Colon and rectosigmoid junction cancer: clinical guidelines

List of Abbreviations

NOS – not otherwise specified

IV – intravenous

WHO – World Health Organization

CT – computed tomography

PT – physical therapy

mAb – monoclonal antibody

ICD – International Statistical Classification of Diseases and Related Health Problems

ICD-O – International Classification of Diseases for Oncology, specific domain extension of ICD

MRI – magnetic resonance imaging

PCR – polymerase chain reaction

PET – positron emission tomography

PET-CT – positron emission tomography combined with computed tomography

CEA – carcinoembryonic antigen

Ultrasound – ultrasound examination

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

ECOG – Eastern Cooperative Oncology Group MEK – mitogen-activated protein kinase kinase gene (MAPK kinase).

MSI – microsatellite instability

RAS – family of NRAS and KRAS genes.

** – vital and essential drugs

# – drugs prescribed outside of the indications, contraindications, administration routes, and dosages specified in the drug package insert (off-label)

Terms and Definitions

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

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

Grades of recommendation – unlike levels of evidence, reflect the degree of certainty not only regarding the true effect of an intervention, but also that following the recommendations in a specific situation will produce more benefits than harms.

Stage I rehabilitation – rehabilitation during the period of specialized treatment of the underlying disease (including surgical treatment / chemotherapy / radiation therapy) in departments of medical organizations specialized in the underlying disease;

Phase II rehabilitation – rehabilitation during the early recovery period, late recovery period, and the period of residual effects of the disease in an inpatient setting of medical organizations (rehabilitation centers, rehabilitation departments);

Phase III rehabilitation – rehabilitation during the early and late recovery periods and the period of residual effects of the disease in outpatient departments (offices) of rehabilitation, physical therapy, exercise therapy, acupuncture, manual therapy, psychotherapy, medical psychology, day hospitals, by mobile home-care teams (including health resort facilities), and speech-language pathology offices.

FOLFIRI – chemotherapy regimen: irinotecan** (180 mg/m² as a 90-minute infusion on day 1), leucovorin** (calcium folinate, 400 mg/m² IV over 2 h) followed by fluorouracil** bolus (400 mg/m² IV bolus) and 46-hour fluorouracil** infusion (2400 mg/m², 1200 mg/m² per day). The next cycle starts on day 15.

mFOLFOX6 (hereinafter referred to as FOLFOX) – chemotherapy regimen: oxaliplatin** (85 mg/m² as a 2-hour infusion on Day 1), calcium folinate** (400 mg/m² IV over 2 h) followed by bolus fluorouracil** (400 mg/m² IV push) and a 46-hour infusion of fluorouracil** (2,400 mg/m², at 1,200 mg/m² per day). The next cycle starts on Day 15.

FOLFOXIRI – chemotherapy regimen: irinotecan** (165 mg/m² as a 90-minute infusion on day 1), oxaliplatin** (85 mg/m² as a 2-hour infusion on day 1), leucovorin** (calcium folinate, 200 mg/m² IV over 2 h) followed by a 46-hour fluorouracil** infusion (3200 mg/m²). The next cycle starts on day 15.

FLOX – chemotherapy regimen: oxaliplatin** (85 mg/m² over 2 h on Days 1, 15, and 29 of each cycle), calcium folinate** (250 mg/m² IV push) followed by bolus fluorouracil** (500 mg/m² weekly for 6 weeks followed by a 2-week rest) or oxaliplatin** (85 mg/m² over 2 h on Day 1), calcium folinate** (60 mg/m² IV push) followed by bolus fluorouracil** (500 mg/m²) on Days 1 and 2 every 2 weeks.

Nordic FLOX – Oxaliplatin** 85 mg/m² IV over 2 h on Day 1 + calcium folinate** 60 mg/m² IV push followed by bolus fluorouracil** 500 mg/m² on Days 1 and 2. The next cycle starts on Day 15

XELOX – chemotherapy regimen: oxaliplatin** (130 mg/m² IV infusion on Day 1), capecitabine** (1,000 mg/m² twice daily on Days 1–14). The next cycle starts on Day 22.

XELIRI – chemotherapy regimen: ^#irinotecan** as a 90-minute infusion (180–200 mg/m² on Day 1), ^#capecitabine** (1,600–1,800 mg/m² per day orally on Days 1–14). The next cycle starts on Day 22.

IFL – combination of irinotecan** with bolus calcium folinate** and fluorouracil**

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Colon and rectosigmoid junction cancer – a group of malignant tumors originating from the colonic mucosa.

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

In 3–5% of patients, colon cancer is associated with known hereditary syndromes, the most common being Lynch syndrome, familial adenomatous polyposis, MUTYH-associated polyposis, and rare hamartomatous polyposis syndromes. In the remaining patients, colon and rectosigmoid junction cancer is sporadic. Risk factors for this pathology include chronic inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease), smoking, alcohol consumption, a diet high in red meat, diabetes mellitus, obesity or elevated body mass index, and physical inactivity [1–13].

1.3 Epidemiology of the Disease or Condition

Colon and rectosigmoid junction cancer ranks among the leading malignant tumors in terms of incidence and mortality. In 2022, 44,349 new cases of colon cancer were registered in Russia, and 23,364 patients died from this disease [14].

1.4 Features of Coding the Disease or Condition

C18 Malignant neoplasm of colon

C18.0 Malignant neoplasm of cecum

C18.1 Malignant neoplasm of appendix

C18.2 Malignant neoplasm of ascending colon

C18.3 Malignant neoplasm of hepatic flexure

C18.4 Malignant neoplasm of transverse colon

C18.5 Malignant neoplasm of splenic flexure

C18.6 Malignant neoplasm of descending colon

C18.7 Malignant neoplasm of sigmoid colon

C18.8 Overlapping malignant lesion of colon

C18.9 Malignant neoplasm of colon, unspecified

C19 Malignant neoplasm of rectosigmoid junction

D01.0 Carcinoma in situ of colon

1.5 Classification of the disease or condition

WHO International Histological Classification (2019)^[1] [7, 205]

Epithelial tumors

I. Benign tumors:

8211/0 Tubular adenoma

8261/0 Villous adenoma

8263/0 Tubulovillous adenoma

8220/0 Adenomatous polyp

8213/0 Serrated dysplasia

II. Intraepithelial neoplasia (dysplasia) associated with chronic inflammatory bowel disease:

8148/2 High-grade glandular intraepithelial neoplasia

8148/0 Low-grade glandular intraepithelial neoplasia

III. Carcinoma:

8140/3 Adenocarcinoma, NOS^[2]

8213/3 Serrated adenocarcinoma^[3]

8262/3 Adenoma-like adenocarcinoma^[4]

8265/3 Micropapillary adenocarcinoma

8480/3 Mucinous adenocarcinoma^[5]

8490/3 Diffuse-type carcinoma.

8490/3 Signet ring cell carcinoma^[6]

8560/3 Adenosquamous carcinoma.

8510/3 Medullary carcinoma^[7]

8220/3 Undifferentiated carcinoma, NOS^[8]

8033/3 Carcinoma with sarcomatoid component^[9]

8240/3 Neuroendocrine tumor, NOS.

8240/3 Neuroendocrine tumor, G1.

8249/3 Neuroendocrine tumor, G2.

8249/3 Neuroendocrine tumor, G3.

8246/3 Neuroendocrine carcinoma, NOS^[10]

8041/3 Small cell carcinoma.

8013/3 Large cell neuroendocrine carcinoma.

8154/3 Mixed neuroendocrine-non-neuroendocrine neoplasm^[11]

According to the WHO Classification (2019), the histological grading of colorectal adenocarcinoma is now two-tiered instead of the previously used 4-tier scale (G1–G4):

- low-grade adenocarcinoma (including well- and moderately differentiated G1-G2 carcinomas),

- high-grade adenocarcinoma (including poorly differentiated G3 carcinomas).

Only colorectal adenocarcinoma and mucinous adenocarcinoma are subject to histological grading. Histological grading is not performed for serrated adenocarcinoma, micropapillary adenocarcinoma, diffuse carcinoma, signet-ring cell carcinoma, sarcomatoid carcinoma, or undifferentiated carcinoma, because these tumors are always high-grade.

Histological grading of adenoma-like adenocarcinoma and medullary carcinoma is not performed because these tumors are characterized by a favorable prognosis.

^[1] The current histological classification is presented in an abridged version.

^[2] Intestinal-type adenocarcinoma, NOS. According to the degree of differentiation (and corresponding grade), tumors are divided into well-differentiated/G1 (96–100% of invasive tumor epithelial elements composed of glandular structures), moderately differentiated/G2 (50–95% of invasive tumor epithelial elements composed of glandular structures), and poorly differentiated/G3 (0–49% of invasive tumor epithelial elements composed of glandular structures).

^[3] For right-sided localization, the tumor is frequently associated with high-level microsatellite instability (MSI-H).

^[4] This nosological entity was first introduced into the ICD-O by the International Agency for Research on Cancer (IARC) and WHO committee in 2019.

^[5] The diagnosis is established if >50% of the tumor volume is composed of extracellular mucin; the presence of signet-ring cell elements is permissible (<50% of all invasive tumor cells). Grading is similar to that of typical adenocarcinoma. For right-sided localization, the tumor is frequently associated with MSI.

^[6] The diagnosis is established if >50% of the tumor cells are composed of signet-ring cell elements. For right-sided localization, the tumor is frequently associated with MSI.

^[7] For right-sided localization, the tumor is frequently associated with MSI.

^[8] This is a diagnosis of exclusion, established only based on additional studies (immunohistochemistry during pathomorphological examination, electron microscopy).

^[9] This nosological entity was first introduced into the ICD-O by the International Agency for Research on Cancer (IARC) and WHO committee in 2019. It is a diagnosis of exclusion, corresponding to G3–G4.

^[10] The diagnosis is established only based on additional studies (immunohistochemistry during pathomorphological examination, electron microscopy).

^[11] The diagnosis is established only based on additional studies: a mixed neuroendocrine-non-neuroendocrine neoplasm is a dimorphic carcinoma combining components of adenocarcinoma and neuroendocrine carcinoma/tumor (the proportion of each component must be at least 30%).

1.6 Clinical presentation of the disease or condition

The disease may manifest with symptoms of gastrointestinal dysfunction (nausea, vomiting, diarrhea, constipation, flatulence, loss of appetite, abdominal pain), anemia, weight loss, weakness, fever, and blood and mucus in the stool. The disease may also present with acute or partial intestinal obstruction.

1.6.1. TNM staging of colon cancer, 8th edition (2017)

A unified classification is used for cancer of the colon and rectosigmoid junction.

The T category includes the following grades:

T – primary tumor.

Tx – primary tumor cannot be assessed.

Tis – carcinoma in situ (intraepithelial invasion or invasion into the lamina propria).

T1 – tumor invades the submucosa.

T2 – tumor invades the muscularis propria.

T3 – tumor invades the subserosa or non-peritoneal pericolic/perirectal tissues.

For tumors located in the rectosigmoid colon (covered by peritoneum), the T3 symbol is used to indicate extension to the subserosa (the tumor does not pierce the serosa).

T4 – tumor perforates the visceral peritoneum and/or directly invades other organs or structures.

T4a – tumor invades the visceral peritoneum.

T4b – tumor invades other organs and structures.

N – regional lymph nodes:

Nx – regional lymph nodes cannot be assessed.

N0 – no regional lymph node metastasis.

N1 – metastasis in 1–3 regional lymph nodes.

N1a – metastasis in 1 regional lymph node.

N1b – metastasis in 2–3 regional lymph nodes.

N1c – tumor deposits in the subserosa, mesentery, or non-peritoneal pericolic/perirectal tissues without regional nodal metastasis.

N2 – metastasis in 4 or more regional lymph nodes.

N2a – metastasis in 4–6 regional lymph nodes.

N2b – metastasis in 7 or more regional lymph nodes.

M – distant metastasis:

M0 – no distant metastases.

M1 – presence of distant metastases.

M1a – distant metastasis confined to 1 organ.

M1b – distant metastasis in more than 1 organ.

M1c – peritoneal metastasis.

Stage grouping is presented in Table 1.

Table 1. Stages of colon cancer

The definition of regional lymph nodes according to tumor localization is presented in Table 2.

Table 2. Location of regional lymph nodes according to the primary tumor site

1.6.2. Kikuchi Staging for Early Colon Cancer

When planning local excision for T1 colon cancer, it is recommended to clarify the stage of the disease based on magnetic resonance imaging (MRI) and colonoscopy combined with simultaneous assessment of the depth of invasion by ultrasound according to the following criteria.

T1sm1 – depth of tumor invasion into the submucosa up to 1/3 of its thickness.

T1sm2 – moderate depth of tumor invasion into the submucosa – up to 2/3 of its thickness.

T1sm3 – complete tumor invasion into the submucosa – through its entire thickness.

Final staging is performed based on the results of pathomorphological examination of the surgical specimen. Staging according to Kikuchi or Haggitt is possible only if the muscular layer of the intestinal wall is present in the removed macrospecimen.

1.6.3. Haggitt Staging for Malignant Colonic Polyps

To determine the treatment strategy for malignant colon polyps, staging based on the results of morphological examination is recommended.

Level 0 – no invasive carcinoma.

Level I – invasion into the "head" of the polyp.

Level II – invasion into the "neck" of the polyp.

Level III – invasion into the "stalk" of the polyp.

Level IV – invasion into the "base" of the polyp.

Levels I–III correspond to T1sm1, while level IV may correspond to T1sm1–T1sm3.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnostic criteria: complaints, medical history, physical examination data, morphological examination of tumor material, instrumental and laboratory studies.

2.1 Complaints and Anamnesis

Comments: in 3–5% of patients with colon cancer, the development of the disease is associated with the presence of known hereditary syndromes. The most common of these are Lynch syndrome, familial adenomatous polyposis, and MUTYH-associated polyposis.

Comments: If the patient's history meets the Amsterdam II criteria, the criteria of the A.N. Ryzhikh National Medical Research Center of Coloproctology, or the Bethesda guidelines, it is advisable to test their tumor sample for mismatch repair protein deficiency using immunohistochemistry (IHC). If this deficiency is detected, subsequent sequencing of the corresponding (single) MMR gene should be performed to search for a hereditary pathogenic variant. If microsatellite instability is tested in the patient's tumor sample and detected, but IHC testing for mismatch repair protein deficiency is not available, sequencing of all 4 MMR genes must be performed. If no pathogenic variant is detected upon MMR gene sequencing, searching for large insertions/deletions using MLPA is desirable.

If the patient does not meet the specified criteria, but their sample reveals microsatellite instability / mismatch repair protein deficiency, further testing of the MMR genes may be considered.

2.2 Physical Examination

• Before starting treatment, patients with colon cancer are recommended a thorough physical examination (including digital rectal examination) to rule out synchronous rectal tumors and an assessment of nutritional status to determine potential tolerance to antineoplastic therapy [15].

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

2.3 Laboratory Diagnostics

Comments: a coagulogram is mandatory for patients scheduled for surgical treatment, and for others – in the presence of clinical indications. Blood carcinoembryonic antigen (CEA) testing is indicated for all patients at the primary staging stage [18]. The treating doctor should determine the list of blood biochemistry and coagulogram parameters for each patient individually, taking into account their characteristics.

Comments: Molecular genetic analysis can be performed on both tumor biopsy material and circulating tumor DNA using either PCR or next-generation sequencing. Circulating tumor DNA analysis can be used when a tumor sample cannot be analyzed and may not reflect the full spectrum of molecular alterations in the tumor. If analysis for the optimal spectrum of mutations in RAS genes cannot be performed, referral to a reference center should be considered. In metastatic colorectal cancer with a microsatellite instability phenotype, determination of gene translocations for NTRK, ROS1 (Molecular genetic testing for ROS1 gene translocations), ALK (Molecular genetic testing for ALK gene translocations), RET (Molecular genetic testing for RET gene mutations in biopsy (surgical) material) may be performed due to a relatively high probability of their presence and the availability of targeted therapies aimed at these mutations. In the absence of microsatellite instability in metastatic cancer, determining somatic mutations in the POLD1 and POLE genes may be considered, provided that only clinically significant mutations are indicated in the report [250-253]. For patients scheduled for chemotherapy including pyrimidine analogues, determination of 4 major DPYD gene variants: c.1905+1G>A (rs3918290), c.2846A>T (rs67376798), c.1679T>G (rs55886062), and c.1236G>A (rs56038477) associated with toxicity of this class of drugs (Determination of DPYD gene polymorphism by PCR) may be considered. However, the presence of heterozygous mutations does not always reflect a clinically significant deficiency of the dihydropyrimidine dehydrogenase enzyme, meaning that the role of allele balance in the phenotypic manifestation must be taken into account when interpreting the result [134]. Nevertheless, the rarity of homozygous variants of these mutations precludes routine testing for all patients. For patients scheduled for chemotherapy including irinotecan**, determination of UGT1A1 gene mutations (Determination of UGT1A1 gene polymorphism) associated with toxicity of this class of drugs may be considered [39–41, 124]. In locally advanced colon cancer (cT3N1-2M0, cT4N0-2M0) prior to treatment initiation, it is advisable to determine microsatellite instability in biopsy (surgical) material using PCR or IHC testing to detect mismatch repair protein deficiency, which may influence patient management regarding the consideration of neoadjuvant systemic therapy [219].

• Genetic testing is recommended in the following cases:

  1.1. Suspicion of Lynch syndrome – sequencing of the MLH1, MSH2, MSH6, and PMS2 genes and search for large deletions/insertions by MLPA (Molecular genetic testing for mutations in the MLH1, MSH2, MSH6, PMS2 genes in blood):

  - if the patient meets the Amsterdam II criteria (Appendix C), the criteria of the A.N. Ryzhikh National Medical Research Center of Coloproctology, or the Bethesda guidelines (Appendix G) and/or has MSI/dMMR in their tumor sample

  2. Suspicion of familial adenomatous polyposis – sequencing of the APC gene and search for large deletions/insertions by MLPA (Molecular genetic testing for mutations in the APC gene in blood):

  - if the patient has more than 100 intestinal polyps, or

  - if the patient has a first-degree relative with a diagnosed familial adenomatous polyposis of the colon (in the presence of a relative with an identified pathogenic APC gene variant).

  3. Suspicion of an attenuated form of familial adenomatous polyposis (20 to 100 polyps) – sequencing of the APC gene (Molecular genetic testing for mutations in the APC gene in blood). MUTYH-associated polyposis – sequencing of the MUTYH gene – patients with more than 20 colonic polyps but a negative test for the pathogenic APC variant:

  - patients with a family history suggesting recessive inheritance of familial adenomatous polyposis;

  - patients in whom polyps are detected at a later age (34–44 years) [2, 16, 17].

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

Comments: with the exception of MUTYH-associated polyposis and Bloom syndrome, all hereditary syndromes associated with the development of colorectal cancer are autosomal dominant in nature. In the presence of a strong family history of malignancies, patients with excluded familial adenomatous polyposis and Lynch syndrome are indicated for a consultation with a clinical geneticist for the potential identification of rarer conditions: Peutz-Jeghers, Li-Fraumeni, Bloom, Cowden, juvenile polyposis, oligodontia and colorectal cancer, NTHL1-associated polyposis, POLD1- and POLE-associated polyposis, PTEN hamartoma tumor syndromes [2] [https://www.insight-group.org/syndromes/] [3]. Given the diversity of hereditary syndromes and the complexity of their diagnosis, the most optimal approach is the use of multigene NGS panels or whole-exome sequencing. In the presence of segmental colonic involvement by multiple polyps, differential diagnosis with inflammatory polyps in the setting of ulcerative colitis is necessary [2]. If a clinical geneticist is not available in the region, referral of the patient to a federal center should be considered.

Comment: The macroscopic description of the resected specimen should reflect the following parameters [196, 199, 203, 205, 220]:

1) Length of the resected intestinal segment (cm).

2) If adjacent organs are involved by the primary tumor in the macrospecimen, list them, indicating their dimensions (cm).

3) Tumor dimensions (cm).

4) Presence of signs of serosal perforation of the intestinal wall near the tumor.

5) Distance from the tumor to the proximal and distal resection margins (cm).

6) If there are two or more primary tumors, reflect items 5–8 for each neoplasm separately.

The microscopic description of the resected specimen should reflect the following parameters to determine the prognosis of the disease and further treatment tactics:

1) Histological type of invasive tumor (WHO Classification, 2019).

2) Tumor grade (not assessed after neoadjuvant therapy).

3) Histological type of pre-invasive precursor lesion (if present).

4) Depth of invasion (pT).

5) Presence of microvascular invasion (a negative result must also be stated).

6) Presence of intramural venous invasion (a negative result must also be stated).

7) Presence of extramural venous invasion (a negative result must also be stated).

8) Indicate the total number of lymph nodes examined.

9) Indicate the number of lymph nodes with metastases (pN+).

10) Indicate the number of lymph nodes with micrometastases^[12] (pN+).

11) Indicate the number of lymph nodes with isolated tumor cells^[13] (pN0).

12) Presence of perineural invasion (a negative result must also be stated).

13) Histological grading of the invasive tumor front (tumor budding) using the 3-tier scheme of the International Tumor Budding Consensus Conference (not assessed after neoadjuvant therapy).

14) Presence of isolated tumor deposits in the pericolic adipose tissue without preexisting structures of a lymph node (otherwise classified as metastasis), vascular structures (otherwise classified as vascular invasion), or nerves (otherwise classified as perineural invasion).

15) Involvement of the proximal resection margin (a negative result must also be stated).

16) Involvement of the distal resection margin (a negative result must also be stated).

17) Involvement of the lymph node most distant from the tumor along the vascular bundle — the lymph node marked by the surgeon (a negative result must also be stated).

18) In the presence of prior neoadjuvant therapy, indicate the degree of tumor regression and the name of the tumor regression grading system used (preferring the Mandard or Ryan grading systems) [220].

^[12] Clusters of tumor cells in a lymph node measuring between 0.2 and 2 mm in greatest dimension.

^[13] Clusters of tumor cells in a lymph node measuring less than 0.2 mm in greatest dimension.

2.4 Instrumental Diagnostics

• Patients with colon cancer before starting treatment are recommended to undergo colonoscopy with biopsy (endoscopic colon biopsy) to determine tumor location, degree of tumor stenosis, rule out synchronous malignancies and polyps of the colon, and obtain material for morphological examination. To obtain a sufficient amount of material, several (3–5) tissue samples should be taken using standard endoscopic forceps [16, 19, 20].

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

Comments: treatment planning should not be performed before receiving the pathology report of the biopsy material. In case of submucosal infiltrative growth of the tumor, a false-negative result is possible, which requires a repeat biopsy. The sensitivity and specificity of the method increase when using modern endoscopic imaging technologies (magnifying endoscopy, narrow-band imaging, chromoendoscopy, fluorescence diagnostics). If synchronous polyps of the colon are detected, their removal (removal of colonic polyp) is indicated before starting colon cancer treatment to rule out cases of synchronous cancer arising in polyps.

• Patients with an established diagnosis of colon cancer when total colonoscopy cannot be performed are recommended to undergo barium enema or CT colonography (computed tomographic colonoscopy) to rule out synchronous tumors before starting treatment, or total colonoscopy within 3–6 months after surgery [19–22].

GRL ALEL 2Grade of Recommendation – A (Level of Evidence – 2).

Comments: in 4–5% of cases, synchronous lesions occur, which may be missed during manual palpation revision during surgery [15, 16]. Therefore, a complete examination of the colon is recommended for all patients prior to surgical treatment, and if technically impossible, no later than 6 months after it. Compared to barium enema, CT colonography is characterized by higher sensitivity in detecting polyps, especially in the proximal colon [21].

• Patients with colon cancer before starting specific antitumor treatment are recommended to undergo computed tomography (contrast-enhanced computed tomography of the abdominal organs with intravenous bolus injection) or contrast-enhanced magnetic resonance imaging of the abdominal organs to assess local tumor spread and rule out metastatic lesions in the abdominal organs [23].

GOR ALOE 1Grade of Recommendation – A (Level of Evidence – 1).

Comments: Abdominal CT with intravenous contrast using non-ionic iodine-containing agents is the standard for staging diagnostics in colon cancer in most developed countries. MRI has higher sensitivity and specificity than CT in detecting liver metastases, but is inferior to CT in assessing local tumor spread due to lower spatial resolution. The CT or MRI protocol should reflect: the distance from the tumor edge to the closest anatomical landmark (cecal pole, hepatic/splenic flexure, or anal verge), tumor length along the intestinal wall, presence and depth of mesocolic invasion, presence of peritoneal invasion, presence and size of mesocolic and retroperitoneal lymph nodes with signs of metastatic involvement, and presence of distant metastases located in the peritoneum and internal organs.

• Patients with colon cancer before starting treatment are recommended to undergo chest computed tomography to rule out thoracic metastases [16, 24].

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

Comments: Pelvic MRI is preferred as it allows a more detailed preoperative assessment of the local spread of the tumor process. Intravenous contrast is not required for pelvic MRI when assessing local spread. When referring for an MRI, the purpose of the study must be clearly stated and the suspected tumor location indicated to select the correct scanning protocol.

• All patients with colon cancer before starting treatment are recommended to undergo electrocardiography to assess potential tolerance to antitumor treatment [27].

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

Comments: contrast-enhanced abdominal MRI is preferred for assessing the resectability of colorectal cancer liver metastases. In patients with contraindications to intravenous contrast, DWI MRI can be performed. MRI allows the detection of metastases not identified by ultrasound in 10-20% of patients and reduces the number of exploratory surgeries and R2 resections [33]. For patients with contraindications to MRI, contrast-enhanced CT or 18F-fluorodeoxyglucose positron emission tomography combined with CT (PET/CT) with intravenous contrast (positron emission tomography combined with computed tomography using tumorotropic radiopharmaceuticals with contrast) is recommended. MRI has the highest sensitivity compared to other diagnostic methods, especially for metastases <1 cm in size [32], with preference given to MRI with paramagnetic contrast agents (gadoxetic acid**) as they improve the method's sensitivity for small liver metastases [135]. Planning metastasis resection based solely on liver ultrasound or non-contrast CT data is not permitted.

Comments: a meta-analysis of randomized trials evaluating the necessity of PET/CT to rule out extrahepatic metastases when deciding on liver metastasectomy showed that this imaging modality changes the treatment strategy in 8% of patients and does not affect overall survival [36].

2.5 Other Procedures

Comment: echocardiography, 24-hour Holter heart rhythm monitoring, pulmonary function testing (body plethysmography), duplex scanning of extrarenal/extracranial brachycephalic arteries and lower extremity blood vessels (ultrasound duplex scanning of lower extremity arteries and veins), and consultations with a cardiologist, endocrinologist, neurologist, and other relevant specialists are performed.

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

The prescription and use of medications specified in the clinical guidelines are aimed at providing the patient with clinically effective and safe medical care; therefore, in a specific clinical situation, they are determined by the instructions for use of specific drugs, taking into account the precautions described in the instructions, and dose adjustments depending on the patient's condition are also possible. Deviations from the instructions must be justified by the clinical situation and confirmed by the decision of the medical organization's medical commission. Changing chemotherapy regimens or altering drug doses within a regimen does not require an oncology board meeting, but is determined by the attending physician. The treatment of neuroendocrine tumors and neuroendocrine cancer of the colon or rectosigmoid junction is covered in a specialized section of the clinical guidelines.

Pain management procedures and recommendations for colon or rectosigmoid cancer correspond to the recommendations presented in the clinical guidelines "Chronic Pain Syndrome (CPS) in Adult Patients Requiring Palliative Medical Care" [161].

No special dietary therapy recommendations differing from those for other forms of malignant neoplasms are required. In the presence of symptoms of intestinal obstruction, the physician provides individual recommendations regarding nutrition and the restriction of certain foods.

Comments: adjuvant/neoadjuvant chemotherapy is additionally administered according to indications.

• For early-stage 0-I colon cancer (Tis-T1N0M0), it is recommended to consider highly effective organ-sparing and function-preserving treatment methods (endoscopic mucosal resection with submucosal dissection [endoscopic mucosal resection of the colon]) [43, 44].

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

Comments: prognostic factors should be considered when determining the treatment strategy. Preference should be given to the endoscopic submucosal dissection technique [42]. If unfavorable prognostic factors are identified after endoscopic removal, resection of the corresponding segment of the colon is performed.

Unfavorable prognostic factors:

• ≥G3,

• resection margin involvement,

• lymphatic, vascular, or perineural invasion,

• Haggitt level IV invasion (involvement of the colonic submucosa).

Endoscopic mucosal resection is permitted for invasive forms of colon cancer (Haggitt levels I–III) in the absence of unfavorable prognostic factors. The detection of poorly differentiated tumor tissue in biopsy pathomorphological studies and/or the determination of Haggitt level IV and/or invasion depth >uT1sm1 (on endoscopic ultrasound) during endoscopy is an absolute contraindication to endoscopic mucosal resection (colonic segment resection is required). The presence of invasive cancer in broad-based polyps (≥T1sm1) is equivalent to Haggitt level IV and requires resection of the corresponding colon segment. Other unfavorable prognostic factors (resection margin involvement, lymphatic, vascular, or perineural invasion) are determined after endoscopic resection. If identified, additional resection of the corresponding colon segment is performed [45].

• For resectable localized and locally advanced stage I-III colon cancer (T1sm2-4N0-2M0), it is recommended, in the absence of absolute contraindications, to perform surgical treatment as the first stage; the extent of surgery is determined by the localization and local spread of the tumor [46].

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

Comments: for resectable locally advanced stage II (T4N0M0) or stage III (T3-4N1-2M0) left-sided colon cancer without MSI/dMMR, it is possible to consider FOLFOX or XELOX chemotherapy for 6–12 weeks in the absence of absolute contraindications and if upfront surgery is not feasible [136]. Neoadjuvant chemotherapy reduces the risk of resection of other organs in stage T4b and does not imply the addition of targeted agents or escalation of the treatment regimen to FOLFOXIRI. For resectable locally advanced stage III (T1-4N1-2M0) colon cancer regardless of location, in the presence of MSI/dMMR, it is possible to consider therapy with pembrolizumab**, nivolumab**, #proлголимабом** [proлголимабом -> prolgolimab] or a combination of ipilimumab** and nivolumab** for 12–27 weeks in the absence of absolute contraindications and if upfront surgery is not feasible [136, 249].

• For unresectable colon cancer (cT4N0–2M0), it is recommended to refer patients to large medical centers experienced in treating this patient cohort for re-evaluation of tumor resectability [48].

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

Comments: for unresectable colon cancer (T4bN0-2M0), induction chemotherapy based on oxaliplatin** and fluoropyrimidines (6–12 weeks) is recommended, followed by referral to large surgical centers for re-evaluation of tumor resectability. In patients with MSI, preoperative immunotherapy (with pembrolizumab**, nivolumab**, #prolgolimab** or a combination of nivolumab** and ipilimumab**) is recommended for up to 12–27 weeks in the absence of progression, and up to 12 months in case of persistent unresectability [249]. If R0-1 surgical resection is impossible, surgery is indicated only in cases of high risk of intestinal obstruction and is limited to bypass anastomosis/colostomy/ileostomy. Subsequently, patients are indicated for systemic anti-tumor drug therapy according to the principles of metastatic colorectal cancer treatment. For colon cancer in a functionally unfit patient (due to severe comorbid conditions), palliative anti-tumor drug therapy or supportive care is recommended (see section 3.3). Tumor stenting or creation of a defunctioning stoma is possible if the risks associated with surgery outweigh the risks associated with cancer progression. The decision regarding contraindications to surgery can only be made by a multidisciplinary tumor board involving a surgeon, general practitioner, and anesthesiologist-resuscitator.

• For generalized colon cancer with resectable/potentially resectable synchronous liver or lung metastases (M1a), it is recommended — if R0 resection of colon cancer liver or lung metastases is initially feasible, or if metastatic lesions in these organs become resectable during chemotherapy — to perform resection of these organs with metastases (atypical liver resection, liver segment(s) resection, hemihepatectomy, radiofrequency ablation, thermoablation, cryodestruction of liver tumors, lung resection (more than one lobe), video-assisted thoracoscopic removal of lung neoplasm (atypical resection)) [16, 49–51, 125].

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

Comments: treatment tactics depend on the initial resectability of metastatic foci. The best results can be achieved with a resection margin of ≥1 mm [49–52]. Surgery should be performed as soon as metastases become resectable. Prolongation of chemotherapy may lead to an increased incidence of hepatotoxicity and the "disappearance" of some metastases, making their identification by the surgeon during resection difficult. In the presence of a symptomatic primary tumor (risk of intestinal obstruction or bleeding), upfront surgical removal of the primary tumor with lymph node dissection is performed. Radiofrequency ablation of liver metastases or stereotactic body radiotherapy can serve both as an adjunct to liver resection to achieve radicality and as an independent treatment method when surgical removal is impossible [54]. The use of local treatment methods for metastases can be considered in oligoprogression as well as in oligometastatic organ involvement in second and subsequent lines of systemic therapy. Intra-arterial chemotherapy remains an experimental method and is not recommended for routine use in the 1st line of therapy.

• For initially resectable metastatic foci, it is recommended to perform surgical removal; in case of functional tolerance, preference is given to simultaneous surgical interventions [16, 49–52].

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

• For initially resectable metastatic foci, following successful R0 or R1 resection, it is recommended to administer adjuvant chemotherapy (6 months of FOLFOX, XELOX, or single-agent pyrimidine analogs) [54, 55].

GOR ALOE 1Grade of Recommendation – A (Level of Evidence – 1).

Comments: an alternative to immediate surgery is perioperative systemic chemotherapy (FOLFOX, XELOX). This strategy should be chosen in case of a high risk of disease progression (e.g., high risk according to the Fong score or any other). After 8–12 weeks of therapy, simultaneous or sequential removal of metastases and the primary tumor is performed, and postoperative chemotherapy is continued to a total duration of 6 months. The addition of monoclonal antibodies (mAbs) to chemotherapy for resectable liver metastases is not indicated, as it may worsen long-term outcomes [51, 53]. In case of a low risk of disease progression (e.g., low risk according to the Fong score or any other), active surveillance is an option if surgical removal of metastases was performed upfront.

• For potentially resectable metastatic foci, it is recommended to administer the most active chemotherapy possible, aimed at achieving an objective response and converting unresectable metastases into resectable ones (FOLFOX, XELOX, or FOLFIRI, XELIRI, FOLFOXIRI) [16, 42, 54, 57, 58, 111–113].

GCP ALoE 1Grade of Recommendation – A (Level of Evidence – 1).

Comments: the optimal option to increase resectability is the use of the "triplet" combination FOLFOXIRI [57, 58]. After 4–6 cycles, resectability should be re-evaluated; in the absence of progression, simultaneous or sequential removal of metastases and the primary tumor is performed. Subsequently, adjuvant chemotherapy with FOLFOX or XELOX is administered to reach a total duration of 6 months (including preoperative chemotherapy). In case of progression of metastatic lesions or impossibility of their removal, treatment is carried out in accordance with the principles specified for patients with unresectable metastases [16].

• For potentially resectable metastatic foci in the absence of RAS and BRAF mutations, absence of Her/2 overexpression or amplification, and absence of MSI, it is recommended to consider adding cetuximab** or panitumumab** to chemotherapy (FOLFIRI, FOLFOX, FOLFOXIRI regimens) regardless of the primary tumor location [16, 39–42, 57].

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

Comments: The combination of FOLFOXIRI with anti-EGFR antibodies is associated with higher toxicity and did not lead to an increase in objective response rates and survival compared to doublet combinations with anti-EGFR antibodies.

• For potentially resectable metastatic foci in the presence of a RAS mutation, it is recommended to consider adding bevacizumab** to FOLFOX, XELOX, FOLFIRI, or FOLFOXIRI chemotherapy regimens regardless of the primary tumor location [16, 39, 42, 59].

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

• For potentially resectable metastatic foci in the presence of a BRAF mutation and absence of MSI, it is recommended to add bevacizumab** to FOLFOX, XELOX, FOLFIRI, or FOLFOXIRI chemotherapy regimens regardless of the primary tumor location [16, 57, 58].

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

Comments: if targeted drugs are prescribed after metastases become resectable and R0 resection of metastatic lesions is performed, chemotherapy is continued until a total duration of 6 months is reached. Cetuximab**, panitumumab**, bevacizumab**, and irinotecan** should be discontinued in the postoperative period. In case of R1/2 resection, it is possible to continue the preoperative combination of chemotherapy and monoclonal antibodies up to a total duration of 6 months.

• For potentially resectable metastases with MSI, it is recommended to prescribe in the 1st line a combination of nivolumab** and ipilimumab** or, in the absence of RAS gene mutations, pembrolizumab**, nivolumab**, or #proлголимаб** (proлголимаб / prolgolimab) as monotherapy until disease progression or the tumor becomes resectable. A combination of FOLFOX or XELOX regimens with nivolumab** or pembrolizumab** is also acceptable. The optimal duration of immunotherapy after R0 resection is not precisely defined, but with satisfactory tolerability, it is recommended to continue for up to 1 year, taking into account the preoperative stage [137, 138, 249].

LOC 2Level of evidence for pembrolizumab** – A (level of data certainty – 2).

LOC 2Level of evidence for the combination of nivolumab** and ipilimumab** – A (level of data certainty – 2).

LOC 4Level of evidence for nivolumab** and #prolgolimab** monotherapy – C (level of data certainty – 4).

• In generalized colon cancer with unresectable synchronous metastases, it is recommended to use chemotherapy combinations (FOLFOX, XELOX, XELIRI, FOLFIRI, FOLFOXIRI) with or without the addition of targeted drugs (cetuximab**, panitumumab**, bevacizumab**) [16] or, in case of MSI, anti-PD-1 antibody monotherapy – nivolumab** or pembrolizumab** or #prolgolimab** – as monotherapy, or the combination of nivolumab** and ipilimumab** [137, 138, 249].

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

Comments: cetuximab** or panitumumab** are used in the absence of RAS and BRAF mutations, HER-2/neu overexpression, and MSI, as well as when the primary tumor is localized in the left colon (the boundary of which is considered to be the splenic flexure of the colon); bevacizumab** is used regardless of RAS and BRAF status and primary tumor localization [16, 40, 42]. Cetuximab** and panitumumab**must notbe used in combination with capecitabine** (capecitabine** monotherapy, XELOX and XELIRI regimens) or bolus pyrimidine analogues (Mayo, FLOX, Nordic Flox, IFL regimens). For left-sided primary tumor localization, preference in combination with anti-EGFR antibodies is given to FOLFOX or FOLFIRI regimens. For right-sided primary tumor localization, preference in combination with bevacizumab is given to the FOLFOXIRI regimen. In patients with RAS and BRAF gene mutations, HER2/neu overexpression, regardless of primary tumor localization, the use of bevacizumab** in combination with FOLFOX, FOLFIRI, XELOX, XELIRI, FOLFOXIRI regimens, or fluoropyrimidine monotherapy is recommended. The goal of treatment is the longest possible disease control while maintaining a satisfactory quality of life; in some patients, it is possible to achieve the conversion of unresectable metastases into resectable ones. During chemotherapy, the treatment efficacy is assessed every 1.5–3 months.

Various methods of hepatic artery embolization (endovascular vessel embolization for liver and biliary tract neoplasms) and intra-arterial chemotherapy can be used in individual patients with isolated or predominant metastatic liver lesions when systemic therapy options are exhausted or to increase the chances of converting liver metastases to operable status. The issue of removing the primary tumor is decided individually, taking into account the risk of associated complications. Patients whose response to treatment is insufficient to render metastases resectable are subject to palliative drug treatment (see section 3.3). In case of isolated peritoneal metastases after achieving remission with systemic therapy for 4–6 months, it is recommended to consider removing peritoneal metastases (extra-organ tumor resection). The use of isolated hyperthermic chemoperfusion in this situation has proved ineffective according to randomized trials. Currently, the PIPAC method in colon cancer can be considered only within clinical trials [221].

• In the case of metachronous resectable liver or lung metastases of colon cancer or resectable recurrences, it is recommended to perform surgery with adjuvant chemotherapy for 6 months (FOLFOX or XELOX or pyrimidine analogues) or perioperative chemotherapy in FOLFOX or XELOX regimens (3 months before surgery and 3 months after it), if adjuvant chemotherapy has not been previously administered or more than 12 months have passed since its completion. Otherwise, treatment is carried out in accordance with the principles described above [16, 55, 56].

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

• In colon cancer in a functionally inoperable patient (against the background of severe comorbid pathology), it is recommended to administer palliative antineoplastic drug therapy or symptomatic therapy (see section 3.3). Tumor stenting or creation of a defunctioning intestinal stoma is possible [60, 114, 115].

GCP CLEL 2Level of Evidence – C (Level of Likelihood of Evidence – 2).

Comments: this situation may be considered when the risk associated with surgery outweighs the risk associated with cancer progression. The decision on the presence of contraindications to surgical treatment can only be made by a multidisciplinary team including a surgeon, a physician (internist), and an anesthesiologist-reanimatologist.

• In case of colon cancer recurrence, it is recommended to consider re-operation [61, 62]; if re-operation is not feasible, systemic chemotherapy is recommended (see Section 3.3).

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

Comments: in complex clinical cases, treatment strategy is determined at a multidisciplinary board involving an abdominal surgeon, radiation oncologist, and medical oncologist based on the results of preoperative evaluation determining the clinical stage of the disease. In unresectable liver metastases (confirmed by a board involving surgeons specializing in liver surgery) with a favorable prognosis (age ≥65 years, disease control achieved for at least 3 months on systemic antineoplastic therapy, no more than 3 lines of treatment administered, ECOG performance status 0–1, wild-type BRAF gene, CEA level less than 80 ng/mL or its decrease by more than 50% compared to baseline before systemic therapy, primary tumor resected, absence of extrahepatic disease manifestations, platelet count greater than 80,000/μL and leukocyte count greater than 2500/μL), liver transplantation may be considered [232]

3.1. Surgical treatment

• Endoscopic treatment of early colon cancer is recommended for:

  • tubulovillous adenomas with high-grade epithelial dysplasia;

  • adenocarcinomas with invasion limited to the mucosal and submucosal layers according to endoscopic ultrasound data;

  • adenocarcinomas with moderate or high differentiation grade [16, 29].

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

Comments:

Contraindications:

• poorly differentiated or mucinous adenocarcinoma;

• lymphovascular invasion;

• signs of polyp stalk invasion or invasion beyond the submucosal layer.

Options:

• endoscopic polypectomy (endoscopic removal of a colon polyp);

• endoscopic submucosal dissection (endoscopic mucosal resection of the colon).

The most frequent complications are pain syndrome, bleeding, perforation.

It should be taken into account that subsequent pathomorphological examination of the endoscopically resected early colon cancer specimen will identify patients who will require resection of the corresponding segment of the colon, for example, patients with >pT1 stage or positive resection margins.

Comments: it has been established that mechanical bowel preparation did not affect the complication rate, but it may be performed at the discretion of the operating surgeon [63].

Comments: laparoscopic colon resections (video-assisted left hemicolectomy, video-assisted right hemicolectomy, video-assisted transverse colon resection, video-assisted sigmoid resection, video-assisted obstructive sigmoid resection, video-assisted anterior rectal resection, laparoscopically assisted colectomy with ileorectal anastomosis) have a number of advantages: early patient rehabilitation, reduced incidence and severity of adhesions, lower requirement for opioid analgesics, shorter hospital stay, and lower risk of postoperative hernias [64–67]. Dissection should be performed along embryonic (fascial) planes aiming to preserve the integrity of the mesocolic fascia. Robotic surgical technology may be used (robotic-assisted left hemicolectomy, robotic-assisted right hemicolectomy, robotic-assisted sigmoid resection).

Comments: it must be taken into account that the scope of surgery should not differ between emergency and elective surgical treatment of colon cancer; therefore, the scope of emergency surgery is determined on an individual basis. If adherence to oncological principles of surgery is impossible (due to lack of technical feasibility, qualifications, or abdominal organ changes associated with acute surgical pathology), or if the patient's severe condition carries a high risk of an extended operation, performing a palliative operation (creation of an intestinal stoma or bypass anastomosis (creation of a colonic bypass anastomosis)) is recommended, followed by referral of the patient for elective surgical treatment to a specialized clinic. For tumors located in the cecum, ascending colon, hepatic flexure, or proximal third of the transverse colon, the creation of a primary anastomosis is acceptable [68, 69, 70].

3.2. Adjuvant Chemotherapy

Comments: biopsy (surgical) material must be tested for DNA microsatellite repeats by PCR (determination of microsatellite instability in biopsy (surgical) material by PCR) or immunohistochemistry for mismatch repair protein deficiency (pathological examination of colonic biopsy (surgical) material using immunohistochemical methods) in stage II disease to determine indications for adjuvant chemotherapy [47, 71, 72]. In stage II disease, if circulating tumor DNA is detected in the postoperative period (determined by a method that has proven its prognostic value in a prospective study), adjuvant chemotherapy is recommended – 4–8 cycles of XELOX or 12 cycles of FOLFOX; in the absence of circulating tumor DNA in blood plasma in the postoperative period in stage II disease (T3N0M0 with clinical risk factors), observation may be considered [223, 231].

• For colon cancer pT3N0M0 with a single adverse prognostic factor and unknown MSI status or microsatellite stability, it is recommended to administer adjuvant monotherapy with pyrimidine analogues for 6 months (which can be used in various regimens: infusion (de Gramont regimen) or oral (capecitabine**) (Table 3) or the XELOX regimen for 3 months. In cases of MSI with pT3N0M0 (with lymphovascular invasion and/or G3), observation is recommended. In cases of MSI with pT3N0M0 (with fewer than 12 lymph nodes examined (data on the risk of progression when examining fewer than 20 lymph nodes are not presented in the literature), presence of perineural invasion, R1 resection), adjuvant chemotherapy with the XELOX regimen for 3 months is recommended. In cases of MSS with pT3N0M0 and combination with 2 or more adverse prognostic factors, adjuvant chemotherapy with the XELOX regimen for 3 months or the FOLFOX regimen for 6 months is recommended [12, 47, 71, 72].

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

Table 3. Regimens of oxaliplatin** and pyrimidine analogues in the treatment of colorectal cancer

• In colon cancer pT4N0M0, regardless of MSI status, adjuvant chemotherapy is recommended according to the XELOX regimen for 3 months or the FOLFOX regimen for 6 months to reduce the risk of disease progression [73].

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

• For patients with stage pT1-3N1M0 colon cancer, adjuvant chemotherapy with the XELOX regimen for 3 months or the FOLFOX regimen for 6 months is recommended to reduce the risk of disease progression [73].

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

Comments: based on a pooled analysis of 6 randomized trials, 3-month XELOX therapy (but not FOLFOX) is non-inferior in terms of 3-year disease-free survival compared to 6-month therapy [73].

• In colon cancer pN2 or pT4N1, adjuvant chemotherapy with the XELOX or FOLFOX regimen for 6 months is recommended to reduce the risk of disease progression [73].

GCP CLEL 2Level of Evidence – C (Level of Likelihood of Evidence – 2).

Comments: according to published data, absolute differences in 5-year overall survival after 3 and 6 months of adjuvant chemotherapy do not exceed 1% [139]. Therefore, even in cases of unfavorable prognosis after 4 cycles of XELOX therapy in the event of poor tolerability, discontinuation or, more optimally, transition to pyrimidine analogue monotherapy can be discussed with the patient [164]. The combination of oxaliplatin** with bolus fluorouracil** (FLOX regimen) has similar efficacy but high toxicity (it is the regimen of choice if cardiotoxicity develops with capecitabine** or 46-hour fluorouracil** infusions) (Table 3). If grade II polyneuropathy symptoms develop during chemotherapy, discontinuation of oxaliplatin** and continuation of pyrimidine analogue monotherapy is recommended. Irinotecan** and targeted therapies, in particular bevacizumab**, cetuximab**, panitumumab**, aflibercept**, regorafenib**, should not be used in the adjuvant treatment of colorectal cancer; there is also no evidence of the efficacy of immunotherapy in the adjuvant setting [74, 75]. The benefit of adding oxaliplatin** to pyrimidine analogues in patients aged 70 years and older is less than in younger patients. Therefore, the use of oxaliplatin** in this age group should be decided individually, depending on the stage, comorbidities, and expected life expectancy. To understand the risks of grade 3–5 adverse events when using drug combinations and the need for dose adjustments in individuals over 70 years of age, a comprehensive geriatric assessment (mycarg.org) is desirable, which will improve the quality of life of these patients and the continuity of treatment [140, 141].

• When administering adjuvant chemotherapy and in the absence of medical contraindications, it is recommended that the 1st cycle of adjuvant chemotherapy be administered no later than 8 weeks from the date of surgery [255].

GCP CLEL 2Level of Evidence – C (Level of Likelihood of Evidence – 2).

Comments: The optimal time to start adjuvant therapy is within 28 days of surgical treatment in the absence of postoperative complications. If the interval is >2 months, adjuvant chemotherapy is of low efficacy. If adjuvant treatment has not been initiated within 3–4 months in the absence of signs of progression, the patient remains under active surveillance.

3.3. Palliative Chemotherapy

• Patients with malignant colon tumors are recommended to receive antitumor drug therapy in accordance with the general principles outlined in the "Practical Guidelines for General Issues of Antitumor Drug Therapy" of the Russian Society of Clinical Oncology [165].

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

• In patients with unresectable metastases and a minimally symptomatic primary tumor, it is recommended not to resect the primary tumor [142].

GRL ALEL 2Grade of Recommendation – A (Level of Evidence – 2).

Comments: according to prospective randomized trials, resection of an asymptomatic primary tumor in unresectable metastases improves neither progression-free survival nor overall survival, but worsens chemotherapy tolerability.

Table 4. Pyrimidine analogue regimens in the treatment of colorectal cancer

End of Table 4

• Patients with a satisfactory performance status are recommended other possible 1st-line chemotherapy options—dual combinations of FOLFOX, XELOX, XELIRI, FOLFIRI, or FOLFOXIRI (regimen details are presented in Tables 3–6) for at least 3–4 months, followed by possible maintenance therapy with pyrimidine analogues [16, 79].

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

Comments: single-agent oxaliplatin** therapy has low efficacy and should be used in combination with pyrimidine analogues. In case of calcium folinate** shortage, it is possible to reduce the dose of calcium folinate** in regimens with infusion or bolus administration of fluorouracil** (e.g., FOLFOX, FOLFIRI, FOLFOXIRI) to a fixed dose of 50 mg on day 1, or even exclude it from the regimens altogether, without a significant impact on their efficacy and tolerability. To prevent febrile neutropenia during the FOLFOXIRI regimen, it is possible to prescribe #filgrastim** at a dose of #300 mcg or #480 mcg or 5 mcg/kg s.c. 24 hours after completion of chemotherapy until neutrophil recovery, or pegfilgrastim** – 6 mg s.c., or empegfilgrastim** – 7.5 mg s.c. 24 hours after the end of chemotherapy once every 15 days [201, 256, 257].

• In patients with clinically significant disease symptoms (ECOG 1–2) and extensive dissemination, it is recommended to use first-line double-drug combinations (FOLFOX, XELOX or XELIRI, FOLFIRI) for at least 3–4 months, followed by possible maintenance therapy with pyrimidine analogues [16, 79].

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

Comments: if the tumor process progresses after first-line therapy, second-line therapy may be prescribed to patients with a satisfactory general status (ECOG ≤2 scores). In case of resistance to the FOLFOX (XELOX) regimen, FOLFIRI/XELIRI or irinotecan** monotherapy is usually prescribed as a second line; in case of resistance to irinotecan** in the first line with the FOLFIRI/XELIRI regimen – FOLFOX/XELOX (see Tables 3, 5) [80]. In the case of chemoresistant tumors (if the disease progresses during therapy or shortly after the end of therapy including irinotecan**, oxaliplatin**, and pyrimidine analogues), further chemotherapy is not indicated (targeted therapy may be considered). If disease progression is observed during adjuvant chemotherapy or within 12 months after it, the optimal first-line regimen will be a regimen using irinotecan** (FOLFIRI/XELIRI), which, according to sub-analyses of randomized trials, yields better results compared to the FOLFOX or FOLFOXIRI regimen. In case of progression during or after first-line therapy with the FOLFOXIRI scheme, the optimal second-line regimen is FOLFIRI. If the performance status is good, re-administration of the FOLFOXIRI regimen can also be considered.

• In patients with MSI in the first line, it is recommended to prescribe pembrolizumab** or nivolumab** or #proлголимаб** (#prolgolimab**) as monotherapy or a combination of ipilimumab** with nivolumab** [137, 138, 249].

LoE: 2The level of concordance for pembrolizumab** is A (level of evidence: 2).

LOC 2Level of evidence for the combination of nivolumab** and ipilimumab** – A (level of data certainty – 2).

LOC 4Level of evidence for nivolumab** and #prolgolimab** monotherapy – C (level of data certainty – 4).

Comments: in patients with a KRAS gene mutation, pembrolizumab** monotherapy was less effective in the first line than in patients without mutations; this trend was not observed with the use of ipilimumab** and nivolumab**. Due to the risk of early progression with anti-PD-1 antibody monotherapy in colorectal cancer patients with a high tumor burden, the combination of the FOLFOX/XELOX regimen with pembrolizumab** or nivolumab** should be considered. The efficacy and safety of the FOLFOX/XELOX combination with anti-PD-1 antibodies in the first line have been demonstrated in phase III randomized trials in advanced gastric cancer, as well as in retrospective studies in colorectal cancer [233, 234]. In the absence of progression, treatment may be discontinued after 1 year of anti-PD-1 antibody therapy [167, 223, 224].

Table 5. Regimens involving irinotecan**, targeted drugs, and immunotherapeutic agents in the treatment of colorectal cancer

Table 5 (cont.)

End of Table 5

* The regimen is characterized by a higher incidence of diarrhea compared to FOLFIRI.

Note: the feasibility of chemotherapy combined with targeted therapy according to the recommendations is determined by drug availability. In case of calcium folinate shortage**, it is possible to reduce the dose of calcium folinate** in regimens with infusion or bolus administration of fluorouracil** (e.g., FOLFOX, FOLFIRI, FOLFOXIRI) to a fixed dose of 50 mg on day 1, or even exclude it from the regimens altogether, without a significant impact on their efficacy and tolerability.

• For frail patients with an ECOG performance status >2, low-toxicity monochemotherapy with pyrimidine analogues with or without targeted therapy, depending on the mutation status and primary tumor localization, or supportive care is recommended; patients with MSI may be prescribed pembrolizumab** or nivolumab** monotherapy or the combination of ipilimumab** and nivolumab** [16].

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

Comment: for patients over 70 years of age it is advisable to conduct a comprehensive geriatric assessment (mycarg.org) to understand the risks of grade 3–5 complications when using drug combinations and the need for dose adjustments, which will improve the quality of life of these patients and the continuity of ongoing treatment.

Comments: bevacizumab** monotherapy has low efficacy and is not recommended. If the results of mutational analysis are delayed, chemotherapy can be initiated, and later, once the results are obtained, a targeted drug can be added starting from cycles 2–4. In case of progression, continuing bevacizumab** with a regimen change is possible (ESMO-MCBS score 1 — according to the ESMO magnitude of clinical benefit scale, drugs are divided into high efficacy level: 4–5 points, moderate level: 2–3 points, low level: 0–1 point). To date, no clinical or molecular factors predicting the efficacy of bevacizumab** are known. Bevacizumab** demonstrates the highest activity in the 1st and 2nd lines of therapy (ESMO-MCBS score 3); adding bevacizumab** to oxaliplatin**- or irinotecan**-based regimens in the 2nd line of treatment significantly increases overall survival. In the 2nd line of therapy, other anti-angiogenic MAbs can be prescribed: aflibercept** (ESMO-MCBS score 1) or ramucirumab** (ESMO-MCBS score 1), which are used only in combination with the FOLFIRI regimen. Indirect comparison of these three anti-angiogenic monoclonal antibodies suggests similar efficacy. Therefore, from a financial perspective and due to lower toxicity, preferential prescription of bevacizumab** is recommended. If significant toxicity develops, therapy can be continued with aflibercept** or ramucirumab**, either alone or in combination with the De Gramont regimen or irinotecan**. Unlike bevacizumab* in unresectable metastases, cetuximab** or panitumumab** are active both as monotherapy and in combination with chemotherapy, but only in patients lacking mutations in RAS and BRAF genes, lacking HER-2/neu overexpression, with a microsatellite stable phenotype, and with primary tumor localization in the left colon. Cetuximab** and panitumumab** must not be used with capecitabine**, FLOX, XELOX, XELIRI, or IFL regimens. The standalone activity of cetuximab** and panitumumab** allows recommending their use as monotherapy in the 3rd–4th line(ESMO-MCBS 4 points). In later lines, panitumumab** or cetuximab** can also be used in cases of right-sided primary tumor localization in the absence of mutations in RAS and BRAF genes. Concomitant use of bevacizumab** and cetuximab** or panitumumab** worsens treatment outcomes and is not recommended. For left-sided primary tumor localization, preference in combination with anti-EGFR antibodies in the first line is given to FOLFOX or FOLFIRI regimens (ESMO-MCBS score 4 when compared with chemotherapy and 3 when compared with combinations with bevacizumab**). For right-sided primary tumor localization, preference in combination with bevacizumab** in the first line is given to the FOLFOXIRI regimen (ESMO-MCBS score 3) regardless of RAS and BRAF mutation status. The goals of palliative chemotherapy are to increase overall survival, reduce symptom severity, and improve quality of life. Patients who have received all 3 active chemotherapy drugs (irinotecan**, oxaliplatin**, and pyrimidine analogues) have a significantly greater overall survival, regardless of the number of treatment lines in which this was achieved. The optimal duration of the 1st line of therapy remains unclear. Possible options are:

1) continuous therapy until disease progression or unacceptable toxicity develops;

2) administering treatment for 3–6 months followed by observation and re-administration of previously effective treatment;

3) using a double combination for at least 3–4 months followed by maintenance with pyrimidine analogues (the maintenance therapy strategy has advantages over complete cessation of treatment). If a combination of chemotherapy and bevacizumab** is used, maintenance therapy with bevacizumab** and pyrimidine analogues should be continued until disease progression or unacceptable toxicity occurs. When using a combination of chemotherapy with cetuximab** or panitumumab**, maintenance therapy with a combination of calcium folinate**, fluorouracil**, and cetuximab** or panitumumab** infusions or MAb monotherapy until disease progression is also recommended [26].

Patient survival is also affected by the sequence of targeted therapy administration. Thus, if bevacizumab** was prescribed in the 1st line of therapy, it is optimal to continue anti-angiogenic therapy in the 2nd line even in the absence of RAS and BRAF mutations, which provides a survival advantage compared to patients who received cetuximab** or panitumumab** in the 2nd line [151, 152]. If cetuximab** or panitumumab** was prescribed in the 1st line, it is optimal to use regimens including bevacizumab**, aflibercept**, or ramucirumab** in the 2nd line. Indirect comparison of these three anti-angiogenic monoclonal antibodies suggests similar efficacy. Therefore, from a financial perspective and due to lower toxicity, preferential prescription of bevacizumab** is recommended. Continuing cetuximab** or panitumumab** upon progression does not improve patient survival rates even in the absence of RAS and BRAF mutations [153]. An exception is when anti-EGFR antibodies were discontinued in the absence of disease progression [241].

• In the 2nd and subsequent lines of therapy in the presence of tumor MSI, if not previously administered, nivolumab** or pembrolizumab** monotherapy or the combination of nivolumab** and ipilimumab** is recommended [82–84]. The latter option is characterized by a higher objective response rate, although data comparing long-term survival parameters are not presented in the scientific literature [82–84]. In the absence of progression, treatment can be discontinued after 1 year of anti-PD-1 antibody therapy [167].

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

Comments: in patients with RAS mutations, pembrolizumab** monotherapy in a randomized study showed lower efficacy in the first line compared to patients without mutations; no such trends were observed with the ipilimumab** and nivolumab** regimen. Given the potential risk of early progression when using anti-PD-1 antibody monotherapy in colon cancer, patients with a high tumor burden may be considered for the combination of FOLFOX/XELOX with pembrolizumab** or nivolumab**. Similar approaches to MSI can be considered when pathogenic POLD1 and POLE mutations are detected in metastatic colorectal cancer.

• In patients with an ECOG performance status of 0–1 with progression or intolerance to oxaliplatin**, irinotecan**, fluoropyrimidine analogues, bevacizumab**, and anti-EGFR antibodies (as indicated), regorafenib** (ESMO-MCBS score 1) is recommended. It is recommended to start regorafenib** therapy in the following regimen: #80 mg/day p.o. — week 1, #120 mg/day p.o. — week 2, #160 mg/day p.o. — week 3, followed by a 1-week break. Dose escalation is possible only with satisfactory drug tolerance [214].

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

Comments: the chance of achieving long-term remission with regorafenib is low in patients with a metastatic disease duration of less than 18 months, metastasis in more than 2 organs, hepatic metastases, elevated LDH levels, and an ECOG performance status of 2–4. In the presence of these factors, regorafenib is not recommended.

• In the 2nd and subsequent lines of therapy in the presence of HER2/neu gene overexpression or amplification and the absence of RAS and BRAF mutations, the administration of combinations of #trastuzumab** and #lapatinib** or #trastuzumab** and #pertuzumab** (Table 5) is recommended [132, 133].

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

• In the 3rd and subsequent lines of therapy, re-administration of chemotherapy regimens with or without targeted therapy that were effective in previous lines of treatment is recommended [154, 215].

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

Comments: repeat use of bevacizumab** in the 3rd and subsequent lines with drugs registered in the Russian Federation lacks sufficient evidence to recommend this approach, especially in the presence of RAS mutations. If rare ALK, RET, or NTRK1-3 translocations or HER2/neu overexpression are detected, the administration of corresponding inhibitors is possible based on the decision of a medical board.

Comments: the use of the FOLFOXIRI regimen with bevacizumab** determines a higher objective response rate, but does not increase progression-free survival or overall survival compared to doublets with bevacizumab**. Some retrospective studies have noted its greater efficacy in right-sided localization and BRAF mutations. In case of disease progression during 1st-line therapy with a BRAF mutation, the FOLFIRI regimen with aflibercept**/bevacizumab**/ramucirumab** [85] or a combination of cetuximab** or panitumumab** with encorafenib/#vemurafenib**/#dabrafenib** and #trametinib** [86, 87] may be prescribed. If anti-EGFR antibodies cannot be administered, the combination of #vemurafenib** and #cobimetinib** may be considered, although this is less preferable. (Table 6) (BRAF mutations are divided into 3 classes (Appendix A5); the described targeted therapy approach is active in class I and II mutations). If chemotherapy cannot be prescribed in the first line of therapy in the presence of a BRAF mutation, therapy with a combination of cetuximab** or panitumumab** with encorafenib/#vemurafenib**/#dabrafenib**, with or without #trametinib**, may be considered. In certain clinical situations requiring rapid achievement of an objective response, a combination of chemotherapy (irinotecan**, FOLFOX, FOLFIRI) and anti-EGFR antibodies with BRAF inhibitors may be prescribed. In class 3 BRAF mutations, treatment is carried out as for the wild-type gene. In the case of a combination of a BRAF mutation and MSI, preference is given to immunotherapy: a combination of ipilimumab** with nivolumab** or pembrolizumab**/nivolumab**/#proлголимаб** as monotherapy.

• Prolonged (over 6 hours) fluorouracil** infusions are recommended to be administered via central venous access using infusion pumps [88].

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

Table 6. Drug regimens in the treatment of colorectal cancer with BRAF mutation

Note: the possibility of administering chemotherapy in combination with targeted therapy in accordance with the recommendations is determined by drug availability.

3.4. Symptomatic Therapy

• Patients with acute bleeding are recommended to undergo an emergency endoscopic examination of the gastrointestinal tract (endoscopic peripheral vessel hemostasis using electrocoagulation, endoscopic hemostasis using thermocoagulation, endoscopic hemostasis using laser photocoagulation), and systemic hemostatic therapy. Depending on the study results, endoscopic hemostasis is performed. If endoscopic hemostasis is impossible or ineffective, emergency surgery is performed [89].

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

• In case of tumor stenosis, it is recommended endoscopic stenting of the tumor stenosis zone (endoscopic stenting for tumor stenosis) or surgical treatment [89, 90].

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

• For the treatment of chronic pain syndrome, it is recommended to perform external beam radiation therapy (external beam radiation therapy for colon tumors), drug therapy, and locoregional anesthesia (local anesthesia) depending on the cause of the pain syndrome [89].

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

• For the treatment of ascites, it is recommended to consider paracentesis [91].

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

Comments: the goals of so-called "best supportive care" are the prevention and alleviation of disease symptoms and the maintenance of the quality of life of patients and their families, regardless of the stage of the disease and the need for other types of therapy. In the case of colon cancer, measures aimed at alleviating core symptoms help increase life expectancy.

• When administering antitumor drug therapy with emetogenic side effects, it is recommended to provide prevention and treatment of nausea and vomiting [1, 2].

GOR ALOE 1Grade of Recommendation – A (Level of Evidence – 1).

Comments: The principles of diagnosis, prevention, and treatment of nausea and vomiting during antineoplastic drug therapy are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Vladimirova L.Yu. et al. Nausea and vomiting [3]. https://rosoncoweb.ru/standarts/?chapter=nausea_vomiting

• In patients with bone metastases, it is recommended to provide prevention and treatment of bone complications [4].

GOR ALOE 1Grade of Recommendation – A (Level of Evidence – 1).

Comments: The principles of diagnosis, prevention, and treatment of bone complications are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Bagrova S.G. et al. Bone tissue pathology [5]. https://rosoncoweb.ru/standarts/?chapter=bone_pathology

• Patients are recommended to receive prevention and treatment of venous thromboembolic complications [6-8].

GOR ALOE 1Grade of Recommendation – A (Level of Evidence – 1).

Comments: The principles of diagnosis, prevention, and treatment of venous thromboembolic complications are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Somonova O.V. et al. Thromboembolic complications [9]. https://rosoncoweb.ru/standarts/?chapter=thromboembolism

• During antineoplastic drug therapy, patients are recommended to receive prophylaxis and treatment for febrile neutropenia and infectious complications [10-12].

GOR ALOE 1Grade of Recommendation – A (Level of Evidence – 1).

Comments: A detailed algorithm for the diagnosis, prevention, and treatment of febrile neutropenia and infectious complications, as well as the principles of antibacterial therapy, are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Sakaeva D.D. et al. Practical guidelines for the diagnosis and treatment of febrile neutropenia [13]. https://rosoncoweb.ru/standarts/?chapter=febrile_neutropenia

• During antineoplastic drug therapy, patients are recommended to undergo management of hepatotoxicity [14, 15].

GOR CLOE 3Grade of Recommendation – C (Level of Evidence – 3).

Comments: The principles of diagnosis, prevention, and treatment of hepatotoxicity are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Tkachenko P.E. et al. Hepatotoxicity [16]. https://rosoncoweb.ru/standarts/?chapter=hepatotoxicity

• When patients receive antitumor drug therapy, it is recommended to provide prevention and treatment of cardiovascular complications [17-20].

GOR ALOE 1Grade of Recommendation – A (Level of Evidence – 1).

Comments: The principles of diagnosis, prevention, and treatment of cardiovascular complications during antitumor therapy are outlined in the Practical Guidelines of the Russian Society for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Vitsenya M.V. et al. Cardiovascular toxicity [21]. https://rosoncoweb.ru/standarts/?chapter=cardiovascular_toxicity

• During antitumor drug therapy, patients are recommended to receive prevention and treatment of dermatological reactions [22].

GOR ALOE 1Grade of Recommendation – A (Level of Evidence – 1).

Comments: The principles of diagnosis, prevention, and treatment of dermatological complications are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Koroleva I.A. et al. Dermatological reactions [23]. https://rosoncoweb.ru/standarts/?chapter=dermatological_reactions

• To maintain the metabolic reserves of a cancer patient and increase their tolerance to treatment (surgical, drug therapy, radiation therapy), nutritional support is recommended. The choice of nutritional support method is determined by the patient's various types of nutritional disorders. Placement of a nasogastric, nasointestinal, percutaneous endoscopic, laparoscopic, or laparotomic stoma, endoscopic stenting for tumor stenosis, or palliative radiation therapy may be recommended [24, 25].

UDD 1Level of Recommendation – 1 (Level of Evidence – 1).

Comments: The principles of nutritional support are presented in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Sytov A.V. et al. Nutritional support [26]. https://rosoncoweb.ru/standarts/?chapter=nutritional_support

• During antitumor drug therapy, patients are recommended to receive prevention and treatment of nephrotoxicity [27-29].

GOR ALOE 1Grade of Recommendation – A (Level of Evidence – 1).

Comments: A detailed algorithm for the diagnosis, prevention, and treatment of nephrotoxicity is presented in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Gromova E.G. et al. Nephrotoxicity [30]. https://rosoncoweb.ru/standarts/?chapter=nephrotoxicity

• During antitumor drug therapy, patients are recommended to receive prevention and treatment of immune-mediated adverse events [31-34].

GOR ALOE 1Grade of Recommendation – A (Level of Evidence – 1).

Comments: A detailed algorithm for the diagnosis, prevention, and treatment of immune-mediated adverse events is outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Protsenko S.A. et al. Immune-mediated adverse events [35]. https://rosoncoweb.ru/standarts/?chapter=immunerelated_adverse_events

• During antitumor drug therapy, patients are recommended to receive prevention and treatment of mucositis [36, 37].

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

Comments: A detailed algorithm for the diagnosis, prevention, and treatment of mucositis is outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Semiglazova T.Yu. et al. Mucositis [38]. https://rosoncoweb.ru/standarts/?chapter=mucositis

• Patients are recommended to receive treatment for anemia, which occurs as a symptom of a malignant neoplasm and as an adverse event during antineoplastic drug therapy [39, 40].

GOR ALOE 1Grade of Recommendation – A (Level of Evidence – 1).

Comments: The procedure and principles for the prevention and treatment of anemia correspond to the principles outlined in the clinical guidelines "Anemia in Malignant Neoplasms" (ID: KR624, approval year 2020, www.cr.rosminzdrav.ru) and in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Orlova R.V. et al. Anemia [41].

• During treatment, patients are recommended to receive treatment for anorexia-cachexia syndrome [42].

GOR CLOE 3Grade of Recommendation – C (Level of Evidence – 3).

Comments: A detailed algorithm for the diagnosis and treatment of anorexia-cachexia syndrome is outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Sytov A.V. et al. Practical guidelines for the treatment of anorexia-cachexia syndrome in cancer patients [43].

https://rosoncoweb.ru/standarts/?chapter=anorexia-cachexia

• When administering cyclic antineoplastic drug therapy involving continuous prolonged (over 6 hours) infusions of antineoplastic agents (fluorouracil**, doxorubicin**, etc.) or in case of poor peripheral venous access, the use of central venous access and infusion pumps is recommended [44].

GOR BLOE 2Grade of Recommendation – B (Level of Evidence – 2).

Comments: The choice of central access option is determined by the planned duration of the entire treatment course, patient preferences, and anatomical features. For long-term courses of therapy (over 3 months), implantation of a subcutaneous venous port system is most convenient. For shorter durations, a peripherally inserted central catheter can serve as an alternative. The principles of using central venous access are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Isyangulova A.Z. et al. Central venous access [45]. https://rosoncoweb.ru/standarts/?chapter=central_venous_access

• During antineoplastic drug therapy, it is recommended to provide prevention and treatment of antineoplastic drug extravasation. When planning antineoplastic drug therapy, the selection of vascular access is important for the prevention of antineoplastic agent extravasation [46].

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

Comments: Algorithms for vascular access selection, prevention, diagnosis, and treatment of extravasation are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Buydenok Yu.V. et al. Extravasation of antineoplastic drugs [47]. https://rosoncoweb.ru/standarts/?chapter=extravasation_antitumor_drugs

• During antineoplastic treatment, it is recommended to manage chronic pain syndrome [48].

GOR ALOE 1Grade of Recommendation – A (Level of Evidence – 1).

Comments: Algorithms for the diagnosis and treatment of chronic pain syndrome in cancer patients are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Kogonia L.M. et al. Chronic pain syndrome [49]. https://rosoncoweb.ru/standarts/?chapter=chronic_pain_syndrome

• During antineoplastic drug therapy, it is recommended to provide prevention and treatment of infusion reactions [50].

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

Comments: Algorithms for the prevention, diagnosis, and treatment of infusion reactions are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Orlova R.V. et al. Infusion reactions [51]. https://rosoncoweb.ru/standarts/?chapter=infusion_reactions

• During therapy, it is recommended to monitor and treat reactivation/exacerbation of chronic viral hepatitis [52].

GCR BLOE 3Grade of Recommendations — B (Level of Evidence — 3).

Comments: Principles of monitoring and management tactics in cancer patients with chronic viral hepatitis are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Feoktistova P.S. et al. Chronic viral hepatitis [53]. https://rosoncoweb.ru/standarts/?chapter=chronic_viral_hepatitis

• During antineoplastic drug therapy, it is recommended to provide prevention and treatment of neurological complications [54].

GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).

Comments: Principles of diagnosis, prevention, and treatment of neurological complications of antineoplastic therapy are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Latipova D.Kh. et al. Neurological complications [55]. https://rosoncoweb.ru/standarts/?chapter=neurological_complication

• During antineoplastic hormone therapy, patients are recommended to undergo prevention and treatment of hormone-mediated adverse events [56].

GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).

Comments: Principles of diagnosis, prevention, and treatment of hormone-mediated adverse events are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Stenina M.B. et al. Hormone-mediated side events [57]. https://rosoncoweb.ru/standarts/?chapter=hormone-mediated_side_events

• For patients with pancreatic cancer, enzyme replacement therapy is recommended in case of secretory insufficiency [58].

GOR ALOE 1Grade of Recommendation – A (Level of Evidence – 1).

Comments. Algorithms for the diagnosis and treatment of exocrine pancreatic insufficiency in pancreatic cancer are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Sytov A.V. et al. Pancreatic enzyme replacement therapy in pancreatic cancer [59]. https://rosoncoweb.ru/standarts/?chapter=pancreatic_enzyme_replacement_therapy

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Comment: there is no evidence or known mechanisms indicating an increased risk of colon cancer progression associated with hormone replacement therapy, any types of spa-resort treatment, or physiotherapy. This statement does not rule out potential contraindications related to long-standing unhealed wounds, foci of chronic inflammation, an increased risk of hernias, and other factors that may be associated with prior treatment. These contraindications are general for wounds and inflammatory foci of any etiology. A history of colon cancer per se is not a contraindication to any methods of medical treatment, physiotherapy, or spa-resort treatment. When assessing indications for any type of non-oncological treatment and rehabilitation, one should be guided solely by the patient's existing health problems, regardless of their etiology, rather than the fact of a history of cancer. The prescription of spa-resort treatment, physiotherapy, and medical treatment for comorbid conditions, including hormone replacement therapy and oral contraceptives, does not require a consultation with an oncologist.

• During prehabilitation, it is recommended to conduct exercise therapy (physiotherapy exercises), psychological and nutritional support, and patient education [92–95].

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

Comments: a comprehensive rehabilitation program for patients with colorectal cancer, which includes home-based exercise therapy (a moderate-intensity exercise routine involving both aerobic and anaerobic loads), nutritional counseling, and psychological support to overcome anxiety and depression (starting 28 days before surgery and continuing for 8 weeks after), significantly improves postoperative quality of life. Psychological rehabilitation utilizing stress management techniques (relaxation, positive mindset building) lasting 40–60 minutes 6 days a week, initiated 5 days before surgery and continued for 30 days postoperatively, significantly improves quality of life.

Comments: the use of incentive spirometry, elevation of the head of the bed, early initiation of breathing exercises, and early mobilization of patients help prevent postoperative pulmonary congestion [97].

To prevent muscle wasting, pulmonary, and thrombotic complications, bed rest is indicated for 2 hours before surgery and no more than 6 hours after it. Breathing exercises begin as soon as the patient's consciousness normalizes postoperatively. Patients are trained in postoperative breathing exercises prior to surgery. Following surgery, patients with colorectal cancer are recommended to practice diaphragmatic breathing, which improves lymph circulation in the body and ventilates the lower lobes of the lungs, which usually do not fill with air sufficiently during thoracic breathing.

• During the 2nd stage of rehabilitation for low anterior resection syndrome, it is recommended to perform a functional assessment, including methods for measuring the contraction of the rectum and anal sphincter (anorectal zone) [98–101, 118, 119].

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

Comments: for this syndrome it is recommended to perform a set of pelvic floor muscle strengthening exercises, biofeedback therapy, tibial neuromodulation, and electrical stimulation of the pelvic floor and perineal muscles [98–101]. For urinary disturbances and erectile dysfunction, pelvic floor muscle strengthening exercises, biofeedback therapy, tibial neuromodulation, and electrical stimulation of the pelvic floor and perineal muscles are indicated. In the event of lower limb lymphedema, complete decongestive therapy should be administered, including wearing compression garments, performing therapeutic exercise routines (exercise therapy for colon diseases), and skin care. In case of lower limb lymphedema, intermittent pneumatic compression of the limbs combined with complete decongestive therapy, low-intensity laser therapy combined with complete decongestive therapy, electrotherapy combined with complete decongestive therapy, low-frequency magnetotherapy combined with complete decongestive therapy, and deep oscillation (alternating electric field massage) combined with complete decongestive therapy should also be prescribed.

• During chemotherapy, it is recommended to perform therapeutic exercise routines (exercise therapy for colon diseases), apply relaxation techniques including diaphragmatic breathing and progressive muscle relaxation, and consider prescribing a course of massage [102–104].

CGR BLEL 1Level of recommendation grade – B (level of evidence – 1).

Comments: the volume and intensity of exercise therapy are selected individually based on the degree of fatigue (mild, moderate, severe). As the general condition improves, the intensity of exercise therapy can be increased. A combination of aerobic and resistance training is recommended.

• During the 3rd stage of rehabilitation, maintaining an active lifestyle and performing therapeutic exercise routines (exercise therapy for colon diseases) following combined treatment for colon cancer is recommended [105–109].

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

Comments: performing exercise therapy regimens by patients with cancer recurrence reduces the risk of all-cause mortality by 29%. Exercise therapy and physical activity in patients with disseminated tumor process reduce fatigue, increase mobility, decrease depression levels, and improve quality of life.

Comment: currently, there are no data, including published studies, indicating an increased risk of tumor progression when using these rehabilitation methods.

5. Prevention and Dispensary Observation

Comments: the objective of monitoring is early detection of disease progression for the purpose of early initiation of chemotherapy or surgical treatment of resectable metastatic sites, recurrent tumors, as well as detection of metachronous colon tumors (Appendix A6). Prevention and treatment of complications caused by systemic antineoplastic therapy and radiation therapy should be carried out according to the relevant guidelines.

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

6. Organization of Medical Care

Medical care, with the exception of medical care within clinical trials, in accordance with Federal Law No. 323-FZ of November 21, 2011 (as amended on May 25, 2019) "On the Fundamentals of Health Protection in the Russian Federation", is organized and provided:

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

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

3) based on these clinical guidelines;

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

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

When colon and rectosigmoid cancer is detected or suspected 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 consultation to an outpatient oncological care center or a primary oncological office or primary oncological department of a medical organization to receive primary specialized health care.

Consultation at the outpatient oncological care center, primary oncological office, or primary oncological department of a medical organization must be conducted no later than 5 working days from the date of issuance of the referral for consultation. The oncologist of the outpatient oncological care center (or, in the absence of such a center, the oncologist of the primary oncological office or primary oncological department) shall arrange for the acquisition of biopsy (surgical) material as well as the performance of other studies 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 obtaining biopsy (surgical) material or performing other diagnostic examinations at the medical organization that includes the outpatient oncological care center (primary oncological office, primary oncological department), the patient shall be referred by the attending physician to an oncological dispensary or a medical organization providing medical care to patients with oncological diseases.

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

When colon and rectosigmoid cancer is detected or suspected 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 specialized antineoplastic treatment methods.

The oncologist of the outpatient oncological care center (primary oncological office, primary oncological department) shall refer the patient to an oncological dispensary or medical organizations providing medical care to patients with oncological diseases to clarify the diagnosis (in cases where the diagnosis, including the extent of the oncological process and the stage of the disease, cannot be established by the oncologist of the outpatient oncological care center, primary oncological office, or primary oncological department) and to provide specialized, including high-tech, medical care.

The time limit for the initiation of specialized, excluding high-tech, medical care for patients with oncological diseases in a medical organization providing medical care to patients with rectal cancer shall not exceed the time limits established in the state guarantee program for the free provision of medical care to citizens, approved by the Government of the Russian Federation — 7 calendar days from the date of morphological verification of the malignancy.

Specialized, including high-tech, medical care is provided by oncologists and radiation therapists in an oncological dispensary or medical organizations providing medical care to patients with colon and rectosigmoid cancer, which possess a license, the necessary material and technical base, and certified specialists, in inpatient and day-hospital settings, and includes prevention, diagnosis, and treatment of oncological diseases requiring the use of special methods and complex unique medical technologies, as well as medical rehabilitation.

In a medical organization providing medical care to patients with colon and rectosigmoid cancer, the medical examination and treatment strategy is determined by a concilium of oncologists and radiation therapists, involving other medical specialists if necessary. The decision of the medical concilium is formalized in a protocol, signed by the participants of the concilium, and entered into the patient's medical documentation.

Indications for hospitalization in a 24-hour or day hospital of a medical organization providing specialized, including high-tech, medical care in the field of oncology are determined by a concilium of oncologists and radiation therapists, involving other medical specialists if necessary.

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

1) presence of complications of colon and rectosigmoid cancer requiring specialized medical care in an emergency and urgent form;

2) presence of treatment complications (surgical intervention, radiation therapy, drug therapy, etc.) of colon and rectosigmoid cancer.

Indications for planned hospitalization in a medical organization are:

1) the need to perform complex interventional diagnostic medical procedures requiring subsequent observation in a 24-hour inpatient unit or day hospital;

2) presence of indications for specialized antineoplastic treatment (surgical intervention, radiation therapy—including contact, external beam, and other types of radiation therapy, drug therapy, etc.) requiring monitoring in a 24-hour or day-hospital setting.

Indications for discharging a patient from a medical organization are:

1) completion of a course of treatment or one of the stages of 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 medical interventions in an inpatient setting;

2) refusal of the patient or their legal representative from specialized, including high-tech, medical care in a 24-hour or day-hospital setting prescribed by the concilium of the oncological medical organization, provided there are no complications of the underlying disease and/or treatment requiring drug correction and/or medical interventions in an inpatient setting;

3) the need to transfer the patient to another medical organization with the appropriate profile of medical care.

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

7. Additional Information

No additional information.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Mamedli Zamar Zaurovich, MD, PhD, Head of Surgical Department No. 3 (Coloproctology), National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health.

2. Gordeev Sergey Sergeevich, MD, PhD, Head of the Department of Research Planning and Coordination, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health.

3. Fedyanin Mikhail Yuryevich, MD, PhD, Professor, Head of the Department of Science, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health; Head of the Chemotherapy Service, Moscow Multidisciplinary Clinical Center "Kommunarka", Moscow Healthcare Department; Head of the Department of Oncology, National Medical Research Center for Pirogov of the Russian Ministry of Health.

4. Achkasov Sergey Ivanovich, MD, PhD, Professor, Director, National Medical Research Center of Coloproctology named after A.N. Ryzhikh of the Russian Ministry of Health.

5. Belokhvostova Anna Sergeevna, PhD, Head of the Department of Drug Treatment of Malignant Neoplasms, A.F. Tsyb Medical Radiological Research Center – Branch of the National Medical Research Center of Radiology of the Russian Ministry of Health.

6. Bolotina Larisa Vladimirovna, MD, PhD, Head of the Chemotherapy Department, Department of Tumor Drug Treatment, P.A. Herzen Moscow Oncology Research Institute – Branch of the National Medical Research Center of Radiology of the Russian Ministry of Health.

7. Karachun Aleksey Mikhailovich, MD, PhD, Professor, Head of the Surgical Department of Abdominal Oncology, National Medical Research Center of Oncology named after N.N. Petrov of the Russian Ministry of Health; Department of Oncology, North-Western State Medical University named after I.I. Mechnikov.

8. Kozlov Nikolay Aleksandrovich, PhD, Pathologist, Department of Pathology, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health.

9. Nevolskich Aleksey Alekseevich, MD, PhD, Deputy Director for Therapeutic Work, A.F. Tsyb Medical Radiological Research Center – Branch of the National Medical Research Center of Radiology of the Russian Ministry of Health.

10. Petrov Kirill Sergeevich, PhD, Radiologist, Department of Diagnostic Radiology, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health.

11. Tryakin Alexey Aleksandrovich, MD, PhD, Professor, Deputy Director for Research, Research Institute of Clinical Oncology, Head of the Department of Antineoplastic Drug Therapy No. 2, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health.

12. Tsukanov Aleksey Sergeevich, MD, PhD, Head of the Department of Laboratory Genetics, National Medical Research Center of Coloproctology named after A.N. Ryzhikh of the Russian Ministry of Health.

Rehabilitation Section

1. Merzlyakova Anna Mikhailovna, PhD, Oncologist, Department of Medical Rehabilitation, P.A. Herzen Moscow Oncology Research Institute – Branch of the National Medical Research Center of Radiology of the Russian Ministry of Health.

2. Obukhova Olga Arkadievna, PhD, Physical and Rehabilitation Medicine Physician, Rehabilitation Department, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health.

Medical Care Organization Section

• Gevorkyan Tigran Gagikovich, Deputy Director for Federal Project Implementation, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health.

• Fomenko Yury Aleksandrovich, PhD, Deputy General Director for Clinical and Expert Work, National Medical Research Center of Oncology of the Russian Ministry of Health.

• Ivanov Sergey Anatolyevich, MD, PhD, Professor, Corresponding Member of the RAS, Honored Physician of the RF, Director, A.F. Tsyb Medical Radiological Research Center – Branch of the National Medical Research Center of Radiology of the Russian Ministry of Health, Chief freelance Oncologist of the Central Federal District of the Russian Ministry of Health.

• Khaylova Zhanna Vladimirovna, PhD, Deputy Director for Organizational and Methodological Work, A.F. Tsyb Medical Radiological Research Center – Branch of the National Medical Research Center of Radiology of the Russian Ministry of Health.

• Komarov Yury Igorevich, PhD, Deputy Director for Organizational and Methodological Work, National Medical Research Center of Oncology named after N.N. Petrov of the Russian Ministry of Health.

Supportive Care Section

1. Gladkov Oleg Alexandrovich, Professor, MD, DSc, Director of EVIMED Medical Center LLC.

2. Karaseva Vera Vitalievna, MD, DSc, Associate Professor, Professor, Department of Oncology, Institute of Continuing Professional Education, Pirogov Russian National Research Medical University of the Russian Ministry of Health.

No conflicts of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1) oncologists,

2) surgeons,

3) radiologists,

4) medical geneticists,

5) radiation therapists,

6) coloproctologists,

7) endoscopists,

8) clinical pharmacologists,

9) medical rehabilitation specialists.

Methods used for evidence collection/selection: search in electronic databases; analysis of current scientific developments on colon and rectosigmoid junction cancer in Russia and abroad; synthesis of practical experience of Russian and foreign experts.

The grading system for the quality of evidence for diagnostic, preventive, therapeutic, and rehabilitation interventions, and the grading system for the strength of recommendations for preventive, diagnostic, therapeutic, and rehabilitation interventions are presented below.

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

Table А2. Level of Evidence (LoE) rating scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

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

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 expert review.

• Internal expert review.

Description of the guideline validation method:

The draft of these guidelines was peer-reviewed by independent experts who were asked to comment primarily on whether the interpretation of the evidence underlying the recommendations is easy to understand.

Comments were received from primary care pediatric oncologists regarding the clarity of the presentation of the guidelines and their assessment of the importance of the guidelines as a tool for daily practice.

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.

Updates to clinical guidelines: updates are performed at least once every 3 years, taking into account new information on the diagnosis and management of colon and rectosigmoid junction cancer, but no more frequently than once every 6 months. The decision to update is made by the Russian Ministry of Health based on proposals submitted by professional medical non-profit organizations. The submitted proposals must take into account the results of comprehensive assessments of medicinal products and medical devices, as well as the results of clinical approbation.

When selecting publications as potential sources of evidence, the methodology used in each study is examined to ensure its validity. 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

Up-to-date instructions for medicinal products mentioned in these clinical guidelines can be found in the State Register of Medicinal Products posted on the website of the Russian Ministry of Health: http://grls.rosminzdrav.ru.

Criteria for genetic testing of patients with suspected Lynch syndrome

Criteria developed by the State Research Center of Coloproctology named after A.N. Ryzhikh for Russian patients:

1. Patient with colorectal cancer under 43 years of age.

2. Along with colorectal cancer, 2 or more additional malignant tumors of any site are registered in the patient or blood relatives, regardless of age.

Amsterdam I criteria

• At least 3 relatives have histologically verified colorectal cancer, one of whom is a first-degree relative.

• The disease is traced through at least 2 generations.

• At least 1 relative was diagnosed with colorectal cancer under the age of 50 years.

• Familial adenomatous polyposis is excluded [121].

Appendix A4. Minimum Panel of RAS Gene Mutations for Testing in Colorectal Cancer

Appendix A5. Classification of BRAF Gene Mutations

Appendix A6. Follow-up Schedule for Patients Following Completion of Treatment

*Performed annually if polyps are detected. If colonoscopy was not performed prior to treatment due to a stenosing tumor, it is performed within 3–6 months after resection.

Note: in patients at high risk of recurrence, the interval between examinations may be shortened.

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

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

Appendix G1. Amsterdam II Criteria

Russian name: Amsterdam II criteria.

Original name: Amsterdam II Criteria.

Source: Vasen H.F., Watson P., Mecklin J.P., Lynch H.T. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 1999;116:1453–6.

Type: criteria.

Purpose: evaluation of the feasibility of MSI testing.

Content:

1. At least 3 relatives developed a cancer associated with Lynch syndrome (colorectal cancer, endometrial cancer, gastric cancer, ovarian cancer, ureter/renal pelvis cancer, brain cancer, small bowel cancer, hepatobiliary tract cancer, and skin cancer (sebaceous gland)), one of whom is a first-degree relative.

2. The disease is traced through at least 2 generations.

3. At least 1 relative has been diagnosed with Lynch syndrome-associated cancer under the age of 50.

4. Familial adenomatous polyposis is excluded in cases of colorectal cancer.

5. Tumors should be verified whenever possible.

Appendix G2. Bethesda Criteria for Microsatellite Instability Testing

Russian name: Bethesda criteria for MSI testing.

Original name: The Revised Bethesda Guidelines for testing colorectal tumors for microsatellite instability (MSI).

Source: Laghi L., Bianchi P., Roncalli M., Malesci A. Re: Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 2004;96(18):1402–3.

Type: criteria.

Purpose: evaluation of the feasibility of MSI testing.

Content:

1. Colorectal cancer in a patient under 50 years of age.

2. Presence of synchronous, metachronous colorectal cancer, or another cancer that may be associated with Lynch syndrome, regardless of age.

3. Colorectal cancer with microsatellite instability (MSI) detected by histological examination in a patient under 60 years of age.

4. Colorectal cancer in one or more first-degree relatives with a disease potentially associated with Lynch syndrome; at least 1 of the cases diagnosed under 50 years of age.

5. Colorectal cancer in 2 or more first- or second-degree relatives with diseases potentially associated with Lynch syndrome, regardless of age.

Appendix G3. Mandard Tumor Regression Grade (TRG) Criteria

Russian title: Mandard tumor regression grade criteria.

Original title: Prognostic value of mandard and dworak tumor regression grading.

Source: Santos M.D. et al. Prognostic value of mandard and dworak tumor regression grading in rectal cancer: study of a single tertiary center // ISRN surgery. – 2014. – Vol. 2014.

Type: criteria.

Purpose: assessment of tumor regression in response to treatment.

Content and interpretation:

Appendix G4. ECOG Performance Status Criteria

Russian title: ECOG performance status criteria.

Original title: The ECOG Scale of Performance Status.

Source: Oken M.M. et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5(6):649–65.

Type: rating scale.

Purpose: clinical assessment of the patient's general condition.

Content and interpretation: