Gastrointestinal stromal tumors: clinical guidelines

List of Abbreviations

i.v. – intravenous

WHO – World Health Organization

GIST – gastrointestinal stromal tumor

EBRT – external beam radiation therapy

GI – gastrointestinal tract

Malignant neoplasms – malignant neoplasms

IHC – immunohistochemistry / immunohistochemical examination

CT – computed tomography

RT – radiation therapy (radiotherapy)

LN – lymph nodes

PT – physical therapy

MI – mitotic index

ICD-10 – International Classification of Diseases, 10th Revision

ICD-O – International Classification of Diseases for Oncology

MRI – magnetic resonance imaging

HPF – high-power field

SC – subcutaneous

PET/CT – positron emission tomography combined with computed tomography

TKI – tyrosine kinase inhibitors (ATC protein kinase inhibitors)

ACD – adequacy of evidence level

Ultrasound – ultrasound examination

FDG – fluorodeoxyglucose

CT – chemotherapy

グレード – strength of recommendation level

EGD – esophagogastroduodenoscopy

EUS – endoscopic ultrasound

AJCC – American Joint Committee on Cancer

ECOG – Eastern Cooperative Oncology Group

FDA – Food and Drug Administration

KIT – proto-oncogene encoding the stem cell factor receptor c-KIT, or the CD117 protein tyrosine kinase

PDGFRA – platelet-derived growth factor receptor A

RECIST – Response Evaluation Criteria in Solid Tumors

SDHB – succinate dehydrogenase subunit B

UICC – Union for International Cancer Control

WT – wild type

** – vital and essential drugs

# – drug used off-label (outside the indications, contraindications, routes of administration, or dosages specified in the approved product labeling)

Terms and Definitions

Adjuvant chemotherapy – a type of chemotherapy administered after complete removal of the primary tumor to eliminate potential micrometastases.

Relapse-free survival (RFS) – the time interval from the start of treatment to disease progression, development of a second tumor, or patient death from any cause. Determined in cases of radical treatment for localized disease.

Time to progression (TTP) – the time interval from the start of treatment (or randomization date in clinical trials) to the date of disease progression, excluding patient death from causes unrelated to disease progression.

Second stage of rehabilitation – inpatient rehabilitation in medical organizations (rehabilitation centers, rehabilitation departments) during the early recovery period of the disease, the late rehabilitation period, and the period of residual disease symptoms.

Progression-free survival (PFS) – the time interval from the start of treatment (or randomization date in clinical trials) to the date of disease progression or patient death from any cause.

Combined treatment – treatment of tumor foci using two different methods with the same therapeutic goal (e.g., surgery and radiotherapy).

Complex treatment – local and systemic treatment of a tumor using various methods (combined use of drug therapy with radiotherapy or surgery, or utilizing all 3 methods).

Chemotherapy course (cycle) – the period of time calculated from the first to the last day of cytostatic drug administration (ATC Antineoplastic agents).

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

Overall survival (OS) – the time interval from the start of treatment to the patient's death from any cause.

R1 resection – removal of the affected organ within healthy tissues along with regional lymph node basins with microscopically positive resection margins (residual tumor present).

First stage of rehabilitation – rehabilitation during the period of specialized treatment for the primary disease (including surgical treatment / chemotherapy / radiation therapy) in departments of medical organizations specialized in the primary disease.

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

Full effect (FE), or complete tumor regression (CR, complete response) – disappearance of all lesions for a period of at least 4 weeks.

Disease progression (DP) – an increase in the sum of measurable lesions by 20% or more compared to the smallest sum recorded during treatment and/or follow-up, or the appearance of at least one new lesion.

Radical surgery (R0) – removal of the affected organ within healthy tissue margins along with regional metastasis zones without residual manifestations of the tumor process.

Symptomatic treatment – a set of therapeutic measures aimed at eliminating the most distressing manifestations of the tumor process, or treating complications, or correcting consequences associated with antitumor treatment.

Concomitant therapy – simultaneous or sequential application of several components of a single treatment method to a tumor (e.g., brachytherapy and external beam radiation therapy, multiple drugs).

Disease stabilization (SD) – a decrease in the sum of measurable lesions by less than 30% or an increase in the sum of measurable lesions by less than 20%, in the absence of new lesions or clear progression of non-measurable lesions.

Targeted therapy – a type of antitumor 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.

Third stage of rehabilitation – rehabilitation during the early and late rehabilitation periods and the period of residual disease symptoms in departments (offices) of rehabilitation, physical therapy, therapeutic exercise, reflexology, manual therapy, psychotherapy, and medical psychology providing outpatient care, in day hospitals, as well as by mobile home-visiting teams (including in sanatorium-resort settings), and speech therapy (defectology) rooms.

Levels of evidence – reflect the degree of certainty that the found effect of applying a medical technology is true. According to epidemiological principles, the certainty of evidence is determined by 3 main criteria: qualitative and quantitative characteristics, and consistency of evidence.

Grades of recommendation – unlike levels of evidence, they reflect the degree of certainty not only in the validity of the intervention effect, but also in the fact that following the recommendations will bring more benefit than negative consequences in a specific situation.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Gastrointestinal stromal tumors (GISTs) are a group of gastrointestinal (GI) tract sarcomas originating from interstitial cells of Cajal. Most GISTs are characterized by mutations in the KIT and PDGFRA genes.

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

Up to 75–80% of GISTs have mutations in the KIT gene (exons 9, 11, 13, 17) and 5–15% in the PDGFRA gene (exons 12, 14, 18). In 10–15% of cases, c-KIT and PDGFRA mutations are not detected – wild type (WT). Additional molecular genetic studies have revealed that wild-type stromal tumors are a heterogeneous group with SDH, BRAF, NF1, NTRK 1, 2, 3, and other mutations [1–8].

1.3 Epidemiology of the Disease or Condition

GISTs are rare tumors. The average global incidence is 1.0–1.5 cases per 100,000 population per year [9, 10]. The incidence in Russia is unknown.

Gastrointestinal stromal tumors are typically sporadic. Hereditary GISTs are extremely rare.

1.4 Features of Coding the Disease or Condition

According to the International Statistical Classification of Diseases and Related Health Problems (hereinafter referred to as ICD-10), such tumors are classified according to the organ of primary tumor origin: for example, GIST of the esophagus will have code C15, and GIST of the jejunum – C17.2 [11].

GIST (C15–20, C48.1)

C15 – Malignant neoplasm of esophagus

C16 – Malignant neoplasm of stomach

C17.0 – Malignant neoplasm of duodenum

C17.2 – Malignant neoplasm of jejunum

C17.3 – Malignant neoplasm of ileum

C18 – Malignant neoplasm of colon

C19 – Malignant neoplasm of rectosigmoid junction

C20 – Malignant neoplasm of rectum

C48.1 – Malignant neoplasm of specified parts of peritoneum

1.5 Classification of the disease or condition

WHO Classification, 5th Edition, 2019

Gastrointestinal stromal tumor [11]

International Classification of Diseases for Oncology, ICD-O (5th Edition, WHO, 2019)

GIST Staging according to the AJCC/UICC TNM Classification, 8th Edition

Histological confirmation of the diagnosis is mandatory for staging. Assessment of primary tumor spread and metastases is performed using clinical examination and instrumental studies.

T criterion reflects the extent of the primary tumor (Table 1).

Table 1. T criterion (primary tumor)

N criterion indicates regional lymph node (LN) metastasis status (Table 2).

Regional lymph nodes are considered to be the nearest lymph nodes corresponding to the pathways of lymphatic drainage from the tumor. Metastasis to regional lymph nodes is staged as stage IV disease.

Table 2. N criterion (regional lymph node involvement)

*Regional lymph node involvement in GIST is rare; therefore, if the status of regional lymph nodes has not been assessed either clinically or pathologically, the category should be classified as N0 rather than Nx or pNx.

M criterion characterizes the distant metastasis status (Table 3).

Table 3. M criterion (distant metastases)

Additional prognostic factors are the mitotic index (MI) and tumor localization.

MI is determined by the number of mitoses in 50 high-power fields (HPF) at high microscope magnification (40× objective, total area 5 mm²).

Criteria for assessing MI are presented in Table 4.

Table 4. Mitotic Index

GISTs are divided into 2 prognostic groups depending on the primary tumor location due to a more favorable prognosis when the primary tumor is located in the stomach: stomach/omentum and extragastric tumors.

For staging gastric GISTs, the criteria summarized in Table 5 should be used. Omental GISTs are staged in the same manner as gastric GISTs.

For small bowel GISTs, the criteria summarized in Table 6 are used. GISTs of the esophagus, colon, rectum, and mesentery are staged according to the criteria for small bowel GISTs.

Stage groupings are presented in Tables 5 and 6.

Table 5. Stage Grouping for Gastric GIST

Table 6. Stage Grouping for Small Bowel GIST

To address the need for adjuvant therapy with imatinib**, it is recommended to use the nomogram presented in Table 7. The risk of progression is determined by 4 prognostic factors: tumor size, MI, primary tumor localization, and tumor capsule rupture [12–15].

Capsule rupture is a high-risk factor regardless of the presence of other risk factors, and patients in whom the integrity of the tumor capsule could not be preserved during surgery are indicated for adjuvant therapy.

Table 7. Risk of disease progression after surgical treatment in patients with resectable GISTs (M.A. Miettinen, J. Lasota, 2006), AFIP

*Risk is unknown, as patients with duodenal GISTs were not included in the study. Nevertheless, small bowel tumors are characterized by a poor prognosis.

**The risk of disease progression is determined by tumor size, MI value, primary tumor localization, and the presence of tumor capsule rupture [12–15].

1.6 Clinical presentation of the disease or condition

The clinical presentation of the disease varies depending on the primary tumor location and disease dissemination.

A characteristic feature of the disease is the submucosal location of the primary tumor(s).

A characteristic feature of disseminated tumors is predominant metastasis to the liver and peritoneum.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnostic criteria:

1. history data;

2. physical examination data;

3. laboratory test data;

4. instrumental examination data;

5. pathological examination data of surgical and/or biopsy material.

Clinical diagnosis is based on the results of:

1. detection of a gastrointestinal neoplasm;

2. verification of a malignant neoplasm (MN) according to the pathological examination report of biopsy and/or surgical material.

2.1 Complaints and Anamnesis

2.2 Physical Examination

2.3 Laboratory Diagnostics

1. tumor localization;

2. tumor dimensions;

3. histological tumor subtype (spindle cell, epithelioid cell, or mixed);

4. number of mitoses in 50 HPF at high magnification (40×);

5. presence of tumor cells at the resection margin;

6. pN (indicating the total number of examined and affected lymph nodes);

7. expression levels of CD117, DOG1, and CD34.

GGR BERL 3Grade of Recommendations – B (Evidence Level – 3).

Comment: in CD117- and/or DOG1-negative tumors, testing for GIST-specific mutations is recommended to confirm the diagnosis.

Comment: spindle cell GISTs are more common, accounting for about 70% of tumors, and in more than 90% of cases are associated with c-KIT mutations. Epithelioid GISTs account for about 20% and are generally associated with WT or PDGFRA mutations. The mixed subtype occurs in approximately 10% of cases.

Comment: in the absence of mutations in the c-KIT and PDGFRA genes, determination of succinate dehydrogenase subunit B expression in the tumor by IHC (determination of SDHB gene expression by immunohistochemistry) is recommended to choose the treatment strategy [14].

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

• In the absence of mutations in c-KIT and PDGFRA genes and normal SDHB expression, it is recommended to test for molecular alterations in NTRK 1, 2, 3 genes and perform molecular genetic testing for mutations in the BRAF gene in biopsy (surgical) material [14].

CGR CLEL 5Level of recommendations validity – C (level of evidence – 5).

2.4 Instrumental Diagnostics

2.4.1. Examination of patients with localized GISTs (surgical treatment planned as the first stage of therapy)

Comment: metastases in the lungs or mediastinal lymph nodes are extremely rare; nevertheless, performing chest CT is advisable in newly diagnosed GISTs. For esophageal GISTs, chest CT with intravenous bolus contrast enhancement is recommended for all patients.

Comment: pathomorphological confirmation of the diagnosis is preferred for planning the extent of surgical treatment.

Comment: in localized GISTs where surgery is planned as the first stage, percutaneous biopsy is associated with an unjustifiably high risk of tumor dissemination and is not recommended.

2.4.2. Examination of patients with locally advanced GISTs without distant metastases

Comment: percutaneous biopsy is only permitted in patients with giant tumors and/or locally advanced tumors for the purpose of diagnosis verification and administration of neoadjuvant preoperative targeted drug therapy.

Comment: 18F-FDG PET/CT is a secondary diagnostic method for early evaluation of targeted therapy efficacy when planning cytoreductive surgeries.

2.4.3. Examination of patients with metastatic GISTs

2.5 Other Procedures

Additional diagnostic tests are prescribed depending on the primary tumor location and planned treatment.

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

3.1. Treatment of patients with localized GISTs

3.1.1. Surgical treatment

Comment: the scope of surgery consists of complete tumor removal within healthy tissues. Removal of the entire affected organ is generally not required. The scope of surgery consists of wedge or segmental resection (of the stomach, small intestine, etc.). For localized GISTs of the stomach, small and large intestines, minimally invasive (endoluminal, laparoscopic, robotic) tumor removal is permitted provided radicality principles are ensured (adequate margin), the pseudocapsule of the tumor is preserved, and the specimen is extracted using a plastic bag. Removal of regional LNs is recommended only for GISTs associated with SDH deficiency or in the presence of pathologically enlarged LNs. Performing multivisceral resections and/or extensive surgeries accompanied by a high risk of complications or functional disorders (esophagectomy, abdominoperineal resection, etc.) at the first stage of treatment is not recommended. In these cases, neoadjuvant therapy is indicated (sec. 3.2.). If a positive resection margin (R1) is present after GIST removal, routine reresection is not indicated. Patients with SDH deficiency are indicated for primary surgical treatment [25].

Comment: tumor enucleation is not an adequate surgical procedure and should not be used for GISTs. Lymphadenectomy is performed only when LN metastases are suspected. Prophylactic resection of the greater omentum as the primary site of peritoneal metastases is justified, but randomized trials evaluating its efficacy have not been conducted.

Comment: there is no evidence indicating worsened overall survival following an R1 resection.

Comment: surgical management of patients with GIST complications is performed in accordance with emergency surgery standards.

3.1.2. Adjuvant Therapy

Comment: according to the randomized trial of the Scandinavian Sarcoma Group (SSGXVIII), adjuvant therapy for 3 years significantly improved recurrence-free and overall survival compared with 1 year of adjuvant therapy in patients at high risk of disease progression. Adjuvant therapy is not administered to patients at low risk of disease progression [35].

3.2. Treatment of patients with locally advanced GIST

3.2.1. Neoadjuvant Therapy

Comment: assessing individual sensitivity to antitumor treatment is a key factor in planning neoadjuvant systemic therapy. Neoadjuvant imatinib** at a dose of 400 mg/day is recommended in patients with locally advanced GISTs. In the presence of a KIT exon 9 mutation, the drug dose should be escalated to 800 mg/day. Neoadjuvant therapy should be administered to reduce tumor burden, prevent multivisceral resection or severe postoperative functional impairment, minimize the risk of capsule rupture in large GISTs (especially in the presence of necrosis), and in cases of borderline resectability (involvement of major vessels and other critical structures) [30–32].

GOR BLOE 3Grade of Recommendation – B (Level of Evidence – 3).

Comment: Given its favorable safety profile, imatinib** can be initiated in all patients as a first step while molecular genetic testing is underway. Once molecular genetic test results are obtained, treatment should be adjusted based on potential sensitivity: continuation of therapy in imatinib**-sensitive cases and surgical treatment in imatinib**-resistant cases. Initiating imatinib** prior to receiving molecular genetic test results helps avoid disease progression in patients with imatinib**-sensitive tumors (Table 8).

Table 8. Correlation between tumor mutations and sensitivity to imatinib**

Surgery is advised as soon as tumor resectability is achieved. Follow-up imaging during neoadjuvant therapy is recommended at least every 3 months. Neoadjuvant therapy with imatinib** increases the rate of R0 resections up to 87% [29]. In tumors localized to the esophagus, cardia, duodenum, or rectum, preoperative imatinib** may be used to downsize the tumor and enable organ-preserving surgery.

3.2.2. Adjuvant Therapy

Comment: according to the randomized trial of the Scandinavian Sarcoma Group (SSGXVIII), adjuvant therapy for 3 years significantly improved recurrence-free and overall survival compared with 1 year of adjuvant therapy in patients at high risk of disease progression. Adjuvant therapy is not administered to patients at low risk of disease progression [35].

3.3. Treatment of patients with metastatic GIST

• Comment: GISTs are resistant to conventional chemotherapy and radiation therapy. TKIs are highly effective in patients with disseminated disease. Survival rates have significantly improved from 12–18 months with various chemotherapy regimens to 76 months with TKIs. Currently, three lines of TKI treatment are approved: imatinib**, sunitinib**, and Medical treatment with TKIs followed by surgery, if TKI therapy is effective and complete cytoreduction is achievable, is recommended to improve recurrence-free survival [22, 39–43].

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

3.3.1. Selection of First-Line Therapy for Patients with Metastatic GISTs

Comment: imatinib** should be taken orally once daily with a meal (along with a non-fatty meal) and a large glass of water. The drug is generally well tolerated, and serious adverse events are rare. However, dose adjustments may be required for hematologic and non-hematologic toxicities. Imatinib** should be withheld if the absolute neutrophil count drops below 1.0 × 10⁹/L and/or platelets drop below 50.0 × 10⁹/L. Resumption at the previous dose is permitted once the absolute neutrophil count reaches 1.5 × 10⁹/L and platelets reach 75.0 × 10⁹/L. In the event of recurrent hematologic toxicity, a 25% dose reduction of imatinib** is required: from 400 to 300 mg/day and from 800 to 600 mg/day, depending on the current dose. Imatinib** should also be interrupted for a 3-fold elevation in bilirubin (above the upper limit of normal) or a 5-fold elevation in transaminases. Resumption is permitted once bilirubin drops below 1.5 × ULN and liver transaminases drop below 2.5 × ULN, with a 25% dose reduction of imatinib**: from 400 to 300 mg/day. It is critical to take into account that the efficacy/toxicity of imatinib** can be significantly altered when co-administered with CYP3A4 inducers/inhibitors.

Comment: the highest efficacy of imatinib** has been observed in GISTs with KIT exon 11 mutations, with response rates reaching 70–85%. Among these, the rate of complete and partial responses was 68%, stable disease was 16%; median time to progression was 20–24 months [39–43]. Lower efficacy was observed in GISTs with KIT exon 9 duplications, wild-type c-KIT, and PDGFRA, with response rates up to 48–50%. Several randomized trials (SWOG, EORTC) demonstrated that dose escalation of imatinib** to 800 mg/day is feasible in the presence of a KIT exon 9 mutation (objective response rate was 59% compared with 17% at 400 mg/day). This provided the rationale for using the standard dose of 800 mg/day for GISTs harboring c-KIT exon 9 mutations.

Comment: lack of therapeutic effect of imatinib** is also observed with other mutations, for example in exons 13 and 17 of KIT. However, in primary tumors these mutations are extremely rare. They typically develop during TKI treatment and lead to secondary resistance to the drug.

Comment: it is recommended to use imatinib** continuously until disease progression or unacceptable toxicity develops. If complete remission is achieved, it is recommended to continue the drug until disease progression. Interruption of treatment leads to a rapid resumption of metastasis growth [44].

Comment: after performing debulking surgery and removing growing metastases in case of local progression, it is recommended to resume imatinib** even in cases of complete cytoreduction. When generalized progression develops during therapy with the drug, debulking surgeries do not lead to improved long-term outcomes.

Comment: sunitinib** is taken orally once daily regardless of food intake. An alternative regimen for pronounced side effects is #sunitinib** 37.5 mg/day daily continuously. This regimen has less pronounced toxicity with comparable efficacy. The median time to progression with this treatment option is 6 months.

In case of SDHB enzyme deficiency and absence of c-KIT and PDGFRA gene mutations, sunitinib** may be prescribed as first-line treatment [58].

It should be noted that the efficacy/toxicity of sunitinib**, as well as imatinib**, may significantly change when co-administered with CYP3A4 enzyme inducers/inhibitors.

3.3.3. Selection of third-line therapy for patients with metastatic GIST

Comment: if an individual metastatic lesion increases in size while a response is maintained in other metastases, a multidisciplinary team may consider its surgical removal.

3.3.4. Additional medicinal products for the treatment of patients with metastatic GIST

• #imatinib** 600 mg once daily orally in combination with everolimus 2.5 mg once daily orally [61]

GCP CLEL 3Grade of Recommendation – C (Level of Evidence – 3).

In the presence of NTRK gene translocations:

• #larotrectinib** 100 mg twice daily orally [62]

• #entrectinib** 600 mg once daily orally [63].

GOM CLOE 4Grade of Recommendation – C (Level of Evidence – 4).

In the presence of a BRAF gene mutation (V600E):

• #dabrafenib** 150 mg twice daily orally [64]

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

• #sorafenib** 400 mg twice daily orally [65, 66]

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

• #dasatinib** 70 mg twice daily orally [67, 68]

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

• #pazopanib** 800 mg once daily orally [69, 70]

GCR CLEL 4Grade of Recommendation – C (Level of Evidence – 4).

• #cabozantinib** 60 mg once daily orally [71]

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

• #nilotinib** 400 mg twice daily orally [72, 73]

LoR CLE 2Level of Recommendation – C (Level of Evidence – 2).

• #zoledronic acid** 4 mg intravenous every 28 days, or denosumab 120 mg subcutaneous every 28 days (for bone metastases) [74]

LoR CLE 2Level of Recommendation – C (Level of Evidence – 2).

Comment: the decision to prescribe additional medications should preferably be made in expert oncology centers. NTRK 1, 2, 3 gene translocations and the BRAF V600E mutation are typically found in wild-type GIST (absence of molecular alterations in c-KIT, PDGFRA, and the SDH gene family); therefore, testing for the aforementioned molecular genetic alterations is recommended specifically for this GIST subtype. NTRK 1, 2, 3 gene translocations occur in 0.3–2.5% of GIST cases, and BRAF mutations in less than 1%. When NTRK translocations are detected, prescribing #larotrectinib and #entrectinib achieves a 100% objective response rate lasting over 5 years. The use of #sorafenib after progression on three standard lines of therapy (imatinib**, sunitinib**, and regorafenib**) achieves a median time to progression of 5.2 months, with disease control in 68% of patients; for pazopanib – 3.4 months with disease stabilization in 84%; for dasatinib – a median time to progression of 2.7 months when mutations are localized in exon 11 of c-KIT and 18 months for mutations in the PDGFRA gene with a 25% objective response rate; for cabozantinib – 5.5 months, with disease control in 82%. Reinitiating imatinib** therapy after progression on standard therapy achieves a time to progression of 1.8 months, disease control at 12 weeks in 32%, and adding everolimus at a dose of 2.5 mg/day to #imatinib** 600 mg/day – 3.5 months with disease control in 36%.

3.4. Pain Management

The principles of pain management and the optimal choice of analgesic therapy in GIST patients with chronic pain syndrome correspond to the principles outlined in the clinical guidelines "Chronic Pain Syndrome in Adult Patients Requiring Palliative Medical Care".

3.5. Supportive care

The principles of treatment and prevention of nausea and vomiting in GIST patients correspond to the principles outlined in the methodological recommendations "Prevention and Treatment of Nausea and Vomiting" (Authors: Vladimirova L.Yu., Gladkov O.A., Kogoniya L.M., Koroleva I.A., Semiglazova T.Yu., DOI: 10.18027/2224–5057–2018–8–3s2–502–511, https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-35.pdf).

The principles for the prevention and treatment of infectious complications and febrile neutropenia correspond to the principles outlined in the methodological recommendations "Treatment of Infectious Complications of Febrile Neutropenia and Administration of Colony-Stimulating Factors" (Authors: Sakaeva D.D., Orlova R.V., Shabaeva M.M., DOI: 10.18027/2224–5057–2018–8–3s2–521–530, https://rosoncoweb.ru/

standarts/RUSSCO/2018/2018-37.pdf).

The principles for the prevention and treatment of hepatotoxicity in GIST patients correspond to the principles outlined in the methodological recommendations "Management of Hepatotoxicity" (Authors: Tkachenko P.E., Ivashkin V.T., Maevskaya M.V., DOI: 10.18027/2224–5057–2018–8–3s2–531–544, https://rosoncoweb.ru/standarts/

RUSSCO/2018/2018-38.pdf).

Principles of prevention and treatment of cardiovascular complications correspond to the principles outlined in the clinical guidelines "Practical Guidelines for the Management of Cardiovascular Toxicity of Anticancer Drug Therapy" (Authors: Vitsenya M.V., Ageev F.T., Gilyarov M.Yu., Ovchinnikov A.G., Orlova R.V., Poltavskaya M.G., Sycheva E.A., DOI: 10.18 027/2224–5057–2018–8–3s2–545–563, https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-39.pdf).

Principles of nutritional support in patients with GIST correspond to the principles outlined in the clinical guidelines "Practical Guidelines for Nutritional Support in Cancer Patients" (Authors: Sytov A.V., Leiderman I.N., Lomidze S.V., Nekhaev I.V., Khoteev A.Zh., DOI: 10.18 027/2224–5057–2018–8–3s2–575–583, https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-41.pdf).

Principles of prevention and treatment of nephrotoxicity correspond to the principles outlined in the clinical guidelines "Practical Guidelines for the Management of Antineoplastic Drug-Induced Nephrotoxicity" (Authors: Gromova E.G., Biryukova L.С., Dzhumabaeva B.T., Kurmukov I.A., DOI: 10.18 027/2224–5057–2018–8–3s2–591–603, https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-44.pdf).

Principles of prevention and treatment of thromboembolic complications in patients with GIST correspond to the principles outlined in the clinical guidelines "Practical Guidelines for the Prevention and Treatment of Thromboembolic Complications in Cancer Patients" (Authors: Somonova O.V., Antukh E.A., Elizarova A.L., Matveeva I.I., Selchuk V.Yu., Cherkasov V.A., DOI: 10.18 027/2224–5057–2018–8–3s2–604–609, https://rosoncoweb.ru/standarts/RUSSCO/

2018/2018-45.pdf).

Principles of prevention and treatment of drug extravasation sequelae correspond to the principles outlined in the clinical guidelines "Guidelines for the Management of Antineoplastic Drug Extravasation Sequelae" (Author: Buydenok Yu.V., DOI: 10.18 027/2224–5057–2018–8–3s2–610–616, https://rosoncoweb.ru/standarts/RUSSCO/2018/2018-46.pdf).

Principles of prevention and treatment of immune-mediated adverse events in patients with GIST correspond to the principles outlined in the clinical guidelines "Practical Guidelines for the Management of Immune-Mediated Adverse Events" (Authors: Protsenko S.A., Antimonik N.Yu., Bershtein L.M., Novik A.V., Nosov D.A., Petenko N.N., Semenova A.I., Chubenko V.A., Yudin D.I., DOI: 10.18 027/2224–5057–2018–8–3s2–636–665, https://rosoncoweb.ru/

standarts/RUSSCO/2018/2018-48.pdf).

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Currently, there are no clinical studies involving GIST patients for all types of medical rehabilitation. These recommendations are based on the fact that numerous studies, including meta-analyses (D. Steffens et al., 2018, etc.) and systematic reviews (Nicole L. Stout et al., 2017, R. Segal et al., 2017, etc.), have proven that various types of medical rehabilitation significantly accelerate functional recovery, shorten hospital stays after surgery, and reduce the incidence of complications and mortality in patients with other malignant neoplasms.

Medical rehabilitation should be performed in accordance with clinical guidelines depending on the primary tumor location (esophagus, stomach, small intestine, colon and rectum, etc.).

4.1. Pre-rehabilitation

4.2. First stage of rehabilitation after surgical treatment

4.3. Second stage of rehabilitation after surgical treatment

• It is recommended to use exercise complexes (physical therapy for diseases of the esophagus, stomach, duodenum, and colon) in all GIST patients following radical surgical treatment for digestive system tumors, as this promotes faster physical recovery and improves the patient's quality of life (Appendix A3. Table A3-1) [84, 85].

  Grade of Recommendations — C (Level of Evidence — 4).

• It is recommended to include aerobic exercises in exercise therapy complexes for all GIST patients. This leads to an improved quality of life and psychological state, as well as better body weight control [87, 88].

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

4.4. Third stage of rehabilitation after surgical treatment

Comment: maintaining a stable body weight and an active lifestyle increases overall survival time. The goal is at least 30 minutes of moderate-intensity physical activity on several (most) days of the week, taking into account the presence and severity of anticancer treatment complications [92].

4.5. Rehabilitation during drug therapy

Comment: physical exertion leads to increased cardiorespiratory endurance in patients and a reduced risk of chemotherapy-induced cardiotoxicity [97].

5. Prevention and Dispensary Observation

6. Organization of Medical Care

Medical care, with the exception of medical care provided as part of clinical trials, in accordance with Federal Law No. 323-FZ dated November 21, 2011, "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 the provision of medical care by types of medical care, which is approved by the authorized federal executive body;

2. in accordance with the procedures for the provision of medical care approved by the authorized federal executive body and 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 ambulatory oncological care center, or in its absence, at a primary oncological office, or 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, family physicians, medical specialists, and mid-level medical personnel shall refer the patient in the established manner for a consultation at an ambulatory oncological care center, or in its absence, at a primary oncological office or the outpatient department of an oncological dispensary (oncological hospital) for the provision of primary specialized health care.

A consultation at an ambulatory oncological care center, a primary oncological office, or the outpatient department of an oncological dispensary (oncological hospital) must be conducted no later than 3 working days from the date of issuance of the referral for consultation. The oncologist of the ambulatory oncological care center (or in the absence of such a 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 and also organize other diagnostic examinations necessary to establish a diagnosis, including the extent of the oncological process and the stage of the disease.

In the event that it is impossible to obtain biopsy (surgical) material or perform other diagnostic examinations within the medical organization that incorporates the ambulatory oncological care center (primary oncological office), the patient shall be referred by the oncologist 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 pathomorphological department (laboratory).

The timeframe 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, which is 7 working days from the date of prescribing the examinations.

The diagnosis of an oncological disease is established by a medical specialist based on the results of diagnostic examinations, including cytological and/or histological verification of the diagnosis, except for cases where obtaining biopsy and/or puncture material is not feasible.

An oncologist from an outpatient oncological care center (primary oncology office) refers the patient to an oncological dispensary (oncology hospital) or another medical organization providing medical care to cancer patients, including one subordinate to a federal executive body (hereinafter referred to as a federal medical organization), to clarify the diagnosis (if establishing the diagnosis is impossible, including the extent of the oncological process and disease stage), 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 those corresponding to the codes of the International Classification of Diseases for Oncology (ICD-O), 3rd edition: 8936, 906–909, 8247/3, 8013/3, 8240/3, 8244/3, 8246/3, 8249/3, the oncologist of the oncological dispensary (oncological hospital) or another medical organization providing medical care to patients with oncological diseases shall arrange a medical consultation or a medical board meeting (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 order to determine the treatment strategy.

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, transmitted to the fourth-group pathomorphological department (reference center) through information exchange, including the use of telemedicine technologies for remote interaction between medical personnel;

• digital images obtained from diagnostic imaging methods, transmitted to the remote consultation center for diagnostic radiology through information exchange, including the use of telemedicine technologies for remote interaction between medical personnel;

• biopsy (surgical) material for repeat pathomorphological, immunohistochemical, and molecular genetic testing sent to the fourth-group pathomorphological 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.

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

For record-keeping purposes, information regarding 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 constituent entity of the Russian Federation responsible for registering patients with newly diagnosed malignant neoplasms, including via the Unified State Health Information System. If the presence of an oncological disease is confirmed in a patient, information regarding the refined diagnosis shall be sent from the oncological dispensary or the organization of the constituent entity of the Russian Federation responsible for registering patients with newly diagnosed malignant neoplasms to the medical organization providing follow-up care (dispensary observation) to the patient.

Specialized, including high-tech, medical care in medical organizations providing medical care to the adult population for oncological diseases is provided based on medical indications stipulated by the regulations on organizing the provision of specialized, including high-tech, medical care.

Specialized medical care, excluding high-tech medical care, in medical organizations subordinate to federal executive bodies 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 bodies for the provision of specialized (excluding high-tech) medical care, provided in the Appendix to the Regulations on the Organization of Specialized, Including High-Tech, Medical Care. (Paragraph 5: to receive specialized medical care on a planned basis, the choice of a federal medical organization is made upon the referral of the attending physician.) If the Program involves the participation of several federal medical organizations providing specialized medical care for diseases, conditions (group of diseases, conditions) matching the patient's diseases, conditions (group of diseases, conditions), the attending physician is obliged to inform the patient (the patient's legal representative) about the possibility of choosing a federal medical organization, including the potential waiting times for specialized medical care, which may exceed the waiting times established by the Program of State Guarantees of Free Medical Care to Citizens.

The waiting time for the provision of specialized (excluding high-tech) medical care must not exceed the timeframe established in the program of state guarantees of free medical care for citizens, approved by the Government of the Russian Federation, which is 7 working days.

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 regulations on organizing the provision of palliative medical care, including the procedure for interaction between medical organizations, social service organizations, and 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.

Indications for hospitalization of a patient in a medical organization in an emergency or urgent form are:

1. presence of oncological disease complications requiring emergency and urgent specialized medical care;

2. the presence of complications from oncological treatment (surgery, radiation therapy, drug therapy, etc.) requiring the provision of specialized medical care in an emergency and urgent form.

Indications for hospitalization of a patient in a medical organization in a planned form are:

1. the need to perform complex interventional diagnostic medical procedures, as well as endoscopic examinations that cannot be performed on an outpatient basis and require subsequent monitoring in an inpatient or day-care setting.

2. presence of indications for specialized antitumor treatment (surgical intervention, radiation therapy including brachytherapy, external beam radiation therapy, and other types of radiation therapy, drug therapy, etc.) requiring inpatient or day-hospital monitoring.

Indications for discharging a patient from a medical organization are:

1. completion of a course of treatment or one of the stages of providing specialized, including high-tech, medical care in a 24-hour or day hospital setting, provided there are no treatment complications requiring drug correction and/or inpatient medical interventions;

2. refusal of the patient or their legal representative from specialized, including high-tech, medical care in an inpatient or day-care setting, as determined by a medical concilium of the oncology-providing organization

3. in cases of non-compliance by the patient with prescriptions or internal regulations of the medical and prophylactic institution, provided this does not threaten the patient's life and the health of others;

4. need to transfer the patient to another medical organization in the relevant medical specialty.

The conclusion on the advisability of transferring a patient to a specialized medical organization is made after a preliminary consultation on the provided medical documents and/or a preliminary examination of the patient by specialist physicians of the medical organization to which the transfer is planned.

Indications for referring a patient to another medical organization:

1. clinical guidelines are designed to maximize the quality of medical care provided to patients in various clinical situations. If a medical organization lacks the capacity to deliver the recommended scope of medical care (for example, the inability to perform sentinel lymph node biopsy), it is recommended to use the routing system to refer patients to other medical organizations, including those outside the federal subject, such as federal centers with appropriate equipment and personnel;

2. clinical guidelines cannot describe 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 (atypical disease course, need to initiate antitumor therapy despite contraindications, progression during recommended treatments, etc.), it is recommended to use the telemedicine consultation system or referral to national medical research centers to clarify treatment tactics;

3. identification or exacerbation of a comorbid condition unrelated to the oncology profile that impedes this stage of treatment (e.g., acute myocardial infarction, acute stroke, etc.) and requires referral to specialized medical organizations.

7. Additional Information

Prognostic factors in GIST include: localization, histological tumor type, mutation status, malignancy grade, stage, and radicality of surgery.

Criteria for Evaluating the Quality of Medical Care

Criteria for evaluating the quality of specialized medical care for adult patients with GIST are listed in Table 8.

Table 8. Criteria for evaluating the quality of medical care

References

Appendix A1. Working Group Composition

1. Anurova O.A., Candidate of Medical Sciences, National Medical Research Center for Radiology, Russian Ministry of Health.

2. Arkhiri P.P., Candidate of Medical Sciences, N.N. Blokhin National Medical Research Center of Oncology, Russian Ministry_of_Health.

3. Zhabina A.S., Candidate of Medical Sciences, St. Petersburg Clinical Scientific and Practical Center for Specialized Types of Medical Care (Oncological) named after N.P. Napalkov

4. Karachun A.M., Doctor of Medical Sciences, Professor, A.M. Petrov National Medical Research Center of Oncology, Russian Ministry of Health.

5. Mazurenko N.N., Doctor of Medical Sciences, Professor, N.N. Blokhin National Medical Research Center of Oncology, Russian Ministry of Health.

6. Meshcheryakov A.A., Doctor of Medical Sciences, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine, Federal Medical-Biological Agency.

7. Nikulin M.P., Candidate of Medical Sciences, N.N. Blokhin National Medical Research Center of Oncology, Russian Ministry of Health.

8. Poddubnaya I.V., Doctor of Medical Sciences, Professor, Academician of the Russian Academy of Sciences, Russian Medical Academy of Continuous Professional Education, Russian Ministry of Health.

9. Ryabov A.B., National Medical Research Center for Radiology, Russian Ministry of Health.

10. Soldatkina N.V., Doctor of Medical Sciences, National Medical Research Center of Oncology, Russian Ministry of Health

11. Stylidi I.S., Doctor of Medical Sciences, Professor, Academician of the Russian Academy of Sciences, N.N. Blokhin National Medical Research Center of Oncology, Russian Ministry of Health.

12. Ter-Ovanesov M.D., Doctor of Medical Sciences, Professor, N.N. Blokhin National Medical Research Center of Oncology, Russian Ministry of Health

13. Tkachenko O.B., Endoscopist, A.M. Petrov National Medical Research Center of Oncology, Russian Ministry of Health.

14. Filonenko D.A., Candidate of Medical Sciences, A.S. Loginov Moscow Clinical Scientific Center

15. Khomyakov V.M., Candidate of Medical Sciences, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Center for Radiology, Russian Ministry of Health.

Medical Rehabilitation Section:

1. Gameeva E.V., Doctor of Medical Sciences, Acting General Director, Federal Research and Clinical Center of Medical Rehabilitation and Balneology, Federal Medical-Biological Agency

2. Konchugova T.V., Doctor of Medical Sciences, Professor, Physiotherapist, Head of the Department of Preformed Physical Factors, National Medical Research Center for Rehabilitation and Balneology, Russian Ministry of Health.

3. Ivanova Galina Evgenyevna, Doctor of Medical Sciences, Prof., Chief freelance specialist in medical rehabilitation, Russian Ministry of Health, Head of the Department of Medical Rehabilitation, Faculty of Additional Professional Education, Pirogov Russian National Research Medical University, Russian Ministry of Health

4. Obukhova O.A., Candidate of Medical Sciences, Physiotherapist, Head of the Rehabilitation Department, N.N. Blokhin National Medical Research Center of Oncology, Russian Ministry of Health, member of the European Society for Clinical Nutrition and Metabolism (ESPEN), member of the Russian Society for Parenteral and Enteral Nutrition (RESPEN).

5. Semiglazova T.Yu., Doctor of Medical Sciences, Associate Professor, Head of Department - Leading Researcher of the Scientific Department of Innovative Methods of Therapeutic Oncology and Rehabilitation, A.M. Petrov National Medical Research Center of Oncology, Russian Ministry of Health, Associate Professor of the Department of Oncology, Mechnikov North-Western State Medical University, Russian Ministry of Health.

6. Stepanova A.M., Candidate of Medical Sciences, Deputy General Director for Science and Education, Federal Research and Clinical Center of Medical Rehabilitation and Balneology, Federal Medical-Biological Agency.

7. Filonenko E.V., Doctor of Medical Sciences, Professor, Oncologist, Head of the Center for Laser and Photodynamic Diagnostics and Therapy of Tumors, P.A. Herzen Moscow Oncology Research Institute - branch of the National Medical Research Center for Radiology, Russian Ministry of Health.

Healthcare Organization Section:

1. Gevorkyan T.G., Deputy Director of the Research Institute of Clinical and Economic Research, N.N. Blokhin National Medical Research Center of Oncology.

2. Ivanov S.A., Doctor of Medical Sciences, Professor of the Russian Academy of Sciences, Director of the A.F. Tsyb Medical Radiological Research Center - branch of the National Medical Research Center for Radiology, Russian Ministry of Health.

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

4. Khaylova Zh.V., Doctor of Medical Sciences, Deputy Director for Organizational and Methodological Work, A.F. Tsyb Medical Radiological Research Center - branch of the National Medical Research Center for Radiology, Russian Ministry of Health.

   Conflict of interest:

   None of the working group members had any conflict of interest during the development of these clinical guidelines, specifically personal interest in obtaining, personally or through a company representative, material gain or other advantage that affects or may affect the proper performance of their professional duties and other obligations, including those related to the development and review of clinical guidelines, due to a contradiction between the personal interest of said persons and the interests of patients.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience of these clinical guidelines:

1. radiotherapists;

2. oncologists;

3. radiologists;

4. radiologists;

5. surgeons;

6. anesthesiologists-resuscitologists;

7. general practitioners (internal medicine);

8. general practitioners (family medicine);

9. medical geneticists;

10. pathologists;

11. healthcare organization and public health physicians;

12. rehabilitation specialists (specialists in medical rehabilitation);

13. clinical pharmacologists;

14. medical students, residents, and postgraduate students.

In these clinical guidelines, all data are ranked by level of reliability (evidence) depending on the quantity and quality of studies on the issue.

Methods used for evidence collection/selection: search in electronic databases; analysis of modern scientific developments on GIST in Russia and abroad; synthesis of practical experience of Russian and foreign specialists.

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

Table A2. Levels of Evidence (LoE) grading scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, rehabilitation interventions)

Table P3. Levels of Evidence (LoE) grading scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Good Practice Points (GPPs): best practice recommendations are based on the qualification and clinical experience of the authoring group.

Methods used for formulating recommendations – expert consensus.

Economic analysis:

Cost analysis was not performed, and pharmacoeconomic publications were not analyzed.

Method of recommendation validation:

• External peer review

• Internal expert review.

Description of the guideline validation method:

The preliminary version of these guidelines has been reviewed by independent experts who were asked to comment primarily on whether the interpretation of the evidence underlying the recommendations is accessible and understandable.

Comments received from experts were carefully systematized and discussed by the chair and members of the working group. Each point was discussed, and the resulting changes made to the recommendations were logged. If no changes were made, the reasons for refusing to make changes were logged.

Consultations and peer review:

The draft guidelines were also reviewed by independent experts, who were asked to comment primarily on the clarity and accuracy of the interpretation of the evidence base underlying the recommendations.

For the final editing and quality control, the guidelines were re-analyzed by the members of the working group, who concluded that all comments and feedback from the experts had been taken into account, and the risk of systematic bias in the development of the guidelines was minimized.

Procedure for updating clinical guidelines

The mechanism for updating clinical guidelines provides for their systematic revision at least once every 3 years, as well as upon the emergence of new evidence from the perspective of evidence-based medicine regarding the diagnosis, treatment, prevention, and rehabilitation of specific conditions, or in the presence of reasoned additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

When selecting publications as potential sources of evidence, the methodology used in each study is examined to ensure its reliability. The result of this examination affects the level of evidence assigned to the publication, which in turn affects the strength of the recommendations derived from it.

Appendix A3. Reference Materials

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

1. Federal Law No. 323-FZ of November 21, 2011 "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation".

2. Order of the Ministry of Health of the Russian Federation No. 915n dated November 15, 2012 'On approval of the Procedure for providing medical care to the population in the profile "oncology".'

3. Order of the Russian Ministry of Health No. 804n of October 13, 2017 "On Approval of the Nomenclature of Medical Services" (Registered with the Ministry of Justice of Russia on November 7, 2017, No. 48808).

4. Letter of the Federal Compulsory Medical Insurance Fund No. 5071/26-2/i of April 23, 2019. http://www.ffoms.ru/documents/the-orders-oms/.

5. Order of the Ministry of Health of the Russian Federation No. 541n dated July 23, 2010. Unified Qualification Handbook of Positions of Managers, Specialists and Employees, section 'Qualification characteristics of healthcare worker positions.'

6. Federal Law No. 489-FZ dated December 25, 2018 'On amendments to Article 40 of the Federal Law "On compulsory health insurance in the Russian Federation" and the Federal Law "The fundamentals of protecting the health of citizens in the Russian Federation" regarding clinical guidelines.'

7. Order of the Russian Ministry of Health No. 103n of February 28, 2019 "On Approval of the Procedure and Terms for the Development of Clinical Guidelines, Their Revision, the Standard Form of Clinical Guidelines and Requirements for Their Structure, Composition, and Scientific Validity of Information Included in Clinical Guidelines".

8. Order of the Ministry of Health of the Russian Federation No. 4n dated January 14, 2019 'On approval of the procedure for prescribing medicinal products, prescription forms for medicinal products, the procedure for issuing said forms, their accounting and storage.'

9. State Register of Medicines: https://grls.rosminzdrav.ru.

Current package inserts for the medicinal products mentioned in these clinical guidelines can be found in the State Register of Medicines hosted on the website of the Russian Ministry of Health: http://grls.rosminzdrav.ru, as well as on the RUSSCO website.

 Table A3-1. Terms describing procedures in the clinical guideline and possible (closest) terms from the current nomenclature of medical services. 

Appendix B. Physician Action Algorithms

Diagnostic and treatment protocol for patients with GIST

Appendix C. Patient Information

The patient is informed about the clinical presentation and methods of GIST diagnosis/staging, introduced to various treatment methods and their potential outcomes/complications. The choice of treatment method should be made as a result of this discussion after the patient has had the opportunity to ask all questions of interest.

It is necessary to reassure the patient and help them overcome psychological discomfort related to the disease.

The patient should be informed about the nature of post-treatment follow-up and the importance of regular examinations.

Patients should also be informed about clinical trials being conducted in the Russian Federation for patients with relevant nosologies.

Independent self-monitoring of the disease course by the patient is not possible; the frequency of physician visits is determined individually in each specific case.

Benefits of quitting smoking and alcohol consumption:

• Higher survival rates

• Greater treatment efficacy

• Fewer and less severe side effects of antineoplastic treatment (cardiopulmonary complications, fatigue, weight loss, mucositis, loss of taste)

• Accelerated recovery of general condition after treatment

• Lower risk of recurrence

• Lower risk of second primary tumors

• Lower risk of infections

• Higher quality of life

Recommendations for complications of chemotherapy/radiation therapy/targeted therapy – contact your oncologist/chemotherapist/radiation therapist!

1) If body temperature rises to 38 °C or higher:

2) For stomatitis:

• Diet – mechanical and thermal sparing;

• Frequent mouth rinsing (every hour) with chamomile, oak bark, or sage decoction; apply sea buckthorn (or peach) oil to the oral mucosa;

• Treat the oral cavity as recommended by your oncologist/chemotherapy specialist.

3) For diarrhea:

• Diet – exclude fatty, spicy, smoked, sweet, dairy, and high-fiber foods. Lean meat, flour products, fermented milk products, and rice broth are permitted. Drink plenty of fluids.

• Take medications as recommended by your oncologist/chemotherapy specialist.

4) For nausea:

• Take medications as recommended by your oncologist/chemotherapy specialist.

5) For edema:

• Take medications as recommended by your oncologist/chemotherapy specialist.

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

No.