders, cognitive impairments, memory loss, and emotional sphere disturbances.

2.2 Physical Examination

Comments: Assessment of height and body weight makes it possible to calculate the body surface area required to determine the doses of antineoplastic drugs. A general physical examination is performed to assess the functional status using the Karnofsky or ECOG scale. Accurate assessment of functional status is necessary for further treatment planning. In case of visual impairment or neurological symptoms, a consultation with a neurologist and ophthalmologist is required.

2.3 Laboratory Diagnostics

• A patient with metastatic brain involvement is recommended to undergo laboratory tests in accordance with the clinical guidelines for malignant neoplasms of primary localizations [18].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

Comments: laboratory test results are necessary to assess the functional state of the body of a patient with brain metastases prior to neurosurgery, radiotherapy, and drug therapy, as well as for timely correction of identified changes during treatment and follow-up.

2.4 Instrumental Diagnostics

The standard for neuroimaging of metastatic lesions in the brain is contrast-enhanced (intravenous) magnetic resonance imaging (MRI) of the brain.

• Contrast-enhanced (intravenous) brain MRI is recommended to be performed for the purpose of detecting potential brain metastases in patients with: small cell lung cancer (at all stages of the disease); non-small cell lung cancer (starting from stage II); melanoma (starting from stage IIIC); metastatic breast cancer (HER2-positive and triple-negative subtypes) [9; 17-19].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• Contrast-enhanced (intravenous) brain MRI is recommended to be performed in cancer patients upon the onset of neurological symptoms for the early detection of brain metastases [2; 17–19].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• Follow-up contrast-enhanced (intravenous) brain MRI is recommended in patients with brain metastases every 2–3 months during antineoplastic drug therapy or during the follow-up period after the completion of local and systemic treatment for the early detection of disease relapse [2; 18; 19].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

Comments: Contrast-enhanced brain MRI is recommended to be performed in the following modes: prior to intravenous contrast administration in T1 axial mode (slice thickness 1-1.5 mm), T2, DWI, FLAIR (slice thickness 3-5 mm). After intravenous contrast administration: T1 axial mode (slice thickness 1-1.5 mm), 3D T1 high-resolution weighted images in the axial (or sagittal) plane covering the entire head using isotropic voxel technology (1mm×1mm×1mm).

• Positron emission tomography combined with brain computed tomography with intravenous contrast administration using radiolabeled tracers (V09IX: Radiopharmaceuticals for tumor diagnostics, other) is recommended in patients after radiotherapy for brain metastases for the differential diagnosis of tumor recurrence versus radionecrosis [17-19].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

Comments: Computed tomography perfusion of the brain makes it possible to measure cerebral blood flow volume of the tumor and normal brain tissue and is used for the differential diagnosis of tumor recurrence and radionecrosis [2].

2.5 Other Procedures

• For patients with brain metastases, a multidisciplinary team including an oncologist, a radiation therapist, and a neurosurgeon is recommended to determine the scope of diagnosis and treatment [17; 19].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• Pathological examination of biopsy (surgical) material in patients with brain metastases who underwent neurosurgical intervention. [18, 28]

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

Comments: Consultation with a neurosurgeon, radiation therapist, and oncologist is necessary to determine the optimal treatment strategy within a multidisciplinary approach. If clinically indicated, a neurologist, ophthalmologist, radiologist/diagnostic radiologist should be included in the multidisciplinary team. Appendix A3

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

Both local and systemic treatment modalities are used in patients with brain metastases. Local treatments include neurosurgical treatment and external beam radiotherapy, which can be delivered as whole-brain radiotherapy (WBRT) or stereotactic radiotherapy (either as radiosurgery or hypofractionation).

The optimal treatment approach for patients with brain metastases is a combination of local treatment modalities. The options for combining local treatments are determined by the number and volume of brain metastases. Systemic treatments include systemic anti-tumor drug therapy.

• For patients with brain metastases, systemic anti-tumor drug therapy and/or chemoradiotherapy and/or external beam radiotherapy and/or surgical treatment is recommended (depending on medical indications and in the absence of contraindications) [18, 28].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

Comment: The treatment plan for patients with brain metastases is determined based on the decisions of the oncology board (with the mandatory participation of a neurosurgeon), which is conducted in accordance with Order of the Russian Ministry of Health No. 116n dated February 19, 2021, "On Approval of the Procedure for Providing Medical Care to Adults with Oncological Diseases" (Registered on April 1, 2021, No. 62964). Appendix A3.

3.1. Neurosurgical treatment

The goal of neurosurgical treatment (microsurgical resection of brain neoplasms, A16.23.024) is to achieve local control of metastatic lesions, reduce the severity of neurological symptoms, eliminate life-threatening conditions, reduce the risk of mortality from intracranial progression, and preserve quality of life [11; 17; 19]. The organization of neurosurgical treatment is carried out in accordance with the orders listed in Appendix A3.

Neurosurgical treatment for patients with brain metastases is recommended in the presence of:

• a large metastatic lesion in the brain with pronounced perifocal edema and mass effect [11; 17].

• resection of metastatic lesions located in or near functionally eloquent areas should be performed using neurophysiological monitoring.

• In multifocal brain involvement with several large lesions requiring resection through different surgical approaches, either single-stage or multi-stage intervention is possible, depending on the clinical situation.

• Brain metastases causing clinical symptoms of intracranial hypertension, displacement of midline brain structures, extensive perifocal edema, or the threat of cerebrospinal fluid pathway obstruction [11; 17].

• Brain metastases without a primarily identified primary site. Neurosurgical intervention is the only method for morphological verification of the diagnosis [11; 17].

• clinical situations that cannot be controlled by other therapeutic measures (local recurrence after stereotactic radiotherapy, symptomatic radionecrosis resistant to ongoing therapy) [11; 17].

• in clinical situations accompanied by signs of cerebrospinal fluid pathway obstruction or the threat of its development, when the removal of lesions causing the obstruction is impossible, cerebrospinal fluid shunting procedures are indicated.

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

Comments: In some cases, a brain metastasis may be the sole manifestation of the disease. In such instances, resection of the lesion followed by pathological examination of the biopsy (surgical) material and determination of the molecular-biological characteristics of the tumor makes it possible to establish the diagnosis and initiate systemic anti-tumor therapy.

Options for combined treatment of brain metastases include preoperative radiosurgery followed by resection, or postoperative SRT of the resection cavity of the removed metastasis (in accordance with clause 3.2)

3.2. Radiotherapy

External beam radiotherapy (radiotherapy) for central nervous system and brain involvement is performed using specialized equipment that generates a targeted beam of photon (gamma or bremsstrahlung) or corpuscular (proton) ionizing radiation.

Conformal and stereotactic external beam radiotherapy is a variant of external beam radiotherapy based on the determination of the three-dimensional tumor volume and the anatomy of critical organs and structures in order to minimize irradiation of adjacent normal tissues. (Medical service codes: A07.30.009; A07.30.009.001). Radiotherapy is organized in accordance with the orders in Appendix A3.

Radiotherapy:

Comments: the scope of local therapy for brain metastases is determined by the clinical and radiological presentation of the oncological disease.

The choice of the SRT fractionation regimen is determined by the volume of the lesion, dose load on surrounding tissues, and the number of brain metastases. In patients with newly diagnosed brain metastases and a lesion size of:

• <2 cm in maximum dimension, SRT in a radiosurgery regimen at a dose of 20–24 Gy is recommended, provided that the volume (including the volume of the irradiated lesion and the perifocal part of normal brain tissue) receiving an irradiation dose of 12 Gy does not exceed 10 cm³ (V_12Gy ≤10 cm³) [6].

Level of Evidence – AGrade of Recommendation – 2Level of Clinical Usability – A (Level of Evidence – 2)

• ≥2 cm to <3 cm in maximum dimension, SRT in a radiosurgery regimen at a dose of 18 Gy is recommended, provided that V_12Gy ≤10 cm³. If V_12Gy >10 cm³, SRT in a hypofractionated regimen is recommended [6].

Level of Evidence – AGrade of Recommendation – 2Level of Clinical Usability – A (Level of Evidence – 2)

• ≥3 cm to <4 cm in maximum dimension, SRT in a hypofractionated regimen is recommended. SRT in a radiosurgery regimen at a dose of 15 Gy is possible, provided that V_12Gy ≤10 cm³ [6].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• ≥4 cm in maximum dimension, SRT in a hypofractionated regimen is recommended [6].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

Comments: Hypofractionated SRT is the optimal option for patients with brain metastases located in critical brain structures (optic pathways, brainstem, etc.). Recommended hypofractionation regimens are 3 fractions of 8 Gy / 9 Gy, 5 fractions of 6 Gy, and 7 fractions of 5 Gy. When performing hypofractionation, it must be taken into account that a volume of 10 cm³ (volume of the irradiated lesion and perifocal normal brain tissue) should not be irradiated with a dose higher than: 19.2 Gy (in 3 fractions); 23.4 Gy (in 5 fractions); 26.5 Gy (in 7 fractions)

In patients with a favorable overall survival prognosis and:

• ≤4 newly diagnosed brain metastases, SRT in a radiosurgery or hypofractionation regimen is recommended [6; 19].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• 5 to 10 newly diagnosed brain metastases, SRT in a radiosurgery/hypofractionation regimen or WBRT is recommended [6; 19].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• multiple, disseminated brain metastases, WBRT is recommended [28].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

Comments: a favorable overall survival prognosis is determined by the presence of a Karnofsky score ≥80 (or ECOG 0-1), a diagnosis-graded GPA score–2.5-4, with absence or drug stabilization of extracranial metastases, and available systemic anti-tumor treatment reserves.

The standard fractionation regimen for WBRT is a total dose (TD) of 30 Gy, fractional dose (FD) of 3 Gy (10 fractions) or TD of 37.5 Gy, FD of 2.5 Gy (15 fractions). Increasing the FD for WBRT above 3 Gy leads to an increased incidence of neurocognitive impairment and does not improve treatment outcomes. Older age and a higher fractional dose of WBRT are the most significant prognostic factors for cognitive decline following WBRT.

In certain clinical situations in patients with multiple BMs (5 or more lesions), with a good overall survival prognosis, absence or stabilization of extracranial metastases, and available reserves of systemic antineoplastic therapy, stereotactic radiotherapy (either as radiosurgery or hypofractionated radiotherapy) can be administered as a standalone treatment modality.

In patients with BMs and a favorable overall survival prognosis undergoing neurosurgical treatment:

Comments: postoperative SRT is performed 3–4 weeks after neurosurgical treatment. Depending on the volume of the postoperative cavity, the ionizing radiation doses are: <4.2 cm³ – 20 Gy; ≥4.2 – <8.0 cm³ – 18 Gy; ≥8.0 – <14.4 cm³ – 17 Gy; ≥14.4 – <20.0 cm³ – 15 Gy; ≥20.0 – <30.0 cm³ – 14 Gy. When the postoperative cavity volume is >8 cm³, hypofractionated stereotactic radiotherapy is the optimal treatment [6].

In cases of preoperative radiosurgery, it is advisable to resect the irradiated lesion within the next 24–48 hours after irradiation.

When performing neurosurgical treatment in patients with multiple BMs for whom SRT in radiosurgery or hypofractionation mode is unfeasible due to exceeding the tolerance dose limits for normal brain tissue, WBRT may be administered.

• In patients with an unfavorable overall survival prognosis, it is recommended to provide palliative care [6].

CGR CLOE 5Level of Clinical Guidance - C (Level of Evidence - 5)

Comments: an unfavorable overall survival prognosis is defined by the presence of: a Karnofsky performance score below 50 (or ECOG of 2 or higher), a Graded Prognostic Assessment (GPA) score of 0–2, and the lack of systemic antineoplastic treatment options.

3.3. Antineoplastic drug therapy

The goal of antineoplastic drug therapy in patients with BMs is to improve overall survival rates by achieving control of extracranial metastatic lesions, reducing the risk of developing new (distant) BMs, and achieving regression of BMs in certain nosological forms. Antineoplastic drug therapy is carried out in accordance with clinical guidelines for the treatment of the primary tumor, taking into account the biological characteristics of the tumor. [17; 19] The arrangement of antineoplastic drug therapy is carried out in accordance with the orders listed in Appendix A3.

In patients with newly diagnosed, asymptomatic BMs:

Comments: the decision to postpone local therapy (neurosurgery, radiotherapy) should take into account such factors as: the presence of neurological symptoms, the size of brain metastases, their localization, number, availability of systemic therapy options with established intracranial activity and the probability of response to them, availability of neuroimaging methods, and the possibility of performing local treatment (radiotherapy and/or neurosurgery) in case of BM progression while on systemic therapy.

Comments: The administration of systemic antineoplastic drug therapy based on the histological and molecular characteristics of the primary tumor and taking into account previous treatment should be considered for the majority of patients with BMs.

To select the tactics of antineoplastic drug therapy, it is advisable to take into account the molecular genetic characteristics of BMs.

In the presence of NSCLC with activating mutations / translocations of EGFR/ALK/ROS1/BRAF/NTRK, targeted drugs are preferred. In the presence of mutations in exons 19 and 21 of the EGFR gene – osimertinib**( L01EB04), with ALK translocation – alectinib**( L01ED03), lorlatinib (L01ED05), with ROS1 translocation – entrectinib** (L01EX14), with the BRAF V600E mutation – dabrafenib**( L01EC02) + trametinib**( L01EE01), with NTRK translocation – entrectinib**( L01EX14), with rare mutations in exons 18 and 20 of EGFR – afatinib**( L01EB03), osimertinib**( L01EB04).

Patients with asymptomatic BMs from NSCLC without EGFR/ALK/ROS1 mutations/translocations may receive monotherapy with immune checkpoint inhibitors (L01XC: Monoclonal antibodies) if PD-L1 >50%, or systemic chemotherapy combined with immune checkpoint inhibitors (L01XC: Monoclonal antibodies) if PD-L1 <50%.

Immune checkpoint inhibitor therapy (L01XC: Monoclonal antibodies) (nivolumab**( L01FF01) and ipilimumab**( L01FX04)) may be the preferred first-line treatment option in patients with asymptomatic melanoma BMs regardless of tumor BRAF status. Patients with newly diagnosed brain metastases from BRAF-mutated melanoma may be prescribed therapy with BRAF and MEK inhibitors (L01EC: B-Raf (BRAF) serine-threonine kinase inhibitors, L01EE: Mitogen-activated protein kinase (MEK) inhibitors) (dabrafenib** (L01EC02) and trametinib**(L01EE01)).

Comments: in the presence of clinical and radiological data of leptomeningeal involvement and/or cytological detection of tumor cells in the cerebrospinal fluid, systemic treatment may be supplemented with intrathecal antineoplastic drug therapy.

3.4. Leptomeningeal disease

Leptomeningeal metastasis (LM) is diagnosed in approximately 10% of patients with advanced cancer. Typical clinical manifestations of LM in cancer patients include headache, nausea, vomiting, papilledema, cranial nerve deficits (e.g., visual impairment, diplopia, abducens nerve palsy, convergent strabismus, facial numbness, hearing loss, dizziness, swallowing disorders), sensorimotor symptoms, radicular pain, cauda equina syndrome, and others. Appendix A3

• In the presence of clinical or radiological signs suggestive of leptomeningeal tumor involvement, it is recommended to perform a cytological examination of the cerebrospinal fluid for the presence of tumor cells [18].

CGR CLOE 5Level of Clinical Guidance - C (Level of Evidence - 5)

• Classification of LM by two main criteria:

Type I – diagnosis was confirmed cytologically or histologically.

Type II – diagnosis was not confirmed cytologically or histologically.

• Classification of LM by neuroimaging:

Type A – linear LM

Type B – nodular LM

Type C – linear and nodular LM

Type D – ventricular system involvement [Sundriyal Deepak et al., Classification of Leptomeningeal Metastases from Solid Organ Malignancies and Clinical Outcomes: Series from a Cancer Research Centre, Indian J Surg Oncol. 2020 Apr 17;11(2):308–312]

Comments: Lumbar puncture is contraindicated in patients with LM who also have a brain lesion with signs of midline shift.

• In patients with LM presenting with clinical and neuroimaging signs of non-communicating hydrocephalus, the feasibility of cerebrospinal fluid shunting procedures should be considered [Nayan Lamba et al., Management of hydrocephalus in patients with leptomeningeal metastases: an ethical approach to decision-making, J Neurooncol, 2018 Jul 18;140(1):5–13].

• Patients with leptomeningeal disease should also be considered for radiation therapy [6, 17–19].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

Comments: Favorable overall survival prognostic factors: see 3.2

• in patients with leptomeningeal metastasis, it is recommended to administer antineoplastic drug therapy taking into account the molecular genetic characteristics of the primary tumor [6, 17–19].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• Intratehcal administration of antineoplastic drugs is recommended in patients with cytologically confirmed leptomeningeal involvement [6, 17–19, 26, 27].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• In patients with leptomeningeal metastasis and an unfavorable overall survival prognosis, it is recommended to provide palliative care [6, 17–19].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

3.5. Intracranial progression

Intracranial progression is defined as the appearance of new lesions or the progression of existing lesions compared to the time of initial local or systemic treatment. Appendix A3

Comments: The choice of treatment for intracranial progression is determined by the scope of prior treatment, the number of progressing lesions, and the overall survival prognosis.

In case of target lesion progression and a limited (<4) number of brain metastases, stereotactic radiotherapy (in radiosurgery/hypofractionation mode) or neurosurgical treatment is considered (in accordance with clauses 3.1–3.2).

In case of target lesion progression and a multiple (>5) number of brain metastases, stereotactic radiotherapy (in radiosurgery/hypofractionation mode), WBRT (if not administered in the 1st line of therapy), or neurosurgical treatment is considered (in accordance with clauses 3.1–3.2).

In case of non-target lesion progression, WBRT (if not administered in the 1st line of therapy) or systemic anti-tumor therapy is considered (in the presence of asymptomatic progressing lesions and drugs with established intracranial activity).

Proton therapy may be used as a treatment option for local recurrences following stereotactic radiotherapy, which may potentially reduce the risk of post-radiation complications.

In patients with intracranial progression and an unfavorable overall survival prognosis, a short course of WBRT (5 fractions of 4 Gy each) may be administered

3.6. Steroid and anti-edema therapy

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

Comments: as a rule, the minimum necessary dose of steroids (dexamethasone** 0.5–4 mg or more, if necessary (H02AB02)) should be used for the shortest possible time, attempting to taper the dose whenever possible.

Depending on the severity of symptoms of intracranial hypertension, perifocal edema, and midline shift, patients with brain metastases may be prescribed corticosteroid therapy – orally or intramuscularly, at doses corresponding to the severity of these symptoms.

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

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

Comments. Dexamethasone** doses are tapered gradually over 2 weeks or more, based on individual clinical dynamics and taking into account potential complications of steroid therapy. Tapering/discontinuing dexamethasone** prior to surgical resection and/or radiotherapy is impractical.

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.

Comments: bevacizumab** is prescribed as a means of correcting post-radiation changes. Bevacizumab** therapy should be considered in patients: with contraindications to steroid therapy; with radiation necrosis and local recurrence (according to PET-CT with tyrosine and methionine) in a previously irradiated focus to optimize the volume of re-irradiation; with symptomatic metastases in whom immune checkpoint inhibitor therapy is planned.

The dose of #bevacizumab is 5 mg/kg of body weight every 2 weeks or 7.5 mg/kg at 3-week intervals and is administered until symptom regression or radiological improvement (usually 4 administrations) [23-25].

3.7. Anticonvulsant therapy

• In cases where patients have a seizure syndrome (including a history thereof), it is recommended to consult a neurologist (epileptologist) for the purpose of prescribing/adjusting anticonvulsant therapy. [5]

GPR CLEL 5Grade of Recommendation C (Level of Evidence - 5).

Comments: in patients without seizure syndrome, prophylactic administration of anticonvulsant therapy is not recommended

3.8. Palliative and supportive care

Supportive care in patients with metastatic brain disease is carried out in accordance with the practical guidelines of the Russian Society of Clinical Oncology (RUSSCO). [22]

• Palliative and symptomatic therapy is recommended in patients with brain metastases and/or disseminated leptomeningeal disease in the presence of a poor overall survival prognosis [6, 17-19].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• The principles of prevention and treatment of anemia in patients with brain metastases comply with the principles set forth in the clinical guidelines "Anemia in Malignant Neoplasms", published in the rubricator of clinical guidelines of the Russian Ministry of Health https://cr.minzdrav.gov.ru.

• The principles of treatment and prevention of nausea and vomiting in patients with brain metastases comply with the principles set forth 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 brain metastases comply with the principles set forth 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 brain metastases comply with the principles set forth in the methodological guidelines "Correction 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 brain metastases comply with the principles set forth in the methodological guidelines "Practical Guidelines for the Correction 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 brain metastases comply with the principles set forth in the methodological guidelines "Practical Guidelines for the Drug 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 brain metastases comply with the principles set forth in the methodological guidelines "Practical Guidelines for the Correction of Antineoplastic Drug Nephrotoxicity" (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 brain metastases comply with the principles set forth 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 drug extravasation consequences in patients with brain and meningeal metastases correspond to the principles outlined in the guidelines «Recommendations for the management of complications of antineoplastic drug extravasation» (Authors: Boydenok 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 brain and meningeal metastases correspond to the principles outlined in the 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).

3.9. Diet therapy.

Organization of therapeutic nutrition for patients with secondary malignant neoplasms of the brain and meninges 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 healthcare 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 brain and meningeal metastases correspond to the principles outlined in the guidelines «Practical guidelines 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 primary tumors.

Currently, for most types of medical rehabilitation, there are no clinical studies involving patients with metastatic brain lesions. Available data from systematic reviews indicate that various types of medical rehabilitation accelerate functional recovery, shorten hospital stays after surgery, and reduce the incidence of complications and mortality in patients with malignant tumors. Rehabilitation measures in patients with brain metastases are carried out after local treatment. The scope of rehabilitation measures is determined by the severity of neurological deficit and is performed in specialized rehabilitation departments according to the general principles of rehabilitation for patients with neurological disorders, taking into account the type and characteristics of the disease.

4.1. Principles of psychological rehabilitation of patients with metastatic brain lesions

• It is advisable to provide educational activities and psychological support (self-assessment of pathological psychological reactions; stress-coping methods; monitoring the mutual influence of psychological reactions and physical state), 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 [1, 18].

LoR CLoE 5Level of Recommendation — C (Level of Evidence — 5

• It is advisable to conduct targeted psychocorrective interventions for psychological reactions associated with metastatic brain lesions (astheno-anxious-depressive reactions, narcissistic reactions, etc.), as this reduces anxiety and health-related disorders, and leads to positive changes in coping with the disease [1, 18].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

5. Prevention and Dispensary Observation

Comments: in patients at high risk of intracranial recurrence, the interval between examinations may be shortened. Screening for extracranial metastases is performed according to the primary tumor site.

The objective of follow-up is the early detection of disease progression for the prompt initiation of radiation, drug, or surgical treatment of intracranial progression.

If neurological symptoms occur while the patient is being monitored at an outpatient cancer care center (or in a primary oncology office, oncology department, or outpatient department of an oncology dispensary), a consultation with a neurologist (neurosurgeon) and an ophthalmologist (if indicated) is required.

6. Organization of Medical Care

Medical care, excluding medical care within the framework of clinical trials, in accordance with Federal Law No. 323-FZ dated November 21, 2011 (as amended on May 25, 2019) «The Fundamentals of Healthcare Legislation in the Russian Federation»; Order of the Russian Ministry of Health No. 116n dated February 19, 2021 «On approval of the Procedure for providing medical care to adult patients with oncological diseases», and 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) for which the use of a medicinal product is permitted in accordance with indications (characteristics) not specified in its instructions for use», 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 Authority;

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 Authority.

Primary specialized health care is provided by an oncologist and other specialist physicians at an outpatient oncological care center or in a primary oncological office, or in the outpatient department of an oncological dispensary (oncological hospital).

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.

Consultation at an outpatient oncological care center, a primary oncological office, or the outpatient department of an oncological dispensary (oncological hospital) must be performed no later than 5 working days from the date of issuance of the referral for consultation. The oncologist of the outpatient oncological care center (in the absence of an outpatient oncological care center, the oncologist of the primary oncological office or the outpatient department of the oncological dispensary (oncological hospital)) shall arrange for the acquisition of biopsy (surgical) material, as well as other diagnostic tests necessary to establish the diagnosis, including the extent of the oncological process and the stage of the disease.

In the event of the impossibility of acquiring biopsy (surgical) material or performing other diagnostic tests within the medical organization that incorporates the outpatient oncological care center (primary oncological office), the attending physician shall refer the patient to an oncological dispensary (oncological hospital) or to a medical organization providing medical care to patients with oncological diseases.

The timeframe for performing pathological examinations necessary for the histological verification of malignant neoplasms shall not exceed 15 working days from the date of receipt of the biopsy (surgical) material by the pathoanatomical bureau (department).

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 diagnosis of an oncological disease is established by an oncologist, and in the case of malignant neoplasms of lymphoid, hematopoietic, and related tissues included in ICD-10 categories C81–C96, also by a hematologist.

The oncologist of the ambulatory cancer care center (primary oncology office) refers the patient to an oncological dispensary (cancer hospital) or another medical organization providing medical care to patients with oncological diseases, including those subordinate to a federal executive authority (hereinafter referred to as a federal medical organization), to clarify the diagnosis (in case of the impossibility of establishing a diagnosis, including the extent of the oncological process and the stage of the disease), determine treatment tactics, and in the presence of medical indications for specialized, including high-tech, medical care.

For oncological diseases included in ICD-10 categories C37, C38, C40–C41, C45–C49, C58, D39, C62, C69–C70, C72, C74, as well as corresponding International Classification of Diseases for Oncology (ICD-O) 3rd edition codes 8936, 906–909, 8247/3, 8013/3, 8240/3, 8244/3, 8246/3, 8249/3, the oncologist of an oncological dispensary (oncological hospital) or other medical organization providing medical care to patients with oncological diseases shall, in order to determine treatment tactics, 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 for the purposes of this Procedure as national medical research centers).

In complex clinical cases, to clarify the diagnosis (in the event of the impossibility of establishing the diagnosis, 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 pathomorphological examinations to the pathomorphological bureau (department) of the fourth group (reference center) via information exchange, including the use of telemedicine technologies for remote interaction between medical personnel;

digital images obtained from radiation imaging results to the remote diagnostic consultation center for radiation diagnostics through information interaction, including via telemedicine technologies for remote interaction between medical workers;

biopsy (surgical) material for repeat pathomorphological, immunohistochemical, and molecular genetic studies: to the pathomorphological bureau (department) of the fourth group (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 the adult population with oncological diseases is provided on the basis of medical indications stipulated by the regulations on the organization of specialized, including high-tech, medical care.

Specialized medical care, with the exception of high-tech medical care, in medical organizations subordinate to federal executive authorities is provided based on the medical indications provided for 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 provision on organizing 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 hospitalization in a medical organization in an emergency or urgent form are:

• the presence of metastatic brain lesions with corresponding clinical symptoms requiring emergency or urgent medical care;

• the presence of treatment complications (surgical, radiation, drug, etc.) in patients with brain metastases requiring emergency or urgent medical care.

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

• the need to perform complex interventional diagnostic medical procedures requiring subsequent monitoring in an inpatient or day care setting;

• the presence of indications for specialized treatment (surgical, radiation, drug) requiring monitoring in an inpatient or day care 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 as primary specialized medical care (i.e., on an outpatient basis) under the supervision of an oncologists:

• organization of consultations with specialized medical specialists;

• administration of steroid therapy if indicated;

• referral for CT, MRI, PET if indicated.

6.5. Indications for transferring 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 brain metastases represent a heterogeneous group with various clinical and biological tumor characteristics and overall survival rates. Therefore, it is important to consider various clinical factors affecting the prognosis of patients with brain metastases before making treatment decisions.

The concept of a "prognostic factor" is defined as a clinical situation that can be used to estimate the probability of recovery or disease recurrence (National Institutes of Health et al. National Cancer Institute. NCI Dictionary of Cancer Terms., 2015).

Numerous studies, although retrospective in nature, have identified various prognostic factors and enabled the development of various prognostic scoring systems to predict overall survival in patients with brain metastases.

Currently, the optimal prognostic scale is the diagnosis-specific graded prognostic assessment (GPA), which allows estimating patients' overall survival prognosis based on a number of factors that vary across patients with different primary tumor types. Overall survival prognosis can be determined using the online calculator (http://brainmetgpa.com/). [15]

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

"Diagnostics Block"

Pronin, Igor Nikolaevich, Academician of the RAS, Doctor of Medical Sciences, Deputy Director, National Medical Research Center for Neurosurgery named after Academician N.N. Burdenko of the Russian Ministry of Health

Dolgushin, Mikhail Borisovich, Professor, Doctor of Medical Sciences, Head of the PET Department, Research Institute of Clinical and Experimental Radiology, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health

Kobyakova, Ekaterina Alekseevna, Chief Physician of the Research Institute of Clinical and Experimental Radiology, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health

Pronin, Artem Igorevich, Candidate of Medical Sciences, Physician at the PET Department, Research Institute of Clinical and Experimental Radiology, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health

Ryzhova, Marina Vladimirovna, Doctor of Medical Sciences, Head of the Department of Pathology, National Medical Research Center for Neurosurgery named after Academician N.N. Burdenko of the Russian Ministry of Health

Kozlov, Nikolay Alexandrovich, Candidate of Medical Sciences, Pathologist, Department of Pathology, Research Institute of Clinical Oncology, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health.

"Surgical Block"

Krylov, Vladimir Viktorovich, Academician of the RAS, Professor, Doctor of Medical Sciences, Head of the Department of Neurosurgery and Neuroreanimation, Moscow State University of Medicine and Dentistry named after A.I. Evdokimov, Chief Researcher

Usachev, Dmitry Yuryevich, Academician of the RAS, Professor, Doctor of Medical Sciences, Director, National Medical Research Center for Neurosurgery named after Academician N.N. Burdenko of the Russian Ministry of Health

Bekyashev, Ali Khasyanovich, Professor, Doctor of Medical Sciences, Head of the Neurosurgical (Oncological) Department, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health

Danilov, Valery Ivanovich, Doctor of Medical Sciences, Professor, Head of the Department of Neurology and Neurosurgery, Faculty of Advanced Training and Professional Retraining of Physicians, Kazan State Medical University

Zaitsev, Anton Mikhailovich, Candidate of Medical Sciences, Head of the Neurosurgery Department, Herzen Moscow Oncology Research Institute – branch of the National Medical Research Center for Radiology of the Russian Ministry of Health

Kirsanova, Olga Nikolaevna, Candidate of Medical Sciences, Junior Researcher, Neurosurgery Department, Herzen Moscow Oncology Research Institute – branch of the National Medical Research Center for Radiology of the Russian Ministry of Health

Aleshin, Vladimir Alexandrovich, Candidate of Medical Sciences, Senior Researcher, Neurosurgical (Oncological) Department, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health.

Belov, Dmitry Mikhailovich, Candidate of Medical Sciences, Researcher, Neurosurgical (Oncological) Department, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health.

Mitrofanov, Alexey Andreevich, Candidate of Medical Sciences, Researcher, Neurosurgical (Oncological) Department, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health.

Tanyashin, Sergey Vladimirovich, Professor, Doctor of Medical Sciences, Leading Researcher, 5th Neurosurgical Department, National Medical Research Center for Neurosurgery named after Academician N.N. Burdenko of the Russian Ministry of Health

"Radiotherapy Block"

Andrey V. Golanov, Corresponding Member of the RAS, Professor, D.Sc. (Medicine), Head of the Department of Radiology and Radiosurgery, National Medical Research Center for Neurosurgery named after Academician N.N. Burdenko of the Russian Ministry of Health

Timur R. Izmailov, D.Sc. (Medicine), Head of the Radiotherapy Department, National Pirogov Medical Surgical Center of the Russian Ministry of Health

Sergey M. Banov, D.Sc. (Medicine), Senior Researcher, National Medical Research Center for Neurosurgery named after Academician N.N. Burdenko of the Russian Ministry of Health

Elena R. Vetlova, Ph.D. (Medicine), Radiation Oncologist, National Medical Research Center for Neurosurgery named after Academician N.N. Burdenko of the Russian Ministry of Health

Sergey N. Novikov, D.Sc. (Medicine), Head of the Radiotherapy Department, N.P. Napalkov National Medical Research Center of Oncology of the Russian Ministry of Health

Igor A. Gulidov, D.Sc. (Medicine), Head of the Department of Radiation Therapy, A.F. Tsyb Medical Radiological Research Center - Branch of the National Medical Research Center for Radiology of the Russian Ministry of Health

Pavel V. Datsenko, D.Sc. (Medicine), Head of the Department of Neuroradiology, Radiation Therapy Division, P.A. Herzen Moscow Oncology Research Institute – Branch of the National Medical Research Center for Radiology of the Russian Ministry of Health

Ivan K. Osinov, Ph.D. (Medicine), Radiation Oncologist at the Gamma Knife Center

Aleksandr N. Savateev, Ph.D. (Medicine), Radiation Oncologist at the Gamma Knife Center

"Antineoplastic Drug Therapy Block"

David R. Naskhletashvili, Ph.D. (Medicine), Senior Researcher at the Neurosurgical (Oncological) Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

Sergey L. Gutorov, D.Sc. (Medicine), Leading Researcher at the Department of Chemotherapy and Combined Treatment of Malignant Tumors, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

Aleksey V. Smolin, Ph.D. (Medicine), Head of the Radiological Center, Main Military Clinical Hospital named after N.N. Burdenko

Sergey M. Banov, D.Sc. (Medicine), Senior Researcher, National Medical Research Center for Neurosurgery named after Academician N.N. Burdenko of the Russian Ministry of Health

Grigory L. Kobyakov, D.Sc. (Medicine), Head of the Chemotherapy Group, National Medical Research Center for Neurosurgery named after Academician N.N. Burdenko of the Russian Ministry of Health

Aleksandr A. Fedenko, D.Sc. (Medicine), Head of the Department of Drug Treatment of Tumors, P.A. Herzen Moscow Oncology Research Institute – Branch of the National Medical Research Center for Radiology of the Russian Ministry of Health

Larisa V. Bolotina, D.Sc. (Medicine), Head of the Chemotherapy Department, Department of Drug Treatment of Tumors, P.A. Herzen Moscow Oncology Research Institute – Branch of the National Medical Research Center for Radiology of the Russian Ministry of Health

Tatyana Yu. Semiglazova, D.Sc. (Medicine), Leading Researcher at the Scientific Department of Innovative Methods of Therapeutic Oncology and Rehabilitation, N.P. Napalkov National Medical Research Center of Oncology of the Russian Ministry of Health.

Vladislav O. Sarzhevsky, D.Sc. (Medicine), Deputy Chief Medical Officer for Oncology, National Pirogov Medical Surgical Center of the Russian Ministry of Health

"Healthcare Organization Block"

Tigran G. Gevorkyan, Ph.D. (Medicine), Deputy Director of the Institute of Clinical and Economic Research, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

Sergey A. Ivanov, Professor of the RAS, D.Sc. (Medicine), Director of the A.F. Tsyb Medical Radiological Research Center – Branch of the National Medical Research Center for Radiology of the Russian Ministry of Health

Aleksey A. Nevolskikh, D.Sc. (Medicine), Deputy Director for Medical Work, A.F. Tsyb Medical Radiological Research Center – Branch of the National Medical Research Center for Radiology of the Russian Ministry of Health

Zhanna V. Khaylova, Ph.D. (Medicine), Deputy Director for Organizational and Methodological Work, A.F. Tsyb Medical Radiological Research Center – Branch of the National Medical Research Center for Radiology of the Russian Ministry of Health

Anton V. Snegovoy, D.Sc. (Medicine), Head of the Outpatient Chemotherapy Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

Timur R. Izmailov, D.Sc. (Medicine), Head of the Radiotherapy Department, National Pirogov Medical Surgical Center of the Russian Ministry of Health

Tanyashin, Sergey Vladimirovich, Professor, Doctor of Medical Sciences, Leading Researcher, 5th Neurosurgical Department, National Medical Research Center for Neurosurgery named after Academician N.N. Burdenko of the Russian Ministry of Health

No conflict 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 brain tumors in Russia and abroad; synthesis of practical experience of Russian and international specialists.

Table 1. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Level of Evidence (LoE) grading scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Grade of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

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 Citizens' Health 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. Effective from January 1, 2018. As amended by Order of the Russian Ministry of Health No. 148n dated March 5, 2020.

• Order of the Russian Ministry of Health No. 931n dated November 15, 2012, "On Approval of the Procedure for Providing Medical Care to the Adult Population 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) in 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 Medical Nutrition Standards."

• Order of the Ministry of Health of the Russian Federation No. 1008n dated September 23, 2020, "On Approval of the Procedure for Providing Patients with Medical Nutrition."

Type of care.

Diagnostic and therapeutic measures for patients with brain metastases can be either scheduled or emergency. Emergency measures are performed in case of hypertension-hydrocephalus syndrome, signs of brain herniation, or tumor hemorrhage.

Conditions for providing medical services.

Diagnostic measures at the stage of diagnosis, during the follow-up period, between treatment stages, as well as preoperative examinations (including laboratory tests), are performed in an outpatient setting. 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 the Adult Population in the Profile 'Neurosurgery'," possessing experience in performing this type of surgery and relevant specialists.

Radiotherapy can be performed in a 24-hour inpatient or day hospital setting (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

Treatment algorithm for patients with metastatic brain disease

Appendix C. Patient Information

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. Karnofsky Performance Scale

Russian title: Karnofsky Performance Scale

Original title (if applicable): KARNOFSKY PERFORMANCE STATUS

Source (official developer website, validated publication): Karnofsky DA, Burchenal JH: The clinical evaluation of chemotherapeutic agents in cancer. In: Evaluation of chemotherapeutic agents. edn. Edited by MacLeod C. New York: Columbia University Press; 1949: 191-205

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):

Key (interpretation): provided within the scale itself

Appendix G2. WHO/ECOG performance status scale

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

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

Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982, 5(6):649-655

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.).

Contents:

Key (interpretation): provided within the scale itself

Appendix G3. RANO BM (Response Assessment in Neuro-Oncology Brain Metastases) criteria for evaluating treatment response in brain metastases

Title in Russian: RANO BM criteria for evaluating treatment response in brain metastases

Original title (if available): Response assessment criteria for brain metastases (Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM))

Source (official developer website, validation publication): Lin N. U. et al. Response assessment criteria for brain metastases: proposal from the RANO group //The lancet oncology. – 2015. – Vol. 16. – No. 6. – P. e270-e278.

Type: assessment criteria

Purpose: Evaluation of treatment efficacy for metastatic brain lesions

Content, key, and template:

Appendix G4. GPA overall survival prognostic scale.

Original title: Graded Prognostic Assessment

Source (official developer website, validation publication):

1. Tai C. H. et al. Single institution validation of a modified graded prognostic assessment of patients with breast cancer brain metastases //CNS oncology. – 2018. – Vol. 7. – No. 01. – P. 25-34.

2. Sperduto P. W. et al. A new prognostic index and comparison to three other indices for patients with brain metastases: an analysis of 1,960 patients in the RTOG database //International Journal of Radiation Oncology* Biology* Physics. – 2008. – Vol. 70. – No. 2. – P. 510-514.

Type: index

Purpose: diagnostic tool for assessing survival in patients with brain metastases, and potential selection of treatment tactics.

Content, key: http://brainmetgpa.com/