Rectal Cancer: Clinical Guidelines

List of Abbreviations

IV – intravenous(ly)

IHC – immunohistochemistry

Malignancy – malignant neoplasm

mAb – monoclonal antibodies

CRC – colorectal cancer

CT – computed tomography

RT – radiotherapy

RT 5x5 Gy – radiation therapy with a dose per fraction of 5 Gy, total dose of 25 Gy

PT – physical therapy

MRI – magnetic resonance imaging

NACT – neoadjuvant chemotherapy

PCR – polymerase chain reaction

PET/CT – positron emission tomography combined with computed tomography

FDD – fraction dose delivery

RFA – radiofrequency ablation

CEA – carcinoembryonic antigen

MINEN – mixed neuroendocrine-non-neuroendocrine neoplasm

TSD – total absorbed dose

USDG – ultrasonic Dopplerography

Ultrasound – ultrasound examination

5-FU – fluorouracil

CRT – chemoradiotherapy (a course of external beam conformal radiotherapy combined with chemotherapy using pyrimidine analogues with a fraction dose of 1.8–2 Gy, total dose of 44 Gy to regional metastasis zones, total dose of 50–54 Gy to the primary tumor.

ChT – chemotherapy

CRM – circumferential resection margin

ECG – electrocardiography

CTCAE – Common Terminology Criteria for Adverse Events

ECOG – Eastern Cooperative Oncology Group

EGFR – epidermal growth factor receptor

IMRT – intensity-modulated radiation therapy

MSI – microsatellite instability

dMMR – mismatch repair protein deficiency

MEK – mitogen-activated protein kinase kinase gene.

RAS – family of NRAS and KRAS genes.

VMAT – volumetric-modulated arc therapy

3DCRT – three-dimensional conformal radiotherapy

** – vital and essential drugs

# – drug used off-label (not in accordance with the instructions for use, contraindications, routes of administration, or doses contained in the product information)

Terms and Definitions

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

Pyrimidine analogues – antimetabolite chemotherapy drugs.

Metastasectomy – a surgical procedure involving the removal of a metastasis.

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

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

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

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

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

Stage I rehabilitation – rehabilitation during specialized treatment of the underlying disease (including surgery/chemotherapy/radiotherapy) in departments of medical organizations specialized in the underlying disease.

Stage II rehabilitation – rehabilitation in inpatient settings of medical organizations (rehabilitation centers, rehabilitation departments) during the early recovery period of the disease, the late rehabilitation period, and the period of residual effects of the disease.

Stage III rehabilitation – rehabilitation in the early and late rehabilitation periods, and the period of residual effects of the disease in departments (offices) of rehabilitation, physiotherapy, therapeutic exercise, reflexology, manual therapy, psychotherapy, medical psychology, speech therapy (defectology) offices providing outpatient medical care, day hospitals, as well as by mobile teams at home (including sanatorium-resort organizations).

3DCRT – a radiotherapy technique, three-dimensional conformal radiotherapy.

IMRT – a radiotherapy technique, intensity-modulated radiotherapy.

RapidArc – image-guided radiotherapy technology.

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

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 FOLFOX) – chemotherapy regimen: oxaliplatin** (85 mg/m² as a 2-hour 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.

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), leucovorin** (calcium folinate, 250 mg/m² IV bolus) followed by fluorouracil** bolus (500 mg/m² weekly for 6 weeks followed by a 2-week break) or oxaliplatin** (85 mg/m² over 2 h on day 1, leucovorin** (calcium folinate, 60 mg/m² IV bolus) followed by fluorouracil** bolus (500 mg/m²) on days 1 and 2 once every 2 weeks.

MEK – mitogen-activated protein kinase kinase gene.

RAS – the NRAS and KRAS gene family.

XELOX – chemotherapy regimen: oxaliplatin** (130 mg/m² intravenous infusion on day 1), capecitabine** (825 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** (1600–1800 mg/m² per day orally on days 1–14). The next cycle starts on day 22.

External beam conformal radiotherapy (RT) refers to one or more medical services (A06.30.002.015, A06.30.021, A07.19.001, A07.19.001.001, A07.19.001.002, A07.19.001.003, A07.19.001.004, A07.19.001.005, A07.19.002, A07.19.003, A07.19.006, A07.19.007, A07.19.008, A07.30 020.082, A07.30.009, A07.30.009.001, A07.30.009.015, A07.30.009.077, A07.30.020, A07.30.020.004, A07.30.020.008, A07.30.020.009, A07.30.020.010, A07.30.020.013, A07.30.021, A07.30.044, A07.30.046, A07.30.047, A07.30.048, A07.30.049, A07.30.055, A23.30.043, A25.30.014.002, B01.027.004, B01.027.004.001, B01.027.005, B01.027.005.001, B01.027.009)

Surgical treatment (of rectal cancer) refers to one of the range of services (A16.19.020–A16.19.021.014)

Abdominoperineal resection of the rectum or Hartmann's operation (obstructive resection of the rectum) – ICD/medical service codes (A16.19.020–A16.19.021.014)

Surgical intervention (for potentially resectable rectal cancer metastases) – medical service codes in the range (A16.14.036–A16.14.036.011; A16.09.009–A16.09.009.011, A16.09.013–A16.09.015)

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Rectal cancer – a heterogeneous group of malignant epithelial tumors of the rectum, differing in clinical course, prognosis, and drug sensitivity, located within 15 cm of the anal verge as measured by a rigid sigmoidoscopy. In clinical practice and scientific research, rectal cancer is divided into low rectal (0–5.0 cm from the anorectal junction), mid rectal (5.1–10.0 cm from the anorectal junction), and high rectal (10.1–15.0 cm from the anorectal junction).

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

In 3–5% of rectal cancer patients, the development of the disease is associated with known hereditary syndromes. The most common are Lynch syndrome, familial adenomatous polyposis, and MUTYH-associated polyposis, along with rare hamartomatous polyposis syndromes. In the remaining patients, colorectal cancer is sporadic. Risk factors for this disease include: chronic inflammatory bowel diseases (e.g., ulcerative colitis, Crohn's disease), smoking, alcohol, red meat-predominant diet, diabetes mellitus, obesity or elevated body mass index, and low physical activity [1–5].

1.3 Epidemiology of the Disease or Condition

Rectal cancer is a leading cause of morbidity and mortality among malignant tumors. In 2022, 29,724 new cases of rectal cancer (C19–C21) were registered in Russia, and 15,864 patients died from it [6].

1.4 Features of Coding the Disease or Condition

D01.2 Carcinoma in situ of rectum

D37.5 Neoplasm of uncertain or unknown behavior of rectum

C20 Malignant neoplasm of rectum

1.5 Classification of the disease or condition

Board W. C. o. T. E. WHO classification of tumours // Book WHO classification of tumours / EditorWorld Health Organization Lyon, France, 2019. [7]

Epithelial tumors

I. Benign tumors:

A. 8211/0 Tubular adenoma.

B. 8261/0 Villous adenoma.

C. 8263/0 Tubulovillous adenoma.

D. 8220/0 Adenomatous polyp.

E. 8213/0 Serrated dysplasia.

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

A. 8148/2 High-grade glandular intraepithelial neoplasia.

B. 8148/0 Low-grade glandular intraepithelial neoplasia.

III. Carcinoma:

A. 8140/3 Intestinal-type adenocarcinoma^[1].

B. 8213/3 Mucinous adenocarcinoma^[2].

C. 8262/3 Serrated adenocarcinoma^[3].

D. 8265/3 Micropapillary adenocarcinoma.

E. 8480/3 Adenoma-like adenocarcinoma^[4].

F. 8490/3 Medullary carcinoma^[5].

G. 8490/3 Signet-ring cell carcinoma^[6].

H. 8560/3 Adenosquamous carcinoma.

I. 8510/3 Medullary carcinoma^[7].

J. 8220/3 Undifferentiated carcinoma, NOS^[8].

K. 8033/3 Carcinoma with sarcomatoid component^[9].

L. 8240/3 Neuroendocrine tumor, NOS.

M. 8240/3 Neuroendocrine tumor, grade 1.

N. 8249/3 Neuroendocrine tumor, grade 2.

O. 8249/3 Neuroendocrine tumor, grade 3.

P. 8246/3 Neuroendocrine carcinoma, NOS^[10].

Q. 8041/3 Small cell carcinoma.

R. 8013/3 Large cell neuroendocrine carcinoma.

S. 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] Colorectal adenocarcinoma is the most frequent histological type of colorectal cancer (75% of cases).

^[2] Mucinous adenocarcinoma accounts for 15% of colorectal cancer cases. The tumor is associated with microsatellite instability.

^[3] Serrated adenocarcinoma accounts for no more than 10% of cases. The tumor is associated with microsatellite instability.

^[4] This nosological entity was first introduced by the IARC/WHO committee in the ICD-O in 2019. Adenoma-like adenocarcinoma accounts for no more than 4% of cases.

^[5] Medullary carcinoma accounts for no more than 4% of cases. The tumor is associated with microsatellite instability.

^[6] Diagnosed when >50% of the tumor cells are composed of signet-ring cell elements. The tumor always corresponds to G3. When located on the right side, the tumor is frequently associated with MSI.

^[7] The tumor always corresponds to G3. When located on the right side, the tumor is frequently associated with MSI.

^[8] Is a diagnosis of exclusion—established only based on additional diagnostic methods (immunohistochemical examination during pathomorphological assessment, electron microscopy), corresponds to G4.

^[9] This nosological entity was first introduced by the IARC/WHO committee in the ICD-O in 2019. It is a diagnosis of exclusion, corresponding to G3-G4.

^[10] The diagnosis is established only based on additional diagnostic methods (immunohistochemistry, electron microscopy), and always corresponds to G3.

^[11] The diagnosis is established only based on additional diagnostic methods: MANEC/MiNEN is a dimorphic carcinoma combining components of adenocarcinoma and neuroendocrine carcinoma/tumor (the proportion of either component must be at least 30%).

1.6 Clinical presentation of the disease or condition

1.6.1. Rectal cancer staging according to the TNM-8 system (2017)

A single classification is used for colon and rectal cancer.

The T category includes the following grades:

T_X – primary tumor cannot be assessed.

T_is – carcinoma in situ (intraepithelial invasion or invasion of the lamina propria).

T₁ – tumor invades the submucosa of the bowel wall.

T₂ – tumor invades the muscularis propria.

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

For tumors located in the upper rectum and rectosigmoid junction (covered by peritoneum), the T₃ category defines tumor extension into the subserosal layer (without penetrating the serosa).

T₄ – tumor perforates the visceral peritoneum or directly invades other organs or structures (including tumors located in the upper rectum and rectosigmoid junction covered by peritoneum).

T_4a – tumor penetrates the visceral peritoneum.

T_4b – tumor invades other organs or structures.

The N symbol indicates the presence or absence of regional lymph node metastases:

N_X – regional lymph nodes cannot be assessed.

N₀ – no regional lymph node metastasis.

N₁ – metastases in 1–3 regional lymph nodes.

N_1a – metastasis in 1 regional lymph node.

N_1b – metastases in 2–3 regional lymph nodes.

N_1c – tumor deposits in the subserosa or mesentery without regional lymph node metastasis.

N₂ – metastases in more than 3 regional lymph nodes.

N_2a – metastases in 4–6 regional lymph nodes.

N_2b – metastases in 7 or more regional lymph nodes.

The M category describes the presence or absence of distant metastases:

M₀ – no distant metastasis.

M₁ – distant metastasis present.

M_1a – distant metastasis confined to one organ.

M_1b – distant metastasis in more than one organ.

M_1c – peritoneal metastasis.

Stage grouping is presented in Table 1.

Table 1. Colon cancer stages

1.6.2. Kikuchi staging of early rectal cancer

When planning local excision for T₁ rectal cancer, detailed staging based on MRI and endorectal ultrasound is recommended using the following criteria:

T_1sm1 – submucosal invasion depth up to 1/3.

T_1sm2 – moderate submucosal invasion depth – up to 2/3.

T_1sm3 – complete invasion of the entire submucosa by the tumor.

Definitive staging is performed based on the pathomorphological examination of the surgical specimen. Kikuchi staging is only possible if the muscularis propria of the bowel wall is present in the removed macro-specimen.

1.6.3. MRI subclassification of T3 rectal cancer

To personalize indications for preoperative treatment of T3 rectal cancer, an additional MRI-based classification is used [8]:

T3a – invasion into the mesorectal fat <1 mm.

T3b – invasion into the mesorectal fat 1–5 mm.

T3c – invasion into the mesorectal fat 5–15 mm.

T3d – invasion into the mesorectal fat >15 mm.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnostic criteria for rectal cancer include:

- tumor localization above the dentate line and within 15 cm from the anal verge

- malignant epithelial tumor verified by histological examination

2.1 Complaints and Anamnesis

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

• In all patients suffering from rectal cancer, it is recommended to take a family history and evaluate it for compliance with the Amsterdam II criteria, Bethesda guidelines, or the criteria of the A.N. Ryzhikh National Medical Research Center of Coloproctology (Appendix G) to identify patients with hereditary forms of the disease [1, 12–14].

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

Comments: If the patient's anamnesis meets the Amsterdam II criteria, 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 (MMR) protein deficiency using immunohistochemistry (IHC). If such a deficiency is detected, subsequent sequencing of the corresponding (single) MMR gene should be performed to search for a hereditary pathogenic variant. If microsatellite instability (MSI) is being tested in the tumor sample and is detected, but IHC testing for MMR 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

2.3 Laboratory Diagnostics

Comments: a coagulogram (exploratory hemostasis assessment) must be performed prior to surgical treatment, and in other patients – when clinically indicated. The specific set of parameters for routine blood chemistry and the coagulogram (exploratory hemostasis assessment) should be determined by the attending physician individually, taking into account the characteristics of the specific patient.

Comments: Blood testing for carcinoembryonic antigen (CEA) is indicated for all rectal cancer patients. The specific set of blood chemistry and coagulogram parameters should be determined by the attending physician individually, taking into account the characteristics of the specific patient.

2.4 Instrumental Diagnostics

Comments: when determining tumor localization based on data from examinations using flexible endoscopes, an artificial overestimation of the distance from the anocutaneous line may occur due to the fact that endoscopes can bend further within the intestinal lumen. This can lead to an incorrect diagnosis and a wrong treatment plan selection. Determining the distance from the anocutaneous line based on pelvic MRI data can be accurate, but this technique is not standardized and largely depends on the radiologist's experience.

Comments: the treatment plan should not be formulated until biopsy results are obtained. In case of submucosal infiltrative tumor growth, a false-negative result is possible, which requires a repeated deep biopsy. The sensitivity and specificity of the method increase when using modern endoscopic visualization technologies (magnifying endoscopy, narrow-band imaging, chromoendoscopy, fluorescence diagnostics). If total colonoscopy was not performed at the preoperative stage, it must be performed within 3–6 months after surgical treatment.

Comment: the need to perform a complete examination of the colon is dictated by the high risk of detecting synchronous polyps and cancer in the upper segments of the colon. When rectal cancer and synchronous colonic polyps are detected, if technically feasible, their removal prior to the initiation of rectal cancer treatment is preferred to avoid the risk of their growth and malignant transformation, taking into account the potential delay in endoscopic removal after anticancer treatment and the risk of patient non-compliance with medical recommendations.

Comments: Pelvic MRI allows for the determination of tumor localization, extent, and depth of invasion, as well as the assessment of regional lymph node status. Intravenous contrast enhancement is not required for pelvic MRI when assessing local spread. When referring for an MRI, the purpose of the examination and the suspected tumor localization must be clearly formulated to select the correct scanning protocol.

Comments: Pelvic MRI after the completion of neoadjuvant treatment makes it possible to identify 3 groups of patients: with complete, near-complete, and incomplete MRI responses [28].

Comments: modern MRI modes using diffusion-weighted imaging can increase the informativeness of the study. Intravenous contrast enhancement does not increase the informativeness of tumor spread assessment [30]. Final decision-making regarding the treatment tactics for rectal cancer patients is only possible based on the MRI results.

Comments: contrast-enhanced abdominal MRI is preferred for assessing the resectability of colorectal cancer (CRC) liver metastases. In patients with contraindications to intravenous contrast enhancement, MRI with DWI sequence can be performed. MRI allows the detection of ultrasound-occult metastases in 10-20% of patients and reduces the number of exploratory and R2 resections. For patients with contraindications to MRI, contrast-enhanced CT using iodine-containing radiocontrast agents or 18F-fluorodeoxyglucose PET-CT with intravenous contrast is recommended. MRI has the highest sensitivity compared to other diagnostic modalities, especially for metastases less than 1 cm in size [35], with preference given to MRI with hepatobiliary contrast agents (gadoxetic acid), as they increase the sensitivity for small liver metastases [36]. Planning metastasis resection based solely on liver ultrasound or unenhanced CT is not permitted.

Comments: performing an ECG is recommended prior to planning any type of treatment. In patients receiving systemic anticancer therapy, ECG is performed according to clinical indications.

Comments: a meta-analysis of randomized trials evaluating the necessity of PET/CT (positron emission tomography combined with computed tomography using tumor-tropic radiopharmaceuticals with contrast enhancement) to rule out extrahepatic metastases when deciding on liver metastasectomy showed that this diagnostic modality alters treatment strategy in only 8% of patients and does not affect overall survival [43].

2.5 Other Procedures

Comments: echocardiography, 24-hour Holter ECG monitoring, pulmonary function testing (respiratory flowmetry), duplex scanning of the neck vessels (duplex scanning of brachiocephalic arteries with color Doppler flow mapping) and lower extremities (lower extremity venous Doppler ultrasound), consultations with a cardiologist, endocrinologist, neurologist, and other relevant specialists are performed.

• In patients with disseminated or unresectable locally advanced rectal cancer, it is recommended to perform molecular genetic testing of the tumor biopsy sample for somatic mutations in the RAS gene family (exons 2-4 of the KRAS gene and exons 2-3 of the NRAS gene) (molecular genetic testing for KRAS mutations in biopsy/surgical material, molecular genetic testing for NRAS mutations in biopsy/surgical material), specifying the mutation, the BRAF gene, specifying the mutation, microsatellite instability / mismatch repair protein deficiency (determination of DNA microsatellite repeats in biopsy/surgical material by PCR), and HER2 expression or amplification (in the absence of KRAS, NRAS, BRAF mutations and MSS phenotype), which may influence the choice of a targeted agent in metastatic disease management [46-49]. If KRAS, NRAS, and BRAF mutations were assessed by PCR and none were detected, further genetic screening by sequencing may be considered, which can additionally identify alterations in 14-17% of patients (Appendix A3).

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

Comments: Molecular genetic analysis can be performed on both tumor biopsy material and circulating tumor DNA using either PCR or next-generation sequencing. If analysis of the optimal panel of RAS mutations is not feasible, consideration should be given to contacting a reference center. In metastatic colorectal cancer with a microsatellite-instable phenotype, testing for NTRK, ROS1, ALK, and RET gene translocations may be performed due to a relatively high probability of their presence. In the absence of microsatellite instability in metastatic cancer, testing for somatic mutations in the POLD1 and POLE genes may be considered, provided that only clinically significant ones are reported. In patients scheduled for chemotherapy containing pyrimidine analogues, testing for 4 major variants of the DPYD gene may be considered: c.1905+1G>A (rs3918290), c.2846A>T (rs67376798), c.1679T>G (rs55886062), and c.1236G>A (rs56038477), which are associated with toxicity from this class of drugs. However, the presence of heterozygous mutations does not always reflect a clinically significant deficiency of the dihydropyrimidine dehydrogenase enzyme [50-52]. Nevertheless, the rarity of homozygous variants of these polymorphisms precludes routine testing of all patients. In patients scheduled for chemotherapy containing irinotecan**, testing for the UGT1A1 gene polymorphism associated with toxicity from this class of drugs may be considered [53]. In locally advanced rectal cancer prior to treatment initiation, it is advisable to perform molecular genetic testing of the tumor biopsy for microsatellite instability / mismatch repair protein deficiency, which may influence the choice of patient management strategy [54].

• Molecular genetic testing to rule out hereditary forms of the disease is recommended in the following cases:

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

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

  2. Suspicion of familial adenomatous polyposis — sequencing of the APC gene and detection of large deletions/insertions by MLPA:

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

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

  3. Suspicion of an attenuated form of familial adenomatous polyposis (20 to 100 polyps) — sequencing of the APC gene. MUTYH-associated polyposis — sequencing of the MUTYH gene — for patients who have more than 20 colorectal polyps but test negative for the pathogenic APC variant:

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

     - patients who develop polyps at a later age (34–44 years) [13, 32, 55, 56].

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

Comments: with the exception of MUTYH-associated polyposis and Bloom syndrome, all hereditary syndromes associated with colorectal cancer are inherited in an autosomal dominant manner. In the presence of a strong family history of malignancies, patients in whom familial adenomatous polyposis and Lynch syndrome have been ruled out should be referred for a genetic consultation to screen for rarer conditions: Peutz-Jeghers, Li-Fraumeni, Bloom, and Cowden syndromes, juvenile polyposis, oligodontia and colorectal cancer, NTHL1-associated polyposis, POLD1- and POLE-associated polyposis, and PTEN hamartoma tumor syndromes [2, 3]. Given the phenotypic diversity of hereditary syndromes and the complexity of their diagnosis, the optimal approach is to use multi-gene NGS panels or whole-exome sequencing. In cases of segmental involvement of the colon by multiple polyps, differential diagnosis with inflammatory polyps in the setting of ulcerative colitis is necessary.

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

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

  2) Tumor grade (if applicable).

  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 explicitly stated).

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

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

  13) Histological grading of the tumor invasive front (tumor budding) according to the 3-tier grading system of the International Tumor Budding Consensus Conference (2016).

  14) Presence of isolated tumor deposits in the pericolic adipose tissue without pre-existing structures of a lymph node (otherwise classified as a 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 explicitly stated).

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

  17) Indicate the distance in millimeters from the closest tumor focus (primary lesion, deposit, or metastasis) to the ink-marked circumferential resection margin (according to P. Quirke).

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

  19) If prior neoadjuvant therapy was administered, indicate the tumor regression grade and the name of the tumor regression grading system used.

  20) Following neoadjuvant therapy, the following parameters are not evaluated: tumor grade, tumor budding.

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

Comments: to assess tumor regression, it is preferable to use the Mandard or Ryan [61] grading systems.

^[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.

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, their prescription and use in a specific clinical situation are determined in accordance with the instructions for use of specific medicinal products, implementing the precautions presented in the instructions, and dose adjustments may also be made taking into account the patient's condition. Changing anti-tumor drug therapy regimens or modifying drug doses within a regimen does not require a multidisciplinary oncology panel meeting and is determined by the attending physician.

The treatment of squamous cell carcinoma of the rectum is carried out in accordance with the principles described in the clinical guidelines for the treatment of anal canal squamous cell carcinoma, with the aim of improving treatment outcomes and increasing the rate of organ-sparing treatment [70-72]. The treatment of neuroendocrine tumors and neuroendocrine carcinoma of the rectum is also discussed in a dedicated section of the clinical guidelines.

Procedures and recommendations for pain management in rectal cancer correspond to the recommendations presented in the clinical guidelines "Chronic Pain Syndrome (CPS) in Adult Patients Requiring Palliative Medical Care" [73].

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, radiation therapy, and chemoradiotherapy are additionally performed according to indications.

3.1. Preoperative treatment

The main indications for preoperative treatment are tumor localization ≤5 cm from the outer edge of the anal canal, involvement of the circumferential resection margin (according to pelvic MRI), and involvement of regional lymph nodes (according to pelvic MRI). The algorithm for selecting preoperative treatment is presented in Appendix B (Figure 2). The choice of the preferred treatment regimen in various clinical situations is discussed in separate statements below.

3.1.1. General principles of preoperative treatment.

Comments: further in the text, the RT course with DPF of 5 Gy and TD of 25 Gy will be referred to as 5x5 Gy RT, and the RT course with DPF of 1.8–2 Gy and TD of 50–54 Gy combined with fluoropyrimidine therapy will be referred to as chemoradiotherapy (CRT).

Minor variations in the total dose are permissible taking into account equipment characteristics and the specific clinical situation. The volume of irradiation for the regional metastasis area should include the perirectal, obturator, internal iliac, and inferior mesenteric lymph nodes. External beam radiation therapy begins with 3D volumetric planning and is performed using conformal radiation therapy technology. Pre-radiation topographical preparation includes CT and MRI scans, on the basis of which the irradiation plan is generated. The reproducibility of radiation therapy conditions is controlled using a portal imaging system. Radiation therapy using proton accelerators with an energy of 70-250 MeV using proton complexes may be performed.

Table 2. Pyrimidine analogue regimens used in concurrent chemoradiotherapy for rectal cancer

Comments: waiting longer than 8 weeks after completion of chemoradiotherapy is acceptable, although according to the results of a randomized trial, extending the interval to 11 weeks did not lead to an increase in the rate of complete pathological responses or improved survival.

Comments: other options for total neoadjuvant chemotherapy in combination with this RT regimen have not been studied in prospective trials

Comments: when administered before RT or CRT, neoadjuvant chemotherapy is referred to as induction chemotherapy; when administered after the completion of RT or CRT, it is referred to as consolidative chemotherapy. According to indications, neoadjuvant chemotherapy may be performed without RT or CRT. The principles of its administration remain unchanged in this case.

• For patients with localized rectal cancer (T_1sm3-T_2-3bN_0-1M₀ cancer of the lower and middle ampullary rectum) in medical organizations with experience in performing such treatment, it is recommended to consider the possibility of a course of chemoradiotherapy (with the potential addition of consolidative neoadjuvant chemotherapy) followed by a "watch and wait" strategy with the aim of performing organ-sparing treatment in the event of a complete clinical response to chemoradiotherapy [88, 89].

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

Comments: patients with localized rectal cancer who are candidates for low anterior resection or abdominoperineal resection, which are potentially associated with a significant decrease in quality of life, may undergo a radical course of chemoradiotherapy (total dose at least 50 Gy) followed by active surveillance. Given the limited institutional experience with this treatment strategy, it is recommended to discuss cases of the "watch and wait" approach with federal centers having expertise in this field (preferably using telemedicine). A significant number of patients can achieve a sustained complete tumor regression. The conditions for this treatment strategy are:

- the patient's full informed consent indicating potential complications of chemoradiotherapy and alternative treatment options;

- the patient's ability to attend follow-up examinations at least 4 times a year for at least 3 years after completion of chemoradiotherapy, and the patient's written consent to undergo follow-up examinations with the required frequency.

This strategy is applicable only in medical organizations with experience in such treatment, as it is associated with additional risks for patients and requires a multidisciplinary team including an oncologist, surgeon, endoscopist, radiologist specializing in pelvic MRI, radiation therapist, and chemotherapy specialist experienced in managing patients with the "watch and wait" approach. During each follow-up examination, the patient must undergo: digital rectal examination (digital rectal examination), pelvic MRI, videorectoscopy (videocolonoscopy).

If upfront surgery in the volume of anterior rectal resection with partial mesorectal excision, which is associated with a lower risk of reduced quality of life, is initially feasible, the use of the "watch and wait" approach is not justified and may only be considered in patients with objective contraindications or an extremely high risk of radical surgical treatment.

Criteria for a complete clinical response are considered to be the absence of reliable signs of residual tumor tissue according to pelvic MRI (mrTRG1-2), absence of residual tumor signs or the presence of only a flat white scar or flat white ulcer upon videorectoscopy, and absence of residual tumor signs upon digital rectal examination. The diagnosis of a "complete clinical response" cannot be made without performing all 3 examinations (pelvic MRI, videorectoscopy (videocolonoscopy), digital rectal examination (digital rectal examination)); furthermore, it cannot be made in cases of mrTRG3-5 or when simple rigid rectoscopy (sigmoidoscopy) is performed.

3.1.2. Preoperative treatment of patients with non-metastatic lower rectal cancer.

• Patients with lower rectal cancer cT2-4bN0M0 or cTanyN1-2M0 are recommended to undergo chemoradiotherapy; total dose may be increased up to 56 Gy depending on equipment availability and the specific clinical situation [77, 90-92].

GCR ALOE 2Grade of Recommendation – A (Level of Evidence – 2).

Comments: alternative radiation therapy regimens are less likely to ensure tumor regression and increased resectability.

• In the absence of grade 3–4 complications, patients with lower rectal cancer cT2-4bN0M0 or cTanyN1-2M0 after completion of the chemoradiotherapy course are recommended to consider consolidation neoadjuvant chemotherapy [84].

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

Comments: the timing of surgical treatment must not exceed those specified in section 3.1.1. Consolidation neoadjuvant chemotherapy is preferred in patients whose treatment goal is to achieve maximum tumor regression or a complete clinical response, as well as in patients with circumferential resection margin involvement.

• In rectal cancer (cT_3-4N_0-2M_0, in the lower rectum – cT_2-4N_0-2M₀) with MSI, to achieve a complete clinical effect, it is recommended to consider 6 months of therapy with anti-PD antibodies (pembrolizumab**, nivolumab**) as an alternative to other types of preoperative treatment [93].

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

3.1.3. Preoperative treatment of patients with non-metastatic middle rectal cancer.

• Patients with middle rectal cancer with circumferential resection margin involvement are recommended to undergo chemoradiotherapy; total dose may be increased up to 56 Gy depending on equipment availability and the specific clinical situation [77, 90, 92].

GCR ALOE 2Grade of Recommendation – A (Level of Evidence – 2).

Comments: alternative radiation therapy regimens are less likely to ensure tumor regression and increased resectability. Chemoradiotherapy can also be considered as a treatment option for middle rectal cancer without circumferential resection margin involvement, in stages cT3c-T4aN0M0, cT2-N4aN1-2M0.

• In the absence of grade 3–4 complications, patients with middle rectal cancer with circumferential resection margin involvement after completion of the chemoradiotherapy course are recommended to consider consolidation neoadjuvant chemotherapy [84].

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

Comments: the timing of surgical treatment must not exceed those specified in section 3.1.1. Consolidation neoadjuvant chemotherapy is preferred in patients whose treatment goal is to achieve maximum tumor regression or a complete clinical response, as well as in patients with circumferential resection margin involvement. Consolidation neoadjuvant chemotherapy can also be considered as a treatment option for middle rectal cancer without circumferential resection margin involvement, in stages cT3c-T4aN0M0, cT2-N4aN1-2M0.

Comments: Preference is given to the 5x5 Gy radiation therapy course with consolidation chemotherapy rather than chemoradiotherapy, given the higher risk of systemic rather than local progression in the absence of circumferential resection margin involvement.

Comments: Omission of radiation therapy or chemoradiotherapy in middle rectal cancer is possible only in specialized high-volume clinics (at least 20 rectal resections per surgeon per year).

Comments: Omission of preoperative treatment in middle rectal cancer is possible only in specialized high-volume clinics (at least 20 rectal resections per surgeon per year). Surgical treatment can only be considered in patients with no more than 3 affected lymph nodes and their maximum size less than 8 mm according to pelvic MRI. This tactic is less preferred in male patients due to proximity to the pelvic floor muscles.

3.1.4. Preoperative treatment of patients with non-metastatic upper rectal cancer.

Comments: The preferred treatment option for the majority of patients with upper rectal cancer is radical upfront surgery. Anatomically, the upper rectum is located primarily in the abdominal cavity, which allows extrapolation of clinical trial results on colon cancer treatment [99, 100]. Neoadjuvant chemotherapy may be considered in patients with extensive regional lymph node involvement, tumor deposits, or other individually determined negative prognostic factors.

3.1.5. Preoperative radiotherapy in patients with metastatic rectal cancer.

Comments: in all other situations, the decision to administer radiotherapy in patients with metastatic rectal cancer is made individually, taking into account the disease prognosis and the presence of primary tumor-related symptoms. A prolonged course of chemoradiotherapy is generally not recommended given the high risk of systemic disease progression. Exceptions may include situations where the patient has initially resectable metastases confined to a single organ, and chemoradiotherapy could fundamentally affect the feasibility of sphincter-sparing treatment, as well as when the patient has cT4b metastatic rectal cancer with a low probability of an R0 resection of the primary tumor. The waiting period after completing the radiotherapy course should be utilized for additional systemic therapy or resection of metastatic sites.

Comments: if technically feasible, treatment should be supplemented with induction and/or consolidative neoadjuvant chemotherapy.

3.1.6. Postoperative radiation therapy

Comments: unlike adjuvant chemotherapy, postoperative radiotherapy and chemoradiotherapy do not significantly impact patient survival [104, 105]. The role of postoperative therapy in the setting of total mesorectal excision has not been established.

3.2. General principles of surgical treatment. Surgical treatment of non-metastatic rectal cancer

• If technically feasible and performed by a qualified surgical team in specialized clinics, it is recommended to perform laparoscopic rectal cancer surgery (A16.19.020.002, A16.19.021.003, A16.19.021.012, A16.19.021.013) to accelerate patient recovery and reduce the risk of perioperative complications [106-109].

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

Comments: laparoscopic rectal resection has a number of advantages, including earlier patient recovery, lower incidence and severity of adhesions, reduced opioid analgesic requirements, shorter hospital stays, lower risk of postoperative hernias, and better cosmetic outcomes. In terms of oncological efficacy, laparoscopic rectal cancer surgery is not inferior to open procedures, though it requires appropriate training of the surgical team. Robotic surgical access may be used, but its advantages over laparoscopy have not been proven.

Comments: when the tumor extends beyond the mesorectal fascia, extrafascial rectal excision is indicated. When performing multivisceral resections, electrosurgical and ultrasonic instruments are preferred for tissue dissection to minimize blood loss. The distal resection margin should be at least 2 cm along the bowel wall and at least 5 cm along the mesorectal fat due to the risk of retrograde lymphogenic metastasis.

The inferior mesenteric artery must be ligated directly at its origin from the aorta or immediately below the origin of the left colic artery, and the inferior mesenteric vein should be ligated below the body of the pancreas, which allows mobilization of the left colon (with full mobilization of the splenic flexure if necessary) to create a tension-free colorectal anastomosis. Ligation of the inferior mesenteric vein at the same level as the inferior mesenteric artery is acceptable. Where technically feasible, the preaortic and inferior mesenteric autonomic nerve plexuses should be preserved. Rectal mobilization should be performed in the interfascial plane with preservation (in the absence of tumor involvement) of the right and left hypogastric nerves, pelvic plexuses, and splanchnic nerves. Routine extended aorto-iliac and pelvic lymph node dissection is not recommended. When performing total mesorectal excision (tumor location lower than 10 cm from the anal verge) and constructing a low colorectal anastomosis, creating a diverting colostomy or ileostomy is recommended. Following total mesorectal excision, the operation may be completed with the formation of a colonic pelvic pouch or a side-to-end anastomosis to improve functional treatment outcomes.

Extralevator abdominoperineal excision is indicated for patients with MRI-confirmed tumor invasion into the pelvic floor muscles.

When adjacent organs and tissues are involved in the tumor process, the scope of surgery may be extended to anterior pelvic exenteration, posterior pelvic exenteration, or total pelvic exenteration.

Comments: in patients with medically refractory, clinically significant bleeding and/or perforation with the development of peritonitis caused by rectal cancer, the first-stage indication is surgical treatment of rectal cancer adhering to the principles of total mesorectal excision (A16.19.020-A16.19.021.014). For other complications of the tumor process, preference should be given to the creation of a temporary or permanent intestinal stoma. Performing primary surgical interventions with resection of the primary tumor is permissible only in selected cases by decision of a multidisciplinary oncological team involving a surgical oncologist, radiation oncologist, and chemotherapist, with documented justification of the impossibility of administering preoperative treatment. In isolated cases, provided the clinic has the appropriate expertise and equipment, bowel obstruction may be relieved by stenting followed by preparation of the patient for elective surgery or combined modality treatment. The choice in favor of a transverse or sigmoid colostomy should be determined by the subsequent surgical treatment plan. If the most likely scope of the subsequent operation – abdominoperineal resection of the rectum or Hartmann's procedure (A16.19.020-A16.19.021.014) (when the tumor is located lower than 5 cm from the anocutaneous line and/or with involvement of the pelvic floor muscles in the tumor process and/or with baseline complete anal incontinence), preference should be given to creating a double-barrel sigmoid colostomy. In all other situations (when planning any type of sphincter-sparing surgery), preference should be given to creating a transverse colostomy, which can subsequently be used as a diverting stoma after the creation of a sigmoid-rectal anastomosis.

Comments: in individual patients at low risk of postoperative complications, a multidisciplinary team may decide to close preventive colo- or ileostomies earlier, but only after endoscopic (videocolonoscopy) and radiological (proctography) verification of the integrity of the colorectal anastomosis [116, 117]. In the general population, the risk of complications with early stoma closure is higher [114]. Closing a colostomy or ileostomy during adjuvant chemotherapy is feasible and is not associated with an increased risk of postoperative complications [118, 119].

• For early stage 0–I rectal cancer (T_is–T_1sm1-sm2N₀M₀), it is recommended to perform surgical treatment via transanal full-thickness endoscopic tumor removal or endoscopic submucosal dissection for organ preservation [120–125].

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

Comments: key features include a favorable prognosis (5-year survival rate over 90%) and the feasibility of organ-preserving and function-sparing treatment methods with high efficacy. If the clinic lacks equipment for transanal endoscopic tumor removal or experience in performing endoscopic submucosal dissection, the patient should be referred to a specialized center capable of providing the necessary treatment.

Indications for organ-preserving treatment:

moderately or well-differentiated adenocarcinoma with invasion limited to the submucosal layer (base) of the rectal wall without clear signs of mesorectal lymph node involvement according to pelvic MRI and/or endorectal ultrasound.

If negative prognostic factors are identified after morphological examination of the transanally resected tumor, standard surgery with total mesorectal excision (TME) is performed. Negative prognostic factors:

− stage >pT1sm3;

− positive resection margins;

− lymphovascular invasion;

− poorly differentiated or mucinous adenocarcinoma;

− signet-ring cell carcinoma;

− tumor budding grade 2–3.

Adjuvant therapy is not administered.

• For rectal cancer not requiring preoperative treatment (see section 3.1), it is recommended to perform total or partial mesorectal excision without preoperative treatment to reduce the risk of treatment side effects [96, 126].

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

Comments: In the absence of preoperative treatment for stage II–III rectal cancer, the administration of adjuvant chemotherapy is determined by the guidelines for colon cancer.

Comments: Ovarian transposition does not affect oncological treatment outcomes and should be offered solely to improve quality of life. This intervention is most justified in patients under 40 years of age. Furthermore, ovarian transposition preserves hormonal function in only 60–70% of patients.

3.3. Treatment of patients with resectable metastases

• For generalized rectal cancer with potentially resectable synchronous metastases in the liver and/or lungs, it is recommended to perform surgery (A16.14.036-A16.14.036.011; A16.09.009-A16.09.009.011, A16.09.013-A16.09.015) as soon as metastases are deemed resectable, to improve treatment outcomes [128, 129].

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

Comments: treatment strategy depends on the initial resectability of metastatic lesions. The best results are achieved when a resection margin of at least 1 mm is obtained. If R0 resection of colorectal liver or lung metastases is initially feasible, or if metastatic lesions in these organs become resectable during chemotherapy, R0 surgical treatment can provide a 5-year survival rate in 30–50% of patients. Patients who have previously received chemotherapy should undergo R0 surgery as soon as the metastases become resectable. Prolonging chemotherapy may lead to an increased incidence of hepatotoxicity and the "disappearance" of some metastases, making them difficult for the surgeon to identify during resection. If there is a symptomatic primary tumor (risk of intestinal obstruction/bleeding), the first stage involves primary tumor removal with lymph node dissection (A16.19.020- A16.19.021.014). Radiofrequency ablation (RFA) (percutaneous ultrasound-guided radiofrequency ablation of liver tumors) of liver metastases or stereotactic body radiation therapy can be used as an adjunct to resection to achieve radicality, or as a standalone modality when surgery is not feasible. An alternative to immediate surgery is perioperative systemic chemotherapy (FOLFOX, XELOX). This strategy should be selected in cases of high disease progression risk (e.g., high Fong score or any other). After 8–12 weeks of therapy, simultaneous or sequential removal of metastases and the primary tumor is performed (A16.14.036-A16.14.036.011; A16.09.009-A16.09.009.011, A16.09.013-A16.09.015, A16.19.020- A16.19.021.014), followed by the continuation of prior chemotherapy up to a total duration of 6 months. The addition of monoclonal antibodies to chemotherapy is not indicated for resectable metastases as it may worsen long-term outcomes. The use of local treatment modalities for metastases (surgery, radiofrequency ablation, radiotherapy, etc.) can be considered for oligoprogression as well as oligometastatic organ involvement in second- and subsequent-line systemic therapy.

• For generalized rectal cancer with unresectable synchronous metastases, it is recommended to administer the most effective chemotherapy possible—utilizing double or triple combinations (FOLFOX, XELOX, FOLFIRI, XELIRI, FOLFOXIRI)—with the objective of achieving an objective response and converting unresectable metastases into resectable ones [9–11, 130]. In cases of MSI, monotherapy with anti-PD-1 antibodies—nivolumab** or pembrolizumab** as single agents, or a combination of nivolumab** and ipilimumab**—is recommended [131–133].

Local Quality of Evidence 2Grade of recommendation for pembrolizumab is A (Level of evidence: 2).

Local Quality of Evidence 4Grade of recommendation for nivolumab or the combination of nivolumab and ipilimumab is C (Level of evidence: 4).

Comments: for left-sided primary tumors in the absence of RAS, BRAF mutations, Her2neu overexpression/amplification, and MSS, anti-EGFR monoclonal antibodies (mAbs) may be added to FOLFIRI or FOLFOX chemotherapy regimens (but not XELOX/XELIRI or FLOX), which increases the rate of R0 liver resections and prolongs survival. For right-sided primary tumors, presence of KRAS, NRAS, BRAF mutations, HER2neu overexpression/amplification, or MSS, the addition of bevacizumab to any doublet chemotherapy regimen (regardless of RAS status) is recommended, as it increases the rate of marked therapeutic pathomorphosis compared to chemotherapy alone. Another potential option to increase resectability is the use of the "triplet" combination FOLFOXIRI, to which mAbs may be added; however, the higher toxicity of this regimen requires caution when prescribing it. Intraarterial chemotherapy remains an experimental method and is not recommended for routine use in the first-line therapy. Various methods of hepatic artery embolization and intraarterial chemotherapy may be used in selected patients with isolated or predominant metastatic liver disease when systemic therapy options are exhausted. Patients whose response to treatment is insufficient to render the tumor resectable are subject to palliative drug treatment. The issue of removing the primary tumor is decided on an individual basis, taking into account the risk of complications associated with it. Provided there is a good response to therapy, a reassessment of metastatic lesion resectability is performed.

• For metachronous resectable colorectal cancer metastases in the liver or lungs, surgical treatment with postoperative chemotherapy using doublets (FOLFOX or XELOX) or fluoropyrimidine monotherapy is recommended [130].

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

Comments: if R0 resection of colorectal cancer metastases in the liver or lungs is initially feasible, as well as when metastatic lesions in these organs become resectable during chemotherapy, R0 surgical treatment can ensure 5-year survival in 30-50% of patients. An alternative to this approach in the presence of unfavorable oncological factors (e.g., 3-5 points on the Fong scale) is perioperative chemotherapy (about 3 months of FOLFOX or XELOX therapy before liver resection and the same amount after it).

• For initially resectable metastatic lesions following successful R0 or R1 resection to reduce the risk of disease progression, adjuvant chemotherapy is recommended [130].

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

Comments: for initially resectable metastatic lesions an alternative to immediate surgery is perioperative systemic chemotherapy (FOLFOX, XELOX). This strategy option should be chosen in cases of high risk of disease progression (e.g., high risk according to the Fong classification 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 until a total duration of 6 months is reached. In case of a low risk of disease progression (e.g., low risk according to the Fong classification or any other, with previously administered chemotherapy), observation is also an option if surgical removal of metastases was performed as the first step. The addition of monoclonal antibodies (mAbs) to chemotherapy for resectable liver metastases is not indicated, as it may worsen long-term outcomes.

• For potentially resectable synchronous and metachronous metastatic lesions, maximally intensive chemotherapy is recommended, the goals of which are to achieve an objective response and convert unresectable metastases into resectable ones (FOLFOX, XELOX or FOLFIRI, XELIRI, FOLFOXIRI) [9-11].

LoR CLoE 5Level of Recommendation – C (Level of Evidence – 5).

• For potentially resectable metastatic lesions in the absence of RAS and BRAF mutations, no Her/2 overexpression or amplification, and MSS, it is recommended to consider adding cetuximab** or panitumumab** to chemotherapy (FOLFIRI, FOLFOX, FOLFOXIRI regimens) [130, 134].

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

Comments: The combination of FOLFOXIRI with anti-EGFR antibodies is characterized by higher toxicity and, although it does not lead to an increased objective response rate in all studies can be considered in individual patients in generally good condition, with a left-sided primary tumor and potentially operable metastases.

• In potentially resectable metastatic lesions in the presence of a RAS or BRAF mutation or MSI, it is recommended to add bevacizumab** to any of the chemotherapy regimens specified above (FOLFOX, XELOX, or FOLFIRI, XELIRI). Another possible option to increase resectability is the use of the "triplet" combination FOLFOXIRI, to which bevacizumab** may be added [134, 135]. After 4–6 cycles, resectability is re-evaluated; if there is no progression, simultaneous or sequential removal of the metastases and the primary tumor is performed. This is followed by adjuvant chemotherapy according to the FOLFOX or XELOX regimen or fluoropyrimidine monotherapy for a total duration of 6 months (taking into account preoperative chemotherapy). In case of progression/inability to remove metastatic lesions, treatment is carried out according to the principles specified in the section on treating patients with unresectable metastases [136].

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

• In potentially resectable metastatic lesions in the presence of a BRAF mutation, to increase the likelihood of response to treatment, it is recommended to prescribe the FOLFOXIRI chemotherapy regimen with a monoclonal antibody (bevacizumab**) [9, 134–136].

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

Comments: in case of targeted drug administration, after converting metastases to an operable state and performing R0 resection of metastatic lesions, chemotherapy is administered for a total duration of 6 months. 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 drugs and monoclonal antibodies for a total duration of 6 months.

• In 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 mutations in RAS genes, pembrolizumab** as monotherapy until progression or until the tumor becomes resectable. A combination of FOLFOX or XELOX regimens with nivolumab or pembrolizumab is also acceptable [137–139]. The optimal duration of immunotherapy after performing an R0 resection is not precisely defined, but if well tolerated, it is recommended to continue for up to 1 year, taking into account the preoperative stage [131–133].

Level of Evidence AGrade of Evidence 2Level of recommendation evidence – A (level of data reliability – 2) for pembrolizumab and level of recommendation evidence – C (level of data reliability – 4) for the combination of nivolumab and ipilimumab.

3.4. Rectal cancer in a functionally inoperable patient

• In rectal cancer in a functionally inoperable patient (due to severe comorbidities), it is recommended to administer palliative medical treatment or symptomatic therapy to increase life expectancy and control tumor-related symptoms. Tumor stenting or creation of a diverting loop ileostomy/colostomy is possible [9, 140].

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

Comments: the risk of surgery outweighs the risk associated with cancer progression. The decision regarding contraindications to surgical treatment can only be made by a multidisciplinary team including a surgeon, general practitioner/internist, and anesthesiologist-resuscitologist.

3.5. Rectal cancer recurrence

• In case of rectal cancer recurrence, it is recommended to administer preoperative three-dimensional conformal radiation therapy with a single fraction dose of 2 Gy, total focal dose of 44 Gy to the regional metastasis zone, and total focal dose of 54–58 Gy to the recurrence zone (if radiation therapy was not performed previously), then consider the possibility of re-operation; if re-operation is not feasible, systemic chemotherapy is recommended [141–147].

GOM CLOE 4Level of Evidence – C (Level of Data Reliability – 4).

Comments: even if the patient has previously received radiation therapy, the possibility of additional irradiation or local stereotactic body radiation therapy should be considered. Surgical treatment (A16.19.020-A16.19.021.014) is performed 10-12 weeks after chemoradiotherapy. If radiation therapy and surgical intervention are not feasible, palliative chemotherapy is administered.

Treatment tactics are chosen at a multidisciplinary team meeting involving an oncologist, surgeon, radiation oncologist, and medical oncologist, based on the results of preoperative examination with determination of the clinical stage of the disease.

• In case of rectal cancer recurrence, if radiation therapy was previously administered, in order to increase the likelihood of performing R0 surgical resection, it is recommended to have an appointment (examination, consultation) with an oncologist (radiation oncologist) to assess the feasibility of a repeated course of radiation therapy, and to administer a repeated course of radiation therapy if technically feasible [148].

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

Comments: the specific regimen and doses of repeated courses of radiation therapy are determined individually, as the possibility of re-treatment depends on a large number of factors, including the equipment used during the first course of radiation therapy, the characteristics of the target volume chosen during the primary treatment, and the time elapsed since the completion of the last course of radiation therapy. Repeated courses of radiation therapy are not feasible for all patients. Performing repeated courses of radiation therapy with a cumulative radiation dose (CRD) of less than 30 Gy is impractical.

3.6. Adjuvant chemotherapy

Comments: in cases of preoperative chemoradiotherapy, the prescription of adjuvant chemotherapy is based on the results of the pathological examination of the surgical specimen and the initial clinical staging. The duration of adjuvant therapy recommended below includes the chemotherapy and chemoradiotherapy administered at the preoperative stage.

For an initial extent of cT3c-T4 and/or cN1-2 and/or extramural invasion after preoperative treatment, it is recommended:

⎯ for ypT_3-4N₀ or ypT_1-3N₁ – adjuvant chemotherapy with the XELOX regimen for a total of up to 3-6 months or FOLFOX for a total of up to 6 months of therapy (including the duration of preoperative treatment);

⎯ for ypT_1-4N₂ or ypT₄N_0-2 – adjuvant chemotherapy with the XELOX or FOLFOX regimen for a total of up to 6 months of therapy (including the duration of preoperative treatment);

⎯ for ypT_1-2N₀ – adjuvant chemotherapy with pyrimidine analogues in monotherapy (if MSI is absent in the tumor) or 3 months with the XELOX combination or 3-6 months with FOLFOX; if chemoradiotherapy was performed for cT1-2N0M0 and the tumor pathomorphologically remains staged within stage I, adjuvant chemotherapy may be omitted;

⎯ for ypT₀N₀ adjuvant chemotherapy is not administered or may be administered with pyrimidine analogues in monotherapy ;

For an initial extent of cT1-3a/bN0-1 and absence of extramural invasion after preoperative treatment, it is recommended:

⎯ for ypT_0-2N₀ – adjuvant chemotherapy is not administered;

⎯ for ypT₃N₀ – depending on the initial stage, observation may be considered, or adjuvant chemotherapy with pyrimidine analogues in monotherapy (if MSI is absent in the tumor) for up to 6 months, or 3 months with the XELOX combination, or 3-6 months with FOLFOX;

⎯ for ypT_1-4N_1-3 or ypT₄N_0-2 – adjuvant chemotherapy with the XELOX or FOLFOX regimen for a total of up to 6 months of therapy (including the duration of preoperative treatment);

In the absence of preoperative treatment:

⎯ for pT_3-4N₀ or pT_1-4N_1-2 adjuvant chemotherapy is prescribed according to the treatment guidelines for colon cancer.

The total duration of adjuvant chemotherapy is 6 months. Taking into account the results of the IDEA trial, despite the fact that patients who underwent preoperative chemoradiotherapy were not included in the analysis, in situations of poor treatment tolerability, for ypT_0–3N_0–1 it is possible to limit the course to 3 months of chemotherapy with the XELOX regimen. Tumor MSI detected in stage II indicates a favorable prognosis, and chemotherapy is generally not required provided that pT₄N₀ is absent. The minimum regimen for stage III chemotherapy includes pyrimidine analogues, which can be administered in various ways: infusion (modified de Gramont regimen) or orally (capecitabine**) (Table 3). The optimal regimen for stage III adjuvant chemotherapy includes a combination of oxaliplatin** with pyrimidine analogues for 6 months. FOLFOX or XELOX regimens are optimal. The combination of oxaliplatin** with bolus 5-fluorouracil** (FLOX regimen) has similar efficacy but is associated with high toxicity (it is the regimen of choice if cardiotoxicity develops with capecitabine** or continuous 5-fluorouracil** infusions) (see Table 3). If grade 2 polyneuropathy symptoms develop during chemotherapy, discontinuation of oxaliplatin and continuation of monotherapy with pyrimidine analogues is recommended. Irinotecan** and targeted agents, in particular bevacizumab**, cetuximab**, panitumumab**, aflibercept, ramucirumab, and regorafenib** [156], should not be used in the adjuvant treatment of rectal cancer; there is also no data on the efficacy of immunotherapy in the adjuvant setting. If adjuvant treatment has not been initiated within 2-4 months in the absence of signs of progression, the patient remains under active surveillance.

In patients aged 70 years and older, the addition of oxaliplatin** to pyrimidine analogues does not significantly increase overall survival [130, 157-159], nevertheless, the chemotherapy regimen in this group of patients is determined individually. Therefore, the use of oxaliplatin** in this age group is decided on an individual basis, depending on the stage, comorbidities, and life expectancy. To understand the risks of grade 3-5 complications 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 care

Table 3. Pyrimidine analogue regimens used in the treatment of colorectal cancer

Table 4. Oxaliplatin** and pyrimidine analogue regimens used in the treatment of colorectal cancer

3.7. Palliative chemotherapy

• In patients with rectal cancer, it is recommended to administer 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 [166].

GOW CLOE 5Grade of recommendation – C (level of evidence – 5).

• In patients with unresectable metastases and an asymptomatic primary tumor, it is recommended not to resect the primary tumor in order to improve chemotherapy tolerance and the patient's quality of life [167, 168].

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

Comments: according to prospective randomized trials, removal of an asymptomatic primary tumor in unresectable metastases improves neither progression-free survival nor overall survival, yet it worsens chemotherapy tolerance.

Table 5. Pyrimidine analogue dosing regimens in the treatment of colorectal cancer

• For the overwhelming majority of patients with metastatic rectal cancer, combination drug regimens (mFOLFOX6, XELOX or XELIRI, FOLFIRI, FOLFOXIRI) are recommended for use in first-line chemotherapy for at least 3–4 months, followed by possible maintenance therapy with pyrimidine analogues until disease progression [169-171].

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

Comments: oxaliplatin** monotherapy has low efficacy and should be used in combination with pyrimidine analogues. To prevent febrile neutropenia when using the FOLFOXIRI regimen, filgrastim** may be prescribed at a dose of 300–480 mcg SC 24 hours after completion of chemotherapy until neutrophil counts recover, or pegfilgrastim** 6 mg SC, or empegfilgrastim** 7.5 mg SC 24 hours after completion of chemotherapy once every 15 days [188-190]. In case of tumor progression after first-line therapy, second-line therapy may be prescribed to patients with a satisfactory performance status (ECOG ≤2). In case of refractoriness to the FOLFOX (XELOX) regimen, FOLFIRI/XELIRI or irinotecan** monotherapy is usually prescribed as the second line. In case of refractoriness to irinotecan** in the 1st line with the FOLFIRI regimen – mFOLFOX6/XELOX (see Tables 3, 4). If disease progression is noted after or during adjuvant chemotherapy, the optimal first-line option will be irinotecan-containing chemotherapy (FOLFIRI/XELIRI), which, according to sub-analyses of randomized trials, shows the best results compared with the FOLFOX or FOLFOXIRI regimens. When progressing during or after 1st-line therapy according to the FOLFOXIRI scheme, the optimal 2nd-line regimen is FOLFIRI. If the patient's somatic status is good, re-administration of the FOLFOXIRI regimen may also be considered.

Comments: the dosing regimen is determined by the instructions for medical use of specific medicinal products. Bevacizumab** monotherapy has low efficacy. Continuation of therapy with bevacizumab** and pyrimidine analogues until disease progression is recommended. When mutation analysis results are delayed, it is possible to start chemotherapy and subsequently, upon receiving the result, add the targeted drug starting from cycles 2–4. In case of progression, it is possible to continue using bevacizumab** while changing the regimen (ESMO-MCBS score 1 – according to the ESMO 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 are known to predict the efficacy of bevacizumab**. Bevacizumab** demonstrates the greatest activity in the 1st and 2nd lines of therapy (ESMO-MCBS score 3); the addition of bevacizumab** to oxaliplatin**- or irinotecan**-based regimens in the 2nd line of treatment significantly increases survival. In the 2nd line of therapy, other antiangiogenic MAbs may be prescribed – aflibercept** (ESMO-MCBS score 1) or ramucirumab** (ESMO-MCBS score 1), which are used only in combination with the FOLFIRI regimen. If significant toxicity develops, it is possible to continue therapy with aflibercept** or ramucirumab** either in combination with the de Gramont regimen or with irinotecan**. Indirect comparison of these three antiangiogenic monoclonal antibodies suggests similar efficacy. Therefore, from a financial perspective and to reduce toxicity, preferential prescription of bevacizumab is recommended.

Unlike bevacizumab*, in unresectable metastases, cetuximab* or panitumumab** are active both as monotherapy and in combination with chemotherapy, but only in patients without mutations in the RAS and BRAF genes, without HER-2/neu overexpression, with a microsatellite stable phenotype, and with primary tumor localization in the left colon. Cetuximab** and panitumumab** should not be used with capecitabine*- and bolus 5-fluorouracil-based regimens. The independent activity of cetuximab** and panitumumab** allows them to be used as monotherapy in the 3rd–4th line (ESMO-MCBS score 4). In later lines, panitumumab** or cetuximab** may also be used in cases of right-sided primary tumor localization in the absence of mutations in the RAS and BRAF genes. Co-administration of bevacizumab** and cetuximab** or panitumumab** worsens treatment outcomes and is not recommended. For left-sided primary tumors, FOLFOX or FOLFIRI regimens are preferred in combination with anti-EGFR antibodies in the first line (ESMO-MCBS score 4 compared with chemotherapy and score 3 compared with combinations with bevacizumab). For right-sided primary tumors, the FOLFOXIRI regimen is preferred in combination with bevacizumab in the first line (ESMO-MCBS score 3) regardless of the RAS and BRAF mutational status.

The goals of palliative chemotherapy are to increase life expectancy, reduce the severity of disease symptoms, and improve quality of life. Patients who have received all 3 active chemotherapeutic agents (irinotecan**, oxaplatin**, and pyrimidine analogues) have a significantly higher life expectancy, regardless of the number of treatment lines in which this is achieved. The optimal duration of 1st-line therapy remains unclear. Possible options:

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

2) treatment for at least 3–6 months followed by observation;

3) use of 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 in terms of progression-free survival, but not overall survival). When combining chemotherapy with bevacizumab**, maintenance therapy with bevacizumab** combined with pyrimidine analogues should be continued until signs of disease progression or unacceptable toxicity develop. When combining chemotherapy with cetuximab** or panitumumab**, maintenance therapy with a combination of calcium folinate**, fluorouracil**, and cetuximab** or panitumumab** infusions, or monoclonal antibody monotherapy until disease progression, is also recommended.

The sequence of targeted therapy also affects patient survival. 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 were prescribed cetuximab** or panitumumab** in the 2nd line. If cetuximab or panitumumab was prescribed in the 1st line, it is optimal to use regimens including bevacizumab** (preferred), aflibercept**, or ramucirumab** in the 2nd line. Continuing cetuximab** or panitumumab** upon progression does not improve patient survival rates even in the absence of RAS and BRAF mutations. Exceptions are situations where anti-EGFR antibodies were discontinued in the absence of disease progression [193].

• In patients with MSI in the 1st line, it is recommended to prescribe pembrolizumab** monotherapy or a combination of ipilimumab** with nivolumab**. The latter option is preferred [194, 195].

GCP ALEL 2Level of Evidence Compass – A (Level of Likelihood of Evidence – 2) for pembrolizumab

GCP CLEL 4Level of Evidence Compass – C (Level of Likelihood of Evidence – 4) for the combination of nivolumab and ipilimumab

Comments: in patients with a KRAS gene mutation, pembrolizumab** monotherapy was less effective in the 1st line than in patients without mutations; this trend was not observed with ipilimumab** and nivolumab**. Due to the risk of early progression with anti-PD-1 antibody monotherapy for colon cancer in patients with a high tumor burden, the combination of the FOLFOX/XELOX regimen with pembrolizumab** or nivolumab** should be considered. The efficacy of the FOLFOX/XELOX combination with anti-PD-1 antibodies in the 1st line has been demonstrated in phase III randomized trials in advanced gastric cancer, as well as in retrospective studies [137, 196]. In the absence of disease progression, treatment can be discontinued after 1 year of anti-PD-1 antibody therapy [114, 197].

Comments: adverse prognosis includes patients with a score of 4 or more points based on the following prognostic factors: duration of metastatic disease less than 18 months (2 points), metastasis in more than 2 organs (1 point), liver metastases (1 point), ECOG performance status 1 (1 point), ECOG performance status 2 or higher (4 points).

Comments: repeated administration in 3 or more consecutive lines of bevacizumab in combination with irinotecan-, oxaliplatin-, and/or fluoropyrimidine-based regimens does not have sufficient evidence base to recommend this approach, especially in the presence of RAS mutations.

Comments: in patients with RAS mutations, pembrolizumab** monotherapy in a randomized trial showed lower efficacy in the first line compared to patients without mutations; no such trends were noted when using the ipilimumab** and nivolumab** regimen. Given the potential risk of early progression with anti-PD-1 antibody monotherapy in colorectal cancer, in patients with a high tumor burden, it may be considered to prescribe a combination of the FOLFOX/XELOX regimen with pembrolizumab** or nivolumab**. In the absence of disease progression, treatment can be discontinued after 1 year of anti-PD-1 antibody therapy. Similar immunotherapy approaches, as for MSI, can be considered when pathogenic mutations in the POLD1 and POLE genes are detected in metastatic colorectal cancer.

• In frail patients with ECOG >2, as a first-line treatment, it is recommended to use low-toxicity monochemotherapy with pyrimidine analogues with or without targeted therapy depending on the mutational status and primary tumor localization, or best supportive care, and in the presence of MSI – nivolumab** or pembrolizumab** or a combination of ipilimumab** and nivolumab** [9, 131, 202].

GOM CLOE 4Level of Evidence – C (Level of Data Reliability – 4).

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.

• In the 3rd and subsequent lines of therapy, it is recommended to re-administer chemotherapy regimens with or without targeted therapy that were effective in previously administered treatment lines [203–205].

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

Comments: the use of the FOLFOXIRI regimen with bevacizumab results in a higher overall response rate, but does not increase progression-free survival or overall survival compared with doublet combinations with bevacizumab. Some retrospective studies have noted its greater efficacy in right-sided primary tumors and BRAF gene mutations. In case of disease progression during 1st-line therapy in the presence of a BRAF mutation, it is possible to prescribe the FOLFIRI regimen using aflibercept*/bevacizumab*/ramucirumab** [109] or a combination of cetuximab** or panitumumab** with encorafenib/#vemurafenib**/#dabrafenib** and #trametinib** [110, 111] (Table 6) (BRAF mutations are divided into 3 classes; the described targeted therapy approach is active in class I and II mutations). If chemotherapy cannot be administered in the first-line setting in patients with a BRAF mutation, therapy with a combination of cetuximab** or panitumumab** and encorafenib/#vemurafenib**/#dabrafenib**, with or without #trametinib**, may be considered. If anti-EGFR antibodies cannot be administered, the use of the combination of #vemurafenib** and #cobimetinib** may be considered, which is less preferred. 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. For class 3 BRAF mutations, treatment is administered as for wild-type tumors. 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** as monotherapy (Table 6).

Table 6. Irinotecan**-containing regimens and monoclonal antibodies used in the treatment of colorectal cancer

Table 7. Regimens used in the treatment of colorectal cancer with a BRAF gene mutation in 2nd and subsequent lines of therapy

# regimens are less preferred compared to combinations including anti-EGFR antibodies and are recommended only when the latter cannot be used.

3.8. Prevention and management of complications of malignant tumors and anticancer drug therapy. Symptomatic therapy.

• In patients with acute bleeding, urgent endoscopic examination and systemic hemostatic therapy are recommended to stop the bleeding. Depending on the examination results, endoscopic hemostasis is performed. If endoscopic hemostasis is not feasible or ineffective, emergency surgery (A16.19.020 - A16.19.021.014) is performed [9-11].

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

• In case of tumor stenosis complicated by intestinal obstruction, it is recommended to place a self-expanding stent in the area of tumor stenosis (endoscopic stenting for tumor stenosis) or perform surgical treatment (colostomy/ileostomy) [234] to resolve the obstruction.

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

• In the management of pain in patients with unresectable rectal cancer metastases, it is recommended to administer external beam radiotherapy, pharmacotherapy, or locoregional anesthesia (anesthetic management, including early postoperative care) depending on the cause of the pain syndrome [101, 141, 235].

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

• In the management of ascites in patients with unresectable rectal cancer metastases, it is recommended to consider the use of diuretics and paracentesis. For refractory ascites caused by peritoneal carcinomatosis, intraperitoneal chemotherapy should be considered [236].

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

Comments: the goals of so-called "best supportive care" are the prevention and relief of disease symptoms, as well as maintaining the quality of life of patients and their families, regardless of the disease stage and the need for other types of therapy. In rectal cancer, measures aimed at relieving core symptoms help prolong survival.

• When administering anticancer drug therapy with emetogenic agents, patients are recommended to receive prevention and treatment of nausea and vomiting [237, 238].

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

Comments: The principles of diagnosis, prevention, and treatment of nausea and vomiting during anticancer 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 anticancer drug therapy: Vladimirova L.Yu. et al. Nausea and Vomiting [239].

• In patients with bone metastases, prevention and treatment of bone complications are recommended [232, 240, 241].

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

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 anticancer drug therapy: Bagrov S.G. et al. Bone Tissue Pathology [241].

• Patients are recommended to receive prevention and treatment of venous thromboembolic complications [236, 242-244].

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

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 anticancer drug therapy: Somonov O.V. et al. Thromboembolic Complications [245].

• During anticancer drug therapy, patients are recommended to receive prevention and treatment of febrile neutropenia and infectious complications [246-248].

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

Comments. A detailed algorithm for the diagnosis, prevention, and treatment of febrile neutropenia and infectious complications, along with the principles of antibacterial therapy, is outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the prevention and treatment of complications of malignant tumors and anticancer drug therapy: Sakaeva D.D. et al. Practical Guidelines for the Diagnosis and Treatment of Febrile Neutropenia [249].

• During anticancer drug therapy, patients are recommended to receive management for hepatotoxicity [250, 251].

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

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 anticancer drug therapy: Tkachenko P.E. et al. Hepatotoxicity [252].

• When administering anticancer drug therapy to patients, it is recommended to provide prevention and treatment of cardiovascular complications [253-256].

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

Comments. The principles of diagnosis, prevention, and treatment of cardiovascular complications during anticancer therapy are outlined in the Practical Guidelines of the Russian Society for the Prevention and Treatment of Complications of Malignant Tumors and Anticancer Drug Therapy: Vitsenya M.V. et al. Cardiovascular Toxicity [257].

• During antineoplastic drug therapy, patients are recommended to receive prevention and treatment of dermatological reactions [258].

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

Comments. The principles of diagnosis, prevention, and treatment of skin 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 [259].

• To maintain the body's metabolic reserves in cancer patients and increase their resistance to treatment (surgical, medical, radiation), nutritional support is recommended. The choice of nutritional support method is determined by the patient's specific nutritional disorders. The placement of a nasogastric (A11.16.010), nasointestinal (A03.16.002), percutaneous, endoscopic, laparoscopic, or laparotomic stoma, endoscopic stenting for tumor stenosis, or palliative radiation therapy may be recommended [260, 261].

GOR ALOE 1Grade of Recommendation – A (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 [262].

• During antineoplastic drug therapy, patients are recommended to receive prevention and treatment of nephrotoxicity [263-265].

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 [266].

• During antineoplastic drug therapy, patients are recommended to receive prevention and treatment of immune-mediated adverse events [267-270].

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

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 [271].

• During antineoplastic drug therapy, patients are recommended to receive prevention and treatment of mucositis [272, 273].

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 [274].

• 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 [275, 276].

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

Comments. The procedures and principles for the prevention and treatment of anemia comply with 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 [277].

• During treatment, patients are recommended to receive treatment for anorexia-cachexia syndrome [278].

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

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 [279].

• 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 status, the use of central venous access and infusion pumps is recommended [280].

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

Comments. The choice of central access option is determined by the planned duration of the entire course of treatment, patient preferences, and anatomical features. For prolonged (over 3 months) courses of therapy, 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 [281].

• During antineoplastic drug therapy, patients are recommended to receive prevention and treatment of antineoplastic extravasation. When planning antineoplastic drug therapy, the choice of vascular access is important for the prevention of antineoplastic drug extravasation [282].

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

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 agents [283].

• During antineoplastic treatment, patients are recommended to receive treatment for chronic pain syndrome [284].

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

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 [285].

• During antineoplastic drug therapy, patients are recommended to receive prevention and treatment of infusion reactions [286].

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

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 [287].

• During therapy, patients are recommended to undergo monitoring and treatment for reactivation/exacerbation of chronic viral hepatitis [288].

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

Comments. The 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 [289].

• During antineoplastic drug therapy, patients are recommended to receive prevention and treatment of neurological complications [290] [291].

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

Comments. The 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 [291].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Comment: there is no evidence or known mechanisms that could lead to an increased risk of rectal cancer progression with hormone replacement therapy, any types of spa-resort treatment, or physiotherapy. This thesis does not negate potential contraindications associated with the presence of long-term non-healing wounds, foci of chronic inflammation, an increased risk of hernias, and other factors that may be related to previously administered treatment. These contraindications are general for wounds and inflammatory foci of any etiology. The mere history of rectal cancer is not a contraindication to any methods of drug therapy, physiotherapy, or spa-resort treatment. When assessing indications for any non-oncological treatments and rehabilitation, one should be guided solely by the patient's existing health problems, regardless of their etiology, rather than the fact of having an oncological history. The prescription of spa-resort treatment, physiotherapy, and drug therapy for concomitant diseases, including hormone replacement therapy and oral contraceptives, does not require an oncologist's consultation.

4.1. Pre-rehabilitation

Comments: pre-rehabilitation significantly accelerates functional recovery, shortens hospital stay after surgery, and reduces the incidence of complications and mortality associated with cancer treatment.

Comments: increased physical activity improves postoperative quality of life, allowing a faster return to full daily activities. A comprehensive pre-rehabilitation program for colorectal cancer patients, which includes home-based exercise therapy (moderate-intensity physical activity combining both aerobic and anaerobic loads), nutritional counseling (initial consultation with a nutritionist), and sessions with a medical psychologist (initial psychological testing and consultation) to overcome anxiety and depression (starting 28 days before surgery and continuing for 8 weeks after), significantly improves postoperative quality of life [195].

Psychological support as part of pre-rehabilitation improves mood, reduces anxiety and depression levels. Patients who undergo a course of psychological pre-rehabilitation adapt better to daily life after surgical treatment. Psychological pre-rehabilitation, including stress management techniques (relaxation techniques, positive mindset formation) for 40-60 minutes 6 days a week, starting 5 days before surgery and lasting for 30 days after, significantly improves quality of life [301].

4.2. Rehabilitation Following Surgical Treatment

4.2.1. Stage I rehabilitation in surgical treatment

Comments: this approach does not increase the risks of early postoperative complications or hospital readmission rates.

Comments: these measures help prevent postoperative respiratory complications. Breathing exercises are started as soon as the patient's consciousness normalizes after surgery. The patient is taught the technique of postoperative breathing exercises before surgery. Following surgical treatment in colorectal cancer patients, diaphragmatic breathing is recommended, as it improves lymphatic circulation and ventilates the lower lobes of the lungs, which typically do not inflate sufficiently during thoracic breathing [304].

4.2.2. Stage II rehabilitation in surgical treatment

4.2.3. Stage III rehabilitation in surgical treatment

Comments: increased physical activity reduces fatigue, increases mobility, decreases depression levels, and improves quality of life.

Comments: there is no data indicating an increased risk of tumor progression when using these rehabilitation methods.

4.3. Rehabilitation During Chemotherapy

• During chemotherapy, to reduce the risk of treatment side effects and fatigue, it is recommended to perform exercise therapy (therapeutic exercises for colon diseases) and relaxation techniques, including diaphragmatic breathing and progressive muscle relaxation [311, 312].

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 chemotherapy, to reduce the risk of treatment side effects and fatigue, it is recommended to consider prescribing a course of massage (massage for colon diseases, general medical massage) [311, 312].

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

• During the third stage of rehabilitation, to accelerate patient recovery and reduce fatigue, it is recommended to maintain an active lifestyle and perform exercise therapy (therapeutic exercises for colon diseases) after combined treatment for colorectal cancer [194, 195].

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

Comments: performing exercise therapy in patients with cancer recurrence reduces all-cause mortality risk by 29%. Performing exercise therapy and physical activity in patients with disseminated disease reduces fatigue, increases mobility, decreases depression levels, and improves quality of life.

4.4. Rehabilitation During Radiation Therapy

Comments: performing exercise therapy increases bone mineral density and patient endurance during radiation therapy.

5. Prevention and Dispensary Observation

Comments: the goal of follow-up is early detection of disease progression to allow early initiation of chemotherapy or surgical treatment of resectable metastatic lesions and recurrent tumors, as well as the detection of metachronous rectal tumors (see Appendix A. Patient Follow-up Schedule After Treatment Completion). There are no data on the impact of active surveillance on long-term treatment outcomes. However, in patients with a high risk of recurrence, as well as in cases of suspected recurrence, pelvic MRI may be added at the discretion of the oncologist. The frequency of pelvic MRI in the absence of suspected recurrence (findings from digital rectal examination, rising CEA levels, etc.) typically does not exceed once a year [316].

6. Organization of Medical Care

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

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

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

3) based on these clinical guidelines;

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

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

Upon suspicion or detection of rectal cancer, general practitioners, district general practitioners, family physicians, specialist physicians, and mid-level medical personnel shall refer the patient in the established manner to an outpatient oncological care center, a primary oncological office, or a primary oncological department of a medical organization for the provision of primary specialized health care.

Consultation at an outpatient oncological care center or at a 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 (in the absence of an outpatient oncological care center, the oncologist of the primary oncological office or primary oncological department) shall organize the collection of biopsy (surgical) material, as well as organize other diagnostic studies necessary to establish the diagnosis, including the extent of the oncological process and the stage of the disease.

If it is impossible to collect biopsy (surgical) material or perform other diagnostic tests at the medical organization that houses the outpatient oncological care center (primary oncological office, primary oncological department), the attending physician shall refer the patient to an oncological dispensary or a medical organization providing medical care to patients with oncological diseases.

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

When rectal cancer is suspected and/or detected during the provision of emergency medical care, such patients are transferred or referred to medical organizations providing medical care to cancer patients to determine management tactics and the need for additional specialized anti-tumor treatment methods.

The oncologist at the outpatient oncological care center (primary oncological office, primary oncological department) refers the patient to an oncological dispensary or medical organizations providing care to rectal cancer patients to clarify the diagnosis (in cases where the diagnosis, including the extent of the oncological process and disease stage, 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 timeframe for initiating specialized (other than high-tech) medical care for cancer patients in a medical organization providing care to rectal cancer patients must not exceed the timeframes established in the state guarantee program for free medical care to citizens, approved by the Government of the Russian Federation: 7 calendar days from the date of morphological verification of the malignant neoplasm or 14 calendar days from the date of establishing a preliminary diagnosis of a malignant neoplasm (in the absence of medical indications for outpatient pathological examinations).

Specialized, including high-tech, medical care is provided by oncologists and radiotherapists in an oncological dispensary or medical organizations providing care to rectal cancer patients that hold the necessary license, material and technical base, and certified specialists, in inpatient and day-hospital settings, and includes the 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 care to rectal cancer patients, the medical examination and treatment strategy is established by a multidisciplinary team consisting of oncologists and radiotherapists, involving other specialist physicians as necessary. The decision of the medical board is documented in a protocol, signed by the participating physicians, and entered into the patient's medical records.

Indications for hospitalization in a round-the-clock or day hospital of a medical organization providing specialized, including high-tech, medical care in the field of oncology are determined by a multidisciplinary team of oncologists and radiotherapists, with the involvement of other specialist physicians as necessary.

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

1) the presence of complications of the oncological disease requiring specialized medical care in an emergency or urgent setting;

2) presence of complications from treatment (surgical intervention, radiation therapy, drug therapy, etc.) of the oncological disease.

Indications for elective hospitalization in a medical organization are:

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

2) presence of indications for specialized anti-tumor treatment (surgical intervention, radiation therapy, including brachytherapy, teletherapy, 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 round-the-clock or day hospital setting, provided there are no treatment complications requiring drug correction and/or inpatient medical interventions;

2) refusal by the patient or their legal representative of specialized (including high-tech) medical care in a round-the-clock or day hospital setting prescribed by the medical board of the oncology care organization, provided there are no complications of the underlying disease and/or treatment requiring drug correction and/or inpatient medical interventions;

3) the need to transfer the patient to another medical organization according to the relevant medical profile.

The conclusion regarding the feasibility of transferring a patient to a specialized medical organization is made after a preliminary consultation based on submitted medical documents and/or a preliminary examination of the patient by medical specialists of the target organization.

7. Additional Information

Known prognostic factors in rectal cancer that are recommended to be recorded are presented in Table 2.

Table 2. Prognostic factors in rectal cancer

Criteria for Evaluating the Quality of Medical Care

The criteria for assessing the quality of specialized medical care for patients with rectal cancer are listed below.

References

Appendix A1. Working Group Composition

1. Mamedli Z.Z., MD, PhD, Head of Surgical Department No. 3 (Coloproctology), N.N. Blokhin National Medical Research Centre of Oncology of the Russian Ministry of Health.

2. Gordeev S.S., MD, PhD, Associate Professor, Leading Researcher, Surgical Department No. 3 (Coloproctology), Head of the Department of Research Planning and Coordination, N.N. Blokhin National Medical Research Centre of Oncology of the Russian Ministry of Health.

3. Fedyanin M.Yu., MD, PhD, Senior Researcher, Department of Antineoplastic Drug Therapy No. 2, Drug Therapy Department, N.N. Trapeznikov Institute of Clinical Oncology, N.N. Blokhin National Medical Research Centre of Oncology of the Russian Ministry of Health; Head of the Chemotherapy Service, Kommunarka Moscow Multidisciplinary Clinical Center, Moscow Healthcare Department; Head of the Department of Oncology, Pirogov Russian National Research Medical University of the Russian Ministry of Health.

4. Achkasov S.I., MD, PhD, Professor, Director, A.N. Ryzhikh National Medical Research Centre of Coloproctology of the Russian Ministry of Health.

5. Belokhvostova A.S., PhD, Head of the Antineoplastic Drug Therapy Department, A.F. Tsyb Medical Radiological Research Centre – branch of the National Medical Research Radiological Centre of the Russian Ministry of Health, Associate Professor, Department of Radionuclide Medicine, Institute of Engineering Physics for Biomedicine, National Research Nuclear University MEPhI.

6. Berezovskaya T.P., MD, PhD, Professor, Chief Researcher, Diagnostic Radiology Department, A.F. Tsyb Medical Radiological Research Centre – branch of the National Medical Research Radiological Centre of the Russian Ministry of Health.

7. Bolotina L.V., MD, PhD, Professor of the RAS, Head of the Chemotherapy Department P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Centre of the Russian Ministry of Health.

8. Gevorkyan Yu.A., MD, PhD, Professor, Head of Abdominal Oncology Department No. 2, National Medical Research Centre of Oncology of the Russian Ministry of Health.

9. Karachun A.M., Professor, MD, PhD, Head of the Abdominal Oncology Surgical Department, N.N. Petrov National Medical Research Centre of Oncology of the Russian Ministry of Health, staff member of the Department of Oncology, North-Western State Medical University named after I.I. Mechnikov.

10. Kozlov N.A., PhD, Pathologist, Pathological Anatomy Department, Department of Morphological and Molecular Genetic Tumor Diagnostics N.N. Blokhin National Medical Research Centre of Oncology of the Russian Ministry of Health.

11. Nevolskikh A.A., MD, DSc, Deputy Director for Medical Work, Medical Radiological Research Center named after A.F. Tsyb – branch of the National Medical Research Center for Radiology of the Russian Ministry of Health.

12. Petrov K.S., PhD, Radiologist, X-ray Diagnostics Department, N.N. Blokhin National Medical Research Centre of Oncology of the Russian Ministry of Health.

13. Rybakov E.G., MD, PhD, Professor of the RAS, Head of the Department of Oncoproctology, A.N. Ryzhikh National Medical Research Centre of Coloproctology of the Russian Ministry of Health.

14. Snegovoy A.V., MD, PhD, Head of the Department of Drug Treatment of Tumors, N.A. Lopatkin Research Institute of Urology and Interventional Radiology.

15. Tryakin A.A., MD, PhD, Professor, Deputy Director for Research, Head of Antineoplastic Drug Therapy Department No. 2, Drug Therapy Department, N.N. Trapeznikov Institute of Clinical Oncology, N.N. Blokhin National Medical Research Centre of Oncology of the Russian Ministry of Health.

16. Tsukanov A.S., MD, PhD, Head of the Laboratory Genetics Department, A.N. Ryzhikh National Medical Research Centre of Coloproctology of the Russian Ministry of Health.

17. Chernykh M.V., PhD, Deputy Director for Clinical Work, Research Institute of Clinical and Experimental Radiology, Head of the Radiotherapy Department, N.N. Blokhin National Medical Research Centre of Oncology of the Russian Ministry of Health.

Rehabilitation Section

1. Merzlyakova A.M., PhD, Oncologist, Medical Rehabilitation Department, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Centre of the Russian Ministry of Health.

2. Obukhova O.A., PhD, Physical and Rehabilitation Medicine Physician, Rehabilitation Department, N.N. Blokhin National Medical Research Centre of Oncology of the Russian Ministry of Health.

Medical Care Organization Section

1. Fomenko Yu.A., PhD, Deputy General Director for Clinical and Expert Work, National Medical Research Centre of Oncology of the Russian Ministry of Health.

2. Ivanov S.A., MD, PhD, Professor, Corresponding Member of the RAS, Honored Doctor of the Russian Federation, Director of the A.F. Tsyb Medical Radiological Research Centre – branch of the National Medical Research Radiological Centre of the Russian Ministry of Health, Chief freelance Oncologist of the Central Federal District of the Russian Ministry of Health.

3. Khailova Zh.V., PhD, Deputy Director for Organizational and Methodological Work, A.F. Tsyb Medical Radiological Research Centre – branch of the National Medical Research Radiological Centre of the Russian Ministry of Health.

4. Gevorkyan T.G., Deputy Director, N.N. Blokhin National Medical Research Centre of Oncology of the Russian Ministry of Health.

5. Komarov Yu.I., PhD, Deputy Director for Organizational and Methodological Work, N.N. Petrov National Medical Research Centre of Oncology of the Russian Ministry of Health.

Supportive Care Section

1. Gladkov O.A., Professor, MD, PhD, Director of EVIMED Medical Center LLC.

2. Karaseva V.V., MD, PhD, Associate Professor, Professor, Department of Oncology, Institute of Additional 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) radiologists;

3) radiation therapists;

4) coloproctologists;

5) surgeons;

6) endoscopists;

7) anesthesiologists-resuscitators;

8) general practitioners (internists);

9) general practitioners (family medicine);

10) geneticists;

11) pathologists;

12) healthcare organization and public health specialists;

13) rehabilitologists (medical rehabilitation specialists);

14) clinical pharmacologists;

15) medical students, residents, and postgraduate students.

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

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

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

Table 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)

Good Practice Points (GPPs): good practice points of the recommendations are based on the qualifications and clinical experience of the authoring team.

Methods used for formulating recommendations – expert consensus.

Economic analysis:

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

Method of recommendation validation:

• External peer review

• Internal expert review.

Description of the guideline validation method:

The draft of these recommendations was 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 recommendations and their assessment of their importance as a working tool in 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 of clinical guidelines: updating is carried out at least once every 3 years, taking into account new information on the diagnosis and management of rectal cancer patients.

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

Appendix A3. Reference Materials

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

1) clinical guidelines of the European Society of Coloproctology;

2) Order of the Russian Ministry of Health No. 206n dated April 2, 2010, “On approval of the Procedure for providing medical care to the population with diseases of the colon, anal canal, and perineum in the coloproctological profile (as amended on February 21, 2020);

3) Order of the Russian Ministry of Health No. 915n dated November 15, 2012, “On approval of the Procedure for providing medical care to adult patients with oncology”.

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

Follow-up examination schedule for the patient after completion of treatment

^[14] If polyps are detected, it is performed annually; if colonoscopy was not performed prior to treatment due to a stenosing tumor, it is performed within 3-6 months after resection.

^[2] Pelvic MRI may be performed in patients at high risk of recurrence, at the discretion of the oncologist. This examination does not affect long-term treatment outcomes

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

Criteria for genetic testing in patients with suspected Lynch syndrome

Amsterdam I criteria

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

2. The disease is traced across at least two generations.

3. At least 1 relative was diagnosed with CRC under the age of 50 years.

4. Familial adenomatous polyposis is excluded.

Amsterdam II criteria

1. At least 3 relatives have developed Lynch syndrome-associated cancer (CRC, endometrial cancer, gastric cancer, ovarian cancer, ureteral/renal pelvic cancer, brain cancer, small bowel cancer, hepatobiliary tract cancer, and skin cancer [sebaceous glands]), with one of them being a first-degree relative.

2. The disease is traced across at least two 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 CRC presence.

5. Tumors should be verified whenever possible.

Bethesda criteria for MSI testing

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

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

3. Colorectal cancer with MSI identified on histological examination in a patient under 60 years of age.

4. Colorectal cancer in one or more first-degree relatives with a disease that may be associated with Lynch syndrome, with at least one case diagnosed under the age of 50.

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

A.N. Ryzhikh NMRCC selection criteria for Russian patients

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

2. Along with colorectal cancer, 2 or more additional cases of malignant tumors of any localization in the patient themselves or in blood relatives, regardless of age.

Minimum list of RAS gene mutations for testing in colorectal cancer

Classification of mutations in the BRAF gene

Appendix B. Physician Action Algorithms

Fig. 1. Flowchart for the diagnosis and management of a patient with colon cancer

RC – rectal cancer

TNT – total neoadjuvant therapy (3 months or more of chemotherapy according to the XELOX or FOLFOX regimen)

CRM – circumferential resection margin

CRT – chemoradiotherapy (TDF 50–52 Gy)

RT – radiotherapy (FDF 5 Gy, TDF 25 Gy)

Fig. 2. Algorithm for selecting the preoperative treatment regimen in rectal cancer

Appendix C. Patient Information

Recommendations for chemotherapy complications – contact your oncologist.

1. If body temperature rises to 38 °C or higher: start taking antibiotics as prescribed by your oncologist.

2. For stomatitis:

   • diet with mechanical and thermal sparing of the mucosa;

   • frequent mouth rinsing (every hour) with chamomile, oak bark, or sage decoctions, lubricate the oral cavity with sea buckthorn (peach) oil;

   • treat the oral cavity as prescribed by your oncologist.

3. For diarrhea:

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

   • Take medications as prescribed by your oncologist.

4. For nausea:

   • Take medications as prescribed by your oncologist.

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

Appendix G1. WHO/ECOG Performance Status Scale

Russian name: WHO/ECOG performance status scale.

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

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

Original publication: Oken M.M., Creech R.H., Tormey D.C., Horton J., Davis T.E., McFadden E.T., Carbone P.P. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5(6):649−55 [232].

Type: rating scale.

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

Content (template):

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

Appendix G2. Karnofsky Performance Scale

Russian name: Karnofsky scale.

Original name (if applicable): Karnofsky Performance Status.

Source (official website of the developers, publication with validation): Karnofsky D.A., Burchenal J.H. The clinical evaluation of chemotherapeutic agents in cancer. In: MacLeod C. (ed.). Evaluation of chemotherapeutic agents. New York: Columbia University Press; 1949:191–205 [233].

Type: rating scale.

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

Content (template):

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

Appendix G3. Visual analogue scale for pain assessment

Russian name: Visual Analog Scale for pain assessment.

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

Source (official website of the developers, publication with validation): Hawker G.A., Mian S., Kendzerska T., French M. Measures of adult pain: Visual Analog Scale for Pain (VAS Pain), Numeric Rating Scale for Pain (NRS Pain), McGill Pain Questionnaire (MPQ), Short-Form McGill Pain Questionnaire (SF-MPQ), Chronic Pain Grade Scale (CPGS), Short Form-36 Bodily Pain Scale (SF-36 BPS), and Measure of Intermittent and Constant Osteoarthritis Pain (ICOAP). Arthritis Care Res (Hoboken) 2011;63(Suppl 11):S240–52 [234].

Type: rating scale.

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

Content (template):

“Rate the severity of pain on a scale, where 0 is no pain and 10 is excruciating pain of maximum severity.”

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

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

Appendix D. Terms describing procedures in the clinical guideline and possible (closest) terms from the current nomenclature of medical services