Squamous cell carcinoma of the anal canal, anal margin, and perianal skin: clinical guidelines

List of Abbreviations

3DCRT – Three-Dimensional Conformal Radiation Therapy (Conformal External Beam Radiation Therapy)

AUC (area under the curve) – a measure of drug exposure for a number of chemotherapy agents

CTCAE – Common Terminology Criteria for Adverse Events

HSIL – high-grade anal intraepithelial neoplasia

IMRT – intensity-modulated radiation therapy (conformal external beam radiation therapy, including IMRT, IGRT, VMAT, stereotactic)

NCI-CTCAE – National Cancer Institute Common Terminology Criteria for Adverse Events

RTOG – Radiation Therapy Oncology Group

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

CT – computed tomography

G-CSF – colony-stimulating factors

PT – physical therapy

ICD-10 – International Classification of Diseases 10th Revision

MRI – magnetic resonance imaging

PET-CT – positron emission tomography–computed tomography (positron emission tomography combined with computed tomography using tumorotropic radiopharmaceuticals with contrast enhancement)

USDG – Doppler ultrasonography (duplex scanning of brachiocephalic arteries with color Doppler flow mapping)

US – ultrasound examination

ECG – electrocardiography (recording of an electrocardiogram)

** – vital and essential drugs

# – off-label drug

Terms and Definitions

3DCRT – a radiation therapy technique, three-dimensional conformal radiation therapy (conformal external beam radiation therapy).

IMRT – a radiation therapy technique, intensity-modulated radiation therapy (conformal external beam radiation therapy, including IMRT, IGRT, VMAT, stereotactic).

RapidArc – image-guided radiation therapy technology.

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

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

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

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

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Anal cancer – a group of malignant epithelial neoplasms with squamous differentiation originating in the region whose proximal border is the upper edge of the anorectal line and distal border is the junction of the anoderm with the perianal skin. Neoplasms developing distally from the anal margin to the transition into the hair-bearing skin of the buttocks (ICD-10 code C44.5) are classified as skin (perianal) tumors. Neoplasms primarily involving the anocutaneous line without significant extension into the anal canal are classified as anal margin cancer [1].

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

The development of anal cancer is considered to be associated with oncogenic human papillomavirus (HPV) genotypes (16, 18, etc.). The mechanism of transmission and spread of the virus in the population occurs predominantly through anal sexual intercourse [2].

1.3 Epidemiology of the Disease or Condition

Malignant tumors of the anal canal are a relatively rare disease. According to various authors, their frequency accounts for 1–6% of all malignant colorectal tumors. Exact statistics on the incidence of and mortality from anal cancer in Russia are not maintained.

The median age of patients is 60 years. Women predominate among patients, with a female-to-male ratio of 7:1 [3].

1.4 Features of Coding the Disease or Condition

Malignant neoplasm of the anus and anal canal (C21):

C21.0 – Malignant neoplasm of the anus, unspecified.

C21.1 – Malignant neoplasm of the anal canal.

C21.2 – Malignant neoplasm of the cloacogenic zone.

C21.8 – Malignant neoplasm of rectum, anus, and anal canal overlapping sites.

Other malignant neoplasms of skin (C44):

C44.5 – Malignant neoplasm of skin of trunk (anal margin and perianal skin).

When skin cancer is localized in the perianal region, the principles of diagnosis and treatment are similar to those for squamous cell carcinoma of the anal canal, which allows these nosologies to be considered within the framework of the same clinical guidelines.

1.5 Classification of the disease or condition

WHO International Histological Classification of Tumors of the Anal Canal (2019) The vast majority of anal canal tumors (70–80%) are squamous cell carcinomas. Adenocarcinoma accounts for 10–15%, and other tumors make up no more than 3–5%. Determining the histological type of the tumor is of key importance in choosing treatment tactics.

Epithelial tumors:

I. Benign tumors and pre-invasive lesions.

• Squamous cell papilloma.

- Squamous intraepithelial lesion with mild atypia

- Squamous intraepithelial lesion with severe atypia

II. Malignant tumors.

1. Squamous cell carcinoma, NOS

2. Adenocarcinoma.

4. Neuroendocrine tumor, NOS

5. Neuroendocrine tumor, G1

6. Neuroendocrine tumor, G2

7. Neuroendocrine tumor, G3

8. Neuroendocrine carcinoma, NOS

9. Small cell carcinoma.

10. Large cell neuroendocrine carcinoma.

12. Mixed neuroendocrine-non-neuroendocrine neoplasm.

Changes in the epithelium of the anal canal and perianal skin (precancerous lesions / intraepithelial carcinoma).

8081/2 Bowen's disease.

8542/3 Paget's disease.

*Tumors are divided into well-, moderately-, poorly differentiated, and undifferentiated structures.

The treatment of anal canal adenocarcinoma follows the same principles as the treatment of lower rectal adenocarcinoma (see the relevant section of the guidelines). The principles of treatment for anal canal adenocarcinomas can be found in the section of the guidelines dedicated to rectal cancer. The principles of treatment for neuroendocrine tumors of the anal canal and anorectal melanoma are discussed in the relevant sections of the clinical guidelines.

1.5.1. Staging

Staging according to the TNM8 system (2017). Tumors of the anal canal and perianal skin (within 5 cm of the anocutaneous line) share the same staging (Table 1):

The T descriptor includes the following categories:

T_X – primary tumor cannot be assessed.

T₀ – no evidence of primary tumor.

T_is – carcinoma in situ (Bowen's disease, Paget's disease, anal intraepithelial neoplasia II–III [AIN II–III]).

T₁ – tumor 2 cm or less in greatest dimension.

T₂ – tumor more than 2 cm but not more than 5 cm in greatest dimension.

T₃ – tumor more than 5 cm in greatest dimension.

T₄ – tumor of any size invading adjacent organs and tissues (vagina, urethra, urinary bladder). Tumor invasion into the perianal skin, subcutaneous fat, or sphincter complex is not classified as T₄.

The N symbol indicates the presence or absence of regional lymph node metastases. Regional lymph nodes include: mesorectal lymph nodes (pararectal, sacral), internal and external iliac, and inguinal lymph nodes.

N_X – regional lymph nodes cannot be assessed.

N₀ – no regional lymph node metastases.

N_1a – metastases in mesorectal, inguinal, and internal iliac lymph nodes.

N_1b – metastases in external iliac lymph nodes.

N_1c – metastases in external and internal iliac / inguinal / mesorectal lymph nodes.

The M symbol characterizes the presence or absence of distant metastases:

M₀ – no distant metastases.

M₁ – distant metastases present.

Table 1. TNM staging of anal canal cancer (UICC, 2017, 8th edition)

1.6 Clinical presentation of the disease or condition

Anal canal cancer typically presents with a palpable mass in the anal region. The most characteristic symptoms include bleeding and mucus discharge with stool, anal pain worsening during defecation, and a sensation of a foreign body in the anal region. Anal canal cancer can also be an incidental finding during pathomorphological examination of surgical specimens (Pathological examination of biopsy (surgical) material) following surgeries performed for anal fissures and hemorrhoids.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the disease or condition:

Comment: obtaining biopsy material (biopsy of the anus and perianal region) can be performed during a clinical examination and rectal examination, anoscopy, sigmoidoscopy, or colonoscopy.

2.1 Complaints and Anamnesis

2.2 Physical Examination

− inspection of the perianal skin: presence of tumor growths, fistulous openings, maceration, ulceration, and palpation of inguinal lymph nodes (ultrasound-guided lymph node biopsy) (determining the presence of enlarged nodes, their consistency, and mobility relative to underlying structures and skin);

− gynecological examination for women to assess tumor extension to the posterior vaginal wall and cervical cancer screening (cytological examination of a cervical smear (cytological examination of a cervical micropreparation) must be performed);

− digital rectal examination (transrectal digital examination) to determine the size of the neoplasm [1, 5, 6].

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

Comment: synchronous cervical cancer or cervical intraepithelial neoplasia may be detected in 3–5% of patients with anal canal cancer.

• In all patients with anal canal cancer, nutritional status assessment is recommended prior to treatment initiation to determine indications for supportive care [1, 4].

GCR CLE 5Grade of Recommendation – C (Level of Evidence – 5).

2.3 Laboratory Diagnostics

Comments: this tumor marker has no proven clinical significance in routine use. Its determination should be considered in patients with metastatic disease or initially locally advanced anal canal cancer.

Comments: squamous cell carcinoma of the anal canal can develop as an HIV-associated malignancy; adjustment of the chemotherapy regimen is required if the CD4 cell count is <200/µl.

2.3.1. Pathomorphological examination after surgical treatment

The macroscopic description of the resected specimen should reflect the following parameters:

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

2. If adjacent organs are present in the macro-specimen as part of the primary tumor, list them and indicate their dimensions (cm).

3. Assess the completeness of regional adipose tissue dissection performed by the surgeon within the mesorectal fascia (according to P. Quirke, TME-G1-G3).

4. Assess the extent of levator muscle dissection in the intersphincteric zone performed by the surgeon (according to P. Quirke, TME-G1-G3).

5. Location of the tumor on the bowel wall.

6. Tumor dimensions (cm).

7. Presence of signs of serosal perforation of the intestinal wall proximal to the tumor.

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

9. In the presence of two or more primary tumors, reflect items 5–8 for each neoplasm separately.

The microscopic description of the resected specimen should reflect the following parameters to determine 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 stated).

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

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

8. Indicate the total number of examined lymph nodes.

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

10. Indicate the number of lymph nodes with micrometastases (pN+).

11. Indicate the number of lymph nodes with isolated tumor cells (pN0).

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

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

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

15. Presence of proximal resection margin involvement (a negative result must also be stated).

16. Presence of distal resection margin involvement (a negative result must also be 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. If prior neoadjuvant therapy was administered, indicate the tumor regression grade according to the Mandard scale (TRG1 - TRG5) (Appendix G1) [67].

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

2.4 Instrumental Diagnostics

Comments: both squamous cell carcinoma and adenocarcinoma can occur in the anal canal. The treatment principles for these diseases differ cardinally; therefore, precise morphological verification is required in all cases prior to treatment initiation.

Comments: Pelvic MRI has an advantage in diagnosing the local spread of anal canal cancer, as it allows for the assessment of not only the depth of anal canal wall invasion but also the status of all groups of pelvic and inguinal lymph nodes. If there are contraindications to pelvic MRI, computed tomography (CT) of the pelvis with intravenous contrast (Contrast-enhanced computed tomography of the pelvic organs in women, contrast-enhanced computed tomography of the pelvic organs in men) or positron emission tomography-computed tomography (PET-CT) with fluorodeoxyglucose [18F]) (PET combined with contrast-enhanced CT using tumorotropic radiopharmaceuticals) is indicated.

The pelvic MRI report for primary staging of anal canal cancer and perianal skin should indicate the following parameters:

– maximum tumor size and localization;

– presence, number, and size of involved inguinal lymph nodes;

– presence, number, and size of involved mesorectal lymph nodes and lymph nodes along the inferior mesenteric artery;

– presence, number, size, and localization of involved pelvic lymph nodes;

– data on tumor invasion into adjacent organs and tissues;

– data on the presence of fistulas and peritumoral abscesses.

The pelvic MRI report when assessing the response to chemoradiotherapy should indicate:

• presence of residual tumor; if present, it is mandatory to indicate dimensional changes dynamically compared to the previous study;

• assess the degree of fibrous changes in the tumor structure according to the mrTRG classification;

• in case of initial involvement of regional lymph nodes — describe all initially altered lymph nodes dynamically compared to the previous study;

• upon detection of new lymph nodes suspicious for metastatic involvement — describe them according to the rules adopted for primary staging.

Comments: in a significant proportion of patients, lymph node puncture will reveal only reactive inflammation. If false-negative puncture results are suspected, the procedure must be repeated.

Comment: performing this study is preferred in patients with metastatic and locally advanced forms of the disease.

2.5 Other Procedures

Comment: patients with a CD4+ lymphocyte count above 200 cells/µL, in the absence of other contraindications, may be prescribed a standard course of chemoradiotherapy, similar to patients with an uncompromised immune system.

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 are also possible taking into account the patient's condition. The treatment of anal canal adenocarcinoma is carried out in accordance with the treatment principles for lower ampullary rectal cancer and is discussed in the corresponding section of the guidelines.

Comments: detailed recommendations for radiation therapy and chemotherapy are provided in the sections "Principles of Radiation Therapy" and "Principles of Chemotherapy". Recommendations for the use of pyrimidine analogue medications with registered indications are presented below.

3.1. Principles of radiation therapy

When delivering radiation therapy to patients with anal canal cancer, it is advisable to apply the following principles to achieve maximum treatment efficacy [18–20]:

external beam radiation therapy (conformal external beam radiation therapy)

1) administered daily, with 6–18 MeV photons;

2) the optimal method is three-dimensional conformal radiation therapy (3DCRT) or intensity-modulated radiation therapy (IMRT, VMAT) (conformal external beam radiation therapy, including IMRT, IGRT, ViMAT, stereotactic);

3) pre-radiation topographical preparation includes performing CT (computed tomography of the pelvic organs in men, computed tomography of the lesser pelvis in women) and MRI of the lesser pelvis, performed no more than 30 days prior to the start of treatment. Based on the data obtained, an irradiation plan is generated;

4) the target volume includes the primary tumor and regional lymph nodes;

5) the irradiation volume for regional metastatic sites must include the perirectal, obturator, internal and external iliac, inferior mesenteric, and inguinal lymph nodes;

6) the upper boundary of the irradiation field is located at the level of the L5-S1 vertebrae in cases of N0; up to the aortic bifurcation in cases of N1;

7) the lower boundary of the irradiation field is 2 cm below the distal edge of the primary tumor;

8) the first stage involves radiation therapy with a fractional dose (FD) of 2 Gy, TD of 44–46 Gy to the primary tumor and regional metastasis area;

9) the second stage involves a boost to the area of initially identified disease foci;

10) the boost is administered with an FD of 2 Gy; the TD depends on the initial disease extent (TD 50–52 Gy for T1–T2, TD 54–58 Gy for T3–T4); external beam radiation therapy (conformal external beam radiation therapy) begins with volumetric 3D planning and is performed using conformal radiation therapy technology (3DCRT and its variants: IMRT, volumetric modulated arc therapy (VMAT)) (conformal external beam radiation therapy, including IMRT, IGRT, ViMAT, stereotactic);

11) the precision of radiation delivery is verified using a megavoltage portal imaging system on the linear electron accelerator—OBI (on-board imager) and cone-beam computed tomography (CBCT);

12) if technically available, external beam proton therapy/heavy ion therapy with an energy of 250 MeV using proton therapy facilities may be used;

13) stereotactic body radiation therapy may be used for oligometastatic disease upon the decision of a multidisciplinary team.

Comments: the use of IMRT in the treatment of patients with squamous cell carcinoma of the anal canal significantly reduces non-hematological treatment toxicity and the number of forced treatment breaks. In some low-evidence studies, a potential benefit from adding local hyperthermia during chemoradiotherapy was demonstrated, although the exact regimen, number, and duration of sessions are not standardized [72, 73].

Comment: taking breaks significantly reduces the efficacy of chemoradiotherapy and lowers the probability of a complete response following treatment.

Comments: lower-grade complications should be managed conservatively, do not pose a threat to the patient's life, and should not be a reason to alter the initial treatment plan. These rules are standard for various combined modality treatments of malignant neoplasms and do not require evaluation within clinical trials. The type and severity of complications that caused a forced treatment break must be documented. Before deciding on a treatment break, an attempt at conservative treatment must be made. A break may only be decided upon if it is impossible to reduce the complication severity to grade II or lower (according to RTOG and/or NCI-CTCAE scales) with adequate supportive therapy and/or if there is an immediate threat to the patient's health.

3.2. Principles of chemotherapy

3.2.1. Chemotherapy during radiation therapy

Comments: for localized anal canal cancer, chemotherapy regimens incorporating #fluorouracil** and #mitomycin** concurrently with radiation therapy are preferred. In the presence of contraindications to #mitomycin** or other objective documented reasons preventing its use, a regimen utilizing #cisplatin** (60 mg/m² IV on days 1 and 29) may be used. For convenience, #fluorouracil** can be replaced with #capecitabine**. An alternative administration schedule for #mitomycin**—10 mg/m² IV bolus on days 1 and 29 of radiation therapy—may be used. Neoadjuvant and adjuvant chemotherapy administered before and after completion of chemoradiotherapy has not led to improved overall survival and should not be used in routine clinical practice [14, 15, 16].

Comments: Patients with a CD4+ lymphocyte count greater than 200 cells/µL in the absence of other contraindications may receive a standard course of chemoradiotherapy, similarly to patients with an uncompromised immune system. Replacing #mitomycin** with #cisplatin** significantly reduces the risk of hematological complications during chemoradiotherapy [17]. Studies in the HIV-infected patient population used cisplatin doses of 75–100 mg/m2 IV administered twice [151]. However, the expert panel sees no reason to increase the dose in patients with a pre-existing high risk of complications compared to the dose established in the phase III trial [17] and used in international clinical guidelines [150].

3.2.2. Palliative chemotherapy

Comments: The addition of #atezolizumab** to chemotherapy did not improve treatment efficacy outcomes in patients with metastatic anal canal cancer [85].

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

− FOLFOXCIS (#Cisplatin** 40 mg/m2 as a 40-minute IV infusion on day 1 (with IV hydration of at least 2.5 L), calcium folinate** 400 mg/m2 IV over 2 hours followed by an IV bolus of #fluorouracil** 400 mg/m2 and a 46-hour infusion of #fluorouracil** 2000 mg/m2 (1000 mg/m2 per day). The next cycle starts on day 15) [33, 150],

− mDCF (#cisplatin** 40 mg/m2 as a 40-minute IV infusion on day 1 (with IV hydration of at least 2.5 L), #docetaxel** 40 mg/m2 IV infusion on day 1, followed by a 46-hour infusion of #fluorouracil** 2400 mg/m2 (1200 mg/m2 per day). The next cycle starts on day 15) [34, 150],

− monoclonal antibody monotherapy (anti-PD-1 antibodies; #nivolumab** (240 mg or 3 mg/kg IV drip over 60 min every 2 weeks or 480 mg IV drip over 60 min every 4 weeks) or #pembrolizumab** (200 mg or 2 mg/kg IV drip over 30 min every 3 weeks or 400 mg IV drip every 6 weeks)) in the presence of high PD-L expression levels in the tumor (CPS > 1) [35, 36, 75–77, 150].

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

Comments: Data on the efficacy of these treatment regimens are derived from small studies across various lines of therapy, including the first line (mDCF, FOLFOXCIS), and have a low level of evidence. Nevertheless, their level of evidence is no lower than that for the #fluorouracil** + #cisplatin** regimen recommended as second-line therapy.

Comments: The choice of a specific regimen in the second and subsequent lines of therapy for metastatic anal canal cancer should be made on an individual basis due to the scarcity of high-level evidence resulting from the rarity of the disease. In patients with a poor performance status, monotherapy with #paclitaxel** 80 mg/m2 weekly for 3 weeks every 4 weeks [152], anti-EGFR antibodies (monoclonal antibodies), pyrimidine analogues, #nivolumab**, or #pembrolizumab** may be considered if tumor PD-L expression is elevated. Reintroduction of previously effective treatment regimens is also possible.

3.3. Principles of surgical treatment

3.3.1. Indications for surgical treatment

Comments: Deciding on surgery is one of the most challenging aspects of treating squamous cell carcinoma of the anal canal. Scarring and post-radiation tissue changes, especially after treatment for large neoplasms, can frequently mimic a residual tumor. The 26-week (or 6-month) timeframe for deciding on surgery is justified by data showing a higher rate of complete response when waiting 26 weeks compared to 11 weeks. Cases have been described where a complete response was achieved only after prolonged follow-up [44, 45]; therefore, in individual cases, by decision of the multidisciplinary team, this timeframe may be extended. Making a decision on surgery prior to 26 weeks is permissible only in exceptional cases: in patients whose chemoradiotherapy course was incomplete or violated clinical guidelines, in cases with an initial tumor stage of T4 or higher, or by decision of the oncology board upon confirmation of tumor progression based on objective imaging methods.

1) morphological verification of tumor recurrence/progression, or

2) growth of the residual tumor on two consecutive pelvic MRI scans / endorectal ultrasound examinations performed at an interval of at least 4 weeks, or

3) a combination of pelvic MRI findings + a multidisciplinary team decision regarding the presence of a residual tumor.

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

Comments: In the following clinical situations, a decision to perform surgical treatment may be made earlier than 26 weeks from the completion of CRT (but no earlier than 12 weeks from its completion):

• if RT was previously performed with significant deviations from Clinical Guidelines and there is evidence from two or more diagnostic methods (pelvic MRI, PET/CT, rising SCC tumor marker levels (squamous cell carcinoma antigen blood test), endorectal ultrasound (transrectal ultrasound of the rectum) + a multidisciplinary board decision) indicating the presence of a residual tumor;

• if signs of residual tumor are present 12 weeks after the completion of CRT, a repeat evaluation may be scheduled earlier than 26 weeks, but with an interval of at least 4 weeks. If negative dynamics are detected (growth of the residual tumor on pelvic MRI or lack of tumor regression on pelvic MRI combined with morphological verification of the tumor), surgical treatment in the volume of extralevator abdominoperineal resection is indicated.

3.3.2. Scope of surgical treatment

Comments: Laparoscopic ovarian transposition does not affect oncological treatment outcomes and should be offered exclusively to improve quality of life; this intervention is most justified in patients under 40 years of age. At the same time, laparoscopic ovarian transposition preserves hormonal function in only 60-70% of patients.

3.4. Intraepithelial carcinoma of the anal canal, anal margin, or perianal skin (TisN0M0)

Comment: this group includes patients with high-grade squamous intraepithelial lesion (HSIL, formerly referred to as anal intraepithelial neoplasia grade II–III), intraepithelial adenocarcinoma (Paget's disease), and intraepithelial squamous cell carcinoma (Bowen's disease).

3.5. Early perianal skin and anal margin cancer T1N0M0

Comments: this group is characterized by a favorable prognosis (5-year survival rate exceeding 90%). Organ-preserving treatment modalities should be considered in the first place. Provided that a 1 cm resection margin can be achieved, the tumor is well or moderately differentiated (the vast majority of patients with perianal skin cancer present with well-differentiated tumors), and there is no invasion of the sphincter apparatus, patients with anal margin and perianal skin cancer undergo surgical treatment in the volume of local tumor excision. For patients who do not meet the criteria for local tumor excision, chemoradiotherapy is considered following principles similar to those for stage T2N0-2M0 disease. In selected cases, as decided by a multidisciplinary tumor board, surgical treatment for T2N0M0 perianal skin cancer is possible, provided that a resection margin of at least 1 cm can be achieved and the tumor is of high or moderate differentiation.

3.6. Anal canal cancer T1-2N0-2M0, anal margin or perianal skin cancer T1-2N1-2M0, T2N0M0

Comments: the optimal chemotherapy regimen concurrent with radiation therapy was determined based on data from historical phase III trials ACT II and RTOG 98-11 [16, 17]. Radiation therapy doses were subsequently adapted taking into account the advent of new radiation therapy equipment and technologies [50]. Chemoradiotherapy should be considered the primary treatment modality for all patients with non-metastatic squamous cell carcinoma of the anal canal. Radiation therapy without chemotherapy is only permissible in the presence of objective, documented contraindications to all chemotherapeutic agents included in the available treatment regimens. When technically feasible, patients without regional lymph node involvement may receive a boost using intracavitary radiation therapy at an FD of 3 Gy, TD of 18 Gy. Administration of induction (prior to chemoradiotherapy) or adjuvant (after completion of chemoradiotherapy) chemotherapy does not improve survival rates [16, 17].

3.7. Anal canal, anal margin, or perianal skin cancer T3-4N0-2M0

Comments: this category of patients can only receive chemoradiotherapy. Surgical treatment is indicated exclusively for patients with residual tumor after a full course of treatment, or with a tumor complicated by massive hemorrhage. Depending on the specific extent of the disease, complete tumor regression should be expected in 60–80% of patients following chemoradiotherapy. The optimal chemotherapy regimen concurrent with radiation therapy was determined based on data from historical phase III trials ACT II and RTOG 98-11 [16, 17]. Radiation therapy doses were subsequently adapted taking into account the advent of new radiation therapy equipment and technologies [50]. In the presence of contraindications to #mitomycin** or other objective documented reasons precluding its use, #mitomycin** may be substituted with #cisplatin** (60 mg/m2 IV on days 1 and 29) [16, 17].

Comments: for T1-T2N0 squamous cell carcinoma of the rectum, if radiotherapy is not feasible, upfront surgical treatment is discussed. The advisability of initiating treatment with chemotherapy should be discussed individually at a multidisciplinary tumor board, taking into account the risk of such treatment and the baseline resectability of the tumor. If there is a history of pelvic radiation therapy, re-evaluation of topometric maps is mandatory; if technically feasible, re-irradiation with chemoradiotherapy is the priority.

3.8. Anal canal, anal margin, or perianal skin cancer TanyNanyM1

Comment: there are no data on the effect of chemoradiotherapy on the survival of patients with metastatic anal canal cancer; however, this treatment method effectively relieves pain syndrome and controls other symptoms associated with the primary tumor, if present.

3.9. Pain Management

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

3.10. Diet Therapy

There are no evidence-based indications for diet therapy specific to patients with anal canal cancer.

3.11. Symptomatic Therapy

• When administering antineoplastic drug therapy with emetogenic side effects, patients are recommended to receive prophylaxis and treatment for nausea and vomiting [95, 96].

GCR ALEL 1Grade of Recommendation — A (Level of Evidence — 1).

Comments. The principles of diagnosis, prophylaxis, and treatment of nausea and vomiting during antineoplastic drug therapy are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the prevention and treatment of complications of malignant tumors and antineoplastic drug therapy: Vladimirova L. Yu. et al. Nausea and Vomiting [97]. https://rosoncoweb.ru/standarts/?chapter=nausea_vomiting

• In patients with bone metastases, prophylaxis and treatment of bone complications are recommended [98].

GCR BLEL 1Grade of Recommendation — B (Level of Evidence — 1).

Comments. The principles of diagnosis, prophylaxis, and treatment of bone complications are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the prevention and treatment of complications of malignant tumors and antineoplastic drug therapy: Bagrova S. G. et al. Bone Tissue Pathology [99].

https://rosoncoweb.ru/standarts/?chapter=bone_pathology

• Patients are recommended prophylaxis and treatment of venous thromboembolic complications [100-102].

GCR BLEL 1Grade of Recommendation — B (Level of Evidence — 1).

Comments. The principles of diagnosis, prophylaxis, and treatment of venous thromboembolic complications are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the prevention and treatment of complications of malignant tumors and antineoplastic drug therapy: Somonova O. V. et al. Thromboembolic Complications [103]. https://rosoncoweb.ru/standarts/?chapter=thromboembolism

• During antineoplastic drug therapy, patients are recommended prophylaxis and treatment of febrile neutropenia and infectious complications [104-106].

GCR ALEL 1Grade of Recommendation — A (Level of Evidence — 1).

Comments. A detailed algorithm for the diagnosis, prophylaxis, and treatment of febrile neutropenia and infectious complications, as well as 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 antineoplastic drug therapy: Sakaeva D. D. et al. Practical Guidelines for the Diagnosis and Treatment of Febrile Neutropenia [107].

https://rosoncoweb.ru/standarts/?chapter=febrile_neutropenia

• During antineoplastic drug therapy, patients are recommended management of hepatotoxicity [108, 109].

GCR CLEL 5Grade of Recommendation — C (Level of Evidence — 5).

Comments. The principles of diagnosis, prophylaxis, and treatment of hepatotoxicity are outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the prevention and treatment of complications of malignant tumors and antineoplastic drug therapy: Tkachenko P. E. et al. Hepatotoxicity [110].

• When administering antineoplastic drug therapy to patients, prophylaxis and treatment of cardiovascular complications are recommended [111-112].

GCR BLEL 2Grade of Recommendation — B (Level of Evidence — 2).

Comments. The principles of diagnosis, prophylaxis, and treatment of cardiovascular complications during antineoplastic therapy are outlined in the Practical Guidelines of the Russian Society for the Prevention and Treatment of Complications of Malignant Tumors and Antineoplastic Drug Therapy: Vitsenya M. V. et al. Cardiovascular Toxicity [113]. https://rosoncoweb.ru/standarts/?chapter=cardiovascular_toxicity

• During antineoplastic drug therapy, patients are recommended prophylaxis and treatment of dermatological reactions [114].

GCR BLEL 1Grade of Recommendation — B (Level of Evidence — 1).

Comments. The principles of diagnosis, prophylaxis, 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 [115].

https://rosoncoweb.ru/standarts/?chapter=dermatological_reactions

• To maintain the metabolic reserves of a cancer patient's body and increase their resistance to treatment (surgical, drug, radiation), nutritional support is recommended. The choice of nutritional support method is determined by the patient's various types of nutritional disorders. Placement of a nasogastric, nasointestinal, percutaneous endoscopic, laparoscopic, or laparotomic stoma, endoscopic stenting for tumor stenosis, or palliative radiation therapy may be recommended [116, 117].

GCR BLEL 1Grade of Recommendation — B (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 [118]. https://rosoncoweb.ru/standarts/?chapter=nutritional_support

• During antineoplastic drug therapy, patients are recommended prophylaxis and treatment of nephrotoxicity [119-121].

GCR BLEL 2Grade of Recommendation — B (Level of Evidence — 2).

Comments. A detailed algorithm for the diagnosis, prophylaxis, 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 [122].

https://rosoncoweb.ru/standarts/?chapter=nephrotoxicity

• During antineoplastic drug therapy, patients are recommended prophylaxis and treatment of immune-mediated adverse events [123-126].

GCR BLEL 2Grade of Recommendation — B (Level of Evidence — 2).

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 Antitumor Drug Therapy: Protsenko S.A. et al. Immune-mediated adverse events [127].

https://rosoncoweb.ru/standarts/?chapter=immunerelated_adverse_events

• During antitumor drug therapy, patients are recommended prevention and treatment of mucositis [128,129].

GCR CLEL 5Grade of Recommendation — 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 Antitumor Drug Therapy: Semiglazova T.Yu. et al. Mucositis [130] https://rosoncoweb.ru/standarts/?chapter=mucositis

• Patients are recommended treatment for anemia, which occurs as a symptom of a malignant neoplasm and as an adverse event during antitumor drug therapy [131,132].

GCR BLEL 1Grade of Recommendation — B (Level of Evidence — 1).

Comments. The procedure and principles of 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 Antitumor Drug Therapy: Orlova R.V. et al. Anemia [133].

• During treatment, patients are recommended treatment for anorexia-cachexia syndrome [134].

GCP BLEL 3Grade of Recommendation — B (Level of Evidence — 3).

Comments. A detailed algorithm for the diagnosis and treatment of anorexia-cachexia syndrome is outlined in the Practical Guidelines of the Russian Society of Clinical Oncology for the Prevention and Treatment of Complications of Malignant Tumors and Antitumor Drug Therapy: Sytov A.V. et al. Practical guidelines for the treatment of anorexia-cachexia syndrome in cancer patients [135] https://rosoncoweb.ru/standarts/?chapter=anorexia-cachexia

• When administering cyclic antitumor drug therapy to patients involving continuous prolonged (over 6 hours) infusions of antitumor drugs (fluorouracil**, doxorubicin**, etc.) or in case of poor peripheral vein condition, it is recommended to use central venous access and infusion pumps [136].

GCP BLEL 1Grade of Recommendation — B (Level of Evidence — 1).

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 the most convenient. For shorter periods, a peripherally inserted central venous 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 Antitumor Drug Therapy: Isyangulova A.Z. et al. Central venous access [137]. https://rosoncoweb.ru/standarts/?chapter=central_venous_access

• During antitumor drug therapy, patients are recommended prevention and treatment of antitumor drug extravasation. When planning antitumor drug therapy, the choice of vascular access is important for preventing the extravasation of antitumor drugs [138].

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 Antitumor Drug Therapy: Buydenok Yu.V. et al. Extravasation of antitumor drugs [139] https://rosoncoweb.ru/standarts/?chapter=extravasation_antitumor_drugs

• During antitumor treatment, patients are recommended treatment for chronic pain syndrome [140].

GCR BLEL 2Grade of Recommendation — B (Level of Evidence — 2).

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 Antitumor Drug Therapy: Kogonia L.M. et al. Chronic pain syndrome [141]. https://rosoncoweb.ru/standarts/?chapter=chronic_pain_syndrome

• During antitumor drug therapy, patients are recommended prevention and treatment of infusion reactions [142].

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 Antitumor Drug Therapy: Orlova R.V. et al. Infusion reactions [143].

https://rosoncoweb.ru/standarts/?chapter=infusion_reactions

• During therapy, patients are recommended monitoring and treatment for reactivation/exacerbation of chronic viral hepatitis [144-146].

GCP BLEL 3Grade of Recommendation — B (Level of Evidence — 3).

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 Antitumor Drug Therapy: Feoktistova P.S. et al. Chronic viral hepatitis [147]. https://rosoncoweb.ru/standarts/?chapter=chronic_viral_hepatitis

• During antitumor drug therapy, patients are recommended prevention and treatment of neurological complications [148-149].

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

Comments. The principles of diagnosis, prevention, and treatment of neurological complications of antitumor 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 Antitumor Drug Therapy: Latipova D.Kh. et al. Neurological complications [147]. https://rosoncoweb.ru/standarts/?chapter=neurological_complication

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Comment: there is no evidence or known mechanisms that could lead to an increased risk of progression of squamous cell carcinoma of the anal canal when administering hormone replacement therapy, any types of spa treatment, or physiotherapy. This statement 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 previous treatment. These contraindications are general for wounds and inflammatory foci of any etiology. The mere history of squamous cell carcinoma of the anal canal is not a contraindication to any methods of drug treatment, physiotherapy, or spa treatment. When assessing indications for any types of non-oncological treatment and rehabilitation, one should be guided solely by the patient's existing health problems, regardless of their etiology, and not by the fact of having an oncological history.

4.1. Pre-rehabilitation

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

Comments: increasing physical activity improves quality of life in the postoperative period, allowing a faster return to full daily activities. A comprehensive prehabilitation program, which includes home exercise therapy (a moderate-intensity physical load complex combining both aerobic and anaerobic exercises), nutritional counseling, and working with a medical psychologist to overcome anxiety and depression (starting 28 days before surgery and continuing for 8 weeks after) significantly improves postoperative quality of life [55].

Psychological support as part of prehabilitation improves mood and reduces anxiety and depression. Patients who undergo a course of psychological prehabilitation adapt better to daily life after surgical treatment. Psychological prehabilitation, including techniques aimed at stress management (relaxation techniques, fostering a positive mindset) for 40–60 minutes 6 days a week, starting 5 days before surgery and lasting 30 days after, significantly improves quality of life [56].

4.2. Rehabilitation Following Surgical Treatment

4.2.1. Stage I of rehabilitation in surgical treatment

Comment: these tactics do not increase the risks of early postoperative complications or the rate of readmissions.

Comments: these measures help prevent postoperative respiratory complications. Breathing exercises begin as soon as the patient's consciousness normalizes after surgery. The patient is taught the technique of postoperative breathing exercises before surgery. After surgery, diaphragmatic breathing is considered, which helps improve lymph circulation in the body and ventilates the lower lobes of the lungs, which usually do not receive enough air during thoracic breathing [59].

Comments: massage (General medical massage) is a safe and effective method for treating pain in the early postoperative period in patients undergoing major colorectal procedures. Its use helps reduce pain intensity, anxiety, and tension.

4.2.2. Stage II of rehabilitation in surgical treatment

4.2.3. Stage III of rehabilitation in surgical treatment

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

Comment: there is no evidence of an increased risk of tumor progression with the use of these rehabilitation methods.

4.3. Rehabilitation during chemotherapy

• During chemotherapy, patients with anal canal cancer are recommended to perform a complex of therapeutic physical training (therapeutic physical training with biofeedback for colon diseases), relaxation techniques including diaphragmatic breathing and progressive muscle relaxation, and massage (General medical massage) to reduce the risk of treatment side effects [64, 65].

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

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

• During Stage III of rehabilitation, patients are recommended to maintain an active lifestyle and perform therapeutic physical training complexes (therapeutic physical training with biofeedback for colon diseases) after combined treatment for anal canal cancer to increase treatment efficacy and improve patients' quality of life [54].

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

Comment: performing therapeutic physical training and physical activity in patients with disseminated tumor process reduce fatigue, increase mobility, decrease depression, and improve quality of life.

4.4. Rehabilitation during radiotherapy

Comment: performing therapeutic physical training increases bone density and patient endurance during radiotherapy.

5. Prevention and Dispensary Observation

Scope of examination

Mandatory examination (Appendix A3):

− digital rectal examination;

− anoscopy;

− palpation of the inguinal regions (palpation in sigmoid and rectal pathology);

− pelvic MRI;

− consultation with an obstetrician-gynecologist (gynecological examination) for women;

− ultrasound of the abdominal cavity (comprehensive), pelvic organs (comprehensive pelvic ultrasound [transvaginal and transabdominal]), and inguinal lymph nodes (ultrasound of lymph nodes [one anatomical zone]);

− targeted chest X-ray.

Additional examination:

− MRI or CT of the abdomen and pelvis (computed tomography of the pelvic organs in women, magnetic resonance imaging of the pelvic organs, magnetic resonance imaging of the abdominal cavity, computed tomography of the pelvic organs in men, computed tomography of the abdominal cavity) if monitoring is necessary for patients with T3-4 tumors or baseline involvement of inguinal/iliac lymph nodes;

− pelvic CT with intravenous contrast (computed tomography of the pelvic organs in women, magnetic resonance imaging of the pelvic organs, magnetic resonance imaging of the abdominal cavity, computed tomography of the pelvic organs in men, computed tomography of the abdominal cavity) if pelvic MRI cannot be performed;

− endorectal ultrasound (transrectal ultrasound of the rectum) as an adjunct or if pelvic MRI cannot be performed;

− biopsy sampling is performed only in the presence of a palpable residual tumor (biopsy of the anus and perianal region);

− blood squamous cell carcinoma antigen (SCC) level testing, if elevated at baseline prior to treatment or in case of a high risk of progression.

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

Comments: the objective of follow-up is the early detection of disease progression for the prompt initiation of chemotherapy or surgical treatment of resectable metastatic lesions, recurrent tumors, as well as the detection of metachronous tumors. The conclusion of a pelvic MRI during follow-up after completion of chemoradiotherapy should indicate:

– the presence of a residual tumor, and if present, it is mandatory to indicate changes in size over time compared to the previous study;

– evaluation of the degree of fibrous changes in the tumor structure in accordance with the mrTRG classification;

– in cases of baseline involvement of regional lymph nodes, describe all initially altered lymph nodes over time compared to the previous study;

– upon detecting new lymph nodes suspicious for metastatic involvement, describe them in accordance with the rules adopted for initial staging.

6. Organization of Medical Care

Medical care, excluding medical care within the framework 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 Protecting the Health of Citizens in the Russian Federation", is organized and provided:

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

2) in accordance with the procedure for rendering care in the profile "Oncology", which is mandatory for execution throughout the Russian Federation by all medical organizations;

3) based on these clinical guidelines;

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

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

If anal canal cancer is suspected or detected in a patient, general practitioners, district general practitioners, general practice physicians (family doctors), specialist physicians, and mid-level medical personnel shall refer the patient in the established manner for consultation to an outpatient oncological care center or to a primary oncological office, or a primary oncological department of a medical organization to receive 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.

In the event that it is impossible to collect biopsy (surgical) material or perform other diagnostic studies at the medical organization that includes the outpatient oncological care center (primary oncological office, primary oncological department), the patient shall be referred by the attending physician to an oncological dispensary or a medical organization providing medical care to patients with anal canal cancer.

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

If an oncological disease is suspected and/or detected in a patient during the provision of emergency medical care, such patients are transferred or referred to medical organizations providing medical care to patients with anal canal cancer to determine management tactics and the need for additional specialized anti-tumor treatment methods.

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

The period for initiating specialized, excluding high-tech, medical care for patients with oncological diseases in a medical organization providing medical care to patients with oncological diseases shall not exceed 14 calendar days from the date of histological verification of the malignant neoplasm or 14 calendar days from the date of establishing a preliminary diagnosis of anal canal cancer (in the absence of medical indications for pathoanatomical examinations in outpatient settings).

Specialized, including high-tech, medical care is provided by oncologists and radiation therapists in an oncological dispensary or in medical organizations providing medical care to patients with anal canal cancer that have a license, the necessary material and technical base, 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 medical care to patients with anal canal cancer, the tactics of medical examination and treatment are established by a concilium of oncologists and radiation therapists, involving other specialist physicians if necessary. The decision of the medical concilium is formalized in a protocol, signed by the participants of the medical concilium, and entered into the patient's medical documentation.

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

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

1) presence of complications of the oncological disease requiring the provision of specialized medical care in an emergency and urgent form;

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

Indications for hospitalization in a medical organization in a planned form 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 the course of treatment or one of the stages of providing specialized, including high-tech, medical care in a 24-hour or day hospital setting, provided there are no treatment complications requiring drug correction and/or medical interventions in an inpatient setting;

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

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

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

7. Additional Information

Known prognostic factors in cancer of the anal canal, anal margin, and perianal skin that are recommended to be recorded are presented in Table 2.

Table 2. Prognostic factors in cancer of the anal canal, anal margin, and perianal skin

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Gordeev S.S., MD, PhD, Leading Researcher, Department of Surgical Oncology No. 3 (Coloproctology), National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health.

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

3. Chernykh M.V., Candidate of Medical Sciences, Deputy Director for Radiation Treatment Methods, Research Institute of Clinical Oncology, Head of the Radiotherapy Department, Radiation Oncologist, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health.

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

5. Besova N.S., Candidate of Medical Sciences, Leading Researcher, Department of Antitumor Drug Therapy No. 2, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health.

6. Karachun A.M., Professor, MD, PhD, Head of the Surgical Department of Abdominal Oncology, Leading Researcher, Petrov National Medical Research Center of Oncology of the Russian Ministry of Health, staff member of the Department of Oncology, Mechnikov North-Western State Medical University.

7. Kozlov N.A., Candidate of Medical Sciences, Pathologist, Pathological Anatomy Department, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health.

8. Merzlyakova A.M., Candidate of Medical Sciences, Oncologist, Medical Rehabilitation Department, Herzen Moscow Oncology Research Institute, a branch of the National Medical Research Center for Radiology of the Russian Ministry of Health.

9. Petrov K.S., Candidate of Medical Sciences, Radiologist, X-ray Diagnostics Department, National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health.

10. Petrov L.O., PhD, Head of the Department of Radiation and Surgical Treatment of Abdominal Diseases, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Center for Radiology of the Russian Ministry of Health.

11. Rybakov E.G., MD, Prof. RAS, Head of the Department of Oncoproctology, A.N. Ryzhikh National Medical Research Center of Coloproctology of the Russian Ministry of Health.

12. Sidorov D.V., MD, Head of Oncological Department No. 7, Oncology Center No. 1, S.S. Yudin City Clinical Hospital of the Moscow Healthcare Department.

13. Tkachev S.I., Professor, MD, Consultant at the Radiotherapy Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health.

14. Shelygin Yu.A., Academician of the RAS, Professor, MD, President of the All-Russian Public Non-Profit Organization "Association of Coloproctologists of Russia", Scientific Advisor, A.N. Ryzhikh National Medical Research Center of Coloproctology of the Russian Ministry of Health, Chief freelance specialist-coloproctologist of the Russian Ministry of Health.

15. Droshneva I.V., PhD, Associate Professor, Head of the Radiotherapy Department of the Radiotherapy Division, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Center for Radiology of the Russian Ministry of Health.

16. Bolotina L.V., MD, Head of the Chemotherapy Department, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Center for Radiology of the Russian Ministry of Health.

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

18. Falaleeva N.A., MD, Head of the Department of Drug Treatment of Malignant Neoplasms, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Center for Radiology of the Russian Ministry of Health.

19. Filonenko E.V., Head of the Center for Laser and Photodynamic Diagnostics and Treatment of Tumors, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Center for Radiology of the Russian Ministry of Health.

20. Boyko A.V., MD, Professor, Head of the Radiotherapy Department with Radiomodification, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Center for Radiology of the Russian Ministry of Health.

Healthcare Organization Section:

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

2. Ivanov S.A., MD, Professor, Corresponding Member of the RAS, Honored Doctor of the RF, Director of the A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Center for Radiology of the Russian Ministry of Health, Chief freelance oncologist of the Central Federal District of the Russian Ministry of Health.

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

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

No conflicts of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience of these clinical guidelines:

1. Oncologists.

2. Surgeons.

3. Radiologists.

4. Geneticists.

5. Radiation therapists.

6. Coloproctologists.

7. Endoscopists.

8. Clinical pharmacologists.

9. Medical rehabilitation specialists.

Methods used for collecting/selecting evidence: search in electronic databases; analysis of current scientific developments on the problem in Russia and abroad; synthesis of practical experience of Russian and foreign specialists.

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

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

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

Methods used for formulating recommendations: expert consensus.

Economic analysis

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

Methods of recommendation validation:

● External peer review.

● Internal peer 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 presentation of the recommendations and their assessment of the importance of the recommendations as a practical tool for daily practice.

The comments received from experts were carefully systematized and discussed by the chairman and members of the working group. Each item was discussed, and the resulting changes to the recommendations were recorded. If no changes were made, the reasons for refusing to make changes were recorded.

Consultations and peer review: The draft recommendations 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 three years, but not more often than once every 6 months, taking into account new information on diagnosis and patient management that has become available. The decision to update is made by the Ministry of Health of the Russian Federation based on proposals submitted by professional medical non-profit organizations. The formulated proposals must take into account the results of a comprehensive assessment of medicines, medical devices, and the results of clinical approbation.

When selecting publications as potential sources of evidence, the methodology used in each study is examined to ensure its reliability. The result of the study affects the level of evidence assigned to it

Appendix A3. Reference Materials

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

Systemic therapy regimens used for advanced/metastatic anal canal cancer

*Regimens are characterized by a higher incidence of side effects compared to #carboplatin** with #paclitaxel**.

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

Appendix B. Physician Action Algorithms

Flowchart for the diagnosis and treatment of a patient with squamous cell carcinoma of the anal canal.

Appendix C. Patient Information

As a source of information on the diagnosis, treatment, and prevention of colorectal cancer, it is necessary to use the information resource approved by professional and patient communities: http://www.russcpa.ru/patsientam/.

Recommendations for chemotherapy complications ‒ contact your oncologist.

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

● Take medications as prescribed by your oncologist.

2. In case of stomatitis:

● Diet – mechanical and thermal sparing;

● Take medications as prescribed by your oncologist.

3. In case of diarrhea:

● Diet – exclude fatty, spicy, smoked, sweet, dairy, and fiber-rich foods. Lean meats, flour products, fermented milk products, and rice water are allowed. Drink plenty of fluids.

● Take medications as prescribed by your oncologist.

4. In case of nausea:

● Take medications as prescribed by your oncologist.

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

Appendix G1. Mandard Tumor Regression Grade Scale

Russian title: Mandard tumor regression grade scale.

Original title: Mandard Tumor Regression Grade (TRG).

Source (official developer website, validation publication): Mandard A.-M., Dalibard F., Mandard J.-C., Marnay J., Henry-Amar M., Petiot J.-F., Gignoux M. Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma. Clinicopathologic correlations. Cancer 1994;73(11):2680–6 [67].

Type: rating scale.

Purpose: morphological assessment of the effect of medical and radiation treatment.

Content (template) and Key (interpretation):

Criteria for the degree of tumor regression in response to treatment according to Mandard:

Grade I tumor regression (complete regression) (TRG1) – absence of tumor cells, presence of a fibrosis focus at the site of the tumor (fibrosis may be absent).

Grade II tumor regression (TRG2) – persistence of rare tumor cells amidst fibrous changes.

Grade III tumor regression (TRG3) – numerous residual tumor cells with a predominance of fibrosis.

Grade IV tumor regression (TRG4) – tumor elements predominate over fibrous changes.

Grade V tumor regression (TRG5) – no signs of tumor regression, absence of fibrosis.

Comments: none.

Appendix G2. Radiation Therapy Oncology Group Common Toxicity Criteria

Russian title: Radiation Therapy Oncology Group common toxicity criteria.

Original title: RTOG Cooperative Group Common Toxicity Criteria.

Source (official developer website, validation publication):

https://www.rtog.org/ResearchAssociates/AdverseEventReporting/CooperativeGroupCommonToxicityCriteria.aspx;

https://www.rtog.org/ResearchAssociates/AdverseEventReporting/RTOGEORTCLateRadiationMorbidityScoringSchema.aspx.

Type: rating scale.

Purpose: assessment of the severity of side effects from radiation and chemoradiation therapy.

Content (template) and Key (interpretation):

RTOG scale for assessing acute radiation therapy complications (selected parameters)

Appendix G3. US National Cancer Institute Common Toxicity Criteria

Russian title: US National Cancer Institute common toxicity criteria.

Original title: National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE).

Source (official developer website, validation publication):

https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_50;

https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf.

Type: rating scale.

Purpose: assessment of the severity of side effects from drug and chemoradiation treatment.

Content (template) and Key (interpretation):

NCI-CTCAE v5.0 International Toxicity Scale (selected parameters)

Comments: none.